Foreword
During the last century, transmissible and acute diseases dominated the interests of the research, clinical, and public health communities. Looking back, we can only marvel at the progress that has been made. Indeed, some contagious diseases have been eradicated, totally or virtually, in many parts of the world. Deaths from some acute events, such as myocardial infarction and stroke, have declined remarkably. As a result, quality of life, economic power, and life expectancy have all increased in a number of countries. Over the past 20 years in the United States, for example, life expectancy increased by about six years owing to a reduction in death rates of most major conditions. Chronic diseases of the airways, however, have worked against this favorable trend in life expectancy. Although death rates from asthma are relatively low, chronic obstructive pulmonary disease has a very significant impact on the total number of deaths worldwide. In the United States, it accounted for about 110,000 deaths in 1999, ranking as the fourth most common cause of mortality. Of even greater concern than the death toll from asthma and COPD is their considerable impact on those who live with these chronic diseases. Because of their lingering nature, they constitute an extraordinary burden that reduces the quality of life for the patients and many around them. Furthermore, these diseases have a negative impact on the economic potential of society, especially in developing countries. The burdens on the healthcare system are readily measurable – hospitalizations, emergency room visits, prescription drugs, respiratory therapy, long-term care, among others. But perhaps even more significant are the limitations that these diseases impose on the ability of their victims to fulfill their roles in school, in the workplace, and in the community, to care for their loved ones and, in many cases, even to care for themselves. The strength of a society resides in the independence and productivity of its people, and these qualities, in turn, hinge upon the people’s good health. Asthma and COPD are ominous threats to the strength of societies worldwide. At the end of the twentieth century, several events occurred that may lead to a transformation of this sad situation. First and foremost, the international scientific com-
munity began to arrive at the realization that the path to achievement of its ideal goal – elimination of the main cause of COPD, cigarette smoking – would be a rocky one and that its pursuit must be coupled with an intensive research effort to control and conquer this disease. With regard to asthma, an extraordinary research effort has yielded a greater understanding of the pathogenesis of this disease and a new armamentarium of therapeutic approaches that have proven to be remarkably effective. But there is no room for complacency! Another defining event has been a greater realization of the importance of chronic diseases, especially asthma and COPD, in the newly developed interests of the World Health Organization. This has been largely due to the work of Drs Murray and Lopez.1 They gave the research and public health communities great cause for alarm by demonstrating that the ranking of societal and individual burden from chronic respiratory diseases will rise from twelfth to fifth between the years 1990 and 2020. We, and the public at large, can only applaud the response of these communities. This book is further evidence of that response. First, it presents the best and newest of what is known about these two diseases. The roster of international contributors is stellar. In addition, the volume is comprehensive: all aspects of these two very prevalent diseases are addressed. The reader will soon recognize the complexity of the issues and appreciate the wonderful job that the text does of making them understandable. The most important and innovative feature of this volume, however, is its comparison, where appropriate, of the two diseases. Of course, asthma and COPD are different, but they also share a number of characteristics, and understanding one can greatly help us understand the other. In 1971, the CIBA Foundation sponsored a debate on “Identification of Asthma”.2 One participant led an extensive discussion on the definition of asthma and how it may be differentiated from chronic bronchitis. At its conclusion, another participant wisely observed: “The question that clinicians have to ask themselves before they can apply rational treatment is this: What is the mechanism?”
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Foreword
By comparing and contrasting asthma and COPD, this book helps answer that question. In the end, it is the patients and the societies in which they live who will benefit from this contribution Claude Lenfant, MD Bethesda, Maryland
1. Murray CJL, Lopez AD (eds). The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020. Cambridge, MA: Harvard University Press, 1996. 2. Porter R, Birch J (eds). Identification of Asthma, pp. 132–50. CIBA Foundation Study Group, no. 38. Edinburgh: Churchill Livingstone, 1971.
Contributors
Ian M. Adcock National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK
[email protected] Carlo Agostini Department of Clinical and Experimental Medicine Clinical Immunology Branch Padua University School of Medicine Via Giustiniani 2 35128 Padova Italy Steven M. Albeda Department of Medicine Pulmonary Allergy and Critical Care Division University of Pennsylvania Medical Center 852 BRBII/III 421 Curie Blvd Philadelphia PA 19104-6160 USA Yassine Amrani Pulmonary Allergy and Critical Care Division University of Pennsylvania Medical Center 421 Curie Bvd 805 BRB II/III Philadelphia PA 19104-6160 USA
Morgan Andersson Department of Otorhinolaryngology Lund University Hospital S-221 85 Lund Sweden Nick Anthonisen University of Manitoba 753 McDermot Avenue Winnipeg R3E 0W3 MB Canada
[email protected] Jon G. Ayres Department of Respiratory Medicine Birmingham Hartlands Hospital Bordesley Green East Birmingham B9 5SS UK
[email protected] Peter J. Barnes Department of Thoracic Medicine National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK
[email protected] John Britton Division of Respiratory Medicine City Hospital Hucknall Road Nottingham NG5 1PB UK
[email protected]
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Contributors
A. Sonia Buist Oregon Health Sciences University Mail Code UHN 67 Sam Jackson Park Road 3181 SW Portland OR 97201 USA
[email protected] Pierre-Regis Burgel Division of Medicine and Physiology University of California 505 Parnassus Avenue M-1325 Box 0130 San Francisco CA 94143-0130 USA
[email protected] Edward J. Campbell Department of Medicine University of Utah School of Medicine 410 Chipeta Way Salt Lake City UT 84108 USA Gaetano Caramori National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK S. Cattapan Room A 342, Bldg 1 Hines Hospital 5th and Roosevelt Avenues Hines, IL 60141 USA
[email protected]
George H.F Caughey Department of Medicine Cardiovascular Research Institute University of California Box 0911 San Francisco CA 94143-0911 USA
[email protected] B.R. Celli Tufts Lung Station St Elizabeth’s Medical Center of Boston 736 Cambridge Street Boston MA 02135-2997 USA
[email protected] Richard N. Channick Department of Medicine Division of Pulmonary and Critical Care Medicine University of California San Diego Med Center 9300 Campus Point Drive La Jolla CA 92037-1300 USA
[email protected] Moira Chan-Yeung Respiratory Division Vancouver General Hospital 2775, Heather Street Vancouver B.C. V5Z 3J5 Canada
[email protected] Kian Fan Chung National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK
[email protected]
Contributors
D. W. Cockcroft Division of Respiratory Medicine Royal University Hospital Saskatoon SK S7N 0W8 Canada
[email protected] Chris Corrigan Allergy and Respiratory Medicine 14th Floor, Hunts House Guys Hospital St Thomas’ Street London SE1 9RT UK
[email protected] Adnan Custovic Department of Respiratory Physiology Wythenshaw Hospital Southmoor Road Manchester M23 9LT UK
[email protected] Donna E. Davies Department of Medicine University of British Columbia Vancouver General Hospital Vancouver BC Canada
[email protected] W. Bruce Davis Pulmonary Critical Care AF2024 Medical College of Georgia Augusta Georgia 30912-3135 USA
[email protected] Dawn L. DeMeo Harvard Medical School Channing Laboratory 181 Longwood Avenue Boston MA 02115 USA
Sujal Desai King’s College Hospital London UK
[email protected] Aaron Deykin Pulmonary and Critical Care Division Brigham and Women’s Hospital 75 Francis Street Boston MA 02115 USA
[email protected] Jeffery M. Drazen Pulmonary and Critical Care Division Brigham and Women’s Hospital 75 Francis Street Boston MA 02115 USA
[email protected] Ellen M. Drost Respiratory Medicine Unit Department of Medical and Radiological Science ELEGI/Colt Resarch Laboratories Medical School Teviot Place Edinburgh EH8 9AG UK Jonas S. Erjefalt Department of Physiological Sciences Lund University Hospital S-221 85 Lund Sweden Leonardo M. Fabbri Section of Respiratory Diseases Department of Medicine Oncology & Radiology University of Modena and Reggio Modena Largo del Pozzo 71.41100 Italy
[email protected]
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Contributors
Marlies Feijen Department of Pediatrics University Hospital of Groningen PO Box 30.001 Groningen, 9700 RB The Netherlands
[email protected] Jack Gauldie Department of Pathology and Molecular Medicine McMaster University 1200 Main Street West Hamilton Ontario L8N 3Z5 Canada
[email protected] Jorrit Gerritsen Department of Pediatrics University Hospital of Groningen PO Box 30.001 Groningen, 9700 RB The Netherlands
[email protected] John Gibson Department of Respiratory Medicine Freeman Hospital Newcastle upon Tyne NE7 7DN UK
[email protected] Maurice Godfrey Center for Human Molecular Genetics University of Nebraska Medical Center Omaha NE 68198-5455 USA
[email protected] Simon Godfrey Institute of Pulmonology Hadassah University Hospital Jerusalem Israel
[email protected]
Lemark Grieff Department of Otorhinolaryngology Lund University Hospital S-221 85 Lund Sweden N.J. Gross Room A 342, Bldg 1 Hines Hospital 5th and Rossevelt Avenues Hines, IL 60141 USA
[email protected] Ian Hall Division of Therapeutics University Hospital Nottingham NG7 2UH UK
[email protected] David M. Hansell Royal Brompton and Harefield NHS Trust Sydney Street London SW3 6NP UK
[email protected] James C. Hogg UBC McDonald Research Laboratories St Paul’s Hospital University of British Columbia 1081 Burrard Street Vancouver, BC V6Z 1Y6 Canada
[email protected] Stephen T. Holgate RCMB Division School of Medicine University of Southampton Southampton General Hospital Southampton SO16 6YD UK
[email protected]
Contributors
Gabor Horvath Division of Pulmonary and Critical Care Medicine University School of Medicine PO Box 016910 (R-47) Miami, FL 33101 USA
[email protected] Sebastian L. Johnston Department of Respiratory Medicine National Heart and Lung Institute at St Mary’s Norfolk Place London W2 1PG UK
[email protected] P. Jones Division of Physiological Medicine St George’s Hospital Medical School Cranmer Terrace London SW17 0RE UK
[email protected] Susan Kennedy Occupational Hygiene Program University of British Columbia 2206 E Mall 3rd Floor Vancouver V6T 1Z3 Canada
[email protected] Sergei A. Kharitonov Department of Thoracic Medicine National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK
[email protected] Martin Kolb Centre for Gene Therapeutics Department of Pathology and Molecular Medicine McMaster University 1200 Main Street West Hamilton Ontario L8N 3Z5 Canada
Chakradhar Kotaru University Hospitals of Cleveland 11100 Euclid Avenue Cleveland Ohio 44106-5067 USA Sam Krachman Division of Pulmonary and Critical Care Temple University Philadelphia PA USA
[email protected] Vera P. Krymskaya Pulmonary Allergy and Critical Care Division University of Pennsylvania Medical Center 421 Curie Blvd 805 BRB II/III Philadelphia PA 19104-6160 USA Geoffrey J. Laurent Centre for Respiratory Research Royal Free; and University College Medical School Rayne Institute 5 University Street London WC1E 6JJ UK
[email protected] Aili L. Lazaar Department of Medicine Pulmonary Allergy and Critical Care Division University of Pennsylvania Medical Center 852 BRBII/III 421 Curie Blvd Philadelphia PA 19104-6160 USA
[email protected]
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Contributors
William MacNee Respiratory Medicine Unit Department of Medical and Radiological Science ELEGI/Colt Resarch Laboratories Medical School Teviot Place Edinburgh EH8 9AG UK
[email protected] Robin J. McAnulty Centre for Respiratory Research Royal Free; and University College Medical School Rayne Institute 5 University Street London WC1E 6JJ UK E. R. McFadden Jr Division of Pulmonary and Critical Care Medicine MetroHealth Medical Center – BG3 2500 MetroHealth Drive Cleveland, OH 44109-1998 USA
[email protected] J. L. Malo Sacré Coeur Hospital 5400 W Gouin Boulevarde Montreal H4J 1C5 Canada
[email protected] Fernando D. Martinez College of Medicine University of Arizona 1501 N Campbell Avenue PO Box 245018 Tucson AZ 85724-5018 USA
[email protected] Simon Message Department of Respiratory Medicine National Heart and Lung Institute at St Mary’s Norfolk Place London W2 1PG UK
[email protected]
Andrew W.P. Molyneux University of Nottingham Division of Respiratory Medicine City Hospital Nottingham NG5 1PB UK Jay A. Nadel Division of Medicine and Physiology University of California 505 Parnassus Avenue M-1325 Box 0130 San Francisco CA 94143-0130 USA
[email protected] Paul M. O’Byrne St Joseph’s Hospital Firestone Chest and Allergy Unit 50 Charlton Avenue Hamilton Ontario L8N 4A6 Canada obyrnep@mcmaster Rory A. O’Donnell RCMB Division School of Medicine University of Southampton Southampton General Hospital Southampton S016 6YD UK Reynold A. Panettieri Pulmonary Allergy and Critical Care Division University of Pennsylvania Medical Center 421 Curie Blvd 805 BRB II/III Philadelphia PA 19104-6160 USA
[email protected]
Contributors
Martyn Partridge The Faculty of Medicine Imperial College Charing Cross Campus 5th Floor Charing Cross Hospital Fulham Place Road London W6 8RF UK James E. Pease Leukocyte Biology Section Sir Alexander Fleming Building Imperial College School of Medicine London SW7 2AZ UK John Pepper Royal Brompton Hospital Sydney Street London SW3 6NP UK
[email protected] Carl Persson Department of Clinical Pharmacology Institute of Laboratory Medicine Lund University Hospital S-221 85 Lund Sweden
[email protected] Dirkje S. Postma Department of Pulmonology University Hospital Groningen 9713 GZ The Netherlands
[email protected] Neil B. Pride Thoracic Medicine National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK
[email protected]
David Proud Johns Hopkins Asthma and Allergy Center 5501 Hopkins Bayview Circle Baltimore MD 21224 USA dproud@jhmi Irfan Rahman Respiratory Medicine ELEGI/Colt Research Laboratories University of Edinburgh Teviot Place Edinburgh EH8 9AG Scotland UK
[email protected] Stephen Rennard Department of Internal Medicine University of Nebraska Medical Center 600 S 42nd Street Omaha NE 68198-5300 USA
[email protected] L. Richeldi Section of Respiratory Diseases Department of Medicine Oncology & Radiology University of Modena and Reggio Modena Largo del Pozzo 71.41100 Italy M. Romagnoli Section of Respiratory Diseases Department of Medicine Oncology and Radiology University of Modena and Reggio Modena Largo del Pozzo 71.41100 Italy
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Contributors
Lewis J. Rubin Department of Medicine Division of Pulmonary and Critical Care Medicine University of California San Diego Med Center 9300 Campus Point Drive La Jolla CA 92037-1300 USA
[email protected] Marina Saetta Department of Clinical and Experimental Medicine Clinical Immunology Branch Padua University School of Medicine Via Giustiniani 2 35128 Padova Italy Gianpietro Semenzato Department of Clinical and Experimental Medicine Clinical Immunology Branch Padua University School of Medicine Via Giustiniani 2 35128 Padova Italy
[email protected] Steven D. Shapiro Department of Pediatrics Campus Box 8208 Washington University School of Medicine 660 South Euclid Avenue St Louis MO 63110 USA
[email protected] Sat Sharma Section of Respirology University of Manitoba 753 McDermot Avenue Winnipeg R3E 0W3 MB Canada
Stephanie A. Shore Physiology Program Harvard School of Public Health 665 Huntingdon Avenue Boston MA 02115 USA
[email protected] John R. Spurzem Department of Medicine Omaha VA Medical Center Omaha NE 68198-5300 USA
[email protected] Scott A. Strassels Department of Pharmacy University of Washington Box 357630 Seattle WA 98195 USA
[email protected] Sean Sullivan Department of Pharmacy University of Washington Box 357630 Seattle WA 98195 USA
[email protected] Neil C. Thomson Department of Respiratory Medicine Western Infirmary Glagow G11 6NT UK
[email protected] Martin J. Tobin Division of Pulmonary and Critical Care Medicine Loyola University Chicago Medical Center 2160 South First Avenue Maywood IL 60153 USA
[email protected]
Contributors
Galen B. Toews Division of Pulmonary and Critical Care Medicine University of Michigan 1500 East Medical Center Drive 3916 Taubman Ann Arbor Michigan 48109-0642 USA
[email protected] Rubin M. Tuder Division of Pulmonary Sciences and Critical Care University of Colorado Health Sciences Center Box C272 4200 East Ninth Avenue Denver CO 80262 USA Lena Uller Department of Physiological Sciences Lund University Hospital S-221 85 Lund Sweden Norbert F. Voelkel Division of Pulmonary Sciences and Critical Care University of Colorado Health Sciences Center Box C272 4200 East Ninth Avenue Denver CO 80262 USA
[email protected] Adam Wanner Division of Pulmonary and Critical Care Medicine University of Miami School of Medicine PO Box 016960 (R-47) Miami Florida 33101 USA
[email protected] J. Wedzicha Academic Respiratory Medicine Dominion House St Bartholomew’s Hospital London EC1A 7BE UK
[email protected]
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Scott T. Weiss Channing Laboratory Brigham and Women’s Hospital 181 Longwood Avenue Boston MA 02115 USA
[email protected] Timothy J. Williams Leukocyte Biology Section Sir Alexander Fleming Building Imperial College School of Medicine London SW7 2AZ UK
[email protected] Ashley Woodcock Department of Respiratory Physiology Wythenshaw Hospital Southmoor Road Manchester M23 9LT UK
[email protected] A.J. Woolcock formerly Institute of Respiratory Medicine Level 8 Building 82 Royal Prince Alfred Hospital Camperdown NSW 2050 Australia Miel Wouters Faculteit der Geneskude-Pulmonology Universiteit Maastricht PO Box 5800 6202 MZ Maastricht The Netherlands
[email protected] Z. Xing Centre for Gene Therapeutics Department of Pathology and Molecular Medicine McMaster University 1200 Main Street West Hamilton Ontario L8N 3Z5 Canada
Preface
Asthma and chronic obstructive pulmonary disease are amongst the two commonest chronic conditions in the world today and both are predicted to increase. Because of their high prevalence and chronicity, these diseases impose an enormous and growing economic and social burden. Enormous strides have been made in our understanding of the basic mechanisms of asthma, with a much better appreciation of the inflammatory mechanisms involved and how this underlies the clinical features of the disease. This is one of the reasons why the management of asthma has improved enormously. Currently available medications are highly effective in most asthmatic patients, although there remain a small group of patients who are still not adequately controlled on existing treatments. But although asthma medications are very effective, many patients with asthma continue to have problems and asthma is still a common cause of hospital admission and time lost from work. There is therefore a need for further research in asthma and for the development of new and even more effective therapies. Although COPD is just as large a problem as asthma, there has been less attention given to this disease, and our understanding of the underlying basic mechanisms are far less advanced than for asthma. COPD has a very high morbidity and mortality and is a growing problem, particularly in developing countries. Treatment is less effective than in asthma, and none of the existing medications is able to reduce the progression of the disease. COPD is still commonly treated as poorly responsive asthma, yet the inflammatory process and effects are very different and there is little reason to think that the same treatments should be effective. There is a pressing need for much more research into underlying mechanisms of COPD, in order to identify novel therapies in the future. Management issues in COPD
are also different in many respects from those involved in asthma. Two of us (PJB and NCT) were involved in editing a book on Asthma: Basic Mechansism and Clinical Management. This was most successful and ran to three editions. In considering the next edition we thought that it would be very useful to include COPD as no other book had taken both these diseases together. In putting together this new volume on Asthma and COPD: Basic Mechanisms and Clinical Management we invited the two North American editors in order to make the book more international. We have retained the structure of the original Asthma book, but have added new chapters that are relevant to COPD. However, we have asked authors to consider both diseases in preparing their chapters. Of course, there is far more information about basic mechanisms pertinent to asthma than to COPD, but we hope that by contrasting this information and identifying areas of uncertainty, this may act as a stimulus to further research in COPD. We hope that this new book will be useful to researchers and to clinicians and will serve as a useful reference source. The format has been changed to make it more attractive and more easily read. Despite the advance of on-line publications on the Internet, we feel that there is still an important place for definitive reference books as a source of information. We would like to thank Margaret MacDonald and Simon Crump of Academic Press for all their help in putting together this book and we hope that you will enjoy the result. Peter J. Barnes London
Jeffery Drazen Boston
Stephen Rennard Omaha
Neil C.Thomson Glasgow
Chapter
Definitions
1
A. Sonia Buist Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR, USA
Until recently, the presence or absence of reversibility was considered to be the key distinction between asthma and chronic obstructive pulmonary disease (COPD) – with reversible airflow obstruction the hallmark of asthma, and irreversible airflow obstruction the hallmark of COPD. Better understanding of both diseases has brought new definitions that acknowledge the overlap and highlight the similarities and differences between them. The important change in our understanding is the recognition that chronic inflammation underlies both diseases. The nature of the inflammation differs, however, as does the response to antiinflammatory medications, as described in detail in later chapters.
DEFINITIONS Asthma In the most recent US asthma guideline, the Expert Panel 2 Report,1 asthma is defined as: A chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils,T lymphocytes, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. COPD In the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines,2 COPD is defined as: A disease state characterized by progressive development of airflow limitation that is not fully reversible.The airflow limitation is usually progressive and usually results from an abnormal response of the lungs to noxious particles or gases.
SIMILARITIES AND DIFFERENCES Over the past 30 years, thinking about asthma and COPD has swung between the concept of asthma and COPD belonging to a spectrum of diseases that all cause airflow obstruction, to the concept of them as very different diseases, and most recently to them both being inflammatory diseases with important similarities and differences. The present thinking is illustrated in Fig. 1.1 from the GOLD guidelines, which shows both diseases causing airflow limitation, but through a gene–environment interaction involving different sensitizing agents, different cell populations in the inflammatory response, and a spectrum of reversibility. The airflow limitation resulting from the inflammatory process ranges from completely reversible (the asthma end of the spectrum) to completely irreversible (the COPD end of the spectrum). Table 1.1 highlights the most important similarities between asthma and COPD. Both are chronic inflammatory diseases that involve the small airways and cause airflow limitation; both result from gene–environment interactions;
ASTHMA Sensitizing agent
Asthmatic airway inflammation CD4 T lymphocytes Eosinophils
Completely reversible
COPD Noxious agent
COPD airway inflammation CD8 T lymphocytes Macrophages Neutrophils
Airflow limitation
Completely irreversible
Fig. 1.1. Schematic of the genesis of airflow obstruction in asthma and COPD.
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Asthma and Chronic Obstructive Pulmonary Disease
Table 1.1. Similarities between asthma and COPD
Both are chronic diseases Inflammation present in both Airflow obstruction Involvement of the small airways Mucus Bronchoconstriction Both are consequences of gene–environment interaction
and both are usually characterized by mucus and bronchoconstriction. Although the similarities are striking, it is the differences between the two diseases that define their natural histories and clinical presentations. The key differences are contrasted in Table 1.2. The first obvious difference is that the diseases involve different anatomic sites in the lungs. COPD affects both the airways and the parenchyma; asthma affects only the airways. The small airways are involved in both diseases, and the structural changes at this level are responsible for much of the lung function impairment associated with these diseases. Also, an important difference anatomically is that emphysema, an irreversible, destructive, parenchymal disease, is variably present in COPD, but is not present in asthma. Perhaps the single most important difference between the two diseases is the nature of the inflammation: it is primarily eosinophilic, CD4-driven in asthma and neutrophilic, CD8driven in COPD.1,2 The nature of the inflammation in turn affects the response to pharmacological agents. There is ample evidence now that inhaled corticosteroids are effective against the eosinophilic inflammation that is characteristic of asthma,1–5 but largely ineffective against the primarily neutrophilic inflammation seen in COPD – although this is not a completely consistent finding. The natural histories of asthma and COPD are very different. COPD is a chronic and progressive disease that is characterized by airflow limitation that is not fully reversible and by an accelerated decline in lung function. Asthma is a
chronic disease, but it is usually not considered a progressive disease, and it is not usually characterized by an accelerated decline in lung function, unless there are other risk factors such as smoking.9,10 The airflow limitation is fully reversible in the early stages of asthma but, at least in a subset of asthmatics, may become progressively less reversible as the disease becomes longstanding.11 The difference in the gene–environment interaction in the two diseases has already been alluded to: in asthma, the inflammation is a response to inhaled allergens. In COPD, the inflammation is a response to noxious particles and gases.
D I F F E R E N T I AT I N G B E T W E E N A S T H M A AND COPD It would be easy to differentiate between asthma and COPD if the latter occurred only in smokers and asthma in nonsmokers. In fact, there is a clear diagnostic bias on the part of physicians, with COPD more likely to be diagnosed in men and asthma in women.11 It is important to emphasize that both conditions may coexist in an individual, so many will have the clinical and pathophysiological features of both diseases. This makes differentiating the diseases sometimes challenging for the clinician, especially in older adults who are or have been smokers. The clinician can be guided by information in the clinical history, such as smoking history, age of onset of symptoms, history of atopic conditions, and description of acute episodes of shortness of breath (see Table 1.3). Asthma usually has its onset in early childhood. However, adult-onset asthma does exist, and many are unable to remember childhood events that would provide a clue to the early stages of asthma. Therefore, unless symptoms are continuous from childhood, the onset of asthma symptoms in adult life may be hard to interpret, especially in the presence of other risk factors such as smoking. COPD typically becomes clinically apparent in the sixth and seventh decades of life. If an individual is physically active, he or she may notice reduced exercise tolerance earlier.
Table 1.2. Differences between asthma and COPD
Characteristic
Asthma
COPD
Anatomic site of disease Nature of inflammation Reversibility of airway obstruction Response to inhaled corticosteroids Progression of disease
Airways involved Eosinophilic, CD4-driven Mostly reversible Inflammation reduced Chronic, but not characterized as progressive Normal or slightly accelerated Allergens are main drivers of inflammation
Airways and parenchyma involved Neutrophilic, CD8-driven Mostly irreversible Inflammation mostly nonresponsive Progressive airflow obstruction
Decline in lung function Gene–environment interaction
Accelerated Particles and gases are main drivers of inflammation
Definitions
5
Table 1.3. Clinical features of asthma and COPD
Clinical feature
Asthma
COPD
Age of onset
Usually early childhood, but may have onset at any age May be non-, ex-, or current smoker History of atopic disorder(s) common Common at all levels of severity except mild intermittent Of atopic disorders or asthma commonly present Normal in mild intermittent and mild persistent; airflow obstruction present at all other steps Characteristic of asthma Characteristic of asthma, usually 20% Usually normal
Mid–late adult life
Smoking history Atopy Exacerbations Family history Lung function
Reversibility of airflow obstruction Peak flow variability Diffusing capacity
COPD in developed countries is mostly a disease of smokers. This is not necessarily true in developing countries where other risk factors, such as heavy outdoor and indoor/occupational air pollution, may be important risk factors that are causally related to COPD.2 The relationship between asthma and smoking is complex. Individuals with asthma may be nonsmokers, smokers, or ex-smokers. Since asthma genes and genes leading to the susceptibility to develop airflow obstruction with smoking are common in the population, the likelihood that an individual may have both is high. One of the unresolved questions about asthma relates to the nature of the complex relationship between asthma and atopy. Most asthmatics are atopic, but not all atopic individuals have asthma. A history of atopic disorders, such as allergic rhinitis or eczema, is therefore common in asthma, but is not a characteristic of COPD. As noted above, because asthmatic/atopic genes are widespread in the population, it is not unusual for atopic disorders to coexist with COPD, but it is not a characteristic of the disease as it is for asthma. Pulmonary function tests can also provide guidance. Both diseases are characterized by airflow obstruction except in the early or mild stages. In asthma, lung function is still normal in patients with mild intermittent or mild persistent disease.1 COPD, in comparison with asthma, is defined by airflow limitation, and this becomes progressively greater as the disease advances. Fig. 1.1 shows the spectrum of reversibility ranging from completely reversible (asthmatic end) to completely irreversible (COPD end). Clinically, reversibility is defined as 12% increase in FEV1 (and at least 200 mL) over baseline.12 If clear-cut reversibility of airflow limitation is found, asthma is likely to be present. If the airflow limitation is irreversible, COPD is likely to be the diagnosis.
Usually smoker or ex-smoker Not a prominent feature Increase in frequency with increasing severity of disease Not usually a feature Airflow obstruction a hallmark of COPD Poorly reversible Often does not vary at all Abnormal when there is emphysema
OVERLAP BETWEEN ASTHMA AND COPD Not acknowledged in the definitions is the fact that longstanding asthma can lead to airway remodeling and partly irreversible airflow obstruction. So, in many (but not all) with longstanding asthma, there is an appreciable component of chronic irreversible airflow obstruction with reduced lung function and incomplete response (or at least, not complete reversibility) to a short-acting bronchodilator or to oral or inhaled corticosteroids.13,14 This complicates the diagnosis of asthma in older adults, and requires that the goals of treatment be modified since maintenance of normal lung function can no longer be a realistic goal. Not clear yet is whether early and aggressive treatment with anti-inflammatory drugs can prevent remodeling, or in what proportion of individuals with longstanding asthma remodeling occurs. Whether longstanding asthma with remodeling can be called COPD is intensely controversial. In so far as there is irreversible or poorly reversible airflow obstruction in the remodeled lungs, the term seems appropriate. Conceptually and practically, the recognition that remodeling is a feature of longstanding asthma in many (but not all) reinforces the notion that these diseases constitute a spectrum of disease, as illustrated in Figure 1.1, ranging from fully reversible to fully irreversible.
E X A C E R B AT I O N S The definition of asthma highlights the importance of exacerbations as a feature of asthma, and emphasizes the fluctuations of the disease.1 The definition of COPD does not include any mention of exacerbations.2 Nevertheless, they may be as important in the natural history of COPD as
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Asthma and Chronic Obstructive Pulmonary Disease
they are in asthma15–17 and account for approximately 70% of the COPD-related costs in the US.2 The commonest causes of exacerbations of COPD are infections of the tracheobronchial tree and air pollution,2,18–21 but the causes of about one-third of severe exacerbations cannot be identified. The commonest symptom of an exacerbation of COPD is increased breathlessness, often accompanied by wheezing, chest tightness, increased cough and sputum, change in color and/or tenacity of sputum, and fever. Enquiring about the nature, frequency, and length of exacerbations is an important part of the clinical history in COPD since exacerbations are an important contributor to the erosion of quality of life in severe disease, and should therefore be an important focus of management.
7.
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9. 10.
11.
12.
L I M I TAT I O N S O F T H E D E F I N I T I O N S Definitions for both asthma and COPD have limitations since they can reflect only our current understanding of the diseases, which is quite limited. Both diseases will continue to be redefined as our understanding of them deepens, and as new effective preventive strategies and treatments become available.
REFERENCES 1. National Asthma Education and Prevention Program Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma, National Institute of Health, National Heart, Lung, and Blood Institute. NIH Publication 97-4051, 1997. 2. Pauwels RA, Buist AS, Calverley MA, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary. Am. J. Respir. Crit. Care Med. 2001; 163:1256–76. 3. Haatela T, Järvinen M, Kava T et al. Comparison of a b2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N. Engl. J. Med. 1991; 325:388–92. 4. Haatela T, Järvinen M, Kava T et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N. Engl. J. Med. 1994; 331:700–5. 5. Jeffery PK, Godfrey W, Ädelroth E et al. Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma. Am. Rev. Respir. Dis. 1992; 145:890–9. 6. Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ. Effects of inhaled and oral glutocorticoids on inflammatory indices in
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20.
21.
asthma and COPD. Am. J. Respir. Crit. Care Med. 1997; 155:542–8. Culpitt SV, Maziak W, Loukidis S et al. Effects of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1635–9. Confalonieri M, Mainardi E, Della Porta R et al. Inhaled corticosteroids reduce neutrophilic bronchial inflammation in patients with chronic obstructive pulmonary disease. Thorax 1998; 53:583–5. Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur. J. Respir. Dis. 1987; 70:171–9. Lange P, Groth S, Nyboe J et al. Decline of lung function related to the type of tobacco smoked and inhalation. Thorax 1990; 45:22–6. Dodge R, Cline MG, Burrows B. Comparisons of asthma, emphysema, and chronic bronchitis diagnoses in a general population sample. Am. Rev. Respir. Dis. 1986; 133:981–6. American Thoracic Society, Medical Section of the American Lung Association. Lung Function Testing: Selection of Reference Values and Interpretive Strategies. Official Statement of the American Thoracic Society, adopted by the ATS Board of Directors, March 1991. Busse W, Elias J, Sheppard D, Banks-Schlegel S. Airway remodeling and repair. Am. J. Respir. Crit. Care Med. 1999; 160:1035–42. Fish JE, Peters SP. Airway remodeling and persistent airway obstruction in asthma. J. Allergy Clin. Immunol. 1999; 104:509–16. Burge PS, Calverley PM, Jones PW et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br. Med. J. 2000; 320:1297–303. Gibson PG, Wlodarczyk JH, Wilson AJ, Sprogis A. Severe exacerbation of chronic obstructive airways disease: health resource use in general practice and hospital. J. Qual. Clin. Pract. 1998; 18:125–33. Reguerio CR, Hamel MB, Davis RB et al. A comparison of generalist and pulmonologist care for patients hospitalized with severe chronic obstructive pulmonary disease: resource intensity, hospital costs, and survival. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. Am. J. Med. 1998; 105:366–72. Wilson R. The role of infection in COPD. Chest 1998; 113:242S–8S. Soler N, Torres A, Ewig S et al. Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation. Am. J. Respir. Crit. Care Med. 1998; 157:1498–505. Anderson HR, Spix C, Medina S et al. Air pollution and daily admissions for chronic obstructive pulmonary disease in six European cities: results from the APHEA project. Eur. Respir. J. 1997; 10:1064–71. Chodosh S, McCarty J, Farkas S et al. Randomized double-blind study of ciproflaxacin and cefuroxime axetil for treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis Study Group. Clin. Infect. Dis. 1998; 27:722–9.
Chapter
Epidemiology
2
Dawn L. DeMeo and Scott T. Weiss Channing Laboratory, Brigham and Women’s Hospital, Boston, MA, USA
This chapter discusses the epidemiology of both asthma and chronic obstructive pulmonary disease (COPD). After briefly contrasting the disease definitions, the chapter reviews incidence and prevalence data, risk factors, and natural history.
DEFINING THE DISEASES Asthma The study of asthma epidemiology has been plagued by lack of consensus regarding standards for diagnosis. Most definitions have included variable airflow obstruction; but asthma is a clinical syndrome, without a gold standard for its diagnosis. Epidemiology studies have used questionnaires to assess for the presence of disease, but are limited by recall and misclassification bias. Some have suggested that symptoms should be assessed in conjunction with airway hyperresponsiveness.1 Others argue that airway hyperresponsiveness and symptoms should be analyzed separately owing to the poor correlation between clinical asthma and hyperresponsiveness.2 Population-based epidemiology studies have demonstrated a low sensitivity of airway hyperresponsiveness for detecting asthmatic phenotypes, versus a sensitivity of greater than 90% in clinic studies.3 A standard definition of asthma is as a chronic inflammatory disease of the airways with variable reversible airflow obstruction. Beyond definitions, there are differences between languages for the words used to describe asthma symptoms. A novel solution to this problem has been used in the International Study of Asthma and Allergies in Children (ISAAC), which includes an asthma video questionnaire demonstrating clinical signs of asthma as an attempt to improve uniformity in surveying for asthma.4 COPD Before describing epidemiological trends for obstructive lung disease, agreement on definitions should be achieved such that trends in incidence, prevalence, morbidity, and mortality can be properly ascribed.
COPD includes chronic bronchitis and emphysema, and is characterized by airway obstruction that is fixed or only partially reversible. The degree of airflow obstruction assigned to a given patient depends upon the guidelines used, with some defining mild obstruction as a FEV1 greater than 65%, 70%, or 80% of predicted. As in the case of asthma, the lack of international standardization of criteria for diagnosis in COPD makes understanding relative incidence and prevalence more challenging. This is well illustrated by a study by Viegi et al.5 who compared the prevalence rates of COPD in a general population in the Po Delta Valley using European Respiratory (ERS) criteria, American Thoracic Society (ATS) criteria, and standard clinical criteria. In subjects 25–45 years of age: • ERS criteria revealed a 10.8% prevalence of COPD; • ATS criteria revealed a 27% prevalence; • clinical criteria showed a 9.9% prevalence. Similarly, in subjects aged 46 years or more: • ERS criteria revealed a 12.2% prevalence; • ATS criteria had a 57% prevalence; • clinical criteria showed a 28.8% prevalence. This example highlights the difficulty of comparison between international studies and the effort to understand COPD on a global scale. If such discrepant results are obtained within a single population, then the difficulty of comparison between populations is very clear. In summary, both asthma and COPD lack gold standards for diagnosis, which would facilitate epidemiological studies. As a result, comparison of studies of asthma and COPD between populations and between countries must be viewed in the light of differences in criteria used for disease diagnosis.
INCIDENCE Asthma is predominantly a disease of childhood, with more than 17.3 million persons having asthma in the United
8
Asthma and Chronic Obstructive Pulmonary Disease
COPD vary with the age of the population. Asthma is commonly diagnosed in early childhood; COPD is commonly diagnosed after age 60.
States, 12 million are children of less than age 16. In childhood, incidence rates for asthma are highest among the youngest age groups6,7 and among male children until puberty.8–11 In a recent study of an adult Swedish population, Toren and Hermansson12 found the incidence rate for adult-onset asthma to be highest among females of all ages greater than 20, with an incidence of 1.3 per 1000 personyears; among women 16–20 years of age the rate was 3 per 1000 person-years. Analysis of data from a prospective cohort study in Finland demonstrated no increase in incidence for asthma from 1982 to 1990 in adults aged 18–45 years.13 Early investigation into the increasing prevalence of asthma in the United States was noted in a review of medical records from Olmsted County, Minnesota, where the annual incidence of asthma was found to increase from 183 per 100,000 in 1964 to 284 per 100,000 in 1983. The most significant increase was in children aged 1–14 years, suggesting a potential cohort effect early in life. Despite this increased incidence in asthma among children from 1964 to 1983, constant rates were observed among adults.6 Although these data indicate that asthma incidence is increasing, minimal information is available for trends in COPD incidence. Incidence rates for asthma and
P R E VA L E N C E Recent trends in the prevalence of obstructive lung disease are suggested by an analysis of the National Health and Nutrition Examination Survey (NHANES III).14 This included subjects with asthma, chronic bronchitis, and emphysema (Fig. 2.1). In this cohort, outcome measures included a physician diagnosis of chronic bronchitis, asthma or emphysema, respiratory symptoms, and low lung function. Of note, for the purposes of evaluating this cohort the investigators defined low lung function as present when both the FEV1/FVC ratio was < 0.70 and the FEV1 was less than 80% of predicted. Of the investigated population of 20,050 adults, 6.8% had low lung function as thus defined; 7.2% of the population had an FEV1/FVC ratio less than 0.70 with an FEV1 greater than 80% predicted, and were not included as having low lung function. Of the entire population, 8.5% reported obstructive lung disease.
25 Current COPD Past Chronic Bronchitis or Asthma
Current COPD and Asthma Current Asthma
Percentage with condition
20
15
10
5
Black female
Black male
White female
≥85
75–84
65–74
45–64
25–44
17–24
≥85
75–84
65–74
45–64
25–44
17–24
≥85
75–84
65–74
45–64
25–44
17–24
≥85
75–84
65–74
45–64
25–44
17–24
0
White male
Age Fig. 2.1. Age-specific percentage of individuals, stratified by race and sex, with chronic obstructive pulmonary disease and asthma, current COPD, current asthma, and past chronic bronchitis or asthma. Reproduced from National Center for Health Statistics, Plan and Operation of the Third National Health and Nutrition Examination Survey, 1988–94, US Dept of Health and Human Services publication PHS 94-1308, 1994, with permission.
9
Epidemiology
Importantly, 63.3% of those with documented low lung function had no current or prior doctor diagnosis of obstructive lung disease. In addition to prevalence information regarding low lung function, data from NHANES suggests that there is still a significant proportion of disease that goes undiagnosed in the mild stages, thus leading to an underestimation of the true prevalence of obstructive lung disease. Asthma Data from the United States suggest an increase in prevalence of asthma in children as well as in older adults. During the last several decades studies have suggested an increase in prevalence worldwide of 5–6% per year. Data from the National Health Interview Survey reveal an increase of 75% in self-reported asthma rates from 1980 to 1994 (Fig. 2.2). This trend was demonstrated in all age and race strata as well as in both genders. The most significant increase was among:
COPD Susceptibility to cigarette smoke is not uniform. However, COPD is best understood by understanding first the trends for smoking in populations. Although projected smoking rates throughout the world have increased, smoking prevalence in the United States between 1983 and 1995 declined overall: • • • •
• children 0–4 years of age (increase of 160%); • persons 5–14 years of age (increase 74%).15 The prevalence among inner-city children is much higher.15–17 It has been suggested that a doctor’s diagnosis of asthma is made less frequently than asthma symptom reporting, raising concern that despite increasing prevalence there is still a tendency to underdiagnose asthma, and consequently underestimate true prevalence values.18 The increasing prevalence of asthma has been recapitulated in international data. The International Study of Asthma and Allergies in Children (ISAAC) has as its aim to describe, across 155 centers, the prevalence and severity of asthma in children in 56 countries.4 Phase 1 of this trial has demonstrated a large variation in the prevalence of asthma symptoms in children throughout the world, with the
from from from from
30% 32% 34% 41%
to to to to
24% 23% 26% 29%
in white women; in African American women; in white men; in African American men.
Stang et al.22 utilized smoking rates to create a mathematical model for estimating current COPD prevalence. Using their model, they estimated that 15.3 million people in the United States aged 40 years or more have COPD; this was a reasonable estimate compared to the spirometric prevalence of 17.1 million as estimated by the Third National Health and Nutrition Examination Survey. Using this model, they also predicted the prevalence of COPD in Germany (2.7 million), the United Kingdom (3.0 million), Spain (1.5 million), Italy (2.6 million), and France (2.6 million), and suggested smoking rates as a useful surrogate for estimating COPD prevalence.
Prevalence rates of asthma
16 14 Number (millions)
highest prevalence in centers from Australia, New Zealand, the United Kingdom, and Ireland18–21 (Fig. 2.3). While the prevalence of allergic rhinitis has been noted to be scattered in the groups with the highest prevalence of asthma, the lowest prevalence for rhinitis has been found in countries where the asthma prevalence was lowest, such as in Eastern Europe, Indonesia, Greece, and India. In addition to defining prevalence rates, the ISAAC study represents an effort to establish an international standard to facilitate comparability of data from epidemiological studies of asthma.
<18 years
18–44 years
45 years
12 10 8 6 4 2 0
* 1970
1975
*Younger than age 17 years.
1980
1985
1990
1995
Year
Fig. 2.2. Prevalence of asthma in individuals less than age 18, aged 18–44, and greater than age 45. Between 1979 and 1994 the prevalence of asthma increased in all three age groups. Reproduced from NHLBI Morbidity and Mortality Chartbook, 2000, p. 61, with permission. http://www.nhlbi.nih.gov/resources/docs/cht-book.htm
Percentage of sample 0
5
10
15
20
25
30
35
Australia, Irsland, New Zealand, UK Brazil, Canada, Peru, USA
1
France, Germany, Japan, Kenya, Sweden
1
Iran, Italy, Malaysia, Nigeria, Singapore, Spain Ethiopia, India, Mexico, Iterea, Pakistan
• 1
China, Indonesia, Greece, Russia
Fig. 2.3. Prevalence of wheeze measured in the last 1 2 months prior to survey in the International Study of Asthma and Allergy in Children. O n l y 28 of 56 of the participating countries are highlighted here. Reproduced from reference 102, with permission.
The World Health Organization prediction is that by 2020 C O P D will rise from being the twelfth to the fifth most prevalent disease worldwide, and from being the sixth most common cause of death to the third most common.^^ Recent prevalence estimates of C O P D in the United States suggest that approximately 15 million people have C O P D : 14.1 million with chronic bronchitis and 1.8 with emphysema in 1996 (Fig. 2.4). There was no change in the prevalence of emphysema from 1982 to 1996, although from 1983 to 1995 the prevalence of chronic bronchitis continued to increase. In a study of the Canadian population, prevalence rates of C O P D were 4.6% in the 55-64 age group, 5.0% in the 65-74 age group, and 6.8% in the greater than 75 age group.^ These data may be an underestimation, as there is a suggestion that C O P D prevalence rates are underestimated in the elderly, especially in those with lower incomes.^^ C O P D is thought to be underdiagnosed in both N o r t h American and European populations. The IBERPOC Project (Estudio Epidemiologico de la E P O C en Espana)
Prevalence rates of chronic bronchitis 16 r
<18 years
• 1 8 - 4 4 years
n 4 5 + years
14 12 10 -
1970
1975
1980
"Younger than age 17 years.
1985
1990
1995
Year
(b) 80 r
Prevalence rates of emphysema
ro 60 -
40 -
E
20
0 1980
1982
1984
1986
1990
1992
1994
1996
Year Fig. 2.4. Prevalence measures for chronic bronchitis and emphysema, (a) From 1983 to 1995 the prevalence of chronic bronchitis increased steadily, with most of the increase in those older than age 18 years, (b) Despite fluctuations from year to year there was no overall change in the prevalence rate of emphysema from 1982 to 1996; most of the burden of the disease has been in older individuals. Reproduced from NHLBI Morbidity and Mortality Chartbook, 2000, p. 56, with permission. http://www.nhlbi.nih.gov/resources/docs/cht-book.htm
11
Epidemiology
was a population-based study of prevalence of COPD in Spain.26 The prevalence of COPD in this population (26% current smokers, 24% ex-smokers, 76% men), defined according to European Respiratory Society criteria, was 9.1%. Only 22% of those diagnosed had a prior diagnosis, while 48% had prior respiratory symptoms. The WHO and the National Institute of Heart, Lung and Blood Diseases have collaborated in an effort to broach the increasing present and projected future burdens of COPD by implementing a Global Initiative for Obstructive Lung Disease (GOLD). GOLD aims to promote studies to understand the increasing prevalence of COPD worldwide, as well as to standardize the collection of data for international comparison27 (Fig. 2.5).
• If both asthma and COPD are underdiagnosed, the prevalence estimates underestimate the true burden of these diseases. • Variability in definitions of both asthma and COPD contribute to inexact prevalence estimates and problems with comparisons of prevalence data. • ISAAC (for asthma) and GOLD (for COPD) represent efforts underway to standardize the definitions used in studies to enhance international comparisons of incidence, prevalence, and burden of disease.
U T I L I Z AT I O N A N D H O S P I TA L I Z AT I O N TRENDS
Summary • The prevalences of both asthma and COPD are increasing in Western developed countries.
In the United States, the estimated cost for year 2000 for asthma was projected to be 12.7 billion dollars (8.1 for
Rate/100,000 population 40
30
20
10
Rate/100,000 population 0
0
10
20
30
40
50
60
70
80
Hungary (95) Ireland (95) Romania (96) Scotland (97) New Zealand (94) United Kingdom (97) England/Wales (97) USA (97) Northern Ireland (97) Australia (85)
Women
Men
Spain (95) Poland (96) Netherlands (95) Germany (97) Bulgaria (94) Portugal (96) Norway (95) Canada (95) Austria (97) Italy (93) France (95) Sweden (96) Israel (95) Japan (94) Greece (96)
Fig. 2.5. Age-adjusted death rates for chronic obstructive pulmonary disease by country and sex, for individuals aged 35 to 77. The year of data is shown in parentheses. Reproduced from reference 27, with permission.
12
Asthma and Chronic Obstructive Pulmonary Disease
direct cost, 2.6 related to morbidity, 2.0 related to mortality) and 30.4 billion dollars for chronic obstructive pulmonary disease (14.7 for direct cost, 6.5 related to morbidity, 9.2 related to mortality). Utilization of health services continues to increase for both diseases. An increase in health service use has been documented in many countries, including the United Kingdom, Canada, and the United States; the utilization increase has been concomitant with the documented increase in asthma prevalence.28–30 Increased hospital visits have been documented worldwide, including in England, New Zealand, the United States, Greece, Australia, and Canada.31–38 From 1971 to 1997, hospitalizations for asthma in the United States increased for children less than age 15, remained stable for people aged 15–44, and decreased for those greater than 45 years of age. Overall, hospitalizations with asthma as a primary diagnosis increased in the 1970s until the mid 1980s and then remained constant; this is in contrast to asthma as a secondary diagnosis which increased until 1997. From 1975 to 1995, office visits for asthma more than doubled, from 4.6 to 10.4 million.15 Based on the National Ambulatory Medical Care Survey, in 1995 more than 16 million visits were made to physicians for diagnoses related to COPD, increased from 9.3 million reported in 1985; 10 million were accounted for by chronic bronchitis and 4 million for chronic airways obstruction.This same survey noted nine million office visits coded for asthma in 1995. In 1995, there were 553,000 discharges coded as COPD or allied conditions. Again this may be a definitional problem; more than half of the discharge diagnoses were nonspecifically coded as COPD or allied conditions. In summary, increased health service utilization for asthma and COPD occurred in the last decade. Overall, hospital admissions and discharges increased for asthma and COPD.
M O R B I D I T Y A N D M O R TA L I T Y Asthma The New Zealand epidemic of asthma in the 1970s prompted a review of asthma deaths in Western countries; there was a notable increase of 1.5–2 fold in the asthma mortality rates between the mid-1970s and the mid-1980s.39 The highest mortality rates in the United States have been in the inner-city regions, with particularly high-risk populations studied in East Harlem, New York City, and Cook County, Chicago.17,40 One study found that socioeconomic and racial disparities were attributable to higher incidence of asthma exacerbations among inner-city children, with no excess utilization of medical resources.41 International comparisons of mortality rates have been limited by differences in recording statistics of cause of death.42 Comparison of mortality rates are difficult also because of the lack of standardized definitions for the disease, and because of environmental, genetic, socioeconomic, and occupational influences unique to a given population.
COPD Since 1960 there has been an increased mortality associated with COPD, and in 1998 COPD mortality in the United States increased with age for all racial and gender groups. COPD mortality rates in white men in the United States are the highest, but have remained stable since 1980. During this time period, rates have increased in African American men and have doubled in white and African American women. International mortality trends demonstrate high rates of deaths for COPD in many countries. These differences may be accounted for in part by different smoking behaviors including tobacco type, environment, infectious, and genetic factors. Differences among these death rates are striking, but again lack of standardization in coding practices and death certification as well as practice differences and quality of care are relevant when comparing estimates.27 Although overall asthma mortality remains low compared with COPD, mortality rates for both asthma and COPD have increased in the last decade. Differences in death rates for asthma and COPD between countries are multifactorial (genetic, environmental, occupational, socioeconomic), but differential coding of cause-of-death statistics hinders accuracy of estimates for both diseases.
SMOKING Burrows et al.43 have demonstrated that, for a given level of tobacco smoke exposure, FEV1 varies substantially (Fig. 2.6). In addition, the dose–effect relationship between cigarette smoking and FEV1 decline depends on when an individual is exposed. Dose and timing of tobacco smoke exposure have a differential effect on FEV1 depending on the stage of the life cycle (Table 2.1). Cunningham et al.44 observed that maternal smoking during pregnancy resulted in a 1.3% reduction in FEV1 when children were 8–12 years old. Tager et al.45 found that adolescents who smoke when aged 15–20 have an estimated 8% reduction in FEV1. The Vlagtwedde/Vlaardingen study46 demonstrated a large effect of cigarette smoking in decreasing maximal lung function in individuals less than age 20; this effect exceeded the effect of cigarette smoking on lung function decline seen in older subjects. Smoking is a notable risk factor for both asthma and COPD in children and adults. Overall, smoking is associated with an increase in asthma incidence.47,48 Passive exposure to cigarette smoke increases the risk for the development of asthma and allergic sensitization.49–51 There has also been a suggestion that nonspecific airways responsiveness is increased by environmental and personal smoke exposure.52 Maternal smoking is a risk factor for the development of asthma in children up to one year of age.53 In a case–control study of children whose mothers were heavy smokers, one group demonstrated an odds ratio of 2.15 among 3–4 year olds for the development of asthma; these data were
Epidemiology
30
who continued smoking for 5 years had further losses of several hundred milliliters of FEV1.56 However, chronic obstructive pulmonary disease has been identified in nonsmokers as well, with 4% of men and 5% of women reporting physician-diagnosed obstructive lung disease. Prevalence has been noted to increase with age, to be higher in women than in men, to be particularly high in Hispanic individuals, and to be higher in low-income versus affluent individuals.57
0 pack-years
20 10 0
30
0–20 pack-years
20 10
Summary • For asthma and COPD, smoking has a lifetime influence, starting in utero and continuing into older age. • Smoking is associated with increase airway responsiveness, both in asthma and COPD. • Smoking is sufficient but not necessary for the development of COPD. • Smoking is only one of several risk factors for asthma.
Percentage of population
0
30
13
21–40 pack-years
20 10 0
I N T E R M E D I AT E P H E N O T Y P E S 30
41–60 pack-years
20 10 0
30
61pack-years
20 10 0 40
60
80 140 100 120 Percentage predicted FEV1
160
Fig. 2.6. Distribution of percentage predicted forced expiratory volume in one second (FEV1) in adults with varying smoking histories as measured in pack-years. The proportion of smokers with normal flow decreased with increasing pack-year histories. Yet, many have nearnormal FEV1 with extensive smoking history. Subjects with “respiratory trouble” before age 16 were excluded. Medians and means 1 SD are shown for each group in the abscissae. Note that among the 425 persons with 20 pack-years, only 15% have an FEV1 of 60% of predicted or less. Reproduced from reference 43, with permission.
controlled for family history, past infections, gender, and other demographic variables.54 In a six-year follow-up, the odds ratio for asthma among those exposed to maternal smoking was 3.8.55 As noted above, the single most important risk for COPD is tobacco smoking, although only 10–15% of smokers actually go on to develop obstructive lung disease. Among those smokers already with a decreased FEV1, lung injury and subsequent decrements in lung function secondary to cigarette smoking are more dramatic. In the Lung Health Study, middle-aged smokers (with FEV1 between 55% and 90%)
Allergy Allergy represents immediate hypersensitivity to an antigen and is associated with an increased production of a specific immunoglobulin by sensitized lymphocytes. Elevations in specific IgE and/or total IgE, total eosinophil counts, and skin test reactivity to specific allergens have been used clinically to detect allergic individuals. As measured by skin test reactivity, allergy increases with age until about age 15, at which point it is maximal. The decline in skin test reactivity after age 35 confounds the measurement of this phenotype in older individuals susceptible to both asthma and COPD. This reported association between skin test reactivity and decline in FEV1 is not consistent in the literature. In retrospective studies, Taylor et al.58 and Frew et al.59 demonstrated no relation of skin test positivity to decline in FEV1. However, Gottlieb et al.60 investigated this prospectively in the Normative Aging Study and found that skin test positivity predicted increased annual rates of decline in both FEV1 and FEV1/FVC ratios. Allergic inflammation is characteristic of asthma; 80–90% of childhood asthmatics are atopic, and the degree of atopy appears to be associated with prognosis in childhood asthma.61 Studies have demonstrated that the asthmatic phenotype is associated with elevated serum IgE levels more so than skin test positivity,62 and that increased airways responsiveness is related to total serum IgE levels.63 Weiss has suggested that immediate type I hypersensitivity is a risk factor for the development of chronic obstructive lung disease, and suggests that atopy may influence childhood asthma and limit maximal lung function, accelerate FEV1 decline, and potentially enhance interaction with cigarette smoking to progress to the development of COPD.64 Hargreave and Leigh65 demonstrated, in a subset of COPD patients, that eosinophilic inflammation is important in COPD exacerbations, and potentially leads to a
14
Asthma and Chronic Obstructive Pulmonary Disease
Table 2.1. Effects of cigarette smoking at different stages of the life cycle
Life phase (gender)
Cigarette dose
Total FEV1 reduction
FEV1 reduction (mL/year per packs/day)
In utero (M & F) Adolescence (M) Adolescence (F) Adult (M) Adult (F)
? Intensity for 9 mo 15 cigs/day for 5 yrb 10 cigs/day for 5 yrb Variable Variable
27.3 mLa 390 mL 340 mL N/A N/A
36 104 136 13c 7c
M male, F female a Adjusted for gender and maternal smoking in the past year; based on 1.3% reduction and mean FEV1 = 2.1 liters, 1 pack/day in smoking mothers during pregnancy is assumed for relative FEV1 reduction (ref. 44). b Median values for cigarette smoking (ref. 45). c Estimated values (ref. 46). Adapted from Weiss ST, Silverman EK. Risk factors for the development of chronic obstructive pulmonary disease. In: Severe Asthma, New York: Marcel Dekker, 2000.
decline in lung function. These data indicate that, in both asthma and COPD, allergen sensitization may represent an intermediate phenotype which needs to be considered in understanding disease onset and progression. Airways responsiveness Airways responsiveness to methacholine and histamine has been used in population-based studies to help define individuals susceptible to the development of obstructive lung disease. This intermediate phenotype is a feature of both asthma and a subset of patients with COPD. Baseline levels of lung function, allergy, age, and cigarette smoking history all influence airways responsiveness. Airways hyperresponsiveness has been demonstrated to predict accelerated decline in lung function and the development of COPD.66 More recently, airways responsiveness has been demonstrated to predict COPD mortality.67 Airways responsiveness has been demonstrated to predict the development of asthma.68 The prevalence of airway hyperresponsiveness exceeds the prevalence of asthma; the former is about 20% in the general population. Data from the Childhood Respiratory Disease Study demonstrate that increased airway responsiveness predicts the development of asthma in children and young adults with a 2–3-fold risk.69 Some have found risk increased as much as 5-fold.70 Airways hyperresponsiveness in COPD patients may be demonstrated in 64–100% in situations where it is actually measured.71 Some individuals who develop COPD have an allergic asthma phenotype, as suggested by the Dutch hypothesis.72 Alternatively the hyperresponsiveness may be a consequence of COPD. Results from a 25-year longitudinal study in the Netherlands revealed that increased airways responsiveness is an independent risk factor for FEV1 decline.73 Among those with early-onset COPD, the degree of baseline airways responsiveness determines the response to cigarette smoking; those with early-onset COPD who
have increased airways responsiveness appear more sensitive to the effects of cigarette smoke and have an accelerated decline in FEV1.74 Gender-related influences The epidemiology of asthma is characterized by gender differences that vary with age. Asthma and wheezing have been demonstrated to be more prevalent in young boys than young girls.10 This trend disappears during puberty.75 A recent analysis of the European Respiratory Health Survey76 found that, during childhood, girls had a lower risk of developing asthma than did boys; about the time of puberty the risk was equal. After puberty the risk in women was higher than in men and was a consistent finding in the 16 countries included in this study. Women older than 20 years have higher prevalence and morbidity rates from asthma, and women are more like to present to the emergency department and be admitted with asthma.77 In the multicenter Asthma Collaboration Study,78 women were more likely to be admitted to the hospital and report ongoing symptoms at follow-up, although overall men had less outpatient care and lower pulmonary function. Men have been noted to have an increased risk for the development of chronic obstructive lung disease,79 and cigarette consumption clearly has a role in this gender difference. Yet, Prescott et al.80 have suggested that women are more susceptible to the development of COPD, and observed that smoking was associated with a greater decrement in FEV1 per pack-years of cigarette smoked when compared to male smokers. Mannino et al.81 analyzed data for deaths from obstructive lung disease from 1979 until 1993 and found that the mortality rates for men with COPD have started to stabilize but were continuing to increase among women, reflecting smoking trends. These gender differences most likely represent influences of both dose of tobacco exposure and underlying genetic and hormonal susceptibilities.
15
Epidemiology
Summary • In the adult years women have a higher prevalence of asthma. • The prevalence of COPD in women is increasing, with the prospect that it may equal that of men in the future, in keeping with the parallel trends of cigarette smoking and disease. • The gender differences between asthma and COPD raise speculation as to the nature of hormonal or genetic influences relevant to disease expression in each sex.
DEMOGRAPHICS In the United States, morbidity from asthma has been demonstrated in multiple studies to be greater in children of African American descent. In the United States, physician-diagnosed asthma has been reported in 13.4% of African American children and 9.7% of white children.82 African American children have also been reported to have greater limitation on activity due to asthma, with more hospital admissions and fewer doctors’ visits when compared with white children.83 Mortality from asthma has been higher for African American children when compared with children of other races since the mid-1980s.29,84–88 Studies in Chicago have demonstrated socioeconomic gradients and differing outcomes by race. In 1996, asthma hospitalization rates were more than twice as high as the United States’ rates overall. Age-adjusted mortality was 4.7 times higher in non-Hispanic blacks than in non-Hispanic whites.89 An association with poverty has been suggested,90 and it has also been suggested that severe asthma may occur more frequently in poorer communities.91,92 The association of lower socioeconomic status with increased asthma prevalence is most likely multifactorial: the effects of indoor air pollution, passive cigarette smoke exposure, allergen exposure, and reduced access to medical care may all be relevant. Using education as a surrogate for lower socioeconomic status, some have suggested an association with the development of obstructive lung disease. Bakke et al.93 demonstrated that completion of only primary schooling was associated with a 2.9 odds ratio for the development of obstructive lung disease when compared with those who achieved university level education. Exposure to smoking and occupational hazards decreased with increasing educational status. Overall in both asthma and COPD, there are substantial demographic differences between the prevalence, morbidity, and mortality outcomes.
AGE Infants born prematurely have a risk for asthma that is increased approximately 4-fold.94 There are data that breastfeeding is protective against asthma and, as noted, the risk for asthma increases in children exposed to cigarette smoke
in utero and in childhood. Asthma that begins after age 50 is thought to be more severe and less reversible than asthma that is incident in childhood.95 In childhood, the remission of asthma has been suggested to be about 50%.47,96,97 Less information is available on the epidemiology of asthma in the middle-aged or elderly, yet some suggest that older patients are more severely affected than younger patients.98 Some data support the proposition that adults may outgrow their asthma (with remission rates decreasing with increasing age).99 Other data suggest that remission of asthma and respiratory symptoms are uncommon.100 Aging has been associated with increased airway obstruction overall.101 The association of aging with the development of COPD most likely represents the cumulative insult of a lifetime of smoking and environmental exposure interacting with a susceptible host.
CONCLUSION Ninety percent of all childhood asthma is diagnosed before the age of 6 years. Since there is a crude inverse relationship between respiratory symptoms and level of lung function, it is not surprising that as lung function increases in childhood, respiratory symptoms decrease and often disappear. Thus, a large number of children are left with the intermediate phenotypes of increased airways responsiveness and/or allergy at the time that they reach their maximally attained level of lung function between the ages of 15 and 30. These intermediate phenotypes represent definable host characteristics that confer increased susceptibility to a variety of environmental exposures encountered in adult life, such as viral respiratory illness, occupation, allergen exposure, and perhaps most importantly, cigarette smoking (Table 2.2). Only 10–15% of cigarette smokers subsequently go on to develop fixed airflow obstruction. This is likely to be due to two factors: premature mortality as a result of a variety of fatal illnesses associated with cigarette smoking, and the fact that genetic susceptibility to cigarette smoking is only present in a minority of subjects. The most clearly defined susceptibility factors for premature or early-onset COPD are childhood asthma, increased airways responsiveness, and allergy. It is now absolutely clear that most airways hyperresponsiveness in Table 2.2. Risk factors
Smoking Gender Age Airway responsiveness Allergy
COPD
Asthma
Male female Old
Female male Young
16
Asthma and Chronic Obstructive Pulmonary Disease
adults antedates, precedes, and predicts the development of COPD. Obviously, this construct suggests that most genes that predict susceptibility to asthma may also be important genetic predictors of COPD susceptibility. Both asthma and COPD are defined as syndromes, and the definitions are loose; thus it is not surprising that there is substantial overlap between the conditions at any given age. Indeed, there is nothing to suggest that individuals cannot have both reversible and fixed airflow obstruction, and hence asthma and COPD at the same time. The importance of early life and in-utero events for the subsequent development of disease is a theme that is common in a variety of complex traits. These same issues also present themselves with disorders of the airways. The major barrier to applying this life-cycle approach to disease risk factors and natural history relates to the problem of recall bias and potentially missing or inadequate information about past events in both childhood and adult life, which may then distort the clinical picture. It is only through careful analysis of longitudinal cohort data that the true history of the relationship between the major environmental exposures and disease natural history can be deduced. We need to continue to gather such data, particularly data to link childhood asthma with adult COPD.
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13. Huovinen E et al. Incidence and prevalence of asthma among adult Finnish men and women of the Finnish Twin Cohort from 1975 to 1990, and their relation to hay fever and chronic bronchitis. Chest 1999; 115:928–36. 14. Mannino DM et al. Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988–94. Arch. Intern. Med. 2000; 160:1683–9. 15. Mannino DM et al. Surveillance for asthma–United States, 1960–95. MM Weekly Report 1998; 47(1):1–27. 16. Crain EF et al. An estimate of the prevalence of asthma and wheezing among inner-city children. Pediatrics 1994; 94:356–62. 17. Persky VW et al. Relationships of race and socioeconomic status with prevalence, severity, and symptoms of asthma in Chicago school children. Ann. Allergy Asthma Immunol. 1998; 81: 266–71. 18. Sole D et al. Prevalence of asthma and related symptoms in schoolage children in Sao Paulo, Brazil. International Study of Asthma and Allergies in Children (ISAAC). J. Asthma 1999; 36:205–12. 19. Asher MI, Weiland SK. The International Study of Asthma and Allergies in Childhood (ISAAC). ISAAC Steering Committee. Clin. Exp. Allergy 1998; 28(Suppl. 5):52–66. Discussion 90–1. 20. Duhme H et al. Asthma and allergies among children in West and East Germany: a comparison between Munster and Greifswald using the ISAAC phase I protocol. Eur. Respir. J. 1998; 11:840–7. 21. Aguinaga Ontoso I et al. [The prevalence of asthma-related symptoms in 13–14-year-old children from 9 Spanish populations. The Spanish Group of the ISAAC Study]. Med. Clin. Barcelona 1999; 112(5):171–5. Erratum Med. Clin. Barc. 1999; 112(13):494. 22. Stang P et al. The prevalence of COPD: using smoking rates to estimate disease frequency in the general population. Chest 2000; 117(5 Suppl. 2):354S–9S. 23. Lopez AD, Murray CC. The global burden of disease, 1990–2020 [news]. Nat. Med. 1998; 4:1241–3. 24. Lacasse Y, Brooks D, Goldstein RS. Trends in the epidemiology of COPD in Canada, 1980–95. COPD and Rehabilitation Committee of the Canadian Thoracic Society. Chest 1999; 116:306–13. 25. Enright PL et al. Prevalence and correlates of respiratory symptoms and disease in the elderly. Cardiovascular Health Study. Chest 1994; 106:827–34. 26. Sobradillo V et al. [Epidemiological study of chronic obstructive pulmonary disease in Spain (IBERPOC): prevalence of chronic respiratory symptoms and airflow limitation]. Arch. Bronconeumol. 1999; 35:159–66. 27. Hurd SS. International efforts directed at attacking the problem of COPD. Chest 2000; 117(5 Suppl. 2):336S–8S. 28. Fleming DM, Crombie DL. Prevalence of asthma and hay fever in England and Wales. Br. Med. J. 1987; 294:279–83. 29. Gerstman BB et al. Prevalence and treatment of asthma in the Michigan Medicaid patient population younger than 45 years, 1980–86. J. Allergy Clin. Immunol. 1989; 83:1032–9. 30. Manfreda J et al. Trends in physician-diagnosed asthma prevalence in Manitoba between 1980 and 1990. Chest 1993; 103:151–7. 31. Mitchell EA. International trends in hospital admission rates for asthma. Arch. Dis. Child. 1985; 60:376–8. 32. Anderson HR, Bailey P,West S. Trends in the hospital care of acute childhood asthma 1970–78: a regional study. Br. Med. J. 1980; 281:1191–4. 33. Jackson RT, Mitchell EA. Trends in hospital admission rates and drug treatment of asthma in New Zealand. NZ Med. J. 1983; 96:728–30. 34. Halfon N, Newacheck PW. Trends in the hospitalization for acute childhood asthma, 1970–84. Am. J. Pub. Hlth 1986; 76:1308–11. 35. Priftis K et al.Time trends and seasonal variation in hospital admissions for childhood asthma in the Athens region of Greece: 1978–88. Thorax 1993; 48:1168–9.
Epidemiology
36. Carman PG, Landau LI. Increased paediatric admissions with asthma in Western Australia: a problem of diagnosis? Med. J. Aust. 1990; 152:23–6. 37. Kun HY, Oates RK, Mellis CM. Hospital admissions and attendances for asthma: a true increase? Med. J. Aust. 1993; 159:312–3. 38. Wilkins K, Mao Y. Trends in rates of admission to hospital and death from asthma among children and young adults in Canada during the 1980s. CMAJ 1993; 148:185–90. 39. Jackson R et al. International trends in asthma mortality: 1970–85. Chest 1988; 94:914–18. 40. Carr W, Zeitel L, Weiss K. Variations in asthma hospitalizations and deaths in New York City. Am. J. Pub. Hlth 1992; 82:59–65. 41. McConnochie KM et al. Socioeconomic variation in asthma hospitalization: excess utilization or greater need? Pediatrics 1999; 103(6):e75. 42. Thom TJ. International comparisons in COPD mortality. Am. Rev. Respir. Dis. 1989; 140(3 Pt 2):S27–34. 43. Burrows B et al. Quantitative relationships between cigarette smoking and ventilatory function. Am. Rev. Respir. Dis. 1977; 115:195–205. 44. Cunningham J, Dockery DW, Speizer FE. Maternal smoking during pregnancy as a predictor of lung function in children. Am. J. Epidemiol. 1994; 139:1139–52. 45. Tager IB et al. Effect of cigarette smoking on the pulmonary function of children and adolescents. Am. Rev. Respir. Dis. 1985; 131:752–9. 46. Xu X et al. Smoking, changes in smoking habits, and rate of decline in FEV1: new insight into gender differences. Eur. Respir. J. 1994; 7:1056–61. 47. Strachan DP, Butland BK, Anderson HR. Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort. Br. Med. J. 1996; 312: 1195–9. 48. Kaplan BA, Mascie-Taylor CG. Smoking and asthma among 23year-olds. J. Asthma 1997; 34:219–26. 49. Halken S et al. Passive smoking as a risk factor for development of obstructive respiratory disease and allergic sensitization. Allergy 1995; 50:97–105. 50. Wartenberg D, Ehrlich R, Lilienfeld D. Environmental tobacco smoke and childhood asthma: comparing exposure metrics using probability plots. Environ. Res. 1994; 64:122–35. 51. Cook DG, Strachan DP. Health effects of passive smoking. 3: Parental smoking and prevalence of respiratory symptoms and asthma in school age children. Thorax 1997; 52:1081–94. 52. Weiss ST, Utell MJ, Samet JM. Environmental tobacco smoke exposure and asthma in adults. Environ. Hlth Perspect. 1999; 107(Suppl. 6):891–5. 53. Weil CM et al. The relationship between psychosocial factors and asthma morbidity in inner-city children with asthma. Pediatrics 1999; 104:1274–80. 54. Infante-Rivard C. Childhood asthma and indoor environmental risk factors. Am. J. Epidemiol. 1993; 137:834–44. 55. Infante-Rivard C et al. Maternal smoking and childhood asthma. Am. J. Epidemiol. 1999; 150:528–31. 56. Anthonisen NR et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994; 272:1497–505. 57. Whittemore AS, Perlin SA, DiCiccio Y. Chronic obstructive pulmonary disease in lifelong nonsmokers: results from NHANES. Am. J. Pub. Hlth 1995; 85:702–6. 58. Taylor RG et al. Bronchial reactivity to inhaled histamine and annual rate of decline in FEV1 in male smokers and exsmokers. Thorax 1985; 40:9–16. 59. Frew AJ, Kennedy SM, Chan-Yeung M. Methacholine responsiveness, smoking, and atopy as risk factors for accelerated FEV1 decline in male working populations. Am. Rev. Respir. Dis. 1992; 146:878–83.
17
60. Gottlieb DJ et al. Skin test reactivity to common aeroallergens and decline of lung function. The Normative Aging Study. Am. J. Respir. Crit. Care Med. 1996; 153:561–6. 61. Nelson HS. The importance of allergens in the development of asthma and the persistence of symptoms. J. Allergy Clin. Immunol. 2000; 105(6 Part 2):S628–32. 62. Burrows B et al. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N. Engl. J. Med. 1989; 320:271–7. 63. Sears MR et al. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. N. Engl. J. Med. 1991; 325:1067–71. 64. Weiss ST. Atopy as a risk factor for chronic obstructive pulmonary disease: epidemiological evidence. Am. J. Respir. Crit. Care Med. 2000; 162(3 Part 2):S134–6. 65. Hargreave FE, Leigh R. Induced sputum, eosinophilic bronchitis, and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160(5 Part 2):S53–7. 66. Rijcken B et al. The association of airways responsiveness to respiratory symptom prevalence and to pulmonary function in a random population sample. Bull. Eur. Physiopathol. Respir. 1987; 23:391–4. 67. Hospers JJ et al. Histamine airway hyper-responsiveness and mortality from chronic obstructive pulmonary disease: a cohort study. Lancet 2000; 356:1313–17. 68. Xu X et al. Airways responsiveness and development and remission of chronic respiratory symptoms in adults. Lancet 1997; 350:1431–4. 69. Carey VJ et al. Airways responsiveness, wheeze onset, and recurrent asthma episodes in young adolescents. The East Boston Childhood Respiratory Disease Cohort. Am. J. Respir. Crit. Care Med. 1996; 153:356–61. 70. Weiss ST et al. Effects of asthma on pulmonary function in children: a longitudinal population-based study. Am. Rev. Respir. Dis. 1992; 145:58–64. 71. O’Connor GT, Sparrow D, Weiss ST. The role of allergy and nonspecific airway hyperresponsiveness in the pathogenesis of chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1989; 140:225–52. 72. Sluiter HJ et al. The Dutch hypothesis (chronic non-specific lung disease) revisited. Eur. Respir. J. 1991; 4:479–89. 73. Rijcken B et al. Airway hyperresponsiveness to histamine associated with accelerated decline in FEV1. Am. J. Respir. Crit. Care Med. 1995; 151:1377–82. 74. Tashkin DP et al. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The Lung Health Study Research Group. Am. J. Respir. Crit. Care Med. 1996; 153(6 Part 1):1802–11. 75. Venn A et al. Questionnaire study of effect of sex and age on the prevalence of wheeze and asthma in adolescence. Br. Med. J. 1998; 316:1945–6. 76. de Marco R et al. Differences in incidence of reported asthma related to age in men and women: a retrospective analysis of the data of the European Respiratory Health Survey. Am. J. Respir. Crit. Care Med. 2000; 162:68–74. 77. Skobeloff EM et al. The influence of age and sex on asthma admissions. JAMA 1992; 268:3437–40. 78. Singh AK et al. Sex differences among adults presenting to the emergency department with acute asthma. Multicenter Asthma Research Collaboration Investigators. Arch. Intern. Med. 1999; 159:1237–43. 79. Menkes HA et al. Risk factors, pulmonary function, and mortality. Prog. Clin. Biol. Res. 1984; 147:501–21. 80. Prescott E et al. Gender difference in smoking effects on lung function and risk of hospitalization for COPD: results from a Danish longitudinal population study. Eur. Respir. J. 1997; 10:822–7. 81. Mannino DM, Brown C, Giovino GA. Obstructive lung disease deaths in the United States from 1979 through 1993: an analysis using multiple-cause mortality data. Am. J. Respir. Crit. Care Med. 1997; 156(3 Part 1):814–18.
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82. Taylor WR, Newacheck PW. Impact of childhood asthma on health. Pediatrics 1992; 90:657–62. 83. Coultas DB et al. Respiratory diseases in minorities of the United States. Am. J. Respir. Crit. Care Med. 1994; 149(3 Part 2):S93–131. Erratum AJRCCM 1994; 150:290. 84. Evans RD et al. National trends in the morbidity and mortality of asthma in the US: prevalence, hospitalization and death from asthma over two decades: 1965–84. Chest 1987; 91(6 Suppl.):65S–74S. 85. Clark NM et al. The impact of health education on frequency and cost of health care use by low income children with asthma. J. Allergy Clin. Immunol. 1986; 78(1 Part 1):108–15. 86. Nelson DA et al. Ethnic differences in the prevalence of asthma in middle class children. Ann. Allergy Asthma Immunol. 1997; 78(1):21–6. 87. Joseph CL et al. Prevalence of possible undiagnosed asthma and associated morbidity among urban schoolchildren. J. Pediatr. 1996; 129:735–42. 88. Weitzman M et al. Recent trends in the prevalence and severity of childhood asthma. JAMA 1992; 268:2673–7. 89. Thomas SD, Whitman S. Asthma hospitalizations and mortality in Chicago: an epidemiologic overview. Chest 1999; 116(4 Suppl. 1):135S–41S. 90. Duran-Tauleria E, Rona RJ. Geographical and socioeconomic variation in the prevalence of asthma symptoms in English and Scottish children. Thorax 1999; 54:476–81. 91. Mielck A, Reitmeir P, Wjst M. Severity of childhood asthma by socioeconomic status. Int. J. Epidemiol. 1996; 25:388–93.
92. Strachan DP et al. A national survey of asthma prevalence, severity, and treatment in Great Britain. Arch. Dis. Child. 1994; 70:174–8. 93. Bakke PS, Hanoa R, Gulsvik A. Educational level and obstructive lung disease given smoking habits and occupational airborne exposure: a Norwegian community study. Am. J. Epidemiol. 1995; 141:1080–8. 94. von Mutius E, Nicolai T, Martinez FD. Prematurity as a risk factor for asthma in preadolescent children. J.Pediatr. 1993; 123 :223–9. 95. Vergnenegre A et al. Comparison between late onset and childhood asthma. Allergol. Immunopathol. Madrid 1992; 20(5):190–6. 96. Jonsson JA, Boe J, Berlin E.The long-term prognosis of childhood asthma in a predominantly rural Swedish county. Acta Paediatr. Scand. 1987; 76:950–4. 97. Kelly WJ et al. Childhood asthma in adult life: a further study at 28 years of age. Br. Med. J. 1987; 294:1059–62. 98. Burrows B et al. Characteristics of asthma among elderly adults in a sample of the general population. Chest 1991; 100:935–42. 99. Panhuysen CI et al. Adult patients may outgrow their asthma: a 25-year follow-up study. Am. J. Respir. Crit. Care Med. 1997; 155:1267–72. Erratum AJRCCM 1997; 156(2 Part 1):674. 100. Ronmark E, Jonsson E, Lundback B. Remission of asthma in the middle aged and elderly: report from the Obstructive Lung Disease in Northern Sweden Study. Thorax 1999; 54:611–13. 101. Wise RA. Changing smoking patterns and mortality from chronic obstructive pulmonary disease. Prev. Med. 1997; 26:418–21. 102. Peat Jk, Li J. Reversing the trend: reducing the prevalence of asthma. J. Allergy Clin. Immunol. 1999; 103(1 Part 1):1–10.
Natural History
Chapter
3
Fernando D. Martinez Arizona Respiratory Center, University of Arizona, Tucson, AZ, USA
INTRODUCTION
METHODOLOGICAL APPROACH
There is increasing interest in developing a better understanding of the natural history of the two most frequent chronic lower respiratory diseases, asthma and chronic obstructive pulmonary disease (COPD). The main reason for this interest is the shift in the therapeutic approach to both conditions. In the case of asthma, a growing body of evidence suggests that, although several current treatments for the disease are extremely effective in controlling symptoms, none can change its natural course. It is thus evident that new approaches to the primary and secondary prevention of asthma are needed. These approaches will require a thorough understanding of the factors that determine the inception of asthma and its progression with age. In the case of COPD, it is apparent that, although smoking is the main demonstrated cause of this condition, a simple strategy of discouraging tobacco consumption has proven insufficient to prevent the enormous impact of nicotine addiction on public health. A new understanding of the factors that increase the risk of COPD in smokers seems a more realistic approach, and could perhaps contribute to palliate the increasing social toll of COPD. When discussing the natural history of asthma and COPD, an important issue is the overlap between these two conditions. After the early adult years, subjects with preexisting asthma who smoke are at increased risk of significant declines in lung function and may develop chronic airflow obstruction.1 It becomes thus a semantic issue if these subjects have asthma or COPD, because factors associated with both conditions have most likely contributed to their course. It is often difficult to determine whether smokers who develop asthma-like symptoms and who show significant declines in lung function have asthma or COPD. This issue cannot be resolved at this time, but recent studies indicating that inhaled corticosteroids cannot change the natural course of either asthma2 or COPD3 suggest that an absolute separation between these two conditions may be more semantic than practical with our current level of knowledge.
Any discussion about the natural history of a chronic condition ought to address the different hypothetical phases that such condition undergoes during its lifetime course (Fig. 3.1). There is first a pre-illness period during which subjects without overt disease have the susceptibility for the development of the condition, because of a genetic predisposition or because of injuries or developmental variations that have mutated one or more of the individual’s disease-associated phenotypes. During this pre-illness phase, the susceptible individual is not destined to develop the disease. More likely, he or she may be exposed to environmental factors that, in the presence of genetic variants that predispose to the chronic condition, can further modify their phenotype. We do not know whether genetic factors will be discovered that will be present in all affected individuals, a kind of major gene or universal “switch” that is necessary for the development of these conditions. More likely, both asthma and COPD are heterogeneous diseases, with multiple ways to final common pathways for an array of diverse pathogenetic mechanisms that give rise to more or less reversible airway obstruction. It would obviously be of great help for any prevention strategy if markers of susceptibility were identified that Inception ion
s es
r og
Chronic disease
Pr
No disease
Initial phase
Protection
Re
mi
ss
ion
Intermittent disease
No disease
Triggers Fig. 3.1. Hypothetical representation of the natural history of a chronic condition. For explanation please see text.
Asthma and Chronic Obstructive Pulmonary Disease
could be measured during this pre-illness phase. But the absence of a marker in a specific individual may not exclude susceptibility if that is not the pathway that may be active in that individual. Thus, because the marker phenotype may be influenced by determinants other than the factors that influence asthma or COPD risk, ascertainment of a marker may be fraught with difficulties. This “context-dependency”4 of the phenotypes of markers of disease creates a further layer of complexity for the identification of susceptible individuals. The above discussion points to the importance of determining the “true” time of incidence of the disease under study. Although the event that is easiest to ascertain is the age of initiation of symptoms, this event is modified by patients’ perceptions.What is important is that time of onset ought to be ascertained before the disease has become chronic; i.e. before the individual has evidence of physiological or anatomical changes caused by the disease itself and that predispose to persistent or recurrent symptoms. During this initial phase of the disease, the affected individual has some clinical manifestations, but the condition has not yet fully developed. Moreover, some individuals may not go beyond this initial phase, because remission or stabilization may be fostered by the presence of environmental or genetic protective factors. During this initial phase secondary prevention is possible, but again knowledge of the natural history becomes essential.
N AT U R A L H I S T O RY O F A S T H M A PHENOTYPES Asthma is a heterogeneous condition, and one of the main obstacles in understanding its natural history has been the lack of well-defined markers for the different disease phenotypes grouped under this common label. This hurdle has been addressed lately by a series of longitudinal studies that have assessed incidence and prevalence of asthma at different ages or defined the outcome of persons with asthma-like symptoms enrolled at different ages, and especially during childhood.5–10 Most cases of chronic, persistent asthma start in early life Several longitudinal studies have confirmed that, in most cases of chronic, persistent asthma, the initial clinical manifestations of asthma usually occur during the first five years of life.6,9,10 Studies have ascertained this age of onset of symptoms either by asking parents about the prevalence of wheezing or other asthma-like symptoms in their children at different ages, or by reviewing previous clinical charts in subjects who present to outpatient clinics with signs and symptoms of asthma at any age. Although these studies strongly suggest that asthma started at an early age in these individuals, a simple connection between these two phenomena is not warranted. Many children have asthma-like symptoms during viral infections in their preschool years, but most have transient conditions that subside with age, and only a minority will go on to have persistent asthma.11
Thus it is difficult to distinguish who will go on to develop chronic asthma from those who will not. Studies of this issue have suggested that there are at least three quite distinct groups of children with asthma-like symptoms coexisting up to the adolescent years (Fig. 3.2). The great majority of infants who wheeze during the first 1–2 years of life do so during viral infections, especially those caused by the respiratory syncytial virus (RSV). Most of these children will have one or only a few episodes of wheezing, with no further symptoms beyond the age of 2–3 years. This condition, which has been identified as transient wheezing of infancy,12 is the most frequent form of recurrent airway obstruction in this age group, affecting over twothirds of all infants with asthma-like symptoms. The main predisposing factors for transient wheezing of infancy are maternal smoking during pregnancy and lower levels of lung function, as assessed during the very first months of life and before any wheezing episode has occurred. Interestingly, infants (especially females) whose mothers smoke during pregnancy do have lower levels of lung function early in life that those whose mothers do not smoke.13 This has suggested the possibility that both inherited and acquired characteristics of the lung, the airways, or both may create the structural conditions for the development of airway obstruction during lower respiratory illnesses.14 The factors that determine the remission of early-life wheezing in these children are not well understood, but it is likely that growth of the airways may outpace that of the lung parenchyma after age 2–5 months, the period of the highest incidence of wheezing episodes.15 Thus, the critical size that the airways have to attain in order for airflow to be obstructed may not be as easily reached, thus making noisy breathing less likely.15 It is also possible that changes in the 40
Alternaria negative asthma Alternaria positive asthma Percentage of asthma group
20
30
20
10
0
0 0–1 1–2 2–3 3–4 4–5 5–6 6–7 Age at which asthma diagnosed (years)
Fig. 3.2. Age of diagnosis of asthma for children who are skin-test positive for Alternaria or skin-test negative for Alternaria at age 6 in the Tucson Children’s Respiratory Study. Adapted from reference 20.
21
Natural History
Transient early wheezers
IgE-associated wheeze/asthma
Nonatopic wheezers
Wheezing prevalence
regulation of airway tone may result in decreased bronchial hyperresponsiveness and decreased likelihood of airway obstruction with age.16,17 Young et al.18 analyzed data from a longitudinal study of over 250 children who were also enrolled at birth in Perth, Australia.They found that children who wheezed during the first two years of life had impaired lung function shortly after birth and before any episode of wheezing had occurred. However, they also subdivided their population into those children who wheezed only during the first year of life and those who were still wheezing during the second year or who started wheezing after age one. They found that abnormalities in lung function were present in both groups of children during the first month of life, but these abnormalities had resolved by age 12 months in those whose symptoms remitted by that age, whereas abnormalities persisted in those who were still wheezing during the second year of life.These data suggest that, among children who wheeze during the first year of life, unresolved airway abnormalities are associated with persistence of symptoms beyond that age. The factors that determine enduring or newly developed abnormalities in lung function during the first years of life are the subject of intense scrutiny, because they seem to be clearly associated with the risk of persistent asthma. Zeiger et al.19 showed an inverse relationship between duration of symptoms and level of lung function in school-age children with asthma, and this suggests that the earlier onset of asthma symptoms is associated with greater losses in lung function. Sensitization to local aeroallergens is strongly associated with increased risk of chronic asthma-like symptoms into adult life. Using this knowledge, Halonen et al.20 divided children who had a diagnosis of asthma by age 6 years into two main groups: those who at age six were skintest positive for Alternaria, the main aeroallergen associated with asthma in the study area,21 and those who were not. They observed that, in the majority of children in both groups, symptoms had started before age 3 years. However, among children with asthma who were skin-test negative to Alternaria, inception of the disease had occurred mainly during the first year of life; while in those who were skin-test positive to Alternaria, peak incidence occurred during the second and third years of life (Fig. 3.3). The fact that young children who will go on to develop chronic, atopy-related asthma by age six are diagnosed one or two years later than those with nonatopic asthma suggests that the mechanisms of disease are likely to be different in these two groups. Support for this contention comes from a slightly different analysis of the data from the same cohort on which Halonen and coworkers based their report quoted above. Stein et al.11 assessed the outcome of children with confirmed lower respiratory tract illnesses due to RSV (RSV-LRI), after adjusting for all other known risk factors for subsequent asthma, including skin test reactivity, maternal history of asthma and birthweight, among others. They found that, as previously reported, risk of wheezing during the school years was higher in children with a history of RSV-LRI than in those with no such history. However, the
0
3
6
11
Age (years) Fig. 3.3. Hypothetical yearly peak prevalence of wheezing for three different phenotypes in childhood. Prevalence for each age interval should be the sum of the areas under each curve. The dashed curves suggest wheezing can present different curve shapes due to many different factors, including overlap of groups. Adapted from reference 56.
risk decreased with age and was not statistically significant by early adolescence. There was also no association between RSV-LRI and subsequent risk of sensitization to local aeroallergens either at age 6 or at age 11 years.The only factor that was strongly associated with RSV-LRI in early life was diminished baseline levels of FEV1, as measured at age 11. Interestingly, these deficits were reversed by use of a bronchodilator, suggesting that they were likely to be due to increased bronchomotor tone. Longitudinal studies performed in the early 1980s had also suggested that the outcome of RSV-LRIs is usually benign and unrelated to increased allergic sensitization.22 It thus appears that at least three different forms of “asthma” coexist during infancy and early childhood (Fig. 3.2). Transient infant wheezing is quite frequent, is usually triggered by viruses (especially RSV), and is confined to the first three years of life. Other children who wheeze during viral infections in early life continue to have recurrent airway obstruction during the early school years. This form of nonatopic wheezing is associated with lower levels of lung function during the school years, but these lower levels seem to be reversible after use of a bronchodilator. Finally, children who will develop atopy-related asthma start having symptoms mainly during the second and third years of life. Chronic asthma is most often related to atopy There is now strong evidence indicating that, as a group, individuals with chronic asthma at any age between the school years and mid adult life are either sensitized to local aeroallergens, have elevated total levels of circulating IgE, or both.23 Although the association between asthma and total and specific IgE is well established, the nature of the association is not well understood. For years it was thought that sensitization to specific allergens, especially in early life, was a cause of asthma,24 and that development of specific IgE
22
Asthma and Chronic Obstructive Pulmonary Disease
against these allergens was the first step in the natural history of the disease. The strong association between risk of having asthma and sensitization to the allergens of house dust mites in coastal regions seemed to argue in favor of this hypothesis, and strategies for the primary prevention of asthma based on avoidance of exposure to these allergens were proposed.25 However, several studies performed in desert areas with low exposure to house dust mites showed that the prevalence of asthma was either similar or even higher in these regions than that observed in zones where mite infestation rates were high.21,26 In desert regions, the allergens of the mold Alternaria appeared to be strongly associated with asthma. Moreover, recent studies in northern Sweden, where indoor exposure to either dust mites or molds is very low, showed that the prevalence of school-age asthma is very similar to that observed in southern Sweden, where exposure to house dust mites is high.27 Interestingly, only 50% of all schoolchildren with asthma are sensitive to known aeroallergens in northern Sweden (especially cat and dog), compared with over 90% of children in more temperate regions; but skin-test negative children with asthma have significantly higher IgE levels than nonasthmatic children.27 The association between specific sensitization to allergens and asthma also changes with time. Although most schoolchildren with asthma are sensitive to local aeroallergens, by the late adult years only a fraction of individuals with asthma are skin-test positive.28 This is in part due to the incidence of nonatopic asthma in late adult life, but is also due to the decreasing prevalence of skin-test reactivity to allergens in individuals who were sensitive to these allergens at a younger age.29 However, there seems to be little correlation between changes in skin test reactivity to aeroallergens and remission of asthma with age.30 All these studies suggest that the essential causal mechanism associated with asthma is not sensitization to any specific allergen, but more likely is an alteration in the regulation of responses to many different antigens with the potential of eliciting IgE responses, and especially to aeroallergens. Outcome of childhood asthma in adult life: remission of mild asthma and persistence of severe disease Only a few studies have addressed the outcome of childhood asthma during the adult years. These studies have used longitudinal assessment of asthma symptoms and lung function in children enrolled during the early school years or of birth cohorts for which assessment of asthma symptoms in early life was made through retrospective questionnaires. The longest ongoing study is that initiated by Williams and McNicol in Melbourne, Australia.31 Children with a history of recurrent episodes of wheezing were enrolled at the age of 7 years, together with a small group of controls without such a history. These individuals were then periodically reassessed, and the latest published data refer to information collected when their mean age was 35 years. Information about the age upon initiation of symptoms was obtained by use of questionnaires and, as a consequence, data on a crucial period of life for asthma the development
of asthma was almost certainly biased by preferential recall.32 The second study was the British 1958 birth cohort, in which over 18,000 subjects born between March 3 and March 9, 1958 were enrolled.5 Of these persons, 31% contributed information for ages 7, 11, 16, 23, and 33 years. As with the Melbourne study, information for the first seven years of life was obtained retrospectively at age 7. Kjellman and coworkers30 followed up, to age 30 years, 55 subjects with asthma aged 5–14 years and who were referred to a tertiary care unit in Sweden.These subjects had quite severe asthma: over 40% were hospitalized for the disease before age 16. Finally, the Tasmanian asthma survey enrolled over 8000 children born in 1961 who were also first contacted at age 7.8 Two thousand randomly chosen individuals were reexamined when they were 29–32 years of age. The most important findings of all four studies were that asthma remits in early adulthood in a large proportion of asthmatic children, and that the severity of asthma tracks significantly with age. This second point is important because it reflects a “stability” in the disease: most children with severe symptoms still have severe symptoms as adults, and asthmatic children with mild symptoms either have no asthma or have mild asthma as adults. • Children enrolled in the Melbourne study were divided at the time of enrollment into five groups according to their previous history of wheezing: a control group (no wheezing), a group with mild wheezy bronchitis (less than five lifetime episodes of wheezing associated with colds), a group with wheezy bronchitis (five or more such episodes), a group with asthma (wheezing apart from colds), and a group with severe asthma (selected at age 10 based on severe impairment of lung function). At age 35 years, only a quarter of children with both forms of wheezy bronchitis showed frequent asthma episodes (wheezing during the previous 3 months, but less than once a week) or persistent asthma (once a week or more). However, 50% of children with asthma and 75% of those with severe asthma at the time of enrollment had frequent or persistent wheeze at age 35.32 • Similar results have been reported based on the British 1958 study: 27% of all children whose parents reported they had wheezed before age 7 reported wheezing during the previous year at age 33.5 • In the Swedish study, severity of symptoms decreased significantly with age, especially for males, but only 16% were free of asthma symptoms at the time of the last visit (age 26–35 years). As stated earlier, children included in this follow-up had quite severe disease, but unfortunately no results of lung function testing were reported and severity cannot be compared with that of other studies. • For the Tasmanian study, 25.6% of subjects with “asthma or wheezy breathing” by age 7 reported current asthma at the age of 29–32 years, compared with only 10.8% of subjects without parental reports of childhood asthma. As with the Melbourne study, those with a history of more than ten attacks of asthma by age 7 were almost
23
Natural History
A consistent factor associated with persistent asthma in all four cohorts was evidence of an allergic predisposition. In the Melbourne study, severe asthma in early life was associated with significantly higher prevalence of allergic rhinitis at age 35. In the British cohort, allergic symptoms (e.g. allergic rhinitis or eczema) were significantly associated with persistence of symptoms into adult life. In the Swedish cohort, the proportion of subjects sensitized to three perennial allergens (cat, dog, horse) was much higher in subjects with persistent severe asthma than in those with mild disease. Finally, in the Tasmanian cohort, having a history of eczema in early life was also significantly associated with persistent wheezing at ages 29–32. Both the Tasmanian and the Melbourne studies assessed the association between persistence of asthma into adult life and lung function measured at enrollment (age 7 years). For both studies, low lung function at age 7 was a significant predictor of subsequent persistent wheezing. In the Melbourne study, lung function for each subgroup of subjects classified according to their wheezing history by age 7 was repeatedly assessed up to the age of 35 years. Children with severe asthma at age 10 had very low initial levels of lung function, and this was to be expected because deficits in lung function were used to classify them as having severe asthma in the first place. When compared with their peers, these children did not show further deficits in lung function growth with age, and by age 35 their position relative to subjects with milder symptoms or with no asthma was substantially unchanged. A similar pattern of relatively stable lung function growth was observed for patients with mild asthma who had shown loss of lung function at enrollment, albeit much less pronounced than persons with severe asthma. This finding is very relevant for our understanding of the natural history of chronic obstructive pulmonary disease, and will be discussed in more detail below. The potential role of bronchial hyperresponsiveness in early life has been explored only in a small study in the Netherlands.33 Children with asthma originally assessed at ages 6–14 years were subsequently restudied in early adult life. The proportion of young adults with a history of childhood asthma who were still wheezing was higher (43%) than that observed in the three cohorts described earlier. However, children included in this study were older than those enrolled in those studies, and the great majority were atopic. In this group of individuals, the two most important predictors of persistent wheezing into adult life were the initial level of lung function (as in both Australian cohorts) and the degree of bronchial hyperresponsiveness to histamine in early life. Relapse of asthma symptoms in patients whose asthma remitted in childhood Very little is known about the factors associated with relapses of asthma in adult life among subjects whose symp-
toms remitted during childhood. Only the British cohort study explored those factors. They identified a group of over 1300 persons with a history of wheezing illnesses from birth to age 16 years whose symptoms had remitted by age 23. This group was 50% more likely to report wheezing at age 33 than those with no history of asthma or wheezy bronchitis during childhood (P < 0.001). Interestingly, the association between early childhood asthma and relapses of asthma in adult life was independent of the two main determinants of the prognosis of childhood asthma, namely, allergies and smoking in adult life.5 The authors speculated that persistent, asymptomatic abnormalities in pulmonary function could explain their findings. The potential role of these abnormalities as determinants of COPD will be discussed below.
N AT U R A L H I S T O RY O F C O P D The natural history of COPD overlaps with that of the level of lung function (usually FEV1, expressed as percent of predicted value in relation to a certain height) during adulthood. Three are the main factors that can determine the level of lung function achieved at any age during adult life (Fig. 3.4). First, the individual may either start life with a low level of lung function or show a significant decline in lung function growth during the first years of life. The individual’s level of lung function will fall after a certain age, at the same rate as normal peers, but at a lower level overall. The level of lung function attained by late adolescence or early adult life will thus be lower. Through the normal process of aging, decline in lung function will naturally occur; and this decline, although parallel to that occurring in all the population, will nevertheless predispose to the attainment of a level of lung function (expressed as percentage of normal level in FEV1 (% normal level at age 20)
twice as likely to have persistent wheezing as adults than those who did not.
100 (c)
80
(a)
(d)
60 (b)
40 20 0 0
10
20
30 40 50 Age (years)
60
70
80
Fig. 3.4. Hypothetical mechanisms that may lead to a critically low level of lung function in adult life and to chronic airway obstruction (horizontal line): (a) normal growth and decline; (b) impaired lung growth with a lower plateau phase but a normal rate of decline compared to (a); (c) normal plateau with rapid initial decline in lung function and a subsequent normal rate of decline; (d) normal plateau with normal initial rate of decline but a subsequent accelerated loss in lung function. Adapted from reference 55.
24
Asthma and Chronic Obstructive Pulmonary Disease
early adulthood) that will be lower than the threshold for the expression of clinical symptoms of airway obstruction. A second potential mechanism is that of an early decline in lung function occurring either at the end of adolescence or in early adult life. Again, the main result of such a mechanism would be the attainment of lower level of lung function in these individuals as compared with the rest of the population. A third mechanism is that of a faster rate of decline of lung function during adult life. This may obviously occur both in individuals with a normal level of lung function at the beginning of adult life as in individuals who already have a diminished level of lung function to begin with. The essential determinants of the natural history of COPD are the rate of growth of lung function up to late childhood and the rate of decline of lung function during adult life. Growth of lung function during childhood The three most important determinants of growth of lung function during childhood are: • the level of lung function at birth; • the incidence of lower respiratory illnesses during the first years of life; and • the development of persistent asthma-like symptoms during childhood. Level of lung function at birth The availability of lung function tests that can be performed shortly after birth, and which appear to show good correlation with more invasive tests of airway function,34 has allowed us to study the potential role of the development of the lung in utero on subsequent levels of lung and airway function attained by the individual. Since these methods have been available only for the last 20 years, it is not possible to determine the role of airway function in the postnatal period on events occurring beyond the late teen years. Nevertheless, it is now apparent that there is quite significant tracking between the level of lung function measured shortly after birth and that measured during childhood.35 This may explain, at least in part, the strong association between lower respiratory illness in early life and level of lung function in late childhood and early adulthood (see the discussion below). The factors that determine growth of lung and airways in utero are only now beginning to be understood. The two main determinants of the level of lung function measured shortly after birth are gender and exposure to tobacco smoke products in utero.18 Boys have been found to have consistently lower maximal flows at functional residual capacity (VmaxFRC) throughout the first year of life in comparison with girls. Maternal smoking during pregnancy is associated with lower levels of VmaxFRC in both genders in comparison with unexposed infants.18 Postnatal exposure to tobacco smoke appears to be less important than prenatal exposure, at least in most developed countries.36 The effects of intrauterine exposure to tobacco smoke products persist
for the first year of life,18 and even beyond the first year up to the early adolescent years.37 The role of gender differences in airway function is not well understood. Females have larger airway size, relative to the size of lungs and to body size, as compared with males both at birth and during childhood, up to the plateau of lung growth.38 Although there are clear differences in the patterns of lung growth and development both in utero and during childhood between males and females, the role of these differences as determinants of risk for chronic obstructive pulmonary disease are not well understood. Role of lower respiratory illnesses in early life It has been known for decades that children who have lower respiratory illnesses during the first years of life have lower levels of lung function during childhood and into adult life.39 One possible explanation for this association is that viral infections, which are the main etiological factor for lower respiratory illnesses in early life, may damage lung and airways, and this may predispose for lower levels of lung function.40 This hypothesis seemed attractive, because it suggested a potential strategy for the prevention of early losses in lung function that could predispose to chronic obstructive pulmonary disease. However, several studies in which the techniques to assess lung function in infants, described earlier, were used showed that children who developed lower respiratory symptoms during viral infections in early life had diminished pre-illness levels of lung function.14,18,37 The hypothesis was thus suggested that lower levels of lung function observed after lower respiratory illnesses in early life could be explained by preexisting diminished lung function, the latter being therefore the link between early life episodes of airway obstruction and subsequent deficits in lung function. Unfortunately, the number of infants in whom lung function has been ascertained in early life and who have been followed for a number of years after birth is rather small. Therefore, the possibility that lower respiratory illnesses by themselves may alter lung and airway growth in groups of susceptible individuals cannot be excluded. It is unlikely that pre-illness lung function may explain all forms of infection-associated wheezing during early childhood, and it is legitimate to surmise that immune responses to the viruses themselves may also play a significant role. Bont and coworkers41 studied children who experienced recurrent wheezing episodes within one year of an original lower respiratory illness due to respiratory syncytial virus. In these children, IL-10 production by blood cells during the convalescent phase of the illness was significantly higher than IL-10 production by the same cells in children who had RSV but who did not have subsequent recurrent wheezing. Moreover, the IL-10 responses during the convalescent phase correlated significantly with the number of wheezing episodes occurring during the follow-up period. The mechanisms by which increased production of IL-10 by blood cells (most likely monocytes) leads to recurrent wheezing after RSV remain to be elucidated. Since IL-10 is
Natural History
a potent inhibitor of antigen presentation by macrophages,41 it is conceivable that IL-10 may suppress lower airway antiviral immune responses, thus enhancing the capacity of RSV and other viruses to invade local tissues and cause airway obstruction. On the other hand, IL-10 has been shown to increase airway responsiveness in animal models of allergen-induced airway obstruction.42 The mechanism by which IL-10 may exert this effect is not understood, nor is it known if similar mechanisms are present in humans. However, it is still possible that in human airways increased production of IL-10 in relation to a lower respiratory illness in early life may produce persistent alterations in the regulation of airway tone. Recent very long-term studies in England would support this contention.43 In these studies, men born between 1911 and 1930, whose birthweights, weights at one year, and childhood respiratory illnesses were recorded in early life, were studied at ages 59–70 years. Death from chronic obstructive disease, FEV1, and respiratory symptoms were the main outcome variables. The main early-life determinants of the level of FEV1 in old age were birthweight and history of bronchitis or pneumonia in infancy, and these effects were independent of smoking habit and social class. These data would thus suggest that both interuterine growth (and presumably lung development) and lower respiratory illnesses during the first year of life exert independent effects on the level of lung function attained late during adult life, and thus may be important determinants of the risk of COPD. Interestingly, a history of bronchitis or pneumonia in infancy was associated with increased risk of wheezing and persistent sputum production in adult life independently of birthweight, smoking habit, and social class. Persistent asthma-like symptoms during childhood It has been suggested that persistent asthma-like symptoms are a significant risk factor for the subsequent development of lower levels of lung function, and therefore, an important risk factor for the development of COPD. The hypothesis behind this contention has been that asthma is a progressive disease.44 It has thus been proposed that the presence of chronic airway inflammation is associated with significant lung remodeling and that the latter fosters a significant alteration in lung growth. Although some studies were able to show impairment in the development of lung function in children with asthma,44,45 the main outcome variable used in these studies was pre-bronchodilator lung function. More recently the Childhood Asthma Management Program (CAMP) study was specifically designed to test the hypothesis that mild to moderate childhood asthma is associated with significant deterioration in airway growth and that treatment with inhaled anti-inflammatory therapy could reverse this deterioration in lung function.2 Children aged 6–12 years were treated for 4–6 years with either an inhaled corticosteroid (budesonide), nedocromil, or a placebo. Postbronchodilator FEV1 was considered the outcome variable, because pre-bronchodilator FEV1 could be affected by the
25
degree of activity of the disease at the time of testing. The results of the study showed that, although children with asthma have levels of lung function that are significantly lower than those of children without the disease at any time between the ages of 6 and 15, these levels do not further deteriorate even among subjects who are not systematically treated with anti-inflammatory therapy. Moreover, systematic treatment with anti-inflammatory therapy improves bronchial hyperresponsiveness, but is not associated with a significant improvement in lung function with time. An interpretation of these results is that, in children with a diagnosis of asthma, most of the deterioration in lung function observed during the school years has already occurred by the age of 6–12 years. The results of studies by this author’s group suggest that children who go on to have persistent asthma-like systems during childhood start life with levels of lung function that are slightly but not significantly lower than those of children who will not have these persistent symptoms.46 It is thus likely that, although children with asthma may be predisposed to reaching early adult life with lower levels of lung function, these deficits in lung function growth occur mainly during the first years of life, and treatment with inhaled steroids after age 6 may not prevent the consequences of these deficits in lung function in adulthood. Determinants of early losses in lung function The factors that determine early losses in lung function at the age in which the plateau level of lung function is reached in early adult life have only recently been explored. Xuan et al.47 observed that, between the ages of 17 and 19 years, when growth in height had stopped, FEV1 continued to grow in both males and females. However, children who had recent episodes of wheeze and those with evidence of bronchial hyperresponsiveness showed a reduced rate of growth in airway caliber. Unfortunately, lung function was not assessed after use of a bronchodilator, and it is thus not possible from these data to assess whether the changes are due to increased airway tone or to irreversible alterations in airway structure. More recently, a preliminary report by Holberg et al.48 assessed the role of initiation of smoking during the adolescent years in determining deficits in lung function growth in late adolescence. These authors showed that, at age 16, the level of lung function achieved by males who had started smoking was significantly lower than that of those who had not. No such effect was observed in females. Determinants of increased slope of lung function decline Several longitudinal studies have addressed the role of different intrinsic and extrinsic factors on the rate of decline of lung function after the plateau phase.The role of cigarette smoking has been clearly and consistently established. Camilli et al.49 examined changes in FEV1 in over 1700 adults enrolled in a prospective study of a general population sample. Individuals who smoked more than ten cigarettes per day had excessive rates of decline in FEV1 as
26
Asthma and Chronic Obstructive Pulmonary Disease
compared with nonsmokers. The excess decline of smokers was age-dependent, particularly in men: much of the excess loss of lung function occurred between 50 and 70 years of age. In this study, effects of smoking on decline of FEV1 were greater in men than in women even when controlling for current cigarette dose. Interestingly, ex-smokers showed declines in FEV1 values that were similar to those of nonsmokers. The authors also examined the effect of quitting smoking on the decline of FEV1. In subjects younger than 35 years, quitting smoking during follow-up was associated with an actual increase in FEV1. In men above 50, smoking cessation early in the study led to a return to normal rate of functional decline during follow-up. Burrows and coworkers also reported that smokers who recalled a history of “respiratory trouble” before 16 years of age had significantly steeper rates of decline in lung function as compared with those with no such history.50 This effect was independent of a current or past diagnosis of asthma. It thus appears that intrinsic factors modify the effect of smoking on the rate of decline of lung function, and these factors may be related to events occurring during the first years of life. This conclusion is compatible with the observation by Barker and coworkers quoted earlier,43 that elderly individuals with a history of lower respiratory illness early in life were more likely to have lower levels of lung function than those with no such history. Although the factors that determine the link between “respiratory trouble” in early life and subsequent rate of decline in lung function during adult life are not well established, both genetic and environmental factors may play a role. In a preliminary analysis from the Tucson Longitudinal Study of Airway Obstructive Disease, the author’s group recently observed significant intra-family correlation in the rate of decline of lung function within smokers,51 suggesting that these rates of decline have an important genetic component. The observation by Stein et al.11 that subjects with a history of lower respiratory illnesses due to RSV have significant deficits in lung function growth by age 11 and that deficits are almost entirely reversible by use of a bronchodilator strongly suggest that alterations in the regulation of airway tone may be the link between respiratory illnesses in early life and subsequent risk of airway obstruction during adulthood. In support of this contention are the results of a longitudinal study by Postma and coworkers.52 These authors assessed the course of lung function after 2–21 years of follow-up in 81 nonallergic patients with considerable lung function impairment (<55% FEV1/FVC ratio) at the beginning of the study. They reported that a more favorable rate of change in FEV1 was not only associated with fewer pack-years of smoking but also with less nonspecific bronchial hyperreactivity and a higher degree of reversibility of airflow obstruction. These effects were independent of baseline FEV1 value, both in smokers and in ex-smokers. These results suggested the possibility that the rates of decline in lung function could be the consequence of an ongoing inflammatory process associated with bronchial
hyperresponsiveness in COPD, much like it was supposed to be present in asthma. It was thus suggested that treatment with inhaled corticosteroids could be associated with a lower rate of decline in lung function in subjects with COPD. The results of several long-term studies of the treatment of COPD with inhaled corticosteroids have been reported and recently reviewed.3 The results of these studies show that there seems to be an effect of inhaled steroids on lung function and symptoms during the first 3–6 months of use, but thereafter no further effects of inhaled corticosteroids on subsequent decline of lung function has been found. Although there could be subgroups of patients with COPD that may benefit from long-term use of inhaled corticosteroids, the data presently available do not support the contention that an ongoing inflammatory process is responsible for the decline in lung function observed in most patients with COPD. It thus appears that, although bronchial hyperresponsiveness and its associated alteration in the regulation of airway tone is an important risk factor for the development of COPD, the form of bronchial hyperresponsiveness associated with COPD may be different from that related to IgEmediated responses as observed in patients with asthma.53 A very recent observation by Palmer et al.54 may shed new light on this issue. These authors assessed bronchial responsiveness to histamine shortly after birth in a small group of normal newborns and then followed these subjects up to the age of 6 years. They found a significant correlation between bronchial responsiveness at age 1 month and FEV1 level at the age of 6 years, but no association between bronchial responsiveness at age 6 years and bronchial responsiveness at the age of 1 month. Both bronchial responsiveness at 1 month and at 6 years were independent determinants of the risk of wheezing at the age of 6 years. These studies thus suggest that a form of bronchial responsiveness present at birth may be an important risk factor for the development of respiratory symptoms in early life and an important determinant of the level of lung function at the beginning of the school years. Presumably, bronchial hyperresponsiveness at birth would also be a determinant of the level of lung function attained during the plateau phase, since measurements of lung function track markedly with age during childhood. This form of “intrinsic” bronchial responsiveness may differ in nature from that associated with atopic sensitization and may be less susceptible to the effects of anti-inflammatory therapy. The fact that it is present shortly after birth also suggests that genetic factors may explain a significant proportion of the link between lower respiratory illnesses in early life, level of lung function, and risk of COPD during adult life.
REFERENCES 1. Burrows B, Bloom JW, Traver GA et al. The course and prognosis of different forms of chronic airways obstruction in a sample from the general population. N. Engl. J. Med. 1987; 317:1309–14.
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2. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N. Engl. J. Med. 2000; 343:1054–63. 3. Postma DS, Kerstjens HA. Are inhaled glucocorticosteroids effective in chronic obstructive pulmonary disease? Am. J. Respir. Crit. Care Med. 1999; 160(5 Pt 2):S66–71. 4. Martinez FD. Context dependency of markers of disease. Am. J. Respir. Crit. Care Med. 2000; 162(2 Pt 2):S56–7. 5. Strachan DP, Butland BK, Anderson HR. Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort. Br. Med. J. 1996; 312:1195–9. 6. Barbee RA, Dodge R, Lebowitz ML et al. The epidemiology of asthma. Chest 1985; 87(1 Suppl):21S–25S. 7. Oswald H, Phelan PD, Lanigan A et al. Childhood asthma and lung function in mid-adult life. Pediatr. Pulmonol. 1997; 23:14–20. 8. Jenkins MA, Hopper JL, Bowes G et al. Factors in childhood as predictors of asthma in adult life. Br. Med. J. 1994; 309:90–3. 9. Yunginger J, Reed CE, O’Connell EJ et al. A community-based study of the epidemiology of asthma. Incidence rates, 1964–1983. Am. Rev. Respir. Dis. 1992; 146:888–94. 10. Anderson HR, Pottier AC, Strachan DP. Asthma from birth to age 23: incidence and relation to prior and concurrent atopic disease. Thorax 1992; 47:537–42. 11. Stein RT, Sherrill D, Morgan WJ et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999; 353:541–5. 12. Martinez FD, Helms PJ.Types of asthma and wheezing. Eur. Respir. J. 1998; 27:3S–8S. 13. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during pregnancy: effects on lung function during the first 18 months of life. Am. J. Respir. Crit. Care Med. 1995; 152:977–83. 14. Martinez FD, Morgan WJ, Wright AL et al. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. N. Engl. J. Med. 1988; 319:1112–17. 15. Martinez FD. Sudden infant death syndrome and small airway occlusion: facts and hypothesis. Pediatrics 1991; 87:190–8. 16. Montgomery GL, Tepper RS. Changes in airway reactivity with age in normal infants and young children. Am. Rev. Respir. Dis. 1990; 142(6 Pt 1):1372–6. 17. Burrows B, Sears MR, Flannery EM et al. Relation of the course of bronchial responsiveness from age 9 to age 15 to allergy. Am. J. Respir. Crit. Care Med. 1995; 152(4 Pt 1):1302–8. 18. Young S, Arnott J, O’Keeffe PT et al.The association between early life lung function and wheezing during the first 2 years of life. Eur. Respir. J. 2000; 15(1):151–7. 19. Zeiger RS, Dawson C, Weiss S. Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP). J. Allergy Clin. Immunol. 1999; 103(3 Pt 1):376–87. 20. Halonen M, Stern DA, Lohman C et al. Two subphenotypes of childhood asthma that differ in maternal and paternal influences on asthma risk. Am. J. Respir. Crit. Care Med. 1999; 160:564–70. 21. Halonen M, Stern DA, Wright AL et al. Alternaria as a major allergen for asthma in children raised in a desert environment. Am. J. Respir. Crit. Care Med. 1997; 155(4):1356–61. 22. Pullen C, Hey E. Wheezing, asthma, and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy. Br. Med. J. 1982; 5:1665–9. 23. Burrows B, Martinez FD, Halonen M et al. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N. Engl. J. Med. 1989; 320:271–7. 24. Peat JK, Tovey E, Toelle BG et al. House dust mite allergens: a major risk factor for childhood asthma in Australia. Am. J. Respir. Crit. Care Med. 1996; 153:141–6. 25. Platts-Mills TAE, Weck ALD. Dust mite allergens and asthma – a worldwide problem. J. Allergy Clin. Immunol. 1989; 83(2 Pt 1):416–27.
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26. Peat JK, Tovey E, Mellis CM et al. Importance of house dust mite and Alternaria allergens in childhood asthma: an epidemiological study in two climatic regions of Australia. Clin. Exp. Allergy 1993; 23:812–20. 27. Perzanowski MS, Ronmark E, Nold B et al. Relevance of allergens from cats and dogs to asthma in the northernmost province of Sweden: schools as a major site of exposure. J. Allergy Clin. Immunol. 1999; 103:1018–24. 28. Burrows B, Lebowitz MD, Barbee RA et al. Findings before diagnoses of asthma among the elderly in a longitudinal study of a general population sample. J. Allergy Clin. Immunol. 1991; 88:870–7. 29. Barbee RA, Kaltenborn W, Lebowitz MD et al. Longitudinal changes in allergen skin test reactivity in a community population sample. J. Allergy Clin. Immunol. 1987; 79:16–24. 30. Kjellman B, Gustafsson PM. Asthma from childhood to adulthood: asthma severity, allergies, sensitization, living conditions, gender influence and social consequences. Respir. Med. 2000; 94:454–65. 31. Williams H, McNicol KN. Prevalence, natural history, and relationship of wheezy bronchitis and asthma in children: an epidemiological study. Br. Med. J. 1969; 4:321–5. 32. Phelan PD. Asthma in Children and Adolescents: an Overview. London: Baillière Tindall, 1995. 33. Gerritsen J, Koeter GH, Postma DS et al. Prognosis of asthma from childhood to adulthood. Am. Rev. Respir. Dis. 1989; 140:1325–30. 34. Stocks J. Lung function testing in infants. Pediatr. Pulmonol. Suppl. 1999; 18:14–20. 35. Le Souef P,Turner S, Rye P et al. Pulmonary function at four weeks correlates with pulmonary function at 6 and 12 years. Am. J. Respir. Crit. Care Med. 2001; 163:A541. 36. Stein RT, Holberg CJ, Sherrill D et al. The influence of parental smoking on respiratory symptoms in the first decade of life: the Tucson Children’s Respiratory Study. Am. J. Epidemiol. 1999; 149:1030–7. 37. Tager IB, Hanrahan JP, Tosteson TD et al. Lung function, pre- and post-natal smoke exposure, and wheezing in the first year of life. Am. Rev. Respir. Dis. 1993; 147:811–17. 38. Pagtakhan RD, Bjelland JC, Landau LI et al. Sex differences in growth patterns of the airways and lung parenchyma in children. J. Appl. Physiol. 1984; 56:1204–10. 39. Burrows B, Knudson RJ, Lebowitz MD. The relationship of childhood respiratory illness to adult obstructive airway disease. Am. Rev. Respir. Dis. 1977; 115:751–60. 40. Samet JM, Tager IB, Speizer FE. The relationship between respiratory illness in childhood and chronic airflow obstruction in adulthood. Am. Rev. Respir. Dis. 1983; 127:508–23. 41. Bont L, Heijnen CJ, Kavelaars A et al. Monocyte IL-10 production during respiratory syncytial virus bronchiolitis is associated with recurrent wheezing in a one-year follow-up study. Am. J. Resp. Crit. Care Med. 2000; 161:1518–23. 42. Makela MJ, Kanehiro A, Borish L et al. IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization. Proc. Natl. Acad. Sci. USA 2000; 97:6007–12. 43. Barker DJ, Godfrey KM, Fall C et al. Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease. Br. Med. J. 1991; 303:671–5. 44. Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur. J. Respir. Dis. 1987; 70:171–9. 45. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir. Med. 1994; 88:373–81. 46. Martinez FD, Wright AL, Taussig LM et al. Asthma and wheezing in the first six years of life. N. Engl. J. Med. 1995; 332:133–8.
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47. Xuan W, Peat JK, Toelle BG et al. Lung function growth and its relation to airway hyperresponsiveness and recent wheeze: results from a longitudinal population study. Am. J. Resp. Crit. Care Med. 2000; 161:1820–4. 48. Holberg CJ, Stern DA, Sherrill DL et al. Effect of smoking on the development of lung function in adolescence. Am. J. Respir. Crit. Care Med. 2001; 163:A260. 49. Camilli AE, Burrows B, Knudson RJ et al. Longitudinal changes in forced expiratory volume in one second in adults: effects of smoking and smoking cessation. Am. Rev. Respir. Dis. 1987; 135:794–9. 50. Burrows B, Knudson RJ, Cline MG et al. A reexamination of risk factors for ventilatory impairment. Am. Rev. Respir. Dis. 1988; 138:829–36. 51. Kurzius-Spencer M, Sherrill DL, Holberg CJ et al. Familial correlation of the slope of FEV1 in smoking and non-smoking pairs. Am. J. Respir. Crit. Care Med. 2000; 161:A580. 52. Postma DS, de Vries K, Koeter GH et al. Independent influence of reversibility of airflow obstruction and nonspecific
53.
54.
55.
56.
hyperreactivity on the long-term course of lung function in chronic airflow obstruction. Am. Rev. Respir. Dis. 1986; 134:276–80. Burrows B, Sears MR, Flannery EM et al. Relationships of bronchial responsiveness assessed by methacholine to serum IgE, lung function, symptoms, and diagnoses in 11-year-old New Zealand children. J. Allergy Clin. Immunol. 1992; 90(3 Pt 1):376–85. Palmer LJ, Rye PJ, Gibson NA et al. Airway responsiveness in early infancy predicts asthma, lung function, and respiratory symptoms by school age. Am. J. Respir. Crit. Care Med. 2001; 163:37–42. Weiss ST, Ware JH. Overview of issues in the longitudinal analysis of respiratory data. Am. J. Respir. Crit. Care Med. 1996; 154(6 Pt 2):S208–11. Stein RT, Holberg CJ, Morgan WJ et al. Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood. Thorax 1997; 52:946–52.
Chapter
Genetics Jorrit Gerritsen, Marlies Feijen, and Dirkje S. Postma*
4
Departments of Pediatrics and Pulmonology,* University Hospital Groningen, The Netherlands
The inheritance of asthma and atopic diseases is evident from family histories. Notwithstanding the fact that twin studies have shown that heritability in asthma is as high as 60–70%,1,2 the mode of inheritance still is not clear.There is even more uncertainty about the mode of inheritance of chronic obstructive pulmonary disease (COPD). It is likely that continuous injury to the lungs by environmental factors, especially smoking, interacts with genetic factors in the development of COPD. This chapter discusses the current knowledge of the genetics of atopic diseases, asthma, and COPD.
H E R I TA B I L I T Y O F A S T H M A A N D C O P D Asthma Asthma tends to cluster in families (familial aggregation). Over 85 years ago Cooke and van der Veer3 concluded, on the basis of family studies of 504 patients, that inheritance is a definite factor in human allergy. Leigh and Marley4 showed that the prevalence of asthma was significantly higher (13%) in relatives of asthma patients than in relatives of a matched group of nonasthmatic subjects (6%). The question is whether this familial aggregation can be explained mainly by genetic factors, and what part the environment plays. A glossary of the common terms used in genetics is presented in Table 4.1. No single gene accounts for the familial segregation of asthma. Rather, data demonstrate that models with oligogenic loci (i.e. a handful of loci being responsible for most of the genetic control) provide the best fit to the data.5 However, there are strong environmental influences,6 which modify phenotypic expression (Fig. 4.1). In studies of the heritability of asthma and COPD, the absence of unambiguous criteria for the diagnosis of these diseases has been a major obstacle to gene finding. Different genes can lead to the same phenotype (genetic heterogeneity), or the same genotype may result in different phenotypes (pleiotropy). Genes with DNA sequence variants do not always express the phenotype (incomplete penetrance), and the specific phenotype under study can be
PATIENT CHARACTERIZATION
DNA analysis
Genetic analysis
Sub-phenotyping of the patient
Fig. 4.1. Schematic of the approach to finding susceptibility genes for diseases like asthma and COPD.
expressed without the genetic mutation (phenocopy). In asthma, polygenic inheritance (i.e. mutation(s) of different genes) also seems to be important. Thus asthma fits the definition of a complex genetic disease. COPD Both environmental and genetic factors contribute to the development of COPD. Active sustained cigarette smoking contributes to the origin of COPD in more than 90% of the affected population in subjects who are susceptible.7 However, in Caucasians only 10–20% of chronic heavy cigarette smokers develop symptomatic COPD, suggesting that genetic factors are likely to be important in determining which cigarette smokers are at risk to develop airflow limitation.8 Furthermore, some patients develop severe airflow limitation at an earlier age, again an indication for a genetic origin of COPD. Notwithstanding the influence of environmental factors, there is considerable evidence that COPD has a hereditary component as well. In a population of 5003 adults there were significant correlations in lung function in sibling pairs
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Asthma and Chronic Obstructive Pulmonary Disease
Table 4.1. Glossary of common genetic terms
Allele
An alternative form of the same gene present at a given genetic locus.
CentiMorgan (cM)
Relative genetic distance between two loci on a chromosome. The chance of recombining during a single meiosis is 1:100 if two loci are separated by 1 cM.
Complex disorder
A disorder coming from the inheritance of more than one genetic locus, influenced by environmental factors, and/or genotype-by-environment interaction.
Genetic map
A diagram of a particular chromosome in which the relationship of one genetic locus to another, both with respect to linear order and distance along the chromosome, is depicted.
Genome
All genetic material in a chromosome.
Genotype
The specific set of alleles inherited by a given individual.
Haplotype
The specific alleles on a chromosome inherited from one parent (haploid genotype). A haplotype typically refers to closely grouped loci.
Linkage
The inheritance of genetic material at two loci which, because of their physical proximity on the chromosome, do not assort independently.
Linkage disequilibrium
Association of a particular allele with a specific allele at a nearby locus more frequently than expected by chance.
Locus
The unique location of a gene or DNA sequence on a chromosome.
LOD-score
The log10 of the odds ratio, and reflects the (un)linkage of two loci.
Pharmacogenetics
The study of hereditary variations underlying differences among individuals in drug response.
Phenocopy
Individuals without the genotype show the study’s phenotype.
Phenotype
The physical characteristics of an individual.
Polymorphism
Frequency of >1% in the population of variant loci present at two or more alleles.
SNP
Single nucleotide polymorphism; i.e. those variants at a single nucleotide base that lead to inheritance of different alleles.
and in parents and their offspring, but only trivial correlations between spouses;9 and these findings have been replicated.10 Although accurate estimates of heritability are difficult, the heritability of FEV1, the major component of the expression of COPD available in clinical practice, is as high as 77%.11 Moreover, twin studies have shown that there is a closer similarity in lung function between monozygotic twins than between dizygotic twins. In a recent investigation in early-onset severe COPD, current and ex-smoking relatives of the probands had an increased risk to have reduced FEV1 and chronic bronchitis. This observation suggests a genetic risk factor for COPD that is expressed in response to cigarette smoking.12
population.13,14 The risk is thought to reflect sharing of both genes and environment. The genetic component of asthma has been studied in twin studies and segregation analyses (Fig. 4.2).
APPROACHES TO GENETIC STUDIES
MZ twins share virtually 100% of their genetic information and DZ twins 50%. A higher disease concordance in MZ twins compared with DZ twins can be ascribed to genetic factors, whereas the observations that in many genetically identical MZ twins one of the pair has asthma is a strong
A first-degree family member of a patient with asthma has a 2–6 fold higher risk to develop the disease than individuals unrelated to a patient with asthma in the general
Studies of twins The main assumptions in twin studies: • the environment for monozygotic (MZ) and dizygotic (DZ) twins is similar; • the twin pairs are otherwise representative of the general population; • in questionnaire-based studies, self-reported zygosity is correct.
Genetics
1
1
3
2
3 4
5
6 7
8
31
9
2
4
5
6
7
Confidence interval
8
9
Families
Genotyping using DNA markers
Localization of susceptibility genes
Fig. 4.2. Example of genetic analysis.
indication for environmental influences.2,15–20 A Swedish population-based study of 6996 twin pairs revealed that MZ concordance for self-reported asthma was 19.0% and DZ concordance 4.8%.21 In 8- to 18-year-old twins, genetic associations for asthma (as reported by questionnaire), atopy (revealed by skin-prick test) and bronchial hyperresponsiveness (assessed by hypertonic saline challenge) were ascertained, as odds ratios. The ratios were greater in MZ pairs compared with DZ pairs for asthma: 25.6 versus 1.9; for atopy 14.6 versus 2.5; and for airway hyperresponsiveness 14.1 versus 4.2. Since strong cross-sectional associations exist between these three traits, genetic factors are involved in the expression of each of these three traits.22 Only scanty information is available about the heredity of allergy as indicated by specific IgE levels and skin-prick test results, but the specific IgE response seems mainly to be determined by the environment.16,23,24 A twin study in smokers showed that there is a high risk to develop chronic airflow limitation in MZ twins, whereas this is not the case in DZ twins who smoke, even if they were raised apart.25,26 Segregation analysis The hypothesis that the aggregation of a trait in families comes from the action of a major gene has been tested by
segregation analysis, in which the number of individuals with a certain trait in a family is compared with the expected number using different genetic models of inheritance. The models used have been: • a Mendelian component (dominant or recessive gene model); • a non-Mendelian component (multiple genes with small effect); • a mixed model (a single gene on a polygenic background); or • a nongenetic environmental model. Segregation analysis identifies the genetic model which is the best fit to the data. From the optimal model the mode of inheritance, and parameters such as the penetrance, the heritability, and allele frequencies, can be estimated.27 A study in 13,963 patients with a self-reported family history of asthma, participating in the European Community Respiratory Health Survey, provided evidence for a two-allele gene with codominant inheritance.28 Familial aggregation of asthma and wheeze was also shown in four smaller studies, consistent with the action of multiple genes each with a small effect.5,29–31 Airway responsiveness to carbachol has been studied in nonasthmatic parents of patients with asthma and in healthy
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Asthma and Chronic Obstructive Pulmonary Disease
controls.32 In the healthy controls, 10% of the parents had airway hyperresponsiveness, in contrast to 50% of the nonasthmatic parents of the patients with asthma. This familial clustering was also studied in complex segregation analyses of 83 and 131 families;31,33 the findings were similar but there was no evidence for a single major gene for airway responsiveness. A number of groups have studied the segregation of total serum IgE; the results have been quite variable. The best fitting models, using a single-locus approach, have pointed to a single major gene, either dominant,34 codominant,35,36 recessive,37 or mixed recessive inheritance.38 Polygenic models provide good fits in a multi-locus approach.31,39 A two-locus approach to total serum IgE levels in 92 Dutch families, ascertained through a proband with asthma, fitted the data significantly better than a one-locus model. It provided evidence for two unlinked loci; one single locus explained 56% of the variance of the level of total serum IgE, and the second 19%. Jointly the two loci accounted for 78.4% of the variability of total serum IgE levels.40
LINKAGE STUDIES Chromosome 11q The first reports of linkage of atopy, asthma, and rhinitis to the microsatellite marker D11S97 on chromosome 11q13 in seven extended UK pedigrees were presented by Cookson and coworkers in 1988 and 1989.41,42 They found a maximum LOD score of 5.58 for atopy, defined as an elevated IgE, raised allergen-specific IgE, or the presence of one or more positive skin-prick tests; the recombination fraction was 0.105. Linkage to the same marker was replicated by the same group in other population samples, among others in 64 nuclear families where a LOD score of 3.8 was found, at a recombination fraction of 0.067. It was suggested that atopy at this locus was inherited via the maternal line.43–45 Since those reports there have been a number of further independent publications claiming either positive46–48 or negative49–54 findings for linkage to this chromosomal region for asthma, airway hyperresponsiveness, and atopy. The negative finding of Zhu et al.54 can be ascribed to the age group (12 months) investigated. Almost all recent studies have failed to replicate the evidence for a candidate gene on chromosome 11q13 for asthma and atopy. Chromosome 5q Numerous candidate genes for asthma and atopy are located on chromosome 5q31 to q33. Linkage between total serum IgE levels and chromosome 5q was reported in a US Amish population and at the same time in a study of Dutch families who were ascertained through a proband with asthma.55,56 In the Dutch families it was shown that linkage exists with airway hyperresponsiveness to histamine in the same region of chromosome 5q, indicating that a gene governing airway hyperresponsiveness might be located near a gene regulating total serum IgE.57
In studies from Japan, the UK, and the US, chromosome 5q was also mentioned as a region containing one or more susceptibility genes for asthma.47,58–60 The finding of linkage to asthma or atopy on chromosome 5q has not been confirmed in many other studies.61–65 The importance of this region for the development of asthma and atopy remains unknown. Novel chromosomal regions of interest for asthma In an Australian and British sample, potential linkages (P < 0.001) were found between chromosome 4 and airway responsiveness, chromosome 6 and eosinophils, chromosome 7 and airway responsiveness, chromosome 11 and skin tests and total IgE, and chromosome 16 and total IgE.45 A US multicenter study was performed in 140 asthmatic families ascertained through two or more affected siblings with asthma in three racial groups – Hispanics, Caucasians, and Afro-Americans. The outcome was that different regions were linked in these different racial groups. In AfroAmericans, regions of interest for asthma-associated phenotypes were on chromosome 5p15 and 17p11.1 to q11.2, in Caucasians on chromosome 11p15 and 19q13, whereas in Hispanics on chromosome 2q33 and 21q21.59 In two European populations, consisting of 124 Finnish and Catalonian families, three phenotypic markers (total serum IgE, asthma, and specific IgE level for a mixture of the most common aeroallergens in Finland) were investigated and associated with the FceRII gene on chromosome 19p13. They found that chromosome 19p13 might harbor a genetic determinant of IgE-related traits, and concluded that other population samples are needed to verify this finding.66 The Hutteries are an American religious group that emigrated from the Tyrolean Alps in the 1500s. In the 1870s, about 900 of these members migrated to what is now South Dakota, and roughly half settled on three communal farms. The Hutteries have expanded dramatically and since they arose from less than 90 ancestors, they are a homogeneous population. If the subjects had either airway hyperresponsiveness to methacholine and reported asthma symptoms they were diagnosed as “strict” asthma. “Loose” asthma was defined if one of the two were positive. Linkages for “strict” asthma were found on chromosomes 19q13 and 21q21. For “loose” asthma these were 3p24.2–22, 5q23–31, and 12q15–24.1. This implies that also in a homogeneous population multiple susceptibility genes are involved in asthma.60 A more detailed study on chromosome 12q in Italian families revealed that asthma susceptibility factors are located on this chromosome.67 These findings have not been consistent; in a sibling-pair linkage analysis and transmission disequilibrium testing (Fig. 4.3) using four highly polymorphic microsatellite markers on 12q13–24, no linkage could be found with atopy.68 In 97 German families, including 415 single individuals and 156 sibling pairs, a genome-wide search was performed for asthma defined by clinical history and/or a history of at least 3 years of recurrent wheezing episodes in children over
Genetics
(a)
Allele frequency (log10 P value)
25
ApoE4
20 15 10 5 0 0
200 400 600 800 1000 1200 1400 1600 1800 2000
Distance (kb)
33
In 108 Dutch probands and their families, a genome-wide screen was performed using variance-component analysis. Significant linkage of IgE was found at chromosome 7q with a LOD score of 3.36, flanked by markers D7S820 and D7S821. Furthermore, linkage for previously reported regions on chromosome 5q and 12q was confirmed.70 The genome screen studies show that the findings in different populations are not consistent, although in most screens linkages have been found on chromosome 5q, 11q, and 12q. Thus far no linkage studies on COPD have been published. A summary of the results of genome screens in asthma is presented in Table 4.2.
(b)
C A N D I D AT E G E N E S
25
Allele frequency (log10 P value)
ApoE4 20 15 10 5 0 460 465 470 475 480 485 490 495 500 505 510 515 520 525
Distance (kb) Fig. 4.3. An example of transmission disequilibrium testing, showing the significance of SNP allele frequency differences in an affected Alzheimer’s disease population and age-matched controls. (a) Association data for dozens of ordered SNPs from a region of 2 million bases on either side of ApoE. When the allele frequencies of each SNP are compared in large series of Alzheimer’s disease patients and controls, a sharp peak of several SNPs can be readily observed in linkage disequilibrium, with no significant difference in the frequencies of background alleles. (b) If the peak is enlarged to illustrate a region of only 60,000 bases around ApoE, three SNPs from the map that are each highly significantly associated with Alzheimer’s disease can be identified. Only two genes, ApoC1 and ApoE, are coded in the physical DNA segment defined by the SNPs associated with Alzheimer’s disease. The association data from the SNP defining the ApoE4 polymorphism, known to be associated with earlier onset of disease, is also illustrated. Reproduced from reference 135, with permission.
age 3. Linkages were found at chromosome 2p (marker D2S2298) for asthma, airway responsiveness to methacholine and specific and total IgE; at chromosome 6p for asthma, eosinophils, total and specific IgE; at chromosome 9q for asthma, total and specific IgE; and at chromosome 12q for specific IgE.14 A genome-wide screen in France was conducted in 107 nuclear families with at least two siblings with asthma. The subjects were characterized by skin-prick tests, total serum IgE, lung function, and methacholine challenge. Linkages were found at the chromosomes 1p31 for asthma; at 11p13 for IgE and asthma; at 12q24.31 and 13q31 for eosinophil count; at 17q12 for asthma and skin-prick tests; and at 19q13 for airway responsiveness.69
After linkage of a disease to a specific chromosomal region, the region can be screened for candidate genes associated with the disease. A candidate gene has to meet the following criteria: • the product of the gene must be functionally relevant to the disease under study; • mutations within the gene have to alter the function; • the disease has to be linked to the chromosomal region harboring the candidate gene; • the disease has to show association with different alleles of the gene. Candidate genes in asthma Among the candidate genes studied in asthma are: • the b2-adrenergic receptor; • the b-chain of the high-affinity IgE receptor at chromosome 11q13; • the cytokine cluster at chromosome 5q31-q33; • the IL-4 receptor a-chain at chromosome 16p; • the major histocompatibility complex; • the tumor necrosis factor-a at chromosome 6. The b2-adrenergic receptor The gene encoding the b2-adrenergic receptor is located on chromosome 5q31. Nine polymorphisms have been identified in this gene; four code for a change in amino-acid sequence at positions 16, 27, 34, and 164 of the F13 residual protein (Fig. 4.4). Multiple studies show that these polymorphisms of the b2-adrenergic receptor do not contribute to the risk of asthma.71–74 However, they may play an important role in modifying the clinical severity; i.e. they are associated with nocturnal and/or severe asthma, as evidenced by using more corticosteroids and immunotherapy.71,75,76 The response to regular use of a b-agonist is impaired in patients homozygous for the genotype Arg16 of the b2-receptor. These patients may benefit by avoiding regularly scheduled b-agonists and might be candidates for earlier intervention with anti-inflammatory agents.77 In
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Asthma and Chronic Obstructive Pulmonary Disease
Table 4.2. Results of genome screen in different populations
Chr 2p 2q 3p 3q 4q 5p 5q 6p 7p 9p 9q 10q 11p 11q 12q 13q 14q 16q 17p 17q 19q 21q
US asthma
Dutch
Australia
Hutteries
Germany Asthma
Hispanic
“Asthma” BHR/asthma symptoms BHR
BHR
BHR Afro-American Caucasian Caucasian
BHR
“Asthma” IgE/eos/atopy IgE/eos/BHR
Asthma BHR “Asthma”
Asthma
Asthma
Asthma
IgE Caucasian IgE/Skin-test Caucasian Hispanic Caucasian Caucasian
IgE Atopy
BHR
IgE/BHR Afro-American IgE Caucasian Hispanic
homozygous Arg-16 patients it has been shown that they are susceptible to clinically important increases in asthma exacerbations during chronic dosing with the short-acting b2agonist salbutamol.78 Children with the Gly16 polymorphism of the b2adrenergic receptor have been shown to have a decreased bronchodilation after the use of a short-acting b2-agonist compared with those with the Arg16 allele. It was suggested that the diminished response of the Gly16 variant to shortacting b2-agonists was related to the increased use of inhaled corticosteroids.73 A number of studies have focused on the b2-adrenoreceptor desensitization.79–81 The effect of two common polymorphic forms of the b2-adrenoreceptor on acute and long-term b2adrenergic receptor desensitization in human smooth muscle cells has been examined.81 Cells with any Arg16 allele showed significantly greater acute and long-term desensitization of isoprenaline-induced c-AMP formation than did cells without the Arg16 allele (54% versus 2%, P < 0.01, for short-term desensitization; and 73% versus 35%, P < 0.05, for long-term desensitization). Owing to the strong linkage disequilibrium it is difficult to assign causation to a single locus.
Asthma BHR/Asthma
The b-chain of the high-affinity IgE receptor The high-affinity IgE receptor (FceRI) consists of three chains, one a, one b, and two c chains. The abc1,2-complex is located on the surface of mast cells, basophils, eosinophils, and Langerhans cells. Binding of allergens to IgE on mast cells gives activation and excretion of cytokines such as IL-4, which in their turn increase IgE production of the B lymphocytes. The function of the a-subunit is ligand binding; the c-dimer mediates both the assembly of the receptor as well as signal transduction.The b-subunit amplifies the signal mediated by the c-dimer.82 Sequence variants in the a- and c-chains have not been associated to asthma or atopy.47 The b-chain is situated on chromosome 11q.83 A number of polymorphisms have been investigated in relation to atopy and asthma: the isoleucine (Ile)181/leucine (Leu)181 variant was associated with atopy, if the Leu-181 variant was inherited maternally.84,85 Also the Leu-181/Leu-183 variant, when inherited maternally, was associated with atopy.86 The results of the Leu-181/Leu-183 variants have not been replicated in Japanese, UK, Italian, and Dutch populations.50,87–90 One of the variants of a polymorphism resulting in two restriction sites for the restriction enzyme, RsaI, was
Genetics
Val34
Met (GTG
35
D P A H S R N P A L L F A S G N G P Q G M NH2 H D Arg16 Gly (AGA GGA) V Y A C T N N E Q I T Q Gln27 Glu (CAA GAA) A C R E C D Q D E 175 (CGG AGG) F T H W G N F V M T F F W W A K T V N L I R C Q D M N V R K G M G L I H E F W Y W H Q A Y I V H E V Y I V M S A A G F T S I D M Q I P A I A S V I N V I L L N L I V P V V L F S V L C S I V I F F W I G ATG) L A I V A L G M T L G S V T A S S F Y V P L W C Y V N S F G N V L D V I W I E T P L V L T F G F N V L V I A C A L V M L I L C V I I M V F T G M I P L I Y T A I S T I I V R A V D V Y S I G L C R S F T A R A R P K D F Y K Y K V L R I F N A F A N F F K H A Q T E R E K L K V C Q I L Q T E F T E T A K R Q L Q L L K K 84 (CTG CTA) S L L S S P F K I Y Q C S V H F R G E S K D Q R L N R R L S Q V E Q D G R T G H G L Thr164 Ile (ACC ATC) R S 366 (TAT TAC) S L Y G S Q E G T N G N S S Y G N G Y A K H V 351 (GGG GGC) E Q E K E N K L L C E D L P G T E D F V G H Q G T HOOC L L S D N T S C N R G Q S D I N D S P V
413 (CTG
CTA)
Fig. 4.4. Primary amino-acid sequence and proposed membrane topography of the human b2-adrenergic receptor. The darkened circles indicate codons where degenerate polymorphisms of the receptor were found. The four polymorphisms which result in changes in the amino-acid sequence are indicated. Reproduced from reference 136, with permission.
associated with atopy in a Japanese population, and with atopic dermatitis in a British population, which could however not be confirmed in another population.91–93 The Gly237→ Glu237 polymorphism, a mutation in about 5% of Australian and Japanese populations, was strongly associated with asthma and airway hyperresponsiveness.87,88 It can be concluded that the high-affinity receptor FceRIb is related to asthma and atopy, although it is plausible that other variants of the gene or other genes on chromosome 11 are more informative for the development of atopy and asthma. The cytokine cluster Chromosome 5q31–q33 region contains a cluster of genes coding for proinflammatory cytokines important in immune regulation (IL-4, IL-5, IL-9, IL-13, CD-14, and interferon-c). Two members of this cluster, IL-4 and IL-13, have been genetically and functionally implicated in the pathogenesis of asthma and atopy.94–97 These cytokines are
produced by Th2 cells and are capable of inducing isotype class switching of B cells to produce IgE. They also share a receptor component, IL4Ra, which is an important factor in the development or expression of atopy and asthma. The IL-13 receptor consists of one IL4Ra subunit and either a low-affinity IL13Ra1 or a high-affinity IL13Ra2 subunit. The complete receptor for IL-4 is composed of one IL4Ra subunit and an IL4Rc subunit. Van der Pouw Kraan was the first to establish that the IL13 1055TT genotype was associated with allergic asthma, and altered regulation of IL-13 production.95 In addition, an Arg130Gln polymorphism in exon 4 has been shown to be associated with high total serum IgE levels,96,98 atopic dermatitis,98 and asthma,97 – in German,96,98 American,99 British,68 and Japanese97 populations. These results provide evidence that variation in the IL-13 gene is involved in the pathogenesis of asthma, airway hyperresponsiveness, and skin-test reactivity. Further investigation in this region of the chromosome is required.
36
Asthma and Chronic Obstructive Pulmonary Disease
The IL-4 receptor a-chain The production of IgE by the B cell and the switch of the T helper cell into the Th2 cell are mainly regulated by IL-4 and IL-13 and their receptors. IL-4 and IL-13 are located on chromosome 5q and share the IL-4 receptor a-chain which is located at chromosome 16p12. The polymorphisms of the IL-4 receptor (Ile50 allele, Arg551 allele) are predominantly linked to atopy, atopic asthma, and serum total IgE;99–103 but not in all populations.104 After a genome-wide screen in the Hutterites, the IL4Ra gene was examined as the 16p-linked susceptibility locus of asthma and atopy in both Hutterites and Hispanics.105 It appeared that there was an association to atopy or a lose definition of asthma. Since the alleles or haplotypes showing the strongest evidence differed between the Hutterite and Hispanic families, variation outside the coding region of the gene influences susceptibility.105 Others have found a lower IgE level in a population with a combination of the Pro478 and Arg551 allele.106 In one study it is shown that the IL4Ra*576R allele is associated with increased IgE and a low level of lung function in asthmatic subjects.90 From these studies it has become clear that the IL4Ra gene is of importance in the pathogenesis of atopy, IgE, and asthma. The precise place in larger populations has to be investigated. The human leukocyte antigen (HLA) region The human major histocompatibility complex (MHC) is a region of DNA on chromosome 6 (6p21.3) and contains over 200 genes, more than 40 of which encode leukocyte antigens.107 The HLA region and the tumor necrosis factor-a are located on chromosome 6p. The HLA molecules are membrane-bound glycoproteins involved in antigen presentation. The HLA class I is present on virtually every somatic cell, although the level of expression varies depending on the tissue. By contrast, class II genes are normally expressed by a subgroup of immune cells that includes B cells, activated T cells, macrophages, dendritic cells, and thymic epithelial cells. In the presence of interferon-c, however, other types of cells can express class II HLA molecules.107 Polymorphisms in the genes encoding the HLA class II molecules are associated with total serum IgE and specific IgE responses to several specific allergens, such as ragweed pollen, and cockroach.108–110 Also, associations with sensitization to cockroach allergens and the HLA-DRB1*01 alleles has been found.112 Others have failed to extend these findings to common major allergens, like house dust mite.110,111 In industrial isocyanate-induced asthma, certain HLA class II traits may be important.113 Although these are positive associations, the importance of this class II region for asthma is not universal.114,115 Tumor necrosis factor-a Inflammation of the airways is a key issue in asthma, as assessed by bronchial biopsies and bronchoalveolar lavage. One of the important cytokines in asthma is tumor necrosis factor-a; the gene encoding for TNF-a is situated on the
HLA class III locus of chromosome 6p near to the leukotriene A and B gene.107 The 308G→308A polymorphism (TNF1 allele) is associated with a 6- to 7-fold upregulation in transcription of TNF-a and results in a 5-fold increased risk of physician-diagnosed asthma requiring prophylactic medication. The patients studied had positive skin tests to one or more common aeroallergens and a family history of asthma and/or atopic disease in first-degree relatives.116 Positive associations between asthma (based on questionnaires) and TNF-a polymorphism (LTaNcol*1) have been found.117–119 Others have not replicated these findings,120 so no definitive statements can be made about TNF-a in asthma. Candidate genes in COPD There is one proven genetic risk factor for COPD: severe a1-antitrypsin deficiency. The human genes encoding a1-antitrypsin, a1-antichymotrypsin, and protein C inhibitor all map to human chromosome 14q32.1. The serine protease inhibitor (serpin) gene cluster also contains an antitrypsin-related sequence.121 Mutations in the 3 flanking region of the a1-antitrypsin gene have been reported to be associated with COPD, whereas in another study this could not be confirmed.122 A combination of a family history of COPD with homozygosity for His113/His139 mEH haplotype has been reported to be associated with rapid decline of lung function with an odds ratio of 4.9 and a P value of 0.04.123 Pulmonary surfactant, a lipoprotein complex essential for normal lung function, innate host defense of the lung, and the regulation of inflammatory processes known as the collectins, might play a role in the etiology of COPD. Transgenic mice that express the PDGF-B gene driven by the lung-specific surfactant protein C promoter have been shown to have distinct abnormalities in the developing and adult lung. This leads to a complex phenotype that encompasses aspects of both emphysema and fibrotic lung disease.124,125 Recently it has been confirmed, in humans, that polymorphisms of the surfactant protein gene are linked to COPD.126 In a Taiwanese population the TNF-308 polymorphism, which has previously been shown linked to asthmatic phenotypes, is disproportionately represented in patients with chronic bronchitis. Others found that TNFa*1/2 alleles are significantly associated with the presence of smoking-related COPD.127 Moreover, TNF-a may have an amplifying effect on the inflammatory process by activating NF-jB and other transcription factors to increase the expression of inflammatory genes, including IL-8. However, in a Caucasian population of smokers (86 COPD, and 62 healthy smokers) this was not confirmed. Moreover, there was no association between a polymorphism of TNF-a and level of FEV1 in COPD patients.128 Thus, more studies in larger groups are needed to assess the viability of TNF-a as a candidate gene in COPD. There are other, less well studied causative loci in COPD, including the IVS8 5T allele of the CFTR gene and the human mucin genes.129–131
Genetics
PHARMACOGENETICS
THE PERSPECTIVES OF GENETICS OF ASTHMA AND COPD
Individual variation in response to drugs is a major problem in clinical practice, but also in drug development. Such variation ranges from failure to respond to a drug to adverse drug reactions and drug interactions when several drugs are taken concomitantly.132,133 The research on single nucleotide polymorphisms (SNPs) of, for example, the b2-adrenergic, the glucocorticoid, and the leukotriene receptor will be important in identifying the response on the different drugs by the patients and will be a target to individualize therapy. An example is the effect of b2-adrenergic agents on desensitization in human airway smooth muscle. The Glu27 allele polymorphism of the b2adrenergic receptor on chromosome 5q was significantly associated with increased acute and long-term desensitization in human airway smooth muscle after pretreatment with isoprenalin.81 In a clinical trial of the efficacy of ABT-761, a compound derived from zileuton, the DNA-sequence variants of the 5lipoxygenase (ALOX5) were investigated. The 114 individuals receiving high-dose active treatment were compared with the placebo group. The average improvement of FEV1 was 18.8 3.6% in the wild-type patients and 23.3 6.0% in the heterozygous patients. This was in contrast with the ten patients with the mutant genotype who had no benefit from active treatment (change in FEV1 of 1.2 2.9%) (Fig. 4.5).134 These findings suggest that the use of genetic information to stratify treatment responses will become very important in the near future and will optimize therapy in asthma and COPD. Day 8 25
Day 84 P < 0.001
FEV1 (% change from baseline)
20 P 0.026
15
37
P 0.004
P 0.039
10 5 0 5
10 Fig. 4.5. Percentage change in FEV1 from pretreatment baseline for patients with the wild-type genotype at the ALOX5 core promotor locus treated for 8 and 84 days with either ABT-761g (dark bar) or placebo (light bar); and for patients with no wild-type alleles at this locus (open bar). Reproduced from reference 134, with permission.
In asthma and COPD the heterogeneity of the diseases with complex hereditary traits and many (sub)phenotypes are obstacles to the identification of genes. In the pathogenesis of asthma and COPD it is reasonable that the interactions between multiple genes and multiple environmental triggers are also important; again this will make it difficult to identify genes. When a linkage has been found in a certain population, repetition of the results in different populations is crucial. Collaborative efforts worldwide are needed if we are going to unravel the complex genetics of asthma and COPD. This will ultimately only be possible by close collaboration between, for example, clinicians, (molecular) geneticists, statisticians, and immunologists.
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102. Hershey GKK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA. The association of atopy with a gain-of-function mutation in the a-subunit of the interleukin-4 receptor. N. Engl. J. Med. 1997; 337:1720–5. 103. Izuhara K, Yanaghihra Y, Hamasaki N, Shirkawa T, Hopkin JM. Atopy and the human IL-4 receptor a chain. J. Allergy Clin. Immunol. 2000; 106:S65–71. 104. Noguchi E, Shibasaka M, Arinami T et al. No association between atopy/asthma and the ile50val polymorphism of IL-4 receptor. Am. J. Respir. Crit. Care Med. 1999; 160:342–5. 105. Ober C, Leavitt SA, Tsalenko A et al. Variation in the interleukin 4 receptor gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am. J. Hum. Genet. 2000; 66:517–26. 106. Mitsuyasu H, Yanagihara Y, Mao XQ et al. Cutting edge: dominant effect of Ile50Val variant of the human IL-4 receptor alpha-chain in IgE synthesis. J. Immunol. 1999; 162:1227–31. 107. Klein J, Sato A. The HLA system I. N. Engl. J. Med. 2000; 343:702–9. 108. Howell WM, Holgate ST. HLA genetics and allergic disease. Thorax 1995; 50:815–18. 109. Donfack J,Tsalenko A, Hoki DM et al. HLA-DRB1*01 alleles are associated with sensitisation to cockroach allergens. J. Allergy Clin. Immunol. 2000; 105:960–6. 110. Mansur AH, Williams GA, Bishop DT et al. Evidence for a role of HLA DRBI alleles in the control of IgE levels, strengthened by interacting TCR A/D marker alleles. Clin. Exp. Allergy 2000; 30:1371–8. 111. Young RP, Dekker JW, Wordsworth BP et al. HLA-DR and HLADP genotypes and immunoglobulin E-responses to common major allergens. Clin. Exp. Allergy 1994; 24:431–9. 112. Hollaway JW, Doull I, Begishvilli B et al. Lack of evidence of a significant association between HLA-DR, DQ and DP genotypes and atopy in families with HDM allergy. Clin. Exp. Allergy 1996; 26:1142–9. 113. Bignon JS, Aron Y, Ju LY et al. HLA class II alleles in isocyanateinduced asthma. Am. J. Respir. Crit. Care Med. 1994; 149:71–5. 114. Li PK, Lai CK, Poon AS et al. Lack of association between HLADQ and -DR genotypes and asthma in southern Chinese patients. Clin. Exp. Allergy 1995; 25:323–31. 115. Aron Y, Swierczewski E, Lockhart A. HLA class II haplotype in atopic asthmatic and non-atopic control subjects. Clin. Exp. Allergy 1995; 25:S65–S67. 116. Albuquerque RV, Hayden CM, Palmer LJ et al. Association of polymorphisms within the tumor necrosis factor (TNF) genes and childhood asthma. Clin. Exp. Allergy 1998; 28:578–84. 117. Moffatt MF, Cookson WO. Tumour necrosis factor haplotypes and asthma. Hum. Mol. Genet. 1997; 6:551–4. 118. Moffatt MF, James A, Ryan G et al. Extended tumour necrosis factor/HLA-DR haplotypes and asthma in an Australian population sample. Thorax 1999; 54:757–61. 119. Wa LK, Mansur AH, Britton J et al. Association between 308 tumour necrosis factor polymorphism and bronchial hyperreactivity in asthma. Clin. Exp. Allergy 1999; 29:1204–8.
120. Louis R, Leyder E, Malaise M, Bartsch P, Louis E. Lack of association between adult asthma and the tumour necrosis factor alpha-308 polymorphism gene. Eur. Respir. J. 2000; 16:604–8. 121. Rollini P, Fournier RE. A 370-kb cosmid contig of the serpin gene cluster on human chromosome 14q32.1: molecular linkage of the genes encoding alpha 1-antichymotrypsin, protein C inhibitor, kallistatin, alpha 1-antitrypsin, and corticosteroidbinding globulin. Genomics 1997; 46:409–15. 122. Sandford AJ, Spinelli JJ, Weir TD, Pare PD. Mutation in the 3 region of the alpha-1-antitrypsin gene and chronic obstructive pulmonary disease. J. Med. Genet. 1997; 34:874–5. 123. Sandford AJ, Chagani T, Weir TD et al. Susceptibility genes for rapid decline of lung function in the Lung Health Study. Am. J. Respir. Crit. Care Med. 2001; 163:469–73. 124. Hoyle GW, Li J, Finkelstein JB et al. Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice overexpressing platelet-derived growth factor. Am. J. Pathol. 1999; 154:1763–75. 125. Suga T, Kurabayashi M, Sando Y et al. Disruption of the klotho gene causes pulmonary emphysema in mice: defect in maintenance of pulmonary integrity during postnatal life. Am. J. Respir. Cell Mol. Biol. 2000; 22:26–33. 126. Guo X, Lin HM, Lin Z et al. Polymorphisms of surfactant protein gene A, B, D, and of SP-B-linked microsatellite markers in COPD of a Mexican population. Chest 2000; 117:249S–50S. 127. Sakao S, Tatsumi K, Igari H et al. Association of tumor necrosis factor a gene promotor polymorphism with the presence of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 163:420–2. 128. Higham MA, Pride NB, Alikhan A, Morrell NW. Tumour necrosis factor-a gene promoter polymorphism in chronic obstructive pulmonary disease. Eur. Respir. J. 2000; 15:281–4. 129. Noone PG, Pue CA, Zhou Z et al. Lung disease associated with the IVS8 5T allele of the CFTR gene. Am. J. Respir. Crit. Care Med. 2000; 162:1919–24. 130. Keatings VM, Cave SJ, Henry MJ et al. A polymorphism in the tumor necrosis factor-a gene promotor region may predispose to a poor prognosis in COPD. Chest 2000; 118:971–5. 131. Vinall LE, Fowler JC, Jones AL et al. Polymorphism of human mucin genes in chest disease: possible significance of MUC2. Am. J. Respir. Cell Mol. Biol. 2000; 23:678–86. 132. Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet 2000; 356:1667–71. 133. Wolf CR, Smith G, Smith RL. Pharmacogenetics. Br. Med. J. 2000; 320:987–90. 134. Drazen JM,Yandava CN, Dube L et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat. Genet. 1999; 22:168–70. 135. Roses AD. Pharmacogenetics and the practice of medicine. Nature 2000; 405:857–65. 136. Liggett SB. Genetics of b2-receptor variants in asthma. Clin. Exp. Allergy 1995; 25:89–94.
Pulmonary Physiology
Chapter
5
Neil B. Pride National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
Asthma is conventionally regarded as a disease confined to the airways, probably involving narrowing of all sizes of airways. The magnitude of narrowing usually varies considerably over time, either spontaneously or following treatment, but can become persistent. In contrast, airflow obstruction in chronic obstructive pulmonary disease (COPD) is due to a variable combination of predominantly fixed obstructive disease of the peripheral airways and loss of airway distending forces due to destructive changes in the lung parenchyma. Inflammatory changes in and around the airway wall are widespread in both asthma and COPD, and are also found in alveolar walls when emphysema is present. This chapter concentrates on the pathophysiology of the lungs in COPD and asthma.
A I R WAY F U N C T I O N Tests of overall airway function, whether measured during tidal breathing or forced expiration, reflect the summed effects of the total luminal cross-sectional areas of the airways which are available for gas flow. Before considering assessment by these tests, the factors which determine luminal caliber of an individual airway will be outlined. Factors determining airway caliber: area–transmural pressure curves At any lung volume, the luminal area of an airway depends on a combination of (1) luminal contents, such as mucoinflammatory plugs; (2) structural features of the airway wall; (3) functional features, notably the contractile state of airway smooth muscle; and (4) the effective transmural pressure of the airway (Ptm), which, except in central airways during forced expiration, tends to distend the airway. Therefore the cross-sectional intraluminal area (A) is determined by the elastic properties of the airway (i.e. its wall compliance which is the product of (2) and (3) above) and Ptm. Invivo secretions may occupy some of the lumen. A/Ptm curves are characteristically S-shaped with limits to their maximum size, perhaps set by the fully stretched dimensions of the basement membrane, and sometimes also limits to
minimum size preventing complete closure. Increases in airway caliber with lung inflation are determined by the accompanying increase in Ptm. Airway smooth muscle (ASM) The large differences in bronchoconstrictor responsiveness found in vivo cannot be explained by the differences in the contractility of human ASM in vitro as conventionally measured under static conditions; human ASM excised from normal lungs invariably contracts in response to bronchoconstrictor drugs such as histamine, and it has been difficult to demonstrate large interindividual differences in this response, even in the limited studies available using ASM from subjects with asthma.1 However, increased velocity of contraction has been shown in ASM derived from allergen-sensitized animals.2 Of equal potential importance, the behavior of ASM has been shown to be highly dependent on the volume and time history to which it is subjected.3 Thus it has been suggested that the normal tidal excursions of breathing4 (with occasional deep breaths) keep ASM in a relatively high-compliance state but that its state stiffens with lack of stretch. The direct relevance of these findings to asthma remain to be established (see Chapter 17). The most consistent abnormality of ASM is the increased mass found in asthma5 and, to a lesser extent, in COPD.6 These changes are responsible for some of the increase in wall thickening seen in both diseases. Thickening of airway wall Enhanced reductions in luminal caliber can occur with normal shortening of ASM if there is thickening of the airway wall internal to the contracting muscle. On average, the thickness of the airway wall was doubled in lungs from 18 subjects with fatal asthma.7 These changes involved all sizes of airways and all layers internal and external to the ASM. Calculations suggest that these changes would greatly enhance the effects of constrictor challenge but would hardly increase basal airway resistance.7 Less dramatic airway wall thickening was found in lungs from subjects with asthma who died of nonrespiratory causes8 and in patients with COPD9,10. It has also been hypothesized that rapid
44
Asthma and Chronic Obstructive Pulmonary Disease
expansion of the blood volume in and around the airway wall, acutely increasing its thickness, might be responsible for the airway narrowing that occurs after exercise or isocapnic hyperventilation in asthmatic subjects.11 Thickening of the wall external to ASM increasing the external perimeter may have effects of lung airway coupling. Airway wall compliance An increase in airway wall compliance would amplify the effects of ASM contraction, whereas a reduction might restrict the extent of narrowing with ASM contraction. In central intrathoracic but extrapulmonary airways, cartilage restricts the extent of luminal narrowing. In the trachea, the attachments of the muscle to the cartilage rings, at least in experimental animals, are such that smooth muscle contraction results in the formation of complete cartilage rings encircling the lumen.12,13 In the central conducting airways there are separate plates of cartilage, but these are also brought closer together to “fortify” the airway walls by ASM contraction. Apart from reducing wall compliance, this may limit narrowing and prevent luminal closure. As discussed above, contraction of ASM itself may directly decrease wall compliance.3,14 Conversely, occasional paradoxical decreases in maximum expiratory flow after bronchodilators in normal subjects have been attributed to enhanced collapsibility of central airways due to loss of the stabilization provided by the normal tonic contraction of ASM.15 A further factor preventing complete closure of the lumen is folding of the mucosa, preserving some lumen between the folds.16 There have been few direct measurements of compliance of individual airways in COPD or asthma. In COPD it would be expected that compliance of large conducting airways would be increased due to loss of cartilage and this would amplify the tendency for central airways to narrow when there is expiratory flow limitation. In the peripheral airways, fibrosis and other pathological changes would be expected to reduce their wall compliance. Surprisingly, tantalum bronchograms obtained at necropsy in lungs from patients dying with severe airflow obstruction showed no reduction in compliance of medium- and small-diameter airways at a standard static lung recoil pressure (PL); reduced compliance was only found in airways less than 1 mm diameter in emphysematous lungs.17 In contrast, in asthma direct intrabronchial measurements in humans have shown lower compliance of central airways in young adults than in healthy controls.18 Limited high-resolution computed tomography (HRCT) studies have shown normal expansion of large airways with lung inflation in mild asthma19 but reduced expansion with more severe asthma, presumably reflecting reduced wall compliance rather than a reduced increase in effective Ptm. Extra-airway distending forces: airway perimeter–lung coupling For the intrapulmonary airways, the most important factor stabilizing the airway wall against the effects of ASM contraction is the attachment of alveolar walls to the external perimeter of the airway wall.20 Theory, and most experimental work, suggest that these extra-airway forces would have their
greatest stabilizing effect at large lung volumes, so that a given amount of activation of ASM would lead to greater shortening at small rather than large lung volume. In humans in vivo, the magnitude of maximum bronchoconstriction to inhaled methacholine is greater at small than at large lung volume and is quite sensitive to small changes in volume above and below functional residual capacity (FRC).21 However, the magnitude of airway narrowing produced by submaximal doses of methacholine appears to be unchanged by moderate changes in lung volume, suggesting that ASM initially may contract freely and that the restraints applied by surrounding lung chiefly act to prevent extreme narrowing or closure.21,22 These restraining forces may be reduced by the modest loss of lung elastic recoil pressure (PL ) found in asthma; coupling between alveoli and airways may also be reduced by enlargement of the outer perimeter of the airway wall or by surrounding inflammatory changes. In COPD, loss of PL is much greater, while breaks in alveolar attachments to the airway perimeter23,24 and peri-airway inflammation would all be expected to reduce restraints to narrowing of smaller airways. There are few direct measurements demonstrating these mechanisms, but they provide a basis for interpreting the significance of changes in tests of “lumped” airway function and the causes of airway hyperresponsiveness. Airway responsiveness Bronchodilator response In clinical practice and in many trials of treatment, the size of the increase in airway function (usually FEV1) after inhaled bronchodilators (either b-agonists alone, or a combination of b-agonists and anticholinergic drugs) is used to make a practical distinction between asthma and COPD. Most patients with COPD show some improvement in airway function after treatment with bronchodilator drugs;25 in contrast to asthma, the response to anticholinergic drugs is similar to (some would say superior to) that to b-agonists.26 This suggests that most of the reversible component in COPD is due to vagal tone;25 and, because vagal motor innervation does not extend to the most peripheral airways, involves more central airways than those in which the major obstructive changes occur.This idea has been supported by a study using an intra-airway catheter.Total lung resistance was reduced equally (30%) by atropine and a b-agonist (fenoterol) aerosol; the b-agonist reduced resistance in all airways to a similar extent but atropine had a larger dilator effect in central than in peripheral (<3 mm diameter) airways.27 It is uncertain whether cholinergic “tone” is greater in COPD than in normal subjects; the absolute increment in FEV1 after antiCh cholinergic treatment is similar in COPD and normal subjects and a study of sensory stimulation of the nose failed to show an enhanced vagally induced bronchoconstriction in COPD compared with normal subjects.28 There is considerable day-to-day variation25 in the size of the bronchodilator response. Response to bronchodilators is usually assessed by changes in FEV1, maximum expiratory flow-volume
Pulmonary Physiology
(MEFV) curves, or resistance (conductance), and there appear to be no distinctive features between the response in COPD and in asthma, although in both the percentage change in resistance is usually greater than in FEV1. Improvement in airway function is usually accompanied by a decrease in FRC and an increase in inspiratory capacity and maximum inspiratory flow in both asthma and COPD; these changes may be more relevant to any improvement in exercise performance. Discrepancies between small changes in maximum flow and in volumes (FRC; residual volume, RV; and vital capacity, VC) probably account for some of the difficulty in predicting improvement in exercise tolerance after bronchodilators in COPD from resting measurements.29 Bronchoconstrictor response Airway hyperresponsiveness (AHR) to inhaled stimuli is a central feature of asthma, included in its definition, but is also found in COPD. Speculations on the origins of AHR in asthma have fluctuated over recent decades, although all give a central role to ASM contraction (Table 5.1). Whatever the initiating mechanism, the effect will be enhanced if baseline airway dimensions are reduced. Abnormalities due to inflammation of airway smooth muscle have predominated as explanations for AHR in asthma, while altered “geometric” or structural changes are regarded as important for AHR in COPD. AHR is characterized by an increase in threshold or sensitivity (lowest stimulus at which contraction is observed), an increase in reactivity (increase in airway narrowing for a given change in stimulus), and a loss of the plateau of maximum narrowing which is found in normal subjects.30,31 This plateau is lost in both asthma and COPD unless disease is very mild. Although reactivity may be lower in COPD than in asthma, in practice almost all information on AHR has been obtained in terms of the stimulus required to give a standard percentage change in airway function (most commonly 20% fall in FEV1) which is chiefly an indication of sensitivity. Patients with COPD show AHR to challenge with spasmogens such as inhaled histamine or methacholine and most of the other “indirect” stimuli used to provoke airway narrowing in asthma. The presence and intensity of AHR in
45
COPD is inversely related to baseline FEV1 (“geometric effect”).32,33 Bronchodilator responses are now usually reported as increase in absolute values (preferably as percentage predicted values) because percentage increase over baseline is enhanced as baseline declines. Bronchoconstrictor responses, however, are still reported as the dose required to produce a given change from baseline; it is widely assumed that when baseline airway function is reduced a smaller absolute reduction in airway cross-sectional area is required to produce a given percentage change from baseline in FEV1 or resistance. In addition more central deposition of inhaled drugs may accentuate the response. More specific structural changes, such as increased thickness of the airway wall (although this is less than in asthma), increase in ASM mass and isometric contractility,6 and loss of support to airways as a result of destructive changes in alveoli attached to the external airway perimeters34,35 may all contribute. The last mechanism has been most clearly shown in a study of methacholine response in patients with alpha 1-antitrypsin deficiency who retained a plateau of maximum narrowing; the plateau value of FEV1 decreased as PL decreased.36 Overall, however, no difference has been shown in AHR to histamine between patients with emphysema and those with predominant airway disease.37 The intensity of hyperresponsiveness in smokers predicts accelerated decline in FEV1, independent of the baseline spirometry.38 In contrast to asthma, almost all studies in COPD have failed to show attenuation of AHR by treatment for 2–3 months with inhaled corticosteroids;39 however, a small attenuation of AHR was shown after 3 years’ treatment in the Lung Health Study.40 In asthma, apart from inflammation and abnormal ASM, structural changes in the airway wall and reduced lung–airway coupling probably also contribute to AHR. Inflammation may be the initiating stimulus for increase in ASM mass and other structural wall changes, but it is unknown whether these changes regress if inflammation is suppressed for a long period. An inverse relation between baseline FEV1 and the intensity of AHR is found also in asthma and extends into the normal range of FEV1.41–43 As discussed below, peripheral lung resistance may be increased even when tests of overall airway function are normal. For a given level of FEV1, AHR is more intense in asthma than in
Table 5.1. Possible causes of airway hyperresponsiveness
Functional change
Implied mechanism
Enhanced mediator or neural responsiveness in airway mucosa
Mucosal inflammation
Increased contraction of ASM due to increased contractility and/or mass
Abnormal airway smooth muscle
Thickening of airway wall
Enhances effect of ASM contraction
Reduced lung–airway perimeter coupling
Loss of normal mechanism restricting airway narrowing
46
Asthma and Chronic Obstructive Pulmonary Disease
COPD (Fig. 5.1),42 presumably reflecting additional effects of airway inflammation and changes in ASM in asthma. This overlap in AHR between asthma and COPD can be interpreted as supporting the Dutch hypothesis.44 AHR related to atopy and predating the onset of smoking is common in the population and inevitably will occur in some patients with COPD. However, cross-sectional studies suggest that the prevalence of AHR increases in middle age in nonatopic smokers,45 so it remains possible that AHR is sometimes acquired and has a different pathogenesis in COPD than in asthma. Site of constrictor response In asthmatic subjects, induced airway narrowing is very heterogeneous among parallel airways, as shown by scans of regional ventilation which suggest that this heterogeneity occurs in conducting airways. High-resolution computerized tomography confirms airway narrowing is heterogeneous and involves all sizes of airways in both normal46,47 and asthmatic47 subjects. A potentially important area is the involvement of lung tissue in the constrictor response. In animals, increases in lung tissue resistance have accounted for a large part of the increase in pulmonary resistance after bronchoconstrictor aerosols, sometimes exceeding the contribution of narrowing of the conducting airways.48 The origins of the increased lung tissue resistance are uncertain; one possibility is contractile elements in the lung periphery, such as smooth muscle or myofibroblasts in alveolar ducts or small pulmonary vessels. But recent work suggests that heterogeneity of airway narrowing and constricted conducting airways may contribute to local distortion of alveolar expansion and geometry which may be responsible for peripheral lung effects.49–51 Studies are required to establish whether animal models of asthma involve very different sites of increase in resistance from those found in humans.
Log PC20 (mg/mL)
2
0
1
COPD
2
Asthma
0 0
20
40
60
80
100
FEV1 (% predicted) Fig. 5.1. Regression lines (95% CI) of log PC20 for histamine against baseline FEV1 (% predicted) in 81 subjects with asthma and 44 with COPD. Reproduced from reference 42, with permission.
Site of increased airflow resistance during tidal breathing COPD In mild disease, changes are found in the lung periphery. These changes are detected as nonuniform behavior of the lungs.52 As disease advances, an increase in peripheral lung resistance develops53 while total airway function remains within the normal range.When moderate airway obstruction (mean FEV1 50–60% of predicted) has developed, studies using an intrabronchial catheter have found that slightly more than half the total pulmonary resistance resides in airways of less than 3 mm internal diameter (Table 5.2).54 This proportion was similar for a group with predominant airway disease (“chronic bronchitis”) and for a group with physiological evidence of emphysema; despite a lower FEV1 in the emphysema group, total lung resistance was lower than in the chronic bronchitis group. For severe disease the best information comes from study of lungs at necropsy. Most of the increase in resistance in lungs of patients dying with COPD is in the peripheral airways of less than 2 mm diameter; on average these account for 75% of the total resistance at lung volumes comparable with those during tidal breathing in life.55–57 Despite pathological changes in their walls, such as mucus gland hypertrophy, the resistance of central airways is increased in only a minority of lungs,58 and even then it is associated with a proportionally greater increase in peripheral airway resistance. Although the increase in resistance is larger during expiration, inspiratory resistance is also increased. These post-mortem studies imply a reduction in peripheral airway dimensions even at a standard PL. This could result from intrinsic disease of the airways (obliteration and narrowing of airway lumina by scarring, wall thickening, inflammation, mucus plugs) or from loss of airway distension caused by a loss or breaks of the attached alveolar walls. In life there is an additional labile component to resistance, presumably resulting from bronchial muscle contraction (“vagal tone”) or mucosal edema, which probably involves more central airways. (See the section on airways responsiveness.) Nevertheless, the available evidence suggests that, when total airway resistance (measured at low flow, for example in a whole-body plethysmograph) is increased, in most patients with COPD it is mainly caused by a very large increase in peripheral airway resistance. A striking feature is the great parallel inhomogeneity of airway narrowing (and also of alveolar destruction) which results in great unevenness of ventilation – as can be visualized on a coarse basis by ventilation scans using radiolabeled gas or aerosols. In emphysema there is also a large increase in collateral ventilation,58,59 presumably reflecting a combination of hyperinflation and gas movement through breaks in alveolar walls; this should allow some gas exchange beyond occluded airways and prevent atelectasis. Asthma The airway narrowing in episodic asthma is due to varying combinations of smooth muscle contraction, mucosal
47
Pulmonary Physiology
Table 5.2. Peripheral lung resistance (Rp) as a percentage of total lung resistance (RL) in normal subjects, chronic persistent asthma, and COPD
Subjects (no.)
RL
Rp
Mean age (years)
FEV1 (% predicted)
Normal (5)
56
88
3.1
0.7
24
Chronic persistent asthma (10)
57
54
9.2
4.1
44
COPD Chronic bronchitis (7)
64
51
8.7
4.8
55
63
39
5.9
3.0
50
Emphysema (8)
(cmH2O per liter per second)
Rp/RL (%)
Reproduced from reference 54, with permission.
swelling, and luminal secretions. Pathological studies suggest that inflammation of the airway mucosa extends throughout the tracheobronchial tree, indicating the potential for narrowing to develop in all airway generations. Attempts to determine the serial site of airway narrowing in asthma have been relatively inconclusive. Narrowing of the large airways has been observed on occasions when bronchoscopy or bronchography have precipitated an asthmatic attack. Although endobronchial pressure measurements are the obvious approach to define the distribution of airflow resistance, intra-airway catheters may stimulate mucosal receptors and induce reflex bronchoconstriction and mucus production and can be used only in central airways without compromising airflow through the catheterized airway. While in a few studies intrabronchial catheters have been placed in central airways, more information has come from studies using a wedged-catheter. In one version, a 3-mm catheter is wedged in a right lower lobe bronchus and lateral pressure measured proximally. With this technique total lung resistance in normal subjects appears about 50% higher than without the presence of a catheter. In asymptomatic young subjects during remission of asthma, peripheral airways resistance remained slightly increased;27,54 in middle-aged patients with persistent airflow obstruction due to chronic asthma, there were increases in both central and peripheral resistance (Table 5.2).54 Allowing for the contribution of the extrathoracic airway to total pulmonary resistance, peripheral resistance accounts for about one-third of intrathoracic resistance in normal subjects and for about 50% in the subjects with chronic, persistent asthma. Another technique measures pressure–flow relations in the occluded lung beyond a bronchoscope wedged in a segmental bronchus. In asthmatic subjects in remission with normal total airways resistance and FEV1, a considerable increase in peripheral lung resistance has been found;60 this technique measures the combined resistance of peripheral airways and collateral channels. These results directly confirm earlier suggestions from pathological and physiological studies that there are residual
changes in the peripheral airways even in remission of asthma, when overall lung function is normal. As in COPD, a striking (and life-saving) feature of attacks of asthma is the enormous parallel inhomogeneity of ventilation resulting in some areas of the lung remaining available for gas exchange. This has been shown by ventilation scans, is implied by detailed analyses of pulmonary gas exchange and mechanics, and heterogeneity of individual airway constrictor responses after inhaling histamine has been directly shown using HRCT. Whereas in COPD these features may be attributed to inhomogeneity of “fixed” pathological changes, there is no such obvious explanation in asthma, nor is it known whether the pattern of inhomogeneity “repeats” or is highly variable between successive episodes. Site of flow limitation during forced expiration In both COPD and asthma, expiratory flow limitation (EFL) is found at all lung volumes during forced expiration; maximum expiratory flow is reduced at all lung volumes and is achieved with lower driving pressures than in normal subjects. Reduction in PL in emphysema enhances dynamic narrowing of the large intrathoracic airways on forced expiration so that there is much greater reduction in maximum expiratory flow than in maximum inspiratory flow.61 In the 1970s there was considerable interest in trying to localize the serial site of airflow limitation in airway disease by measuring the increase in maximum expiratory flow when the density of the expired gas was reduced by breathing a mixture of 80% helium and 20% oxygen.62 If maximum expiratory flow does not show the normal 60% increase when breathing helium–oxygen, this suggests that the major site of flow limitation is no longer in the central airways (as in normal subjects), but has moved to more peripheral airways where flow is presumed to be laminar and independent of density. This change is usually attributed to increased frictional pressure losses in narrowed peripheral airways.62 Most patients with COPD, even those with mild disease, showed a smaller (or absent) rise in maximum expiratory flow when breathing helium.63 Some asthmatic subjects consistently lose or consistently retain density
48
Asthma and Chronic Obstructive Pulmonary Disease
dependence of maximum flow with repeated attacks,64,65 but this is not invariably the case; in general, loss of density dependence becomes more common as expiratory airflow limitation increases in severity and is particularly observed in asthmatic subjects who smoke.66 Reduced density dependence of maximum expiratory flow should not be interpreted as indicating that only peripheral airways are involved, even if they are the site of flow limitation.52 Theoretically, the method analyzed the changes in the airways between the alveoli and the sites of expiratory flow limitation (“choke-points”), but it lost popularity when experimental studies showed that relatively small changes in geometry and position of choke-points could profoundly affect the helium response67 and that there was considerable variation in size of the baseline helium response in the normal population and in disease. Expiratory flow limitation during tidal breathing In normal subjects, levels of expiratory flow generated during tidal breathing at rest are much below maximum expiratory flow and only approach maximum levels during exercise at very high work loads. However, when maximum expiratory flow is severely reduced in COPD or in asthma, this limit may be reached during mild exercise and, when disease is severe, even at rest. Dynamic expiratory narrowing of central airways then develops and airflow resistance measured during expiration becomes unreliable as an indicator of “fixed” airway caliber. A simple test has been proposed to identify expiratory flow limitation (EFL) by applying a negative pressure of 5 cmH2O at the airway opening during tidal expiration and showing that this does not increase expiratory flow.68 Tidal EFL has been found in both asthma and in COPD when airflow obstruction is moderately severe.When EFL is present during tidal breathing at rest, the most effective way to increase total ventilation during exercise is to breathe at a larger lung volume, increasing end-expired lung volume (dynamic hyperinflation).
flow obstruction has developed, even if the predominant site of airway narrowing is in the peripheral airways, as in COPD, values of PEF and maximum flow throughout the vital capacity are reduced. Although changes in conductance and maximum expiratory flow are broadly related, their scaling need not be identical and some information can be obtained from empirical comparisons, particularly if patients with predominant emphysema are compared with asthma. Thus, for a given decrease in FEV1, resistance may be lower (see Table 5.2)54 and peak expiratory flow and maximum inspiratory flows higher in emphysema61 than in asthma. Of course in clinical practice the distinction between asthma and COPD is usually based on spontaneous or drug-induced variation (or lack of variation) in airway function. Summary See Table 5.3. Table 5.3. Site of airway narrowing during tidal breathing
• In COPD, the peripheral airways are the major site of fixed obstruction. When expiratory flow limitation develops, there may also be dynamic narrowing of central intrathoracic airways during expiration. • In acute asthma, distribution of airway narrowing is unknown but probably involves many sizes of airways. • In chronic asthma, there is narrowing of both central and peripheral airways. • Peripheral airway obstruction may persist during clinical remission of asthma. • In both asthma and COPD, extent of narrowing varies greatly between parallel airways.
A LV E O L A R F U N C T I O N Use of tests of airway function to distinguish asthma from COPD Many pathological changes in the airways distinguish asthma and COPD, but available simple measures of airway function have very limited ability to provide information on the site or nature of airway narrowing. Tests of overall airway function such as airway conductance or FEV1 breathing air reflect the dimensions of all the airways in series, but do not provide direct evidence on whether large or small airways are the site of airway narrowing. Because the resistance of peripheral airways at large lung volumes in normal lungs is low, for many years peak expiratory flow (PEF) has been regarded as reflecting mainly large airway function in normal subjects; but examining the relative changes in maximum flow on MEFV curves at large versus small volume only provides useful information about the site of airway disease when there are minor deviations from normal function. Once obvious air-
Perhaps the most striking distinction between asthma and COPD is that emphysema is not believed to develop in nonsmokers with asthma, even when asthma is longstanding and associated with persistent airway obstruction. This conclusion was originally based on post-mortem studies, but it is broadly supported by two tests of lung function – the carbon monoxide transfer coefficient, and the static expiratory pressure/volume curve of the lungs – both of which show less abnormality in asthma than in many patients with COPD. However, only in the last decade have studies of lung function been tested against a contemporary assessment of alveolar structure, as obtained by morphometry of lobectomy specimens or by HRCT; the latter shows permanent changes suggesting emphysema, not only in smokers, but sometimes also in never-smokers with the diagnosis of asthma.69,70 Abnormalities on HRCT scans have been reported also in many unusual diseases causing bronchioli-
Pulmonary Physiology
tis; these appear to be related to air trapping and locally reduced blood volume in the alveoli.71 At present it is not clear whether peripheral airway disease in COPD and asthma also produces distinctive changes in the HRCT scan independent of those due to emphysema. Pulmonary gas exchange Ventilation–blood flow imbalance: arterial blood gases The large alveolar–arterial PO2 difference found in both COPD and asthma is almost entirely due to ventilation– blood flow (V˙A/Q˙) imbalance. In both conditions, scans of pulmonary perfusion show gross regional abnormalities of blood flow in areas which are poorly ventilated giving broadly “matched” defects for the reduction in blood flow. In COPD various mechanisms have been proposed, whose relative importance is unknown: vascular remodeling or destruction in areas of emphysema, active constriction of the vessels in areas of severe alveolar hypoxia, or passive obstruction by the effects of increased alveolar pressure and distension. The latter two mechanisms might also be relevant in acute asthma. The altered distribution of flow is not confined to the gross abnormalities seen on scans, but is accompanied by much more subtle inequalities within a region. Changes in pulmonary blood flow do not, however, compensate fully for the unevenness of ventilation, so that gross inefficiency of pulmonary gas exchange develops. Some relatively subtle differences in the defects in gas exchange between COPD72 and asthma73 have been found using the multiple inert gas elimination technique (MIGET). In general, for a given severity of airways obstruction as assessed by FEV1, patients with asthma have less hypoxemia than patients with COPD. In hypoxemic patients with COPD, a large proportion of the blood flow perfuses lung with V˙A/Q˙ ratios under 0.1; such low ratios are not found in asthma, suggesting a greater compensatory reduction in blood flow to poorly ventilated areas in asthma (Fig. 5.2). A further factor is the increased total ventilation in severe asthma, although this has more effect on arterial PCO2. “Anatomical” shunt (V˙A/Q˙ ratio = 0) is unusual in COPD,72,74 except in the most severe exacerbations requiring assisted ventilation, despite probable complete occlusion of many peripheral airways. This suggests considerable collateral ventilation,58,59 which in part may be via destroyed alveolar walls. Even more surprisingly, anatomical shunt is not found in severe asthma, although in such attacks larger airways are often occluded by muco-inflammatory plugs and collateral ventilation is presumably confined to the pathways present in normal lungs. There is no evidence of a diffusion defect (difference between alveolar and end-pulmonary capillary PO2) at rest in either COPD74 or asthma.73 When 100% O2 is breathed there is an increased dispersion of pulmonary blood flow in both COPD75 and asthma,76 suggesting release of hypoxic pulmonary vasoconstriction. A striking difference between COPD and asthma is that chronic elevation of arterial PCO2 is rare in asthma, even when there is persistent airflow obstruction. The basic
49
mechanism raising arterial PCO2 when there is airflow obstruction is V˙A/Q˙ imbalance which reduces the efficiency of CO2 excretion in the same way that it impairs O2 uptake. However, arterial PCO2 can be kept normal by a small increase in total ventilation, which has a much smaller effect in preventing a fall in arterial PO2. The precise reasons for chronic elevation of PaCO2, occurring commonly in COPD but rarely in asthma, are unclear. Chronic hypercapnia occurs mainly in patients with COPD whose FEV1 is under 1.2 liters,77 a severity of obstruction which is associated with severe hyperinflation and mechanical disadvantage of the inspiratory muscles;78 changes of this magnitude are not often seen in chronic persistent asthma. In acute episodes of asthma, most patients increase total ventilation sufficiently to maintain arterial PCO2 in or below the normal range until a late stage, but a significant minority of patients develop hypercapnia.79 These patients tend to present with a similar PCO2 in each episode and may have a blunted ventilatory response. See Table 5.4 for a summary. Table 5.4. Pulmonary gas exchange
• Impaired O2 uptake and CO2 excretion are dominated by an imbalance in ventilation and blood flow in both COPD and asthma. • For a given severity of airflow obstruction, hypoxemia is less in asthma than in COPD, possibly reflecting greater pulmonary vasoconstriction in poorly ventilated areas in asthma. • Increased ventilation in asthma delays development of hypercapnia as airflow obstruction worsens.
Carbon monoxide transfer Tests of CO uptake were introduced in the 1950s in an attempt to mimic the lungs’ ability to take up O2 at rest and during exercise. Initially CO transfer was directly measured during tidal breathing by analyzing the difference between the concentration of an inspired CO mixture and mixed expired CO. However, this method was extremely sensitive to unevenness of ventilation, gave similar reduced CO uptake values in asthma and COPD, and did not reflect the true gas transfer characteristics of the alveoli. The single-breath CO transfer test (TLCO,sb) – also called CO diffusing capacity (DLCO) – measuring CO uptake during breath-holding at full inflation (total lung capacity, TLC) in contrast discriminates between asthma and emphysema. In this method TLCO is obtained as the product of the CO transfer coefficient (KCO) – also abbreviated as DLCO/VA or TLCO/VA – and the alveolar volume (VA). In airways obstruction, the appropriate alveolar volume is uncertain; the inspired CO mixture will tend to go to the best ventilated areas of the lung which will contribute disproportionately to the expired gas used for analysis so that
50
Asthma and Chronic Obstructive Pulmonary Disease
Normal
Episodic asthma
1.5 0.9
1.0
0.6
0.5
0.2
Shunt 0.0
0.0 0.0
0.1
1.0
100
10
0.0
Chronic severe asthma
0.01
1.0
100
Acute severe asthma
Ventilation and blood flow (L/min)
1.2 0.6
1.0 0.8
0.4 0.6
0.4
0.2
0.2 0.0
0.0 0.0
0.01
1.0
100
0.0
COPD type A
0.1
1.0
10
100
COPD type B 2.0
1.2
0.8 1.0 0.4
0.0 0.0
0.01
0.1
1.0
10
100
0.0
0.01
0.1
1.0
10
100
Ventilation/blood-flow ratio
Fig. 5.2. Frequency histograms of the ventilation/blood-flow ratios, calculated by the multiple inert gas technique, in a normal subject, in three patients with asthma, and in two patients with COPD. Note the different scaling of both axes in the various examples. The normal distribution of ventilation (open circles) and blood flow (solid circles) is over a narrow range of ventilation/blood-flow ratios and is unimodal. Patients with mild or chronic severe asthma have broader but still unimodal distribution of ventilation and blood flow, whereas those with acute severe asthma have a bimodal distribution of blood flow centered around V˙A/Q˙ ratios of 1.0 and 0.1. In COPD type A (emphysema), there is bimodal distribution of ventilation with areas of high V˙A/Q˙ ratio. In COPD type B (chronic bronchitis), blood flow distribution is bimodal with many alveolar units with V˙A/Q˙ ratio 0.1. Shunt (V˙A/Q˙ = 0) was absent in all patients. Reproduced from references 72 and 73, with permission.
Pulmonary Physiology
KCO is weighted towards the least diseased areas within an inhomogeneous lung. Smoking itself reduces T LCO by two distinct mechanisms: • Increases in blood CO, which reduces the pressure gradient across the alveolar–capillary membrane for CO uptake. • Independent of this effect, there is a roughly 10% reduction of T LCO in current smokers,80,81 which rapidly reverses after quitting and probably is due to a reduction in pulmonary capillary volume. In patients with airways obstruction and no additional lung pathology, KCO is a surrogate measurement of the perfused alveolar surface area per unit volume available for CO uptake. In COPD, reduction in KCO is related to the severity of “microscopic” emphysema (and hence reduced alveolar surface area) in the remaining functional lung,82,83 rather than to the extent of gross destructive changes.The fall does not indicate a true diffusion defect in the lung (failure for end-capillary PO2 to equilibrate with alveolar PO2).When airflow obstruction in COPD is predominantly due to airway disease, KCO is normal or only slightly reduced. In asthma, KCO is well preserved and even tends to increase above predicted values as FEV1 decreases.84,85 A possible explanation for this increase is that pulmonary vasoconstriction in poorly ventilated parts of the lung causes a redistribution of cardiac output to better ventilated areas. This leads to a local increase in pulmonary capillary volume and KCO, analogous to that which occurs throughout the lung when total cardiac output increases during exercise. Values of KCO in asthma and emphysema therefore tend to diverge as FEV1 falls. Because the measurements of KCO and T LCO,sb are made under the artificial circumstances of breath-holding at full inflation, they are predominantly indicators of lung structure rather than the efficiency of pulmonary gas exchange. See Table 5.5 for a summary. Table 5.5. Carbon monoxide transfer coefficient (KCO)
• In smokers there is a small reduction (about 10%) in KCO which reverses on quitting. • Reduction in KCO in COPD is related to severity of “microscopic” emphysema in surviving ventilated lung. • In asthma, KCO is normal and tends to increase slightly as airflow obstruction becomes more severe.
LUNG ELASTICITY AND LUNG VOLUMES Dynamic lung compliance Uneven ventilation of the lung leads to reduction in dynamic lung compliance. Indeed, a reduction in compliance as
51
breathing frequency is increased has been proposed as one of the most sensitive techniques for detecting mild airway disease, whether this is caused by asthma or by smoking.86 When significant airflow obstruction develops, dynamic compliance is considerably reduced during tidal breathing in both asthma and COPD. Static elastic properties of the lungs: expiratory pressure–volume curves COPD The similar reductions in dynamic compliance in asthma and all forms of COPD obscure considerable changes in the static elastic properties of the lungs in patients with severe emphysema. Two abnormalities of the static deflation pressure–volume (PV) curve of the lungs are thought to distinguish emphysema from airway obstruction solely caused by intrinsic airway disease: • an altered shape of the curve; • displacement of the whole PV curve to higher absolute volumes. Studies in the early 1980s showed that the plethysmographic technique may overestimate true lung volume in the presence of airway obstruction;87,88 therefore much of the earlier literature is difficult to interpret. Nevertheless, it seems likely that displacement of the PV curve to larger volumes is a much more prominent feature of emphysema than of intrinsic airway disease. Modeling the deflation PV curve as a single exponential allows a shape factor (k) to be obtained, which is virtually independent of the volume, relative expansion, and maximal distending pressure of the lungs, and so is not influenced by artefacts in the plethysmographic method.89 An increased value of k indicates an increase in static lung compliance, which is conventionally measured between FRC and (FRC + 0.5 L). But because static compliance varies with lung size and the volume range over which it is measured, comparisons of k are simpler. There seems little doubt that k is higher in emphysema than in asthma (Fig. 5.3),90,91 although not all studies have shown a clear relationship between k and the morphological changes of emphysema in lungs studied at post-mortem or after surgical removal.92–94 Because the worst areas of emphysema are poorly ventilated, changes in the PV curve reflect changes in the microscopic structure of the remaining functioning lung which accompany, and presumably precede, the gross morphological changes. Similar (but much smaller) changes occur with normal aging.89 Changes in the static PV curve of the lungs are partly responsible for increases in FRC and RV in COPD and are probably essential for any increase in TLC to occur. An increase inTLC acquired in adult life is suggested by loss of the zone of apposition of the diaphragm on images taken at full inflation. Loss of lung recoil pressure occurs at all volumes and leads to an increase in the neutral “relaxation” volume (Vr) of
52
Asthma and Chronic Obstructive Pulmonary Disease
the respiratory system (FRC); Vr may be further increased by reductions in chest wall recoil pressure.95 In patients with severe expiratory airflow obstruction, whether this is due to asthma or COPD, end-expiratory volume may be determined by dynamic factors rather than by the balance of static forces. Low values of expiratory flow then result in expiration being terminated by the initiation of the next inspiration before the respiratory system reaches Vr. In these circumstances, if the airway is occluded at end-expiration a positive alveolar pressure is present (“intrinsic” positive end-expiratory pressure, PEEPi) as a result of the effects of passive recoil of the lungs and chest wall. The increase in end-expired lung volume assists gas exchange by reducing the proportion of the respiratory cycle associated with very low mass movement of gas from the lungs, but the “dynamic hyperinflation” adds to the load placed on the inspiratory muscles. A combination of airway closure or near-closure and loss of lung recoil accounts for the increase in RV in severe COPD. The time to empty the lung is greatly prolonged with expiratory flow continuing at very low levels, presumably through dynamically narrowed airways, so that RV is limited finally by the breath-holding ability of the individual.
H
100
80
Mean k 0.414 cmH2O1 60
40 0 0
8
16
24
Chronic bronchitis CB
32
H
100
80
VL (% TLC)
Asthma Although asthma has been regarded as a disease confined to the airways without significant pathological changes in the lung tissue or air spaces, one transbronchial biopsy study has found alveolar tissue inflammation96 and, as discussed above, some physiological studies have suggested lung tissue may be involved in bronchoconstrictor responses.50,51 In addition most authors have found k is slightly increased and PL is slightly reduced (Fig. 5.3)90 in asthma; larger reductions in PL have been found by a few authors, including in a recent study97 in patients with chronic persistent asthma who had normal HRCT and CO transfer. Probably some change in the PV curve occurs in all forms of chronic airway obstruction with hyperinflation, perhaps due to stress relaxation.98 The consistent preservation of a normal or even increased value of carbon monoxide transfer coefficient (KCO) in nonsmokers with chronic asthma would not be expected in the presence of significant emphysema. Regardless of its cause, any loss of lung recoil pressure, together with enlargement of the airway outer diameter and periairway inflammation, would reduce the distension of the smaller airways by surrounding lung, even although the alveolar attachments themselves were normal. Adults who have had asthma in childhood99 may develop a slightly larger TLC than normal, but any increase in TLC is smaller than in emphysema. Studies before 1980 frequently showed large increases in TLC during acute exacerbations of asthma, but many of these increases were measurement artefacts;87,88 radiographic estimates suggest an increase in TLC of at most 0.3–0.5 liters.100,101 No change inTLC occurs after bronchodilator or bronchoconstrictor challenge.102 Increases in FRC and RV in asthma are mainly due to airway narrowing and closure. Studies with radioactive aerosols
Emphysema E
Mean k 0.206 cmH2O1 60
40 0 0
8
16
24
Asthma A
32
H
100
80
Mean k 0.155 cmH2O1 60
40 0 0
8
16
24
32
40
PL (cmH2O) Fig. 5.3. Range of expiratory pressure (PL)–volume (VL) curves in emphysema (n 24), COPD with primary bronchial disease (chronic bronchitis) (n 19), and asthma (n 24), compared with a range of values in age-matched healthy controls (H) (mean k 0.131 cmH2O1) (stippled areas). Lung volumes are expressed as percentage of TLC, which removes much of the effect of overestimation of lung volume by the plethysmographic technique. Reproduced from reference 90, with permission.
Pulmonary Physiology
show increased and patchy closure at RV in asthma,103 contrasting with the more uniform basal closure found in normal subjects which is believed to occur in the smallest airways. In asthma, closure may be facilitated by intraluminal secretions and/or ASM contraction and so may involve larger airways; in animal studies, closure of conducting airways with contraction of ASM is greater at small lung volumes, but can persist at large lung volumes.104 A large increase in RV with bronchoconstriction may indicate the patient has an increased risk of severe attacks.105 An increase in FRC occurs after bronchoconstrictor challenge even when this does not result in sufficient airway narrowing to cause EFL during tidal breathing;106 at this stage expiration is slowed by glottal narrowing107 and persistent activation of inspiratory muscles.108 The increase in FRC widens the airways and reduces the total work of the respiratory muscles during bronchoconstriction,109 but the precise neurological control mechanisms are unknown. When airflow obstruction increases in severe acute attacks, tidal EFL develops and RV rises and then ventilation can be sustained only by progressive increases in FRC with the development of PEEPi as in COPD. Assessment of contribution of alveolar disease to airway function Tests of maximum flow and resistance measure the combined effects of intrinsic airway disease and alveolar disease on airway function. In normal lungs, PL is a useful indicator of the forces distending the airways during breath-holding or breathing at low flows.110 In some patients with COPD and abnormal conductance–volume slopes, the relationship between conductance and PL remains normal.111–113 In general, the patients showing a normal conductance–lung
Table 5.6 Lung elasticity
• Loss of lung recoil, increased static compliance, and increase in TLC are characteristic of emphysema. • In mild COPD, loss of lung recoil may be the only mechanism reducing airway function. • Impairment of lung–airway coupling may not be fully reflected in disease by value of one lung recoil pressure. • In asthma there are small changes in static elastic properties, possibly related to stress relaxation of the lungs.
recoil relationship have radiologic and other functional evidence of emphysema and do not have the most severe reduction in airway function. In most patients with severe COPD, however, conductance is reduced at a standard PL, as is invariably the case in asthma.112 A normal relationship between conductance and PL does not necessarily imply the total absence of morphological changes in the airways because values of conductance are relatively insensitive to early changes in peripheral airways. Furthermore, the assumption that the pressure distending intrapulmonary airways can be approximated by PL is much more precarious in disease when the transduction of forces distending the alveoli to the external wall may be altered by breaks in alveolar walls or other causes of locally impaired lung–airway coupling and uneven distension of the lung. Maximum expiratory flow can also be related to PL.114 In the early stages of emphysema there may be loss of PL without reduction in maximum expiratory flow.91,115 But when
Table 5.7. Some extrapulmonary manifestations of COPD, which are not found in asthma
Manifestation
Pathogenesis
Increase in pulmonary artery pressure116 Right ventricular hypertrophy and dysfunction
Alveolar hypoxia 117
53
Secondary to increase in pulmonary artery pressure
Peripheral edema117
Secondary to hyperaldosteronism and/or “cor pulmonale”
Chronic hypercapnia78
˙ A/Q ˙ abnormality Severity of V and mechanical disadvantage of inspiratory muscles
Reduced inspiratory muscle strength118
Mechanical disadvantage due to hyperinflation and loss of muscle bulk, associated with cachexia
Reduction in skeletal muscle mass119
Deconditioning and/or cachexia
Weight loss120–122
Poor calorie intake and/or systemic “cachexins”
54
Asthma and Chronic Obstructive Pulmonary Disease
airflow obstruction develops, maximum expiratory flow is invariably reduced disproportionately to any reduction in PL in COPD (or asthma). See Table 5.6 for a summary
E X T R A P U L M O N A RY M A N I F E S TAT I O N S OF COPD Some well-known clinical manifestations outside the lungs are virtually confined to severe COPD (Table 5.7). It is uncertain whether this is because COPD is a more “systemic” disease with release of cytokines, mediators etc. into the circulation; or whether it simply reflects more severe changes in the lungs, the chronicity and unremitting nature of disease, and/or the greater age of subjects with COPD; or, as for example with pulmonary artery pressure, lack of measurements in asthma.
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Pulmonary Physiology
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57.
58.
59. 60.
61. 62. 63.
64.
65.
66.
67.
68.
69.
70.
71. 72.
73.
74.
75.
76.
77.
78.
55
functional–structural relationships. J. Appl. Physiol. 1983; 55:1733–42. Verbeken EK, Cauberghs M, Mertens I, Lauweryns JM, Van de Woestijne KP. Tissue and airway impedance of excised normal, senile and emphysematous lungs. J. Appl. Physiol. 1992; 72:2343–53. Hogg JC, Macklem PT, Thurlbeck WM. The resistance of collateral channels in excised human lungs. J. Clin. Invest. 1969; 48:421–31. Terry PB, Traystman RJ, Newball HH, Batra G, Menkes HA. Collateral ventilation in man. N. Engl. J. Med. 1978; 298:10–15. Wagner EM, Liu MC, Weinmann GG, Permutt S, Bleecker ER. Peripheral lung resistance in normal and asthmatic subjects. Am. Rev. Respir. Dis. 1990; 141:584–8. Stanescu D, Veriter C, Van de Woestijne KP. Maximal inspiratory flow rates in patients with COPD. Chest 2000; 118:976–80. Ingram RH, McFadden ER. Localization and mechanisms of airway responses. N. Engl. J. Med. 1977; 297:596–600. Fairshter RD, Wilson AF. Relationship between sites of airflow limitation and severity of chronic airflow obstruction. Am. Rev. Respir. Dis. 1981; 123:3–7. Fairshter RD, Wilson AF. Relationship between the site of airflow limitation and localization of the bronchodilator response in asthma. Am. Rev. Respir. Dis. 1980; 122:27–32. Partridge MR, Saunders KB. The site of airflow limitation in asthma: the effect of time, acute exacerbations of disease and clinical features. Br. J. Dis. Chest 1981; 75:263–72. Antic R, Macklem PT. The influence of clinical factors on site of airway obstruction in asthma. Am. Rev. Respir. Dis. 1976; 114:851–9. Jadue C, Greville H, Coalson JJ, Mink SN. Forced expiration and HeO2 response in canine peripheral airway obstruction. J. Appl. Physiol. 1985; 58:1788–801. Koulouris NG, Dimopoulou I,Valta P et al. Detection of expiratory flow limitation during exercise in COPD patients. J. Appl. Physiol. 1997; 82:723–31. Paganin F, Séneterre E, Chanez P et al. Computed tomography of the lungs in asthma: influence of disease severity and etiology. Am. J. Respir. Crit. Care Med. 1996; 153:110–14. Jaffuel D, Bousquet J, Paganin FJ. How can we assess remodeling using imaging? In: Howarth PH, Wilson JW, Bousquet J, Rak S, Pauwels RA (eds), Airway Remodeling, pp. 5–25. New York: Marcel Dekker, 2001. Hansell DM. Small airways diseases: detection and insights with computed tomography. Eur. Respir. J. 2001; 17:1294–313. Agusti AGN, Barberà JA. Contributions of multiple inert gas elimination technique to pulmonary medicine. 2: Chronic pulmonary diseases – chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Thorax 1994; 49:924–32. Rodriguez-Roisin R, Roca J. Contributions of multiple inert gas elimination technique to pulmonary medicine. 3: Bronchial asthma. Thorax 1994; 49:1027–33. Wagner PD, Dantzker DR, Dueck R, Clausen JL, West JB. Ventilation–perfusion inequality in chronic obstructive pulmonary disease. J. Clin. Invest. 1977; 59:203–16. Robinson TD, Freiberg DB, Regnis JA, Young IH. The role of hypoventilation and ventilation–perfusion redistribution in oxygen-induced hypercapnia during acute exacerbations of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 161:1524–9. Corte P, Young, I. Ventilation–perfusion relationships in symptomatic asthma: response to oxygen and clemastine. Chest 1985; 88:167–75. Lane DJ, Howell JBL, Giblin B. Relation between airways obstruction and CO2 tension in chronic obstructive airway disease. Br. Med. J. 1968; 3:707–9. Bégin P, Grassino A. Inspiratory muscle dysfunction and chronic hypercapnia in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1991; 143:905–12.
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79. Mountain RD, Sahn SA. Clinical features and outcome in patients with acute asthma presenting with hypercapnia. Am. Rev. Respir. Dis. 1988; 138:535–9. 80. Sansores RH, Paré P, Abboud RT. Effect of smoking cessation on pulmonary carbon monoxide diffusing capacity and capillary blood volume. Am. Rev. Respir. Dis. 1992; 146:959–64. 81. Watson A, Joyce H, Hopper L, Pride NB. Influence of smoking habits on change in carbon monoxide transfer factor over 10 years in middle-aged men. Thorax 1993; 48:119–24. 82. McLean A, Warren PM, Gillooly M, MacNee W, Lamb D. Microscopic and macroscopic measurements of emphysema: relation to carbon monoxide gas transfer. Thorax 1992; 47:144–9. 83. Gevenois PA, De Vuyst P, de Maetelaer V et al. Comparison of computed density and microscopic morphometry in pulmonary emphysema. Am. J. Respir. Crit. Care Med. 1996; 154:187–92. 84. Keens TG, Mansell A, Krastins IRB et al. Evaluation of the single-breath diffusing capacity in asthma and cystic fibrosis. Chest 1979; 76:41–4. 85. Collard P, Njinou B, Nedjadnik B, Keyeux A, Frans A. Single breath diffusing capacity for carbon monoxide in stable asthma. Chest 1994; 105:1426–9. 86. Woolcock AJ,Vincent NJ, Macklem PT. Frequency dependence of compliance as a test for obstruction in the small airways. J. Clin. Invest. 1969; 48:1097–106. 87. Stanescu DC, Rodenstein D, Cauberghs M, Van de Woestijne KP. Failure of body plethysmography in bronchial asthma. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 1982; 52:939–48. 88. Rodenstein DO, Stanescu DC. Reassessment of lung volume measurement by helium dilution and by body plethysmography in chronic airflow obstruction. Am. Rev. Respir. Dis. 1982; 126:1040–4. 89. Gibson GJ, Pride NB, Davis J, Schroter RC. Exponential description of the static pressure–volume curve of normal and diseased lungs. Am. Rev. Respir. Dis. 1979; 120:799–811. 90. Colebatch HJH, Greaves IA, Ng CKY. Pulmonary mechanics in diagnosis. In: deKock MA, Nadel JA, Lewis CM (eds), Mechanism of Airways Obstruction in Human Respiratory Disease, pp. 25–47. Cape Town, SA: Balkema, 1979. 91. Petrik-Pereira R, Hunter D, Pride NB. Use of lung pressure– volume curves and helium–sulphur hexafluoride washout to detect emphysema in patients with mild airflow obstruction. Thorax 1981; 36:29–37. 92. Greaves IA, Colebatch HJH. Elastic behavior and structure of normal and emphysematous lungs post-mortem. Am. Rev. Respir. Dis. 1980; 121:127–36. 93. Paré PD, Brooks LA, Bates J et al. Exponential analysis of the lung pressure–volume curve as a predictor of pulmonary emphysema. Am. Rev. Respir. Dis. 1982; 126:54–61. 94. Nagai A, Yamawaki I, Thurlbeck WM, Takizawa T. Assessment of lung parenchymal destruction by using routine histological tissue sections. Am. Rev. Respir. Dis. 1989; 139:313–19. 95. Sharp JT, Van Lith P, Vej Nuchprayoon C, Briney R, Johnson FN. The thorax in chronic obstructive lung disease. Am. J. Med. 1968; 44:39–46. 96. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am. J. Respir. Crit. Care Med. 1996; 154:1505–10. 97. Gelb AF, Zamel N. Unsuspected pseudophysiologic emphsema in chronic persistent asthma. Am. J. Respir. Crit. Care Med. 2000; 162:1778–82. 98. Rodarte JR, Noredin G, Miller C, Brusasco V, Pellegrino R. Lung elastic recoil during breathing at increased lung volume. J. Appl. Physiol. 1999; 87:1491–5. 99. Greaves IA, Colebatch HJH. Large lungs after childhood asthma: a consequence of enlarged airspaces. Aus. NZ J. Med. 1985; 15:427–34. 100. Blackie SP, Al-Majed S, Staples CA, Hilliam C, Paré PD. Changes in total lung capacity during acute spontaneous asthma. Am. Rev. Respir. Dis. 1990; 142:79–83.
101. Rothstein MS, Zelefsky MN, Eichaker PQ, Rudolph DJ, Williams MH. Radiographic measurement of total lung capacity in acute asthma. Thorax 1989; 44:510–12. 102. Kirby JG, Juniper EF, Hargreave FE, Zamel N. Total lung capacity does not change during methacholine-stimulated airway narrowing. J. Appl. Physiol. 1986; 61:2144–7. 103. King GG, Eberl S, Salome CM, Young IH, Woolcock AJ. Differences in airway closure between normal and asthmatic subjects measured with single-photon emission computed tomography and technegas. Am. J. Respir. Crit. Care Med. 1998; 158:1900–6. 104. Brown RH, Mitzner W. Airway closure with high PEEP in vivo. J. Appl. Physiol. 2000; 89:956–60. 105. Gibbons WJ, Sharma A, Lougheed D, Macklem PT. Detection of excessive bronchoconstriction in asthma. Am. J. Respir. Crit. Care Med. 1996; 153:582–9. 106. Tantucci C, Ellaffi M, Duguet A et al. Dynamic hyperinflation and flow limitation during methacholine-induced bronchoconstriction in asthma. Eur. Respir. J. 1999; 14:295–301. 107. Collett PW, Brancatisano AP, Engel LA. Upper airway dimensions and movements in bronchial asthma. Am. Rev. Respir. Dis. 1986; 133:1143–9. 108. Muller N, Bryan AC, Zamel N. Tonic inspiratory muscle activity as a cause of hyperinflation in asthma. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 1981; 50:279–82. 109. Wheatley JR, West S, Cala SJ, Engel LA. The effect of hyperinflation on respiratory muscle work in acute induced asthma. Eur. Respir. J. 1990; 3:625–32. 110. Butler J, Caro CG, Alcala R, DuBois AB. Physiological factors affecting airway resistance in normal subjects and in patients with obstructive respiratory disease. J. Clin. Invest. 1960; 39:584–91. 111. Jonson B. Pulmonary mechanics in patients with pulmonary disease, studied with the flow regulator method. Scand. J. Clin. Lab. Invest. 1970; 25:375–90. 112. Colebatch HJH, Finucane KE, Smith MM. Pulmonary conductance and elastic recoil relationship in asthma and emphysema. J. Appl. Physiol. 1973; 34:143–53. 113. Leaver DG, Tattersfield AE, Pride NB. Contributions of loss of lung recoil and of enhanced airways collapsibility to the airflow obstruction of chronic bronchitis and emphysema. J. Clin. Invest. 1973; 52:2117–28. 114. Stubbs SE, Hyatt RE. Effect of increased lung recoil pressure on maximal expiratory flow in normal subjects. J. Appl. Physiol. 1972; 32:325–31. 115. Demedts M, Aumann J. Early emphysema: ten years’ evolution. Chest 1988; 94:337–42. 116. Kessler R, Faller M,Weitzenblum E et al. “Natural history” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am. J. Respir. Crit. Care Med. 2001; 164:219–24. 117. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1994; 150:833–52 and 1158–68. 118. Arora NS, Rochester DF. COPD and human diaphragm muscle dimensions. Chest 1987; 91:717–24. 119. Bernard S, Leblanc P, Whittom F et al. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 158:629–34. 120. Di Francia M, Barbier D, Mege JL, Orchek J. Tumor necrosis factor-a levels and weight loss in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1994; 150:1453–5. 121. Schols AM, Creutzberg EC, Buurman WA et al. Plasma leptin is related to proinflammatory status and dietary intake in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1220–6. 122. Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1856–61.
Airway Pathology
Chapter
6
James C. Hogg UBC McDonald Research Laboratories, St Paul’s Hospital, Vancouver, BC, Canada
N O R M A L A N AT O M Y The normal human bronchogram (Fig. 6.1) shows that the length of pathways from the trachea to the terminal airways differs depending on the pathway that is followed. Quantitative studies of the human airway branching system have established that it may take as as few as eight or as many as 24 divisions of airway branching to reach the gas-exchanging surface1 and that the small bronchi and bronchioles 2 mm in diameter are spread from the fourth to the fourteenth generation of airway branching.2 It has also been established that the total airway cross-sectional area expands rapidly beyond the 2 mm airways to provide for rapid diffusion of gas between the distal conducting airways and the gasexchanging surface. Therefore the central conducting airways larger than 2 mm internal diameter are the major site of resistance to airflow in the normal lung.3,4
The conducting airways are lined by epithelium and are surrounded by an adventitial layer.5 The submucosa between the epithelium and muscle layer is often referred to as the “lamina propria,” but this term is technically incorrect because many airways are not completely surrounded by muscle.6 Bronchi are defined by the presence of a layer of fibrocartilage external to the smooth muscle and tubuloalveolar glands, which communicate with the airway lumen via ducts.7 Bronchioles lack both cartilage and glands and become respiratory bronchioles when alveoli open directly into their lumen.7 The lining of the trachea and major bronchi consists of pseudostratified, ciliated columnar epithelium which gradually becomes more cuboidal with fewer ciliated cells as the alveolar surface is approached.6–8 Light microscopy reveals that the basal aspect of airway epithelial cells is attached to a thin basement membrane (80–90 nm width) that contains primarily type IV collagen and elastin.9 Transmission electron microscopy shows that a true basement membrane or basal lamina can be readily distinguished from the connective tissue observed with the light microscope.6,7 Quantitative studies10–12 have shown that the trachea and mainstem bronchi of normal subjects consist of: • • • •
Fig. 6.1. Postmortem bronchogram from an otherwise normal 19-yearold man who died suddenly for reasons unrelated to the lung. Note the difference in airway length depending upon the pathway that is followed.
30% cartilage; 15% mucous glands; 5% smooth muscle; a connective tissue matrix containing the bronchial arterial, venous, and lymphatic vessels.
With progression toward the periphery of the bronchial tree, the amount of cartilage and glands decrease, and the percentage of smooth muscle increases to account for approximately 20% of the total wall thickness in the bronchioles. The degree to which the smooth muscle surrounds the airway lumen varies according to site. In the trachea and mainstem bronchi, the airway smooth muscle is located within the posterior membranous sheath, whereas, in the bronchioles, it surrounds the entire lumen of the airway.7,8,13 Consequently, the same degree of muscle shortening has a smaller effect on the caliber of the trachea and central
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airways than on the distal bronchi and bronchioles.14 The adventitial layer consists of loose bundles of collagen admixed with blood vessels, lymphatics, and nerves. In the peripheral conducting airways, this layer interacts with the surrounding lung parenchyma through alveolar attachments that are distributed along the circumference of the adventitia. These alveolar attachments have the ability to limit the amount of airway narrowing produced by smooth muscle contraction, particularly at higher lung volumes.14 The systemic arterial supply to the bronchial tree originates from the ventral side of the upper thoracic aorta in the left hemithorax, while on the right the origin of the bronchial vessels is more variable. They may originate from the first to the third intercostal artery, from the right internal mammary artery, or from the right subclavian artery.8,15 Miller’s classic anatomical account8 showed that two to three arterial branches accompany each of the larger bronchi and that anastomoses between these branches form an arterial plexus in the outer wall of the airway. Small branches of this plexus penetrate the smooth muscle layer to form a capillary network below the epithelium. Short connecting branches extend from this plexus through the muscle layer to form a second plexus of venules along the outer surface of the airway smooth muscle (Fig. 6.2). In some species, this outer plexus contains large venous sinuses that can extend into the submucosal layer of the major bronchi, where there is no smooth muscle between the cartilage and epithelium.16 The venous blood from the first two or three subdivisions of the bronchial tree drains into the azygous and hemiazygous venous systems, which empty into the vena cava. The remainder of the bronchial venous flow drains directly into the pulmonary circulation, although there is debate as to how much enters at the precapillary, capillary
and postcapillary, levels.8,15 Airway disease increases the anastomotic flow between the pulmonary and the bronchial vascular systems; and in diseases such as bronchiectasis, injection of the bronchial arteries can result in rapid filling of the entire pulmonary vascular tree right back to the pulmonic valve.15 The bronchial circulation accounts for about 1% of cardiac output and delivers approximately 72 liters of blood to the conducting airways over 24 hours at a cardiac output of 5 L/min. Each liter of blood contains between 4 and 11 109 white blood cells, made up of approximately 60% neutrophils, 30% lymphocytes, 5% monocytes, 3% eosinophils, and 2% basophils. The neutrophils, remain within the vascular space unless an inflammatory response is present. In contrast, even in the absense of inflammation, lymphocytes, monocytes, basophils or eosinophils may migrate out of the vessels into the lung and airway tissue. The monocytes and lymphocytes are able to divide and multiply in the tissue and the basophils and eosinophils live surprisingly long lives.
T H E PAT H O L O G Y O F A S T H M A Postmortem studies At post-mortem, the lungs of patients who have died in status asthmaticus remain markedly hyperinflated after the thorax is opened. This hyperinflation is due to air trapping caused by widespread plugging of the segmental, subsegmental, and the smaller conducting airways by mucus and cellular debris.17 Although this lumenal content may extend to the respiratory bronchioles, it usually stops short of these structures and does not fill the alveolar airspaces. Examination of the cut surface of the lung reveals the plugged
Fig. 6.2. Photomicrograph of a bronchiole from a patient who died of asthma. This shows the location of submucosal capillaries (white arrow), connecting vessels passing between muscle bundles (dark arrow) to larger post-capillary venules located outside the muscle layer. On the right, the same features are shown at a higher magnification. Reproduced in colour between pages 56 and 57.
Airway Pathology
airways, but – in contrast to parenchymal destruction seen in hyperinflated emphysematous lungs – the parenchyma of the asthmatic lung remains intact. Huber and Koessler’s18 classic 1922 paper on the pathology of asthma reviewed 15 published cases and provided new data on six more. They noted that the pathology consisted of common features that allowed asthma to be distinguished from other conditions. They emphasized the presence of intraluminal mucus secretion, airway epithelial desquamation, and repair (e.g. goblet cell metaplasia), and airway inflammatory infiltrates consisting of an admixture of mononuclear cells and eosinophils and the presence of a thickened, “hyalinized” subepithelial basement membrane. Later studies based on electron microscopy and immunohistochemistry showed that this feature of the basement membrane was due to deposition of collagen fibrils and extracellular matrix below the true basement membrane, rather than thickening of the basal lamina. Huber and Koessler’s report noted that the tenacious plugs that fill the airway lumen consist of an exudate of plasma containing inflammatory cells, particularly eosinophils, mixed with epithelial cells that had sloughed from the airway surface. Using an eyepiece micrometer to measure the external airway diameters, they concluded that the walls of bronchi and bronchioli of more than 2 mm outside diameter were thickened compared with nonasthmatic persons, and that this difference was due to an increased thickness of all of the components of the airway wall. Over the next several decades, other reports confirmed and extended these findings.19–26 A comparison with Florey’s27 basic studies of the inflammatory process showed that the structural changes associated with asthma are consistent with an inflammatory process involving a mucus secreting surface. This knowledge had relatively little impact on the allergists, pulmonary physicians, and physiologists until the 1970s,28 because they were preoccupied with the concept that asthma was due to the sensitization of mast cells by IgE in a way that allowed specific antigen challenge to release mediators that caused an excessive contraction of airway smooth muscle. Bronchoscopic studies The nature of the asthmatic airways has been further revealed by studies of tissue obtained through the rigid and flexible bronchoscope. These techniques allowed investigators to obtain cells from living asthmatic patients by both bronchoalveolar lavage and bronchial biopsies.29–31 This brought physiologists and clinicians into closer agreement with the pathologist’s view that the inflammatory process was important in the pathogenesis of both bronchial hyperresponsiveness and reversible airflow obstruction. A very important conceptual development in understanding the nature of the inflammatory process is based on the discovery that murine CD4+ T cell clones could be divided on the basis of cytokine messenger RNA (mRNA) and proteins that they produced.32 Studies established that one type of T-cell clone (Th1) produced IL-2 and interferon-c but no
59
IL-4 or IL-5; whereas the second (Th2) produced IL-4 and IL-5, but no IL-2 or interferon-c. Both clones produced IL3 and GMCSF, and interactions between Th1 and Th2 subtypes allowed one type of clone to inhibit the other. As IL-4 is a mast cell growth factor that also stimulates IgE production, and IL-5 promotes the differentiation and survival of eosinophils, what has become known as the “Th2 response” became relevant to the inflammatory process in asthma. Robinson and associates33 were the first to offer the hypothesis that asthma represents a Th2 response using bronchoalveolar lavage and bronchial biopsy. Studies of surgically resected lung specimens from asthmatic patients subsequently established that a similar inflammatory process was also present in the smaller airways.34 It has now become clear that the structural features of the airways from asthmatic patients are the result of an inflammatory process involving tissue with a mucus-secreting surface. This response appears to be driven by a subset of CD4 T lymphocytes producing cytokines that result in an excess of eosinophils and an overproduction of IgE. The end-result is abnormal airway function, characterized by excessive airway narrowing in response to external stimuli, as well as reversible airways obstruction where smaller airways tend to close, leading to gas trapping and a requirement to breathe at a high lung volume. Although the majority of the symptoms produced by the process can be rapidly reversed with appropriate treatment, the process can be life-threatening under some circumstances. The relationship between airway structure and function The concept that the same degree of smooth muscle shortening will cause greater reduction in airway caliber when the wall is thickened by disease has been suggested by several authors.35,36 Moreno and associates36 calculated that the thickening of the airway wall observed in asthma would have only a minor effect on the caliber of the lumen of a fully dilated airway. However, when the smooth muscle in the airway shortens, the increased tissue between the muscle and lumen causes an excess reduction in airway caliber. Subsequent studies by James et al.37 showed that, in asthmatics, this increase in wall thickness was sufficient to close the lumen of the smaller airways when the smooth muscle shortening remained within the accepted normal range, suggesting that normal smooth muscle shortening acting in series with an abnormally thickened airway wall would narrow the airway lumen. It follows that the reduction in airway caliber produced by this mechanism would be reversed when the muscle lengthened by relaxation.This showed that an important feature of the pathology of asthma was the effect of the inflammatory process on the structure of the airway wall, and that these structural changes could result in excess airway narrowing whether or not smooth muscle contraction was abnormal. Wiggs et al.38,39 extended this concept using a computer model of the airways that could test the effect of structural changes on airway function. Their analysis (Fig. 6.3)
60 (a)
Asthma and Chronic Obstructive Pulmonary Disease
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Fig. 6.3. Data from Wiggs et al. (references 38 and 39) showing results from a computer model of the airways. The structural data from normal lungs were used to obtain the control measurements. These show that airway resistance increases from about 1 cmH2O per liter per second to reach a plateau of 12 cmH2O per liter per second, with maximum contraction of the airways smooth muscle. (a) When the structural features of asthmatic airways were used in the same computer model, the airway resistance continued to increase and did not reach a plateau at any physiologically meaningful value. (b) Data obtained from the model when the structural changes caused by asthma were limited to the central airway (i.e. those 2 mm diameter). Note that asthmatic changes in the central airways increased total resistance and resulted in a plateau slightly greater than the control lungs. (c) However, when the asthmatic changes were placed in the peripheral airway, the resistance increased without reaching a plateau. These data suggest that asthmatic changes in the peripheral airways have a much greater effect on overall airway function than changes that occur in the central airways. Reproduced from reference 38, with permission.
showed that maximum stimulation of the smooth muscle caused airway resistance to increase and reach a plateau in the normal lung. This finding was consistent with the previous observations by Woolcock et al.,40 who reported that the changes in the maximum volume of air that can be expired from the lung in one second (FEV1) reached a plateau in normal subjects when maximally stimulated by inhaled bronchoconstrictors. However, when the data on airway structure were changed from normal values to those found in asthmatic lungs, a similar degree of airway smooth shortening resulted in a sustained rapid increase in airway resistance without a plateau. When the effect of disease on the central and peripheral airway function was examined separately, they found that the increase in airway resistance was primarily due to the effect of disease on the peripheral airways, where smooth muscle shortening produced widespread airway closure. The concept that the peripheral airways are the major site of obstruction in asthma has now been confirmed by direct measurements in living asthmatic patients reported by Yanai et al.41 The changes that are produced in the airway surface and lumen also reduce the function of the conducting airways. Lambert42 was the first to systematically study the normal folding pattern of the bronchial mucosa, and suggested that asthma resulted in the replacement of the multiple mucosal folds that occur when normal airways narrow with fewer and larger folds that reduce airway caliber. Both Lambert and Wiggs et al.43 suggested that the mucosal folding pattern was controlled by the stiffness of the subepithelial layer relative to that of the surrounding airway tissue. This analysis suggested that changes in the subepithelial connective tissue that contribute to the appearance of the basement membrane could play a key role in determining the pattern of mucosal folding. Lambert and Wiggs et al. argued that the formation of a large number of folds in the normal airway placed a load on the airway smooth muscle that tended to prevent airway closure at low lung volumes. It followed that a change in this folding pattern in asthma may be one way in which the disease causes peripheral airway dysfunction. Many of the problems associated with mucosal function and its effect on airway caliber are under investigation, and these analyses should lead to a better understanding of small airway function in both health and disease. The caliber of the airway lumen is also influenced by airway surface tension.44 Normally, surface tension is low because these airways are lined with surfactant. Exudation of plasma on to the surface of the lumen will increase surface tension and cause the airways to narrow. This tendency towards an increased surface tension would be further increased by the secretion of mucus into the luminal exudate. The analysis of induced sputum has confirmed that plasma proteins, mucus, and inflammatory cells are present in the airway lumen even in mild asthma, suggesting that some of the abnormalities in airway function of asthmatics might be the result of the inflammatory exudate present in the lumen.
Airway Pathology
T H E PAT H O L O G Y O F C O P D The inflammatory process contributes to the pathogenesis of chronic cough and sputum production,45 peripheral airways obstruction,3,46 and emphysematous destruction of the lung surface47 that define chronic obstructive pulmonary disease (COPD). As tobacco smoking produces lung inflammation in everyone, and only 15–20% of heavy smokers develop COPD, cigarette smoke-induced airway inflammation must be amplified by other host or environmental risk factors to produce clinical disease.48 Chronic bronchitis Cough and sputum production are the features of airways disease that define chronic bronchitis49 and these symptoms can be present either with or without airways obstruction. Fig. 6.4 shows a normal bronchus with the connection between the epithelial lining of the bronchial lumen, the mucus gland, and duct. In early studies, Reid50 used the relative size of the mucus glands as a yardstick for measuring chronic bronchitis and
Fig. 6.4. Low-power photomicrograph of a normal bronchus showing the opening of a bronchial gland duct into the lumen and its connection with the submucosal gland. The bronchial muscle and cartilage are clearly labeled. The inflammatory process associated with chronic bronchitis involves the mucosa, gland ducts, and glands of the bronchi that are between 2 and 4 mm internal diameter. Original photograph taken by the late Dr William Thurlbeck.
61
downplayed the influence of inflammation on increased mucus production. However, a reevaluation of this problem some years later showed that chronic bronchitis was associated with inflammation of the airway mucosal surface, the submucosal glands, and gland ducts, particularly in the smaller bronchi between 2 and 4 mm in diameter.45 The nature of the cells present in the inflammatory process of chronic bronchitis is currently under active investigation, and evidence from biopsy studies suggests that the CD8+ lymphocytes are present in excess numbers in smokers with chronic bronchitis.51,52 Sputum production represents the clearance of a mucoid inflammatory exudate from the lumen of the bronchi. This exudate is formed by an inflammatory process based on the microvessels of the bronchial circulation. It contains plasma proteins, inflammatory cells, and small amounts of mucus added from goblet cells on the surface epithelium and the epithelial glands. In established chronic bronchitis, the size of the bronchial mucous glands tends to increase,50 but Thurlbeck and Angus53 showed that there is no clear separation between patients with chronic bronchitis and controls. Chronic bronchitis also results in an increase in airway smooth muscle, a generalized increase in the connective tissue in the airway wall, degenerative changes in the airway cartilage, and a shift in epithelial cell type that increases the number of goblet and squamous cells.54-58 The site of airways obstruction The site of airway obstruction in COPD is in the smaller conducting airways that include bronchi and bronchioles of less than 2 mm diameter.3 Direct measurements of airways resistance in dogs4 and in similar measurements in postmortem human lungs3 established, in the normal lung, that the small peripheral airways offer very little resistance to air flow. Although van Brabant et al.59 subsequently argued that these peripheral airways account for a larger proportion of the total airways resistance in the normal lung, they agreed that the peripheral airways were the major site of obstruction in COPD. The anatomical features that have been proposed to contribute to the increase in peripheral airway resistance in COPD include destruction of alveolar support of the peripheral airways,60 loss of elastic recoil in the parenchyma supporting the airways,61 a decrease in the elastic force available to drive flow out of the lung,62 and structural narrowing of the airway lumen by the inflammatory process.3,63 The histological appearance of peripheral airways in cases of advanced COPD shows that a chronic inflammatory process is present in these airways and that this process changes the structural feature of the airway wall and narrows the lumen of these small airways. Although the destruction and loss of elastic recoil in the alveolar attachments supporting the airway could also cause these airways to narrow, the author’s group has argued that this is less important because lung inflation does not reverse the increase in peripheral airways resistance in COPD.3
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The lung inflammatory changes that are associated with cigarette smoking have been documented in autopsy studies,64-69 resected lung specimens,45,46,69 lung biopsies,70 and indirectly by examining bronchoalveolar lavage fluid.71–73 These studies support the concept that cigarette smokeinduced inflammation is present in the lungs of all smokers, including those with normal lung function. It follows that the inflammatory process must be amplified in the minority of cases that develop fixed airways obstruction and emphysematous lung destruction as a result of cigarette smoking, but the exact mechanism of this amplification is not understood.
Emphysema Emphysema has been defined as “abnormal permanent enlargement of airspaces distal to terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis.”74 This definition emphasizes the destruction of the alveolar surface with a minimal reparative response in the lung matrix and the ability of this destructive process to reduce the gas-exchanging surface of the lung. The centrilobular form of emphysema (Fig. 6.5) results from dilatation and destruction of the respiratory bronchioles and is most closely associated with smoking.75,76 The panacinar
Fig. 6.5. (a) Normal lung photographed from the pleural surface after a postmortem bronchogram. The connective tissue outlining the secondary lobule is clearly seen (solid arrow) and a terminal bronchiole (TB) indicated by a clear arrow supplies a single acinus. (b) Photomicrograph of an acinus showing a terminal bronchiole, respiratory bronchiole (RB) and alveolar ducts (AD). Their structure is represented by the fine spray of contrast at the end of the terminal bronchiole shown in the bronchogram in (a). (c) Diagram of the lesion in centrilobular emphysema, showing the dilation and destruction of the respiratory bronchioles. (d) Postmortem bronchogram showing a centrilobular emphysematous lesion (CLE) outlined by bronchographic material. Parts (c) and (d) reproduced from references 76 and 79, with permission.
Airway Pathology
form of emphysema, on the other hand, results from a uniform destruction of the entire lobule and is characteristic of the lesions found in the lungs in a1-antitrypsin deficiency.77 The terms “distal acinar,” “mantle” or “periseptal” emphysema are used to describe lesions that occur in the periphery of the lobule and along the lobular septae particularly in the subpleural region. These lesions have been associated with spontaneous pneumothorax in young adults and bullous lung disease in older individuals, and may or may not be related to COPD.78 In far-advanced parenchymal destruction such as that frequently observed in end-stage COPD, these descriptive terms are not particularly helpful because the entire lung lobule is affected and many destroyed lobules coalesce to form single large lesions. Destruction of the lung by centrilobular emphysema results in hyperinflation of that lung region because the pressure–volume relationship of emphysematous lung keeps the tissue fully inflated at very low transpulmonary pressures.79 The decrease in lung elastic recoil diminishes the pressure available to drive air out of the lung during forced expiration,62 and the reduction in the lung surface area reduces the diffusing capacity and interferes with gas exchange.80 Acute exacerbations of COPD In a hospital-based study of 1205 admissions to five hospitals for acute exacerbations of COPD, infections accounted for 520, heart failure for 260, and 122 cases were attributed to a variety of etiologies that included arrhythmia, pulmonary embolism, pneumothorax, postoperative complications, and lung cancer.81 Interestingly, no cause was established for 303 of these 1205 admissions. Early studies by Stuart-Harris and associates82,83 showed that COPD patients with acute upper respiratory infections are more likely to have signs of infec(a)
63
tion in the lower airways than normal controls, and at least two studies have shown an association between acute illness and laboratory evidence of viral infection in patients with COPD.84,85 The normal lung is predisposed to bacterial infection by an acute viral illness because it increases the risk of aspiration of mucoid exudate containing large numbers of bacteria from the upper airways, and reduces both the mucociliary clearance and bacterial killing in the lower airways.86,87 Streptococcus pneumonia, Staphylococcus aureus and Hemophilus influenzae are the most common bacteria infecting the lower airways during an acute viral infection,88 and these infections are probably responsible for the positive effect of antibiotics in some cases of COPD.89 Unfortunately, very few pathological studies have attempted to define the anatomical features of an exacerbation because postmortem studies are confusing and very few biopsy studies have been attempted on these very sick patients. One such study by Saetta et al.90 implicated the eosinophil as the cause of acute exacerbations, but that study was based on patients where the FEV1 averaged 62 7% of predicted, and may not be relevant to the more usual case where FEV1 is much lower.83
S U M M A RY Asthma The pathology of asthma is dominated by widespread plugging of the segmental, subsegmental, and smaller conducting airways that leads to hyperinflation but not destruction of the parenchyma. These airway plugs are a manifestation of the fluid and cellular exudative phase of an inflammatory process based in the airway tissue (Fig. 6.6). (b)
Fig. 6.6. (a) Peripheral conducting airway from a patient who died of asthma. The airway lumen is filled with an inflammatory exudate that contains plasma proteins, inflammatory cells, sloughed epithelial cells, and mucus. This process that causes epithelial sloughing (not shown in figure) results in metaplastic changes in the epithelium, which increases goblet cells. There is also an increase in muscle and connective tissue, but the caliber of the lumen is not reduced. (b) Airway from a patient with COPD, where the caliber of the airways is reduced by a peribronchiolar inflammatory process with connective tissue deposition in the adventitia. Reproduced in colour between pages 56 and 57.
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This process is characteristic of inflammation involving any mucus-secreting surface, in that the exudate contains mucus as well as inflammatory cells, plasma protein, and sloughed epithelium. The cellular content of this process is consistent with a Th2 type of immune response. Quantitative postmortem studies have established that in addition to the exudate that plugs the airways, asthma is associated with sloughing and regeneration of the epithelium, an increase in the thickness of the epithelial basement membrane, an increase in the size of the bronchial glands, and hypertrophy and possibly hyperplasia of the airway smooth muscle. COPD The chronic bronchitis of COPD is defined by excess cough with sputum production and is associated with an inflammatory process located in the mucosa, gland ducts, and glands of intermediate-sized bronchi between 2 and 4 mm internal diameter.The airway obstruction in COPD is the result of an extension of this process to the smaller bronchi and bronchioles under 2 mm internal diameter, which gradually narrows the lumen to cause fixed airway obstruction (Fig. 6.6). Emphysematous destruction of the lung surface by an inflammatory process in the parenchyma contributes to the reduction in FEV1 by reducing lung elastic recoil and is responsible for reduced gas exchange. The acute exacerbations of COPD that occur with increasing frequency as the disease progresses have several causes that include infection, right heart failure, and pulmonary embolism in addition to other cases where no clear cause can be demonstrated.
REFERENCES 1. Horsfield K, Cumming G. Morphology of the bronchial tree in man. J. Appl. Physiol. 1968; 24:373–83. 2. Weibel ER. Morphometry of the Human Lung. New York: Academic Press, 1963. 3. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airways obstruction in chronic obstructive lung disease. N. Engl. J. Med. 1968; 48:421–31. 4. Macklem PT, Mead J. Resistance of central and peripheral airways measured by a retrograde catheter. J. Appl. Physiol. 1967; 22:395–401. 5. Bai A, Eidelman DH, Hogg JC et al. Proposed nomenclature for quantifying subdivisions of the bronchial wall. J. Appl. Physiol. 1994; 77:1011–14. 6. Neutra M, Podykula H, Weiss L (eds). Histology, Cell and Tissue Biology, 5th edn, pp. 658–706. Amsterdam: Elsevier Biomedical, 1983. 7. Serokin S. In: Weiss L (ed.), Histology, Cell and Tissue Biology, 5th edn, pp. 788–868. Amsterdam: Elsevier Biomedical, 1983. 8. Miller WS.The blood vessels in the lung. In: The Lung, 3rd edn, pp. 73–84. Springfield, IL: Charles Thomas, 1943. 9. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989; i:520–4. 10. Dunnill MS. The pathology of asthma with special reference to changes in the bronchial mucosa. J. Clin. Path. 1960; 13:27–33. 11. Dunnill MS. Quantitative methods in the study of pulmonary pathology. Thorax 1962; 17:320–8. 12. Takizawa T, Thurlbeck WM. Muscle and mucous gland size in the major bronchi of patients with chronic bronchitis, asthma and asthmatic bronchitis. Am. Rev. Respir. Dis. 1971; 104:331–6.
13. Plopper CG, Ten Have-Opbroek AAW. Anatomical and histological classification of the bronchioles. In: Epler GR (ed.), Diseases of the Bronchioles, pp. 15–25. New York: Raven Press, 1994. 14. Macklem PT. Bronchial hyporesponsiveness. Chest 1985; 87:158S–159S. 15. Cudkowicz L. The Human Bronchial Circulation in Health and Disease. Baltimore: Williams & Wilkins, 1968. 16. Hill P, Goulding D, Webber SE, Widdicombe JG. Blood sinuses in the submucosa of the large airways of sheep. J. Anat. 1989; 162:235–47. 17. Rigler LG, Koucky R. Roentgen studies of pathological physiology of bronchial asthma. Am. J. Roeentgenol. 1938; 39:353–62. 18. Huber HL, Koessler KK.The pathology of bronchial asthma. Arch. Int. Med. 1922; 30:689–760. 19. Cardell BS, Pearson RSB. Death in asthmatics. Thorax 1959; 14:341–52. 20. Earle BV. Fatal bronchial asthma: a series of 15 cases with a review of the literature. Thorax 1953; 8:195–206. 21. Houston JC, de Navasquez S,Trounce JR.A clinical and pathological study of fatal cases of status asthmaticus. Thorax 1953; 8:207–13. 22. Dunnill MS, Massarella GR, Anderson JA. A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis and in emphysema. Thorax 1969; 24:176–9. 23. MacDonald IG. The local and constitutional pathology of bronchial asthma. Ann. Intern. Med. 1933; 6:253–77. 24. Messer J, Peters GA, Bennet WA. Cause of death and pathological findings in 304 cases of bronchial asthma. Dis. Chest. 1960; 38:616–24. 25. Richards W, Patrick JR. Death from asthma in children. Am. J. Dis. Child. 1965; 110:4–21. 26. Saetta M, di Stefano A, Rosina C, Thiene G, Fabbri LM. Quantitative structural analysis of peripheral airways and arteries in sudden fatal asthma. Am. Rev. Respir. Dis. 1991; 143:138–43. 27. Florey H. The secretion of mucus and inflammation in mucus membranes. In: Florey H (ed.), General Pathology, 3rd edn, pp. 167–96. London: Lloyd-Luke Medical Books, 1962. 28. Ciba Symposium on the Identification of Asthma. January 1971. 29. Djukanovic R, Wilson JW, Lai CKW, Holgate ST, Howarth PH. The safety aspects of fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy in asthma. Am. Rev. Respir. Dis. 1991; 143:772–7. 30. Djukanovic R, Roche WR, Wilson JW et al. Mucosal inflammation in asthma. Am. Rev. Respir. Dis. 1990; 142:434–57. 31. Glynn AA, Michaels L. Bronchial biopsy in chronic bronchitis and asthma. Thorax 1960; 15:142–53. 32. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 1989; 7:145–73. 33. Robinson DS, Hamid Q,Ying S et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 1992; 326:298–304. 34. Hamid Q, Song Y, Kotsimbos TC et al. Small airways inflammation in asthma. J. Allergy Clin. Immun. 1997; 100:44–51. 35. Friedman BJ. Functional anatomy of the bronchi. Bull. Pathophysiol. Respir. 1972; 8:545–51. 36. Moreno R, Hogg JC, Paré PD. Mechanics of airway narrowing. Am. Rev. Respir. Dis. 1986; 133:1171–80. 37. James AL, Paré PD, Hogg JC. The mechanics of airway narrowing in asthma. Am. Rev. Respir. Dis. 1989; 139:242–6. 38. Wiggs BR, Moreno R, Hogg JC, Hilliam C, Paré PD. A model of the mechanics of airway narrowing. J. Appl. Physiol. 1990; 69:849–60. 39. Wiggs BR, Bosken C, Paré PD, James A, Hogg JC. A model of airway narrowing in asthma and chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1992; 145:1251–8. 40. Woolcock AJ, Salome CM, Yan K. The shape of the dose–response curve to histamine in asthmatic and normal subjects. Am. Rev. Respir. Dis. 1984; 130:71–5.
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41. Yanai M, Sekizawa K, Ohrui T, Sasaki H, Takishima T. Site of airway obstruction in pulmonary disease: direct measurements of intrabronchial pressure. J. Appl. Physiol. 1992; 72:1016–23. 42. Lambert R. The role of the bronchial basement membrane and airway collapse. J. Appl. Physiol. 1991; 71:666–73. 43. Wiggs BR, Hrousis CA, Drazen JM, Kamm RD. The implications of airway wall buckling in asthmatic airways. Am. J. Respir. Crit. Care Med. 1994; 149:A585. 44. Macklem PT, Proctor DF, Hogg JC. The stability of peripheral airways. Respir. Physiol. 1970; 8:191–203. 45. Mullen JBM,Wright JL,Wiggs B, Paré PD, Hogg JC. Reassessment of inflammation in the airways of chronic bronchitis. Br. Med. J. 1985; 291:1235–9. 46. Cosio M, Ghezzo M, Hogg JC et al.The relation between structural changes in small airways and pulmonary function tests. N. Engl. J. Med. 1978; 298:1277–81. 47. Janoff A. Biochemical links between cigarette smoking and pulmonary emphysema. J. Appl. Physiol. 1983; 55:285–93. 48. Speizer FE, Tager IB. Epidemiology of chronic mucus hypersecretion and obstructive airways disease. Epidemiol. Rev. 1979; 1:124–42. 49. Ciba Guest Symposium Report: Terminology, definitions and classifications of chronic pulmonary emphysema and related conditions. Thorax 1959; 14:286–99. 50. Reid L. Measurement of the bronchial mucous gland layer: a diagnostic yardstick in chronic bronchitis. Thorax 1960; 15:132–41. 51. O’Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD-8+T lymphocytes with FEV1. Am. J. Resp. Crit. Care Med. 1997; 155:382–7. 52. Saetta M, Di Stefano A, Turato G et al. T lymphocytes in the peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Resp. Crit. Care Med. 1998;157:822–6. 53. Thurlbeck WM, Angus GE. The distribution curve for chronic bronchitis. Thorax 1964; 19:436–42. 54. Jamal K, Cooney TP, Fleetham JA, Thurlbeck WM. Chronic bronchitis: correlation of morphological findings and sputum production and flow rates. Am. J. Respir. Dis. 1984; 129:719–22. 55. Carlile A, Edwards C. Structural variations in the main bronchi of the left lung; a morphometric study. Br. J. Dis. Chest 1983; 77:344–8. 56. Mackenzie HI, Outhred KG. Chronic bronchitis in coal miners: antimortem/postmortem comparisons. Thorax 1969; 24:527–35. 57. Haraguchi M, Shemura S, Shirata K. Morphologic analysis of bronchial cartilage in chronic obstructive pulmonary disease and bronchial asthma. Am. J. Respir. Crit. Care Med. 1999; 159:1005–13. 58. Thurlbeck WM, Pun R, Toth J, Fraser RG. Bronchial cartilage in chronic obstructive lung disease. Am. Rev. Respir. Dis. 1974; 109:73–80. 59. van Braband T, Cauberghs M, Verbeken E et al. J. Appl. Physiol.: Respir. Environ. Exercise Physiol. 1983; 55:1733–42. 60. Dayman H. Mechanics of airflow in health and emphysema. J. Clin. Invest. 1951; 3031:1175–90. 61. Butler J, Caro C, Alkaler R, Dubois AB. Physiological factors affecting airway resistance in normal subjects and in patients with obstructive airways disease. J. Clin. Invest. 1960; 39:584–91. 62. Mead J, Turner JM, Macklem PT, Little J. Significance of the relationship between lung recoil and maximum expiratory flow. J. Appl. Physiol. 1967; 22:95–108. 63. Matsuba K, Thurlbeck WM. The number and dimensions of small airways in emphysematous lungs. Am. J. Pathol. 1972; 67:265–75. 64. McLean KA. Pathogenesis of pulmonary emphysema. Am. J. Med. 1958; 25:62–74. 65. Niewoehner DE, Kleinerman J, Reisst DB. Pathologic changes in the peripheral airways of young cigarette smokers. N. Engl. J. Med. 1974; 291:755–8.
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66. Auerbach O, Garfinkle L, Hammond EC. Relation of smoking and age to findings in lung parenchyma: a microscopic study. Chest 1974; 65:29–35. 67. Auerback O, Hammond EC, Garfinkle L, Benante C. Relation of smoking and age to emphysema: whole lung section study. N. Engl. J. Med. 1972; 286:853–7. 68. Petty TL, Silverds GW, Stanford RE, Baird ME, Mitchell MS. Small airway pathology is related to increased closing capacity and abnormal slope of phase III in excised human lungs. Am. Rev. Respir. Dis. 1980; 121:449–56. 69. Wright JL, Lawson LM, Paré et al. Morphology of peripheral airways in current smokers and ex-smokers. Am. Rev. Respir. Dis. 1983; 127:474–7. 70. Ollerenshaw SL, Woolcock AJ. Characteristics of the inflammation in biopsies from large airways in subjects with asthma and chronic airflow limitation. Am. Rev. Respir. Dis. 1992; 145:922–7. 71. Gadek JE, Fells JA, Crystal RG. Cigarette smoking induces a functional antiprotease deficiency in the lower respiratory tract of humans. Science 1979; 206:315–16. 72. Hunninghake GW, Crystal RG. Cigarette smoking and lung destruction: accumulation of neutrophils in the lungs of cigarette smokers. Am. Rev. Respir. Dis. 1983; 128:833–8. 73. Stone DJ, Galor JD, McGowan SE et al. Functional 1-protease inhibitor in lower respiratory tract of cigarette smokers is not decreased. Science 1983; 221:1187–9. 74. Snider GL, Kleinerman JL, Thurlbeck WM, Bengally ZH. Definition of emphysema. Report of a National Heart, Lung and Blood Institute, Division of Lung Disease Workshop. Am. Rev. Respir. Dis. 1985; 132:182–5. 75. Anderson AE, Hernandez JA, Holmes WL, Foraker AG. Pulmonary emphysema: prevalence, severity and anatomical patterns with respect to smoking habits. Arch. Environ. Hlth 1966; 12:569–77. 76. Leopold JG, Goeff J. Centrilobular form of hypertrophic emphysema and its relation to chronic bronchitis. Thorax 1957; 12:219–35. 77. Pratt PC, Kilborn KH. A modern concept of emphysemas based on correlations of structure and function. Hum. Pathol. 1970; 1:445–53. 78. Laurenzi GA, Toreno GM, Fishman AP. Bullous disease of the lung. Am. J. Med. 1962; 36:361–78. 79. Hogg JC, Macklem PT, Thurlbeck WM. The elastic properties of the centrilobular emphysematous space. J. Clin. Invest. 1969; 48:1306–12. 80. McLean A, Warren PM, Gilooly M, Lamb D. Microscopic and macroscopic measurements of emphysema: relation to carbon monoxide gas transfer. Thorax 1992; 47:144–9. 81. Connors AF, Dawson NV, Thomas C et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. Am. J. Respir. Crit. Care Med. 1996; 154:959–67. 82. Stuart-Harris CH. The role of bacterial and viral infection in chronic bronchitis. Arch. Environ. Hlth 1968; 16:586–95. 83. Stuart-Harris CH. Infection, the environment and chronic bronchitis. J. Roy. Coll. Phys. Lond. 1971; 5:351–61. 84. Monto AS, Higgins MW, Ross HW. The Tecumseh study of respiratory illness. VIII: Acute infection in chronic respiratory disease and comparison groups. Am. Rev. Respir. Dis. 1975; 111:27–36. 85. Smith CB, Golden CA, Canner RE, Renzetti AD. Association of viral and mycoplasmal pneumonia infections with acute respiratory illness in patients with COPD. Am. Rev. Respir. Dis. 1980; 121:225–32. 86. Knipe DN. Virus–host interactions. In: Fields BM, Knipe DN, Howley PM (eds), Field’s Virology, pp. 273–99. New York: Lippincott–Raven, 1996. 87. Hers JF, Masurel N, Mulder J. Bacteriology and histopathology of the respiratory tract in fatal Asian influenza. Lancet 1958; ii:1141–3.
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88. Lauria DB, Blumenfield HL, Ellis JT, Kilbourne ED, Rogers DE. Studies on influenza in the pandemic of 1957–58. II: Pulmonary complication of influenza. J. Clin. Invest. 1959; 38:213–65. 89. Anthonisen NR, Manfreda J, Warren CP et al. Antibiotic therapy in exacerbations of COPD. Ann. Int. Med. 1987; 106:196–204.
90. Saetta M, Di Stefano A, Maestrelli P et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am. J. Respir. Crit. Care Med. 1994; 150:1646–52.
Fig. 6.2. Photomicrograph of a bronchiole from a patient who died of asthma. This shows the location of submucosal capillaries (white arrow), connecting vessels passing between muscle bundles (dark arrow) to larger post-capillary venules located outside the muscle layer. On the right, the same features are shown at a higher magnification.
(a)
(b)
Fig. 6.6. (a) Peripheral conducting airway from a patient who died of asthma. The airway lumen is filled with an inflammatory exudate that contains plasma proteins, inflammatory cells, sloughed epithelial cells, and mucus. This process that causes epithelial sloughing (not shown in figure) results in metaplastic changes in the epithelium, which increases goblet cells. There is also an increase in muscle and connective tissue, but the caliber of the lumen is not reduced. (b) Airway from a patient with COPD, where the caliber of the airways is reduced by a peribronchiolar inflammatory process with connective tissue deposition in the adventitia.
Airway Remodeling
Chapter
7
Rory A. O’Donnell, Donna E. Davies, and Stephen T. Holgate School of Medicine, University of Southampton, Southampton, UK
Airway remodeling may be defined as a process of sustained disruption and modification of structural cells and tissues leading to the development of a new airway wall morphology. Although this process was noted as long ago as 1922,1 interest in the mechanisms of airway remodeling in asthma has risen only in recent years. In chronic obstructive pulmonary disease (COPD), though airway structural changes are well recognized,2 the underlying pathogenesis has received less attention, possibly due to their more peripheral location and the overshadowing interest in the adjacent emphysematous tissue destruction. In both conditions a number of remodeling processes occur (Fig. 7.1 and Table 7.1). Principal among these changes are airway fibrosis, an elevation in smooth muscle mass, mucous metaplasia, and glandular hypertrophy, in addition to less well defined alterations of the bronchial vasculature and nerves. The outcome is a very abnormal airway wall. In asthma, segmental and subsegmental bronchial walls are thickened over their entire size range.3 In COPD, only the inner wall area of the large airways is convincingly thicker.4 The peripheral airways (2 mm diameter), normally devoid of either supporting cartilage or bronchial glands, are also conspicuously remodeled in COPD.5,6
N AT U R A L H I S T O RY A N D C L I N I C A L I M P O R TA N C E The natural history of remodeling is not well understood. Though it is surmised to be a consequence of long-term airways disease, studies have revealed early manifestations in asthmatics7 and young smokers,8 suggesting that remodeling is part of the primary pathology of the disease rather than the result of it. However, a considerable degree of variability in susceptibility to remodeling changes exists in both patient groups. In general, asthma is associated with a greater than normal decay in lung function over time.9 In a small proportion of asthma patients with severe chronic disease the decline in lung function is more progressive and associated with persistence of symptoms despite corticosteroid therapy, similar to a COPD-like clinical state.10 These
physiological changes may reflect not only the presence of airway structural modification but also the inadequacy of currently available treatments to modify the remodeling process. Airway remodeling may have a number of clinical consequences for both asthma and COPD. For example, bronchial hyperresponsiveness has been postulated to be a function of the physical effects of overall airway wall thickening, in addition to airway inflammation and smooth muscle reactivity.11 Individual remodeling changes, such as an increased smooth muscle bulk or an enhanced mucusproducing facility, have their own implications for both symptom severity and airway function.
MECHANISMS OF REMODELING Epithelial damage, airway inflammation, and epithelial repair Responses of the airway epithelial barrier to injury and manipulation and abnormalities in the ensuing processes of repair are the most likely causes of remodeling. In asthma, evidence suggests that epithelial repair processes have the crucial capacity, via intercellular signaling between epithelial and subepithelial (myo)fibroblasts, to influence matrix synthesis and the mass and composition of structures lying beneath it. It follows, that, in asthma, dysregulated injury and/or repair responses to innocuous environmental stimuli may result in more permanent changes to airway wall morphology. These epithelial–mesenchymal interactions have invited parallels with the intercellular communication found during branching morphogenesis, and remodeling has been suggested to reflect a reactivation of these early processes. In contrast with asthma, COPD is thought to be due almost exclusively to the toxic effects of cigarette smoke. It is possible that repetitive attempts by the epithelium to protect itself and repair the injury induced by this noxious agent can result in analogous mesenchymal responses. The importance of airway inflammation, integral and intimately linked to the process of epithelial injury, is
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Normal
Cigarette smoke
COPD Allergen
Asthma
Intact epithelium
Stress/damage
Altered epithelial phenotype
Proinflammatory cytokines Chemokines
Profibrogenic growth factors matrix proteins
Inflammatory cells
Fibroblasts
Smooth muscle cells
Blood vessels
Nerves
Fig. 7.1. Schematic of events leading to airway remodeling.
recognized in both diseases.12 In asthma, much interest has focused on the CD4 cell that is skewed toward a Th2 phenotype as the orchestrator of an immune response to allergens.13 The predominant pattern of Th2 cytokine expression results in an inflammatory phenotype where eosinophils and mast cells are prominent but macrophages, fibroblasts, and dendritic cells are also involved.14 The inflammatory milieu differs considerably in COPD. Eosinophils may play a role in a subset that has features in common with asthma,15 but their significance in the majority is outweighed by the contribution of macrophages and neutrophils with possibly a CD8 cell preponderance.16–18
Known perpetrators of epithelial damage include environmental agents such as cigarette smoke toxins, house dust mite allergen19 and pollen enzymes,20 with their effects being augmented by the airway inflammatory response to these agents. Thus generation of reactive oxygen species and the products of infiltrating inflammatory cells including arginine-rich eosinophilic proteins,21 mast cell tryptase,22 neutrophil elastase, and metalloproteases derived from eosinophils and mast cells,23,24 neutrophils and macrophages can all directly induce epithelial injury. The result in asthma is a fragile bronchial epithelium with weakening of junctional adhesion structures. Consequently, columnar
Airway Remodeling
69
Table 7.1. Table of remodeling processes in asthma and COPD
Remodeling process
Asthma
COPD
Cellular inflammation
Predominantly CD3, CD4 Eosinophils Mast cells
Predominantly CD3, CD8 Neutrophils Macrophages
Cytokine expression
Th2 profile – IL-4, IL-5, IL-13 RANTES
TNF-a, IL-8, LTB4
Airway wall thickening
Large and small airways
Large and small airways
Epithelium
Fragile, sloughing, denudation
Squamous metaplasia
Mucous metaplasia
Large and small airways
Large and small airways
Subepithelial basement membrane
Thickened
Normal
Diffuse excess matrix deposition
Large airways
Small airways
Submucosal glands
Hypertrophy
Hypertrophy Increased mucous to serous acini ratio
Smooth muscle
Increased mass in large and small airways
Increased mass in large and small airways
Large airway wall vascularity
Increased
Undetermined
epithelial cells become detached from the basal cells below them25 and are sloughed into the airway lumen.26–28 In COPD, although atrophy and shedding of the epithelium may occur,26 focal squamous metaplasia is much more common.12,29 Altered airway adhesion molecule expression, a hallmark of an active repair process, has been demonstrated in asthma and COPD. This includes enhanced expression of CD44,30 the integrins,31 and E cadherin32 in asthma, while in both asthma and COPD there is augmented expression of ICAM-1.33 Epithelial expression of the epidermal growth factor receptor (EGFR/c-erbB1) is also increased in asthma, and reflects the response seen in other injured epithelial tissues. The EGFR is the target of six distinct ligands: • • • • • •
epidermal growth factor (EGF); transforming growth factor a (TGF-a); amphiregulin (AR); heparin-binding EGF-like growth factor (HB-EGF); betacellulin (BTC); epiregulin.
Activation of the EGFR promotes both migration and proliferation of epithelial cells,34 and there is in-vitro and invivo evidence supporting a role for this receptor in bronchial epithelial repair.35,36 However, in asthma, increased EGFR expression does not appear to be coupled to an appropriate proliferative response by the repairing epithelium.37 This
impairment may explain why EGFR expression, as a marker of tissue injury, correlates positively with both asthma severity and the extent of subepithelial fibrosis.38 The impaired repair has been postulated to be due to the actions of the profibrogenic transforming growth factor beta (TGF-b) family of cytokines which are known inhibitors of epithelial proliferation39 and whose level is increased in asthmatic airways.40 One consequence of impaired EGFR-mediated repair is that the duration of activation of other non-EGFR dependent repair processes, involving release of inflammatory cytokines and profibrogenic growth factors, may be increased, thereby providing constant stimuli for chronic inflammation and remodeling.38 Although studies of the EGFR in COPD have been lacking, it has been reported that cigarette smoke results in enhanced EGFR expression in airways epithelium.41 Augmented expression of both epidermal growth factor (EGF) and TGF-b have been observed in subjects with chronic bronchitis,40 so a potential imbalance exists between proliferative and antiproliferative signaling in the airways in both asthma and COPD. However, as EGFR-mediated mitogen activated protein kinase (MAPK) activation can inhibit TGF-b signaling, the final outcome may differ in each disease depending on the absolute ratios of the EGF and TGF-b growth factor families and the relative levels of expression of their receptors. The relationship between epithelial injury and fibrosis has been demonstrated using co-cultures of bronchial epithelial
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cells and myofibroblasts. In these studies, damage inflicted upon the epithelial cells resulted in enhanced myofibroblast proliferation and collagen gene expression owing to the combined effects of a number of growth factors, including: • • • • • •
basic fibroblast growth factor (bFGF); FGF2; insulin-like growth factor (IGF); platelet-derived growth factor (PDGF); TGF-b; ET-1.42
In addition to these, a range of other potentially important epithelially derived products such as fibronectin, an extracellular matrix component with potent chemotactic properties for fibroblasts,43 and a range of proinflammatory cytokines44–47 are produced by epithelial cells during the repair process. Remodeling of the extracellular matrix The extracellular matrix is composed of a network of fibrous and structural proteins embedded in a hydrated polysaccharide gel to form the strong, resilient framework of the airway wall. Alteration in both the mass and composition of this structure is one of the primary aspects of remodeling in both asthma and COPD, with upregulated airway fibroblast activity being most directly responsible. The repair environment in the airways produces a number of changes in cytokine and growth factor expression to which the fibroblast is receptive. Studies in asthma have indicated that myofibroblasts, a cell population with morphological and biochemical features intermediate between those of fibroblasts and smooth muscle cells,48 are responsible for the particular pattern of matrix deposition in this disease. These cells, lying below and adjacent to the lamina reticularis in a layer referred to as the “attenuated fibroblast sheath” are major producers of collagenous and noncollagenous matrix proteins implicated in matrix accumulation, as well as wound contraction.49 In the absence of specific immunomarkers for this cell type, myofibroblasts are identified by specific ultrastructural criteria and the expression of a-smooth muscle actin (a-SMA) which is also found in smooth muscle cells and myoepithelial cells. Though myofibroblast hyperplasia has been demonstrated in the subepithelium in asthma,48,50 with their numbers correlating with the extent of subepithelial collagen thickness,50,51 their origin in asthma is uncertain. They appear early after allergen challenge, perhaps implying a quiescent precursor cell that differentiates to acquire myofibroblast features.48 Candidates for this include fibroblasts, smooth muscle cells or perhaps other primitive mesenchymal or structural cells. A number of factors have been identified which appear to alter fibroblast a-SMA expression: • most notably TGF-b;52 • heparin;53 • gamma-interferon;
• granulocyte–macrophage (GMCSF).
colony
stimulating
factor
Alternatively, proliferation or preferential chemoattraction of resident myofibroblasts already present beneath the bronchial epithelium may be occurring.50 For example, smooth muscle mitogens have been detected in BAL fluid after allergen challenge,54 and fibronectin has been observed to cause selective recruitment of myofibroblasts from a population of normal fetal lung fibroblasts.55 In COPD, studies investigating the presence or absence of myofibroblasts are lacking. The role of growth factors and inflammatory mediators The use of transgenic animal models of mediator overexpression has provided evidence to link both epithelial growth factor and inflammatory cytokine expression with matrix remodeling. TGF-b, overexpressed in the rat airway epithelium, has been shown to produce severe interstitial and pleural fibrosis,56 while overexpression of IL-6 or IL-11 induces subepithelial fibrosis in the lungs of experimental mice.57,58 Mouse models variously expressing the Th2 cytokines IL-5,59 IL-9,60 and IL-1361 have all, to a greater or lesser degree, developed like matrix changes. In contrast, mice overexpressing IL-4 have demonstrated inconsistent results in this regard.62,63 The TGF-b superfamily of cytokines are among the most studied with respect to fibrosis and remodeling. TGF-b is a multifunctional profibrotic growth factor and a key component in the regulation of tissue growth and differentiation, both during branching morphogenesis and the processes of wound repair. It stimulates fibroblast growth and is responsible for the differentiation of fibroblasts into myofibroblasts, causing myofibroblast hyperplasia.42,64,65 TGF-b promotes synthesis of extracellular matrix components by a number of cells including fibroblasts, bronchial epithelial cells, and macrophages,66 and it blocks matrix degradation by inhibiting proteolytic enzyme synthesis and augmenting the action of protease inhibitors. As stated earlier, studies have demonstrated augmented epithelial and submucosal TGF-b expression in both asthma and COPD.40,67,68 In addition, tissue macrophage TGF-b production is elevated in both diseases, while in asthma eosinophils and epithelial cells have also been identified as important sources.40,69,70 Moreover, in these conditions a significant correlation has been demonstrated between expression of TGF-b and the extent of subepithelial fibrosis and numbers of fibroblasts.40 TGF-b levels are also unaffected by corticosteroid treatment, and so this growth factor probably represents a key mediator of airway matrix remodeling. Another growth factor is platelet-derived growth factor (PDGF). This is produced mainly in the airways by macrophages but may also be derived from the epithelium and most airway inflammatory cell types. Eosinophils rather than macrophages are the more important source of PDGF in asthma.71,72 PDGF is known to promote fibroblast
Airway Remodeling
chemotaxis, fibrosis, and smooth muscle mitogenesis,73 and would seem to be a very plausible promoter of airway remodeling. Indeed, bronchial fibroblasts from asthmatic patients show enhanced responsiveness to this agent.50 Nevertheless, expression of PDGF has not been found to be elevated in the airways of asthmatics or patients with COPD,74,75 so its relevance in these diseases has yet to be demonstrated. Another family of peptides, the endothelins, are found in elevated quantities in both diseases.76–78 These agents, in addition to their vaso- and bronchoconstrictor properties, possess the ability to activate fibroblasts79 and so possibly also contribute to excess matrix deposition. Although epithelial EGFR expression has been shown in asthma to correlate with the extent of subepithelial fibrosis, the importance of the EGFR as an effector of matrix remodeling in cells of nonepithelial origin in asthma and COPD is uncertain and requires investigation. Stimulation of fibroblast-bound EGF and PDGF receptors is reported to work in concert with binding of b1 integrins on the surface of these cells by matrix components such as laminin or fibronectin to stimulate fibroblast chemotaxis and migration.80,81 Thus, alterations in growth factor and receptor expression, matrix composition, and adhesion molecule binding all have the potential to influence fibroblast activity in repair. However, although EGF immunoreactivity has been demonstrated in the submucosa of both asthmatic and COPD subjects, the number of cells found expressing EGF did not correlate with either basement membrane thickness or fibroblast number.40 Epithelial expression of TGF-a, another EGF ligand, results in lung fibrosis; but the effect appears to be mediated via the epithelium rather than by direct action on fibroblasts.34 The role of proteolytic enzymes Alteration in matrix turnover is but one of the ways in which proteolytic enzymes influence the remodeling process. Serine and matrix metalloproteases produced by a variety of inflammatory and stromal cells can digest all the major components of the extracellular matrix.82 Examples studied include MMP3 in asthma,83 MMP1 in COPD (with regard to its potential to induce emphysema),84 and MMP9 and neutrophil elastase in both diseases.24,85 Although in emphysema it is widely believed that a protease/antiprotease imbalance exists favoring the excessive proteolytic digestion of lung parenchyma, there is evidence to suggest that in the remodeled airway wall the reverse holds true. For example, although both MMP9 and neutrophil elastase are elevated in induced sputum of asthma and COPD patients, the augmented presence of these proteases is outweighed by a proportionally larger increase in their natural inhibitors TIMP1 and a1-antitrypsin,86,87 a situation which would favor fibrosis. The release of growth factors that are encrypted in the extracellular matrix or from their cell-membrane bound precursors is another way that proteases may contribute to remodeling. For example, both FGF and TGF-b are bound as inactive forms to heparan sulfate and decorin,
71
respectively,88,89 and can be released by the proteolytic activity of plasmin. In contrast, release of heparin-binding EGF, a potent smooth muscle mitogen, is dependent on MMP3-induced cleavage of its transmembrane precursor.34 In addition, mast cell tryptase acting via cellular PAR2 receptors acts directly on fibroblasts to promote both mitogenesis and collagen secretion,90 and is also mitogenic for epithelial91 and smooth muscle cells. Effects of the altered matrix on remodeling The capacity of the extracellular matrix to influence (directly and indirectly) cell development, migration, and proliferation is indicative of a more dynamic function than simply the provision of structural support.66,92 Matrix components such as decorin, versican, and fibronectin provide stimuli for inflammatory, epithelial and stromal cells by serving as ligands for adhesion molecules93 and by acting as a reservoir for release of cytokines, chemokines, and growth factors such as TGF-b.94 Glycosaminoglycans such as hyaluronic acid (HA), found to be increased in the BAL fluid of asthmatics,95 facilitate cell migration and proliferation during injury and repair,96 while survival of eosinophils is prolonged by interaction with the matrix proteins fibronectin and laminin, an effect due in part to eosinophil GMCSF release.97 Fibronectin is a matrix glycoprotein that has received much attention with regard to its role in repair.66,98 It is produced by many cell types, including bronchial epithelial cells,99 fibroblasts, and macrophages,67 and its production is upregulated by growth factors such as TGF-b100 and integrin ligation.101 Fibronectin is incorporated into the provisional matrix that forms after injury, where it acts as a cheomattractant for both epithelial cells and fibroblasts.43,99 Elevated quantities of fibronectin have been detected in bronchial lavage fluid in COPD, while in asthma it is found abnormally deposited in the sub-basement membrane.50,102 In both diseases the macrophage has been implicated as an important source of this protein.67
R E S U LT S O F M AT R I X R E M O D E L I N G I N ASTHMA AND COPD The pattern and distribution of matrix deposition in the remodeled airway differs between asthma and COPD. Interest in asthma has centered mainly on the larger airways, whereas in COPD what information is available applies generally to the small, peripheral branches of the bronchial tree. Matrix remodeling may be roughly subdivided into either thickening of the subepithelial basement membrane, or a pattern of deeper, more diffuse deposition. Subepithelial basement membrane matrix deposition in asthma and COPD Deposition of protein beneath the true epithelial basement membrane is characteristic of asthma. Electron microscopic and immunohistochemical analysis of bronchial
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biopsy specimens has shown that the true basement membrane, made up of the lamina rara and lamina densa, is normal in both size and composition and that the changes occur in the lamina reticularis. In this region, abnormal deposition of interstitial repair collagen subtypes I, III, and V takes place,102 in addition to noncollagenous matrix components that include fibronectin,102 laminin b2,103 and tenascin.104 Classical epithelially derived membrane subtypes, such as collagens IV and VII, are absent from this abnormal subepithelial matrix layer. Studies of COPD have not, to date, revealed an equivalent to the subepithelial fibrosis observed in asthma. Studies appear to show, rather, a basement membrane thickness within the normal range.16,26 Exceptions may exist, however, in a subset of patients with COPD who display some overlap with the asthmatic phenotype. These individuals who have a BAL eosinophilia and significant corticosteroid reversibility also show demonstrable basement membrane thickening, but the composition remains unknown.15 Further studies are needed to properly define the clinical and pathological characteristics of this subgroup. Diffuse matrix deposition in asthma and COPD Studies evaluating collagen deposition deep to the lamina reticularis in asthma have been few. An excess of collagen including types III and V have been found in large airway samples by some investigators,105,106 but not by others.102,107 Other matrix proteins and glycoproteins found in excess in this region in asthma include decorin, versican, and fibronectin.108 Excess matrix deposition in COPD, thus far, has consistently been identified only in the peripheral, noncartilaginous airways (2 mm diameter). However, though peribronchiolar fibrosis has been repeatedly demonstrated,29,109 the studies have usually been qualitative analyses of small airway morphology rather than specific evaluations of the extracellular matrix. However, one immunohistochemical investigation has demonstrated diminished quantities of the interstitial proteoglycans decorin and biglycan in the peripheral airways, with staining patterns for type IV collagen and laminin similar to those of control lungs.110
M U C O U S M E TA P L A S I A In both asthma and COPD, epithelial mucous metaplasia and hyperplasia occur with hypertrophy of the submucosal gland mass. Submucosal mucous glands are distributed throughout the cartrilagenous airways in normal individuals. An increase in both the number and size of mucus-secreting cells leads to enlargement of these tracheobronchial glands, this being a feature of both diseases.111,112 In COPD, unlike asthma, a variable degree of replacement of serous with mucous acini occurs.113 Epithelial mucous cell metaplasia is observed in both central and peripheral airways in asthma.114,115 However, postmortem studies suggest that a substantial degree of
individual variation exists with more pronounced peripheral airway changes found in those who died from asthma;114 this observation is compatible with the fact that most asthma deaths occur in association with excessive mucous production.116 In COPD, mucous metaplasia and hyperplasia are observed both centrally and peripherally,2,109,111 resulting in a more even distribution of surface secretory cells across the spectrum of airway size. Thus, the smaller (400 lm diameter) airways, which normally have only a sparse population of mucous cells, become important contributors to the excess mucous which characterizes this disease.8,117 The extent of mucous production varies widely across the COPD spectrum of diseases, so there is considerable variation in the degree of metaplastic change in this condition.112 The mucus produced in asthma and COPD is qualitatively and quantitatively abnormal with major alterations in both its cellular and molecular composition. For example, the elevated ratio of mucous/serous acini in COPD results in a more gel-like, thicker substance, lacking in the lysozymes and antiproteases which normally provide protection against both infection and proteolytic injury.118 In chronic and severe asthma, bronchial obstruction due to mucus plugging is found in both central and peripheral airways.114,119 In COPD, partial or complete occlusion of the small (2 mm diameter) airways with mucous plugs is common.5 In both diseases, replacement of surfactant lining the small airways with mucus results in increased surface tension at the air– liquid interface further predisposing to airway collapse.120 Expression of mucin genes, which encode the mucin glycoproteins, has been proposed as the principal factor governing the differentiation of epithelial cells into goblet cells.121 Both environmental and host factors, acting on the epithelium, have been shown to stimulate mucin gene upregulation and mucin secretion. Environmental factors include infectious agents122 and environmental pollutants,123 while host factors include inflammatory mediators124 and cell degranulation products.125,126 Acrolein, a low-molecularweight component of cigarette smoke, induces epithelial MUC5 AC gene expression, and mucous metaplasia in rats in vivo123 while the Th2 cytokines IL-4, IL-9, and IL-13 have been linked to both augmented mucin gene expression, particularly the MUC5AC and MUC2 genes, and goblet cell differentiation, using in-vivo animal models and in-vitro culture systems.60–62,127–130 These observations suggest that mucus overproduction represents an innate defense mechanism designed to limit the access of noxious stimuli to the epithelium. A central role has been postulated for the neutrophil in stimulation of airway mucin production. This is based on the observation of augmented MUC5AC expression by cultured epithelium when exposed to neutrophils,131 possibly through neutrophil elastase and oxidative stress, each of which has been shown to augment both epithelial MUC5AC mRNA and protein expression.126,131–133 It has been further proposed that the EGFR is involved in regula-
Airway Remodeling
tion of airway mucin synthesis,134,135 as mucin gene expression results from ligand-independent transactivation of the EGFR in response to oxidative stress.136 This effect can be blocked by selective inhibitors of the EGFR.131 Both EGF and EGFR expression are elevated in bronchial glandular tissue in asthmatic subjects compared with controls,137 suggesting a similar role for the EGFR in asthma. IL-13 may cause induction of mucin gene expression via an EGFRdependent pathway. This cytokine, like cigarette smoke components such as acrolein, is also believed to cause neutrophil infiltration through stimulation of expression of neutrophilic chemokines.
SMOOTH MUSCLE REMODELING The presence of an augmented airway smooth muscle bulk in both asthma and COPD is well established. In asthma, smooth muscle mass is increased in both large138 and peripheral139,140 airways, though whether hypertrophy or hyperplasia is the major contributor remains uncertain. Autopsy studies suggest the existence of two distinct patterns. The type 1 pattern has increased muscle mass due to hyperplasia restricted to large central airways, while in type 2 there is smooth muscle thickening throughout the bronchial tree caused predominantly by hypertrophy, particularly in the small airways, with a mild degree of hyperplasia in the larger airways.141 The situation is further complicated by the fact that a considerable degree of heterogeneity appears to be present. An increase in smooth muscle mass is not always demonstrated in mild asthma142–144 or in postmortem studies of asthmatics who died from other causes.145 Why different patterns of smooth muscle enlargement should exist in asthma or what factors predispose some but not other asthmatics to the development of either one is unknown. The peripheral airways are also the location of a large increase in smooth muscle mass in COPD,111,117,142,146 though it is suggested that the changes are less marked than those in asthma.142 Studies generally describe these changes under the heading of hypertrophy, but the extent to which hyperplasia plays a role is unclear. Estimates of smooth muscle enlargement in the larger airways in COPD have varied.147 Some investigators have observed no abnormality in smooth muscle area,138 while others have demonstrated up to a 2-fold increase in bronchial smooth muscle thickness, a finding attributable to both hyperplasia and hypertrophy.148 A clinical correlation with the presence of wheeze has been suggested, but there is a substantial degree of individual variation in both wheezing and this particular remodeling change.149 The mechanisms leading to these changes are not known. The exercise-like effects of smooth muscle spasm, the growth promoting potential of an enriched plasma environment due to vascular leakage,150 the mitogenic influences of mediators involved in the inflammatory response, or an intrinsic abnormality of smooth muscle itself have been
73
offered as explanations. However, most of our knowledge of factors promoting smooth muscle growth has come from analysis of cell cultures in vitro.151 An extensive range of potentially important smooth muscle mitogens has been identified, including: • • • •
inflammatory mediators; growth factors; enzymes; components of the extracellular matrix.151
It has been suggested that these can be subdivided into two broad categories depending on the receptor type through which they exert their major mitogenic influences. Group 1 includes mediators such as EGF and PDGF which activate receptors with intrinsic tyrosine kinase activity in human airway smooth muscle (ASM) cells. Group 2 includes those activating receptors coupled to GTP binding proteins such as thrombin.152 Although ET-1 and LTD4 are effective in animal models, they appear to have little effect on human ASM cells, though they are believed to potentiate the effects of thrombin and EGF.152 TGF-b has the ability to either promote or inhibit smooth muscle growth,153 while both EGF and EGFR immunoreactivity is augmented in asthmatic airway smooth muscle.137 Contractile agonists are found in both asthma and COPD, as are inflammatory mediators with known smooth muscle mitogenic potential such as TNF-a.17 A further association between inflammation and smooth muscle function has been suggested by the enhanced expression of adhesion molecules such as ICAM-1 and VCAM-1 on airway smooth muscle cells in response to TNF-a, IL-1, LPS, and IFN.154 Furthermore, the adherence of T cells to smooth muscle cells results in stimulation of ASM DNA synthesis.154 The capacity of these ASM to express adhesion molecules, synthesize ECM components and release inflammatory cytokines and chemokines including RANTES,155 eotaxin, and IL-8151 indicates that smooth muscle remodeling may itself be part of the inflammatory process.
VA S C U L A R A N D N E U R A L A LT E R AT I O N S Elevated airway-wall blood-vessel area has been demonstrated in asthma and is greater than in controls or subjects with COPD.139,142 However, it is unclear whether this vascular remodeling is primarily due to sprouting angiogenesis – the formation of new blood vessels156 – or to enlargement of the existing microvasculature. A study of the membranous bronchioles of subjects with asthma and COPD has suggested the latter,142 and indeed fatal asthma is known to be associated with dilatation of bronchial mucosal blood vessels, congestion, and wall edema.112 On the other hand, Li and colleagues157 have discovered changes suggestive of new vessel formation in mild asthma, and the microenvironment in asthma has been shown to possess the potential for
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angiogenesis. Mediators such as histamine, heparin, and tryptase all possess angiogenic properties, while expression of vascular endothelial growth factor (VEGF), a potent vascular growth factor, is upregulated by agents such as TGF-b, TNF-a and TGF-a that are involved in the inflammatory milieu of the asthmatic airway. There is also evidence in severe asthma of increased airway innervation. This could be due to the secretion of nerve growth factors from epithelial and inflammatory cells. In addition, in both asthma and COPD, the compromised epithelial barrier allows a greater exposure of nerve endings to environmental stimuli. Thus the potential for release of neurotransmitters such as the tachykinins substance P and neurokinin A is increased. These agents, in addition to their effects on vascular and smooth muscle homeostasis, can contribute to local inflammation with the attraction and activation of inflammatory cells.
EFFECTS OF THERAPY Whether any of the current anti-inflammatory strategies can significantly alter the course of remodeling is unknown. Long-term corticosteroid therapy has been shown to slow the annual rate of decline in lung function in asthmatics.158 However, other studies have suggested that a negative relationship exists between response to treatment and duration of disease.159,160 Added to this are reports showing persistent airflow obstruction in some patients, despite both oral and inhaled therapy.161 The implication is that early therapy may, to a limited extent, prevent remodeling, but established structural change is steroid-insensitive. In-vitro work suggests possible benefits from other current therapies such as b2 agonists, shown to inhibit smooth muscle cell proliferation,162 or theophylline, which has a similar effect on cultured fibroblasts.163 However the long-term in-vivo impact on remodeling remains unknown. It has been proposed that more effective strategies for the future would focus directly on remodeling pathways. Suggested approaches include blocking the actions of TGF-b in an attempt to limit fibrosis, or inhibition of EGFR signaling to prevent mucous metaplasia or smooth muscle hypertrophy. Careful assessment of the benefits would be required, however. Mucus overproduction, for example, may be fundamental in limiting the access of damaging environmental agents to the epithelium. A protective role for basement membrane thickening has been postulated also in restricting inflammatory cell passage to the epithelial layer above, while smooth muscle hypertrophy may possibly help to maintain bronchiolar caliber in severe emphysema.164 Thus if a new “anti-remodeling” agent were to emerge, the beneficial effects would have to be weighed against the consequences of interfering with what may, in some ways, be a valuable defense mechanism.
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Animal Models
Chapter
8
Stephanie A. Shore Harvard School of Public Health, Boston, MA, USA
Animal models have been used extensively in the process of discovery of the primary events that underlie asthma and chronic obstructive pulmonary disease (COPD). For example, the demonstration by Gross et al.1 that instillation of papain into the lungs of rats resulted in a syndrome similar to emphysema contributed to the prevailing elastase/ antielastase hypothesis regarding the pathogenesis of emphysema. Animal models have also been used to guide research into pharmacological interventions for the treatment of asthma and COPD. This topic is extensive, so this chapter focuses on only two models:
This chapter will focus on models developed using mice because of the advantages of using this species, including: • low cost; • a short breeding period; • the availability of inbred species with known characteristics; • good genetic markers; • a well-characterized immune system; • the ability to induce genetic modifications. Allergens used in these models have included:
• mouse models of asthma induced by ovalbumin sensitization and challenge and; • animal models of chronic bronchitis as created by exposure to high concentrations of SO2 gas. Each of these areas will be reviewed separately. In each case, the focus will be on changes in the mechanics of the airways, since it is airway obstruction associated with these conditions that ultimately causes lung dysfunction, disability, and death.
MOUSE MODELS OF ASTHMA INDUCED B Y A L L E R G E N S E N S I T I Z AT I O N A N D CHALLENGE Human asthma is characterized by intermittent reversible airway obstruction, airway hyperresponsiveness, and airway inflammation. Although there is no animal that spontaneously mimics all these traits, a syndrome with some features of asthma can be observed in certain horses and cats, and in the Basenji-greyhound cross of dogs. As a result, many investigators have chosen to develop animal models in which an asthma-like phenotype is induced by some intervention. The strategy most often employed is allergen sensitization and challenge. A variety of species have been utilized in such models, including dogs, sheep, guinea pigs, monkeys, rats, and mice.
• • • • •
ovalbumin (OVA); picryl chloride;2 sheep erythrocytes;3,4 short ragweed extracts;5 house dust mite allergen.6,7
Although the last named is likely to be particularly relevant given the importance of house dust mite allergies in asthma, most investigators have used OVA as the allergen, perhaps because of its relatively low cost and availability. Ovalbumin sensitization and challenge Many investigators have used models of asthma in which mice are first sensitized to OVA and then challenged with OVA via the lungs, but both the sensitization and challenge protocols vary widely among investigators. There are differences in the amount of OVA used to sensitize the mice, the route of sensitization (systemic versus airway), whether or not adjuvant is used, the number of sensitizations, and the number and method of pulmonary challenges (intranasal, intratracheal or aerosol). Both single and multiple challenges have been utilized. Mice are usually assessed 1–3 days after the last challenge. Consequently, the characteristics assessed are those related to the late response to allergen challenge, and airway obstruction is not usually evaluated. Consistent features of the model are increased ovalbuminspecific IgE and IgG1, eosinophilia (intraluminal, peribronchial, and perivascular), and recruitment of lymphocytes
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to the airways. Increases in Th2-type cytokines, either in BAL fluid, in lung tissue, or in lymph nodes draining the lungs also occur.3,8,9 Airway hyperresponsiveness (AHR) is often observed, though not always.3,10–12 There are few reports of comparisons of the various protocols in terms of their ability to induce AHR, but those available indicate that both systemic sensitization and pulmonary challenge are required to induce AHR.9 Hamelman et al.13 reported that multiple airway challenges without systemic sensitization can result in pulmonary eosinophilia and changes in the in-vitro responsiveness of the trachea to electrical field stimulation (EFS), but in-vivo AHR was not observed under these conditions. The challenge protocol used may influence AHR by altering the nature of the inflammatory response.9 The intensity of the challenge can also influence the development of AHR, although this varies across strains.11 Investigators using such models have consistently observed an important role for T cells in the development of an asthma-like phenotype.14,15 It is generally agreed that an important function of these cells is the generation of cytokines and their effects on IgE synthesis, eosinophil recruitment, and AHR; so a major focus of investigations using these models has been to understand the relationship among these three characteristics of the response to allergen. However, the results of these studies have not been consistent, perhaps because there are redundant pathways for the development of AHR that are influenced not only by the precise protocols used to sensitize or challenge the mice, but also by differences in the strain of mouse, and the method used to assess AHR. Role of IgE and mast cells in allergen-induced AHR Mast cells express receptors (FceRI) on their surface that bind the Fc portion of IgE with high affinity. Crosslinking FceRI receptors upon binding of allergen to IgE results in the secretion of a panel of mediators including histamine, eicosanoids, and cytokines, many of which have the capacity to elicit AHR. An important role for mast cells and IgE in the early response to allergen inhalation has been demonstrated in multiple species, including the mouse.16 However, their role in the late response to allergen and in allergeninduced AHR in particular is less clear. Animal models, particularly mast cell-deficient KitW/KitW-v mice which are genetically deficient in c-kit, the receptor for an important mast cell growth and survival factor, as well as mice genetically deficient in B cells and which lack IgE, have been utilized to help define this role. Activation of mast cells has the capacity to induce AHR. C57BL/6 mice treated with anti-IgE antibodies 20 minutes prior to measurements of airway responsiveness show increased responses to intravenous methacholine compared with animals treated with an irrelevant antibody.17 The increased responsiveness is not observed in mast celldeficient mice, but is restored when mast cells are reconstituted in these mice by infusion of bone marrow-derived cells. After passive sensitization of mice with OVA-specific
IgE, challenge with aerosolized OVA results in increased responsiveness to EFS of tracheae of these mice.18 Similar results are obtained after passive sensitization with OVAspecific IgG1, consistent with reports that this class of antibodies also participates in allergic responses in the mouse. Mice sensitized and challenged via the airways also develop increased tracheal responses to EFS, but these are not observed in B cell-deficient mice, suggesting that either IgE or IgG1 are necessary to induce this effect.13 Kung et al.19 reported that aerosol OVA challenge of systemically sensitized mast cell-deficient mice resulted in fewer eosinophils in BAL fluid and lung tissue and reduced eosinophil peroxidase levels compared with congenic controls, but these authors did not examine airway responsiveness. Kobayashi et al.20 performed similar experiments and did observe a reduction in AHR. Further, they observed that reconstitution of mast cell-deficient mice with bone marrow-derived cells restored the ability of these mice to develop AHR upon sensitization and challenge. Taken together, the results suggest that IgE acting on mast cells may contribute to allergen-induced AHR, but do not rule out a role for IgG1 or of effects of IgE on low-affinity receptors present on other cell types. In contrast, other investigators have not confirmed a role for either mast cells or IgE. MacLean et al.8 were unable to observe any difference between wild-type and B celldeficient mice in the lung eosinophilia, AHR, or increased serum cytokines induced by systemic sensitization and repeated aerosol challenge, despite unmeasurable levels of IgE and IgG1 in the B cell-deficient mice. Similar results were obtained by Hamelman et al.13 In addition, Takeda et al.21 reported that mast cell-deficient mice were identical to strain-matched controls in their ability to develop pulmonary eosinophilia and AHR after systemic sensitization and repeated airway challenge with ovalbumin. It is apparent that allergen-induced AHR can occur in the absence of an IgE response, since Brewer et al.11 reported that the AKR strain of mouse was among the strains with the most robust changes in airway responsiveness after ovalbumin sensitization and challenge, even though no increase in IgE was observed in this strain after sensitization. Hogan et al.22 also reported that IL-4 deficient mice, which failed to develop IgE after OVA sensitization, nevertheless had robust AHR upon airway challenge. At least part of these discrepancies are likely to be related to the precise protocol used to sensitize and challenge the mice. The studies cited above which support a role for IgE and/or mast cells in the response to allergen13,18–20 used protocols which resulted in the recruitment of only a few eosinophils, while those which suggested that IgE and/or mast cells were unimportant used protocols in which eosinophils constituted the majority of the cells in BAL fluid.8,11,21,22 Indeed, Kobayahsi and colleagues used two distinct protocols to sensitize and challenge mast cell-deficient mice and found reduced responses compared with strain matched controls when relatively mild protocols for airway challenge were employed, but no difference between mast
Animal Models
cell deficient and control mice when more frequent and robust airway challenges were used.20 They suggested, as have others,23,24 that AHR could be induced by at least two mechanisms, one involving mast cell activation in response to IgE crosslinking, and another involving eosinophils. The latter is discussed below. Role of eosinophils in allergen-induced AHR Eosinophils contain cationic proteins such as major basic protein (MBP) that have the capacity to induce AHR by damaging the airway epithelium, thus likely permitting greater access of inhaled bronchoconstrictors to the underlying airway smooth muscle.25 MBP also acts as an antagonist of M2 muscarinic inhibitory receptors on cholinergic nerves, resulting in greater release of aceytlcholine.26,27 Although the role of eosinophils in inducing AHR has been extensively investigated in murine models of asthma, it remains controversial. In support of a causal role for eosinophils in the etiology of allergen-induced AHR, Lee et al.28 generated transgenic mice that constitutively express IL-5 in the lung epithelium where IL-5: • promotes the differentiation of eosinophils from bone marrow precursors; • prolongs eosinophil survival by preventing apoptosis; • promotes eosinophil activation; • acts as an eosinophil chemoattractant. IL-5 trangenic mice have peribronchial and intraluminal accumulations of eosinophils even in the absence of allergen challenge. The mice also have hyperresponsive airways. While it is possible that effects of IL-5 on cells other than eosinophils, for example airway smooth muscle cells,29 might contribute to the AHR observed in these mice, the results suggest that expression of IL-5 in the airways is sufficient to induce airway eosinophilia, and that the presence of eosinophils may lead to AHR. Experiments performed in IL-5 knockout mice also support a role for eosinophils in allergen-induced AHR. Foster et al.30 used IP injection to sensitize C57BL6 mice that were genetically deficient in IL-5, and then repeatedly challenged the mice with aerosolized ovalbumin. Although levels of allergen-specific IgE were not altered, both accumulation of eosinophils in the airways and AHR were prevented in IL-5 deficient compared with wild-type mice. Importantly, the authors also reconstituted IL-5 in the knockout mice by nasal inoculation with a recombinant viral vector expressing IL-5. This treatment restored eosinophil levels in the peripheral blood, pulmonary eosinophilic inflammation, and AHR. Similar results were obtained by Hamelman et al.31 Hogan et al.22 also reported that, although AHR induced by allergen sensitization and challenge was maintained in IL-4 deficient C57BL/6 129Sv mice, treatment of these mice with a monoclonal antibody to IL-5 prior to aerosol challenge abolished both airway eosinophilia and AHR.
81
The observation of Brewer et al.,11 that there is a good correlation between airway eosinophils and AHR across multiple strains of mice all sensitized and challenged in the same way, also argues for a causal relationship between these factors, although the authors also suggested that this correlation could result from a genetic link between the genes which determine airway eosinophilia and those which determine AHR. In contrast to the results described above, data from other investigators do not support a causal relationship between eosinophils and AHR in murine models of allergen sensitization and airway challenge. Corry et al.32 treated BALBc mice with anti-IL-5 antibodies during a 4-week sensitization period prior to airway allergen challenge; they observed no change in allergen-induced AHR. Similar results were obtained by other investigators when they administered the anti-IL-5 antibody just prior to allergen challenge rather than during the sensitization period.20,33,34 Treatment with a soluble IL-5 receptor is also without effect on allergeninduced AHR.35 Despite the lack of effect of IL-5 antibodies on allergen-induced AHR, blood and/or lung eosinophils were markedly reduced in all these studies. The effect of the antibody on eosinophils indicates that an adequate amount of antibody was administered. Indeed Hessel et al.33 administered much higher amounts of antiIL-5 antibody than those required to inhibit eosinophilia and still found no effect on allergen-induced AHR. These results suggest that IL-5 is required for allergen-induced eosinophilia, but that AHR can occur even in the absence of eosinophils. The observation that AHR is observed in BALBc mice even when sensitization and challenge protocols which do not result in prominent airway eosinophilia are used6,10 also suggests that factors other than eosinophils can lead to AHR under these conditions. Genetic background may be an important determinant of the mechanism of allergen-induced AHR. Indeed, genetic background may in part explain the discrepancies in the results of studies examining the role of eosinophils in mediating AHR. The results discussed above supporting a role for IL-5 and eosinophils in allergen-induced AHR were obtained in C57BL/6 mice or offspring of C57BL/6 mice.22,28,30,31 In contrast, the studies which failed to demonstrate an important role for eosinophils in mediating the AHR observed following allergen sensitization and challenge were largely performed using BALBc mice.20,32–35 The BALBc mouse produces more allergen-specific IgE in response to allergen sensitization and challenge than does the C57BL/6 mouse,9,11 and it is possible that IgE and mast cell-mediated mechanisms are more important than eosinophils in this strain. Drazen et al.24 suggested that, because of genetic deficiencies in mast cell tryptase 7 and in secretory phospholipase A2 in the C57BL/6 mouse, these mice may lack the ability to develop IgE-dependent AHR. Although these specific genetic defects may not explain the observed effects on AHR, they are illustrative of the mechanisms that can lead to AHR, and how strain comparisons can help uncover them.
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Differences in the method used to assess AHR may also influence investigators’ ability to observe a role for IgE or eosinophils in its etiology. C57BL/6 are less prone to the development of AHR than are BALBc mice when identical protocols are used to sensitize and challenge the mice and pulmonary resistance (RL) is used as the outcome indicator.9,10 Indeed, AHR based on measurements of RL is sometimes not observed in C57BL/6 mice under conditions where BALBc mice develop robust responses. However, under these conditions AHR can be observed if dynamic compliance (Cdyn) rather than RL is used as the outcome indicator.9 These results indicate that the site of airway narrowing influenced by allergen sensitization and challenge may differ across mouse strains, and that methods insensitive to the lung periphery may fail to detect important changes. Summary The results suggest that in the mouse there are at least two pathways to the development of AHR following OVA sensitization and challenge. One involves IgE-dependent activation of mast cells and the consequent release of several classes of mediators. The other involves recruitment of eosinophils, perhaps through effects of IL-5 on the differentiation of bone marrow-derived precursors, and effects of eosinophilic proteins on target cells in the airways. As mouse models are used to further refine our understanding of the specifics of these pathways or to uncover other as yet uncharacterized mechanisms, it should be borne in mind that the protocol used to sensitize and challenge the mice, the choice of mouse strain, and the end-point used to assess AHR are likely to influence which of these mechanisms dominates. In this respect, some attempt by investigators in the field to standardize protocols appears warranted.
ANIMAL MODELS OF CHRONIC BRONCHITIS Chronic bronchitis is characterized by cough and mucus hypersecretion. Airway obstruction and airway hyperresponsiveness are also common features of this disease.36,37 Animal models have been developed which mimic many of these aspects of human chronic bronchitis. The methods used to generate these models include: • chronic exposure to high concentrations of SO2 gas (see below); • cigarette smoke;38–40 • endotoxin;41 • sodium metabisulfite;42,43 • air pollution.44 This review will focus on chronic SO2 exposure. In most of these studies, animals were exposed to SO2 at concentrations ranging from 200 to 500 ppm, 2–5 hours/day, for
periods of up to 6 months. Most of the published data concern effects in rats and dogs. However, because of the advantages of mouse models of disease as described above, some data generated in mice are included below. The effect of SO2 gas on ciliated epithelial cells In rats and dogs, there is sloughing of ciliated cells following acute exposure to SO2.45–47 After 2–4 days of exposure, ciliated cells are lost throughout the trachea and mainstem bronchi and replaced by one or two layers of small flat cells, whereas peripheral airways and alveoli appear normal.48 The central but not peripheral effects of SO2 are consistent with what could be expected from its highly water-soluble nature, and with studies that have shown that SO2 is removed from inhaled air primarily in the upper respiratory tract.49,50 Hence the lower airways and alveoli are likely to receive a much smaller dose of SO2 than the central airways. After 6 weeks of SO2 exposure, the epithelial layer in the trachea and bronchi begins to regenerate, it becomes thicker than normal, and some of the cilia begin to reappear. Lamb and Reid48 proposed that these changes in the epithelial lining might make it more resistant to injury. In ferrets, chronic exposure to SO2 leads to decreases in the number of cilia per cell, and causes widening of the intercellular spaces at the base of the epithelium.51 This widening may account for the increased epithelial permeability that has been reported in animals exposed to SO2.52 The effect of chronic SO2 exposure on mucus secretion In rats after chronic SO2 exposure, mucus is sometimes present in sufficient quantities as to be apparent either by direct visualization or in histological sections.53,54 There are also increases in the amounts of acidic and neutral mucins extracted from the lungs and tracheae,54 and elevations in the mucus content of bronchoalveolar lavage fluid.55 The amount of mucus recovered increases with increasing duration of exposure56 and may represent an adaptive response in that it protects the regenerating epithelial cells. Mucus hypersecretion is likely to result from both increased mucus synthesis and decreased mucus clearance. The size of the tracheal mucous glands, the abundance of mucus glycoprotein mRNA, and the number of epithelial secretory cells increases in rats exposed chronically to high concentrations of SO2.48,53,55–57 The secretory cells also extend into more peripheral airways. Mucus hypersecretion is also observed with chronic SO2 exposure in dogs.58-60 Tracheal mucus flow rates are reduced by approximately 50% in rats after 4 weeks of exposure to SO2,56 perhaps as a result of changes in the viscoelastic properties of the mucus as well as decreases in the number of ciliated epithelial cells. The nature of airway mucus glycoproteins changes over the course of chronic SO2 exposure in rats,48,54,57,61 consistent with observations in human bronchitis.62 Exposure to SO2 gas increases both acidic and neutral mucus glycoproteins in rat lung extracts, but the percentage increase is much greater for the neutral (PAS staining) mucins than for the acidic (Alcian Blue) staining mucins.54 Similar results
Animal Models
are obtained with chronic metabisulfite exposure.43 The number of PAS compared to Alcian Blue staining bronchiolar epithelial cells also increases with 4–6 weeks of SO2 exposure.48,56 Changes in the composition of mucus are observed with chronic SO2 exposure in dogs.59,60 These changes in mucus composition correlate with changes in its rheological properties.63 Similar results are obtained with chronic cigarette smoke exposure in dogs.64 The mechanisms accounting for mucus hypersecretion in SO2-exposed animals are not known. One possibility is that neutrophils are involved, since neutrophils are present in the airways of animals with SO2-induced bronchitis (see below), and neutrophil proteases are potent mucus secretagogues.65,66 It is also possible that SO2-induced airway injury renders the animals more susceptible to infection. Infections are an important component of human chronic bronchitis,67 and endotoxin exposure alone is known to induce mucus hypersecretion.41 Indeed in rats, mucus hypersecretion induced by chronic SO2 exposure is amplified by bacterial infection.55 Chronic SO2 exposure and airway inflammation Increases in polymorphonuclear (PMN) cells are observed in histological sections of large but not small airways or alveoli of rats with SO2-induced bronchitis.54,68 PMN are also observed in the airway lumen, as indicated by lavage,47 or by examination of mucus.69 Consistent with the histological results, PMN in the lavage fluid are observed earlier and to a greater extent in the central airways than in the peripheral lung. For example, in rats after 2 weeks of SO2 exposure, PMN comprise almost 30% of the cells in airway lavage fluid, but are not increased in lung lavage. After 4 weeks of exposure, the number of PMN in lung lavage does increase relative to air-exposed controls, but even then represents only 2% of total cells.47 Increased numbers of mononuclear cells as well as PMN are observed in histological sections of rats and dogs with SO2-induced bronchitis, but lavage lymphocytes and macrophages are not altered.47,54,70,71 Similarly, increased numbers of mononuclear cells are observed in the airway tissue,72,73 but not in the airway lavage fluid of patients with chronic bronchitis.74,75 It is not known why there are differences in the numbers of inflammatory cells in the airway lumen compared with the airway tissue. It is possible that there are important differences in the nature of the chemotactic factors and adhesion molecules expressed by epithelial versus subepithelial cells. Tracheae from chronic SO2-exposed rats show increased expression of the neutrophil chemokines KC and MIP-2,68 but the cell types responsible for this expression are not known. Airway obstruction and airway hyperresponsiveness Consistent with the airway obstruction observed in patients with chronic bronchitis, chronic exposure to SO2 gas for periods of 4 weeks causes a small (approximately 25%) but significant increase in pulmonary resistance (RL) in rats.54,76
83
In dogs, more substantive (2–3 fold) changes in RL are observed.70,77 The species difference in the magnitude of the response may relate to the mode of SO2 exposure, which was by nasal inhalation in rats, but through a surgically created tracheostomy in dogs. Because much of the SO2 that is inhaled is scrubbed in the nasal passages,49,50 it is likely that the dogs received a much greater dose than the rats of SO2 in their pulmonary airways. Chronic SO2 exposure also causes a substantial increase in airway responsiveness to inhaled aerosolized methacholine in rats, with more pronounced effects observed when RL rather than Cdyn was used as the outcome indicator.54,78,79 This finding has been interpreted to reflect the more pronounced effects on central than peripheral airways. These seem to be the first reports of increased airway responsiveness in an animal model of chronic bronchitis. Patients with chronic bronchitis also show increased airway responsiveness relative to normal subjects.36,37 One explanation for this phenomenon has been that patients with chronic bronchitis have preexisting hyperresponsiveness which predisposes them towards the development of bronchitis. The fact that airway hyperresponsiveness can develop with induction of a syndrome that strongly resembles many of the histopathological features of bronchitis suggests that this is not necessarily the case. We do not know the mechanistic basis for the airway hyperresponsiveness observed in rats with SO2-induced chronic bronchitis. Because airway responsiveness to intravenously administered methacholine is also observed,79 it is unlikely that changes in epithelial permeability leading to more rapid or increased uptake of inhaled methacholine across the epithelium accounts for the changes. Although inflammatory cytokines can induce alterations in the contractility of airway smooth muscle,80 it unlikely that the increased airway responsiveness observed in bronchitic rats is the result of alterations in the airway smooth muscle per se. Neither the sensitivity nor the maximal response to carbachol, eserine, acetylcholine, or serotonin is altered in tracheae of rats exposed chronically to SO2.54,78,81 The amount of airway smooth muscle is also unaffected.78 Instead, the observation that administration of carbocisteine, which reduces the amount of mucus in the airways, attenuates the increases in RL induced by SO2 exposure76 suggests that increased quantities of mucus present in the airways of rats with SO2-induced bronchitis may account for the increased resistance. Mucus hypersecretion may also contribute to the increased airway responsiveness observed with chronic SO2 exposure, since Moreno et al.82 have shown that changes in the diameter of the airway lumen due to the presence of mucus or to edema of the airway wall, even if small, can substantially increase changes in pulmonary mechanics induced by subsequent smooth muscle constriction. In dogs, chronic exposure to high concentrations of SO2 gas results in decreased, not increased, airway responsiveness to inhaled aerosolized methacholine, whereas responsiveness to intravenous methacholine is not altered.70 Similar results are obtained when cigarette smoke rather
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than SO2 gas is used to induce bronchitis.39 The effect is not specific to methacholine: airway responses to inhalation of two other chemically distinct mediators, histamine and PGF2a, are also reduced.77 We do not know why there are differences in the effects of chronic SO2 exposure on airway responsiveness in dogs and rats. Both species develop substantive changes in the epithelium, as well as chronic mucus hypersecretion and chronic airway inflammation.54,59,70 However, it is possible that species differences in the anatomy of the airways coupled with differences in the relative magnitude of the mucus hypersecretion may contribute. For its size, the dog has very large airways. It is possible that, in this species, the airways are sufficiently large that the increase in the thickness of the mucous layer overlying the epithelium resulting from mucus hypersecretion is without effect in augmenting the mechanical consequences of airway smooth muscle contraction. In contrast, the increased layer of mucus may be sufficient to reduce the penetration of methacholine to the underlying smooth muscle. Alternatively, there may be changes in the distribution of inhaled aerosols resulting from mucus hypersecretion83 that result in their deposition in larger airways that contribute less to the changes in pulmonary resistance that result from bronchoconstriction. Either explanation would account for the changes in the response to inhaled but not intravenous methacholine that are observed with induced bronchitis in dogs.39,70 The role of C-fibers in SO2-induced bronchitis in rats C-fibers, a class of unmyelinated sensory neurons which innervate the airways, are stimulated by inhaled irritants, including cigarette smoke and SO2 gas, substances known to induce chronic bronchitis in humans and animals. Stimulation results in central reflex changes in heart rate and breathing pattern, and also results in release of the tachykinins substance P and neurokinin A from the peripheral endings of these neurons. The actions of these neuropeptides include cough, mucus secretion, bronchoconstriction, and airway inflammation, events similar to those observed in chronic bronchitis.84 To test the hypothesis that C-fibers might contribute to the pathogenesis of chronic bronchitis, normal rats and rats treated neonatally with capsaicin to permanently destroy Cfibers85 were exposed to high concentrations of SO2 gas for periods of 1 day to 4 weeks.47,78 Surprisingly, RL increased to a greater extent after chronic SO2 exposure in the capsaicintreated rats. SO2 also resulted in more pronounced airway hyperresponsiveness in the capsaicin-treated rats.78 Airway inflammation was greater and progressed further down the respiratory tract.47 Taken together, these results support the hypothesis that, rather than contributing to the pathophysiological manifestations of bronchitis, C-fibers may protect the airways during induction of chronic bronchitis by SO2 exposure. While C-fibers can cause changes in the pattern of breathing, it is unlikely that such effects constitute the protection afforded against SO2 by C-fibers, since SO2-induced
changes in ventilation were not different in capsaicin- and vehicle-treated rats.47 The induction of chronic bronchitis in rats by SO2 exposure results in a 3-fold increase in the substance P content of the trachea.86 SP levels in induced sputum of patients with chronic bronchitis are also higher than in normal volunteers.87 Taken in light of the observations above, these changes would appear to represent an adaptive response to chronic irritation. Effects of chronic SO2 exposure in mice Adult male C57BL/6 mice were exposed to 250 ppm SO2 gas for 5 hours/day on 5 days/week for periods of 4 weeks. Pathological changes were primarily restricted to the epithelium and included loss of cilia, squamous metaplasia, and focal denudation. These changes were most pronounced in the central airways, with little change in the peripheral airways. The alveoli were normal. In contrast to the results obtained in the rats described above, no evidence was found of mucus plugging or increased amounts of mucus overlaying the epithelium in these mice. Anatomical differences between the two species may in part explain these differences in response to SO2: mouse airways do not contain mucous glands, and serous and mucous cells appear largely confined to the trachea. Johnson et al.88 also exposed mice to SO2, but used a continuous exposure albeit at a much lower concentration (40 ppm).They observed no changes in the lungs, despite changes in the nasal epithelium. To evaluate the extent of airway inflammation induced by SO2 exposure, mice were euthanized, tracheostomized, and a lavage procedure performed. Because of the more prominent central versus peripheral inflammation induced by SO2 in other species,47,54,71 bronchopulmonary inflammation was assessed by first performing an airway lavage (AL) and then performing a bronchoalveolar lavage. For the AL, 0.8 mL of sterile saline was inserted and quickly withdrawn. For the BAL this procedure was repeated 10 more times and the total return pooled. Mice were examined after either 1 week or 1 month of SO2 exposure. In each case, lavage was performed 24 hours after the last exposure. After 1 week of SO2 exposure, the total number of cells and the percentage of cells that were PMN were both greater in mice exposed to SO2 than in air-exposed mice in both the AL and the BAL (Fig. 8.1).There was no effect of SO2 exposure on any other cell type. As the author’s group had previously observed in rats,47 PMN increased to a greater extent in the AL than in the BAL (P 0.005). Similar results were obtained after 1 month of SO2 exposure. The results demonstrating greater percentage increases in PMN in the AL compared to the BAL of SO2 exposed mice also mimic the inflammation characteristic of human chronic bronchitis. Thompson et al.75 observed increased numbers of PMN in lavage fluid from patients with chronic bronchitis. These changes were more pronounced in bronchial than distal lavage samples.75 Effects of chronic SO2 exposure on airway obstruction were measured by whole-body plethysmography.89 The parameter assessed, Penh, is a dimensionless number that empirically correlates with bronchoconstriction in
85
Animal Models
3
24 Air
SO2 – 1 week
SO2 – 1 month
Air SO2 – 250ppm
Penh (dimensionless)
PMN (% total cells)
20
16
12
8
*
*
2
1
4
0
0 AL
BAL
Fig. 8.1. PMN in airway lavage (AL) and bronchoalveolar lavage (BAL) from C57BL/6 mice exposed to filtered air or to SO2 gas for 1 week or 1 month. Results are means SE of data from 35–55 animals in each group.
methacholine-challenged mice.89 Exposure to filtered air for up to 1 month had no significant effect on Penh (Fig. 8.2). In contrast, there was a significant increase in Penh both at 1 week and 1 month of SO2 exposure (P 0.001). Because whole-body plethsymography measures changes in the entire respiratory tract, including the upper airways (nose, pharnyx, larnyx), and because SO2 exposure has important effects on the nasal passages in mice,90–92 the author’s group sought to determine whether the effects observed on Penh were the result of nasal effects, or effects on the pulmonary airways. Penh was first measured with the mice anesthetized and breathing through their noses, and then after a tracheostomy had been created to bypass the upper airways. Penh was significantly greater (P 0.02) in anesthetized SO2-exposed than in anesthetized air-exposed mice. In air-exposed mice, insertion of a tracheostomy tube resulted in a significant increase in Penh (P 0.03). In contrast, in the SO2-exposed animals, there was no statistically significant increase in Penh upon insertion of the tracheostomy tube. Consequently, after tracheostomy, the difference in Penh between the air- and SO2-exposed animals was no longer significant. These results suggest that the increased Penh in the SO2exposed animals was primarily the result of increased airway obstruction imposed by the upper airways (nose, pharnyx, larynx). Once these airways were bypassed, the effect of SO2 was no longer observed. To confirm these results, the author’s group measured RL in air- and SO2-exposed animals that were anesthetized, tracheostomized, and ventilated and found no significant difference between the groups (1.60 0.019 and 1.66 0.04 cmH2O/mL per second, respectively, n 6–9).These results suggest that the changes in Penh induced by SO2 exposure are indicative of
0
1 Weeks
4
Fig. 8.2. Penh values for air- and SO2-exposed mice (10 in each group). Measurements were performed the day before initiating exposures and again 1 week and 4 weeks after SO2 exposure. For the 1-week and 4week elements, mice were studied 24 hours after the last SO2 exposure. Results are expressed as mean SE. An asterisk indicates P 0.001 compared to pre-exposure values (0 weeks).
effects in the upper airways, with no significant effect of SO2 exposure on lower (pulmonary) airway caliber. Chronic exposure to SO2 gas has been shown to induce changes in the olfactory epithelium, including edema, loss of cilia, epithelial thinning, epithelial desquamation, and some serous exudation.90,91 SO2 exposure also increases the numbers of goblet cells in the nasal epithelium.92 Thus either nasal congestion or increased nasal secretions may have contributed to the increased nasal obstruction observed in these animals. The author’s group also measured airway responsiveness to inhaled aerosolized methacholine in air- and SO2exposed mice. In each animal, responsiveness to methacholine was measured prior to initiation of exposure, after 1 week of exposure, and again after 1 month of exposure. In mice exposed to filtered air, airway responsiveness did not change over time. However, chronic SO2 exposure was also without significant effects on airway responsiveness (Fig. 8.3). Summary of the SO2 data Table 8.1 summarizes the changes induced by chronic SO2 exposure in rats, dogs, and mice. In rats, chronic exposure to high concentrations of SO2 gas results in a syndrome that mimics many aspects of human chronic bronchitis. With repeated daily exposure over periods of 4–6 weeks, there is chronic injury and repair of epithelial cells, mucus hypersecretion, airway inflammation, increased airway resistance, and airway hyperresponsiveness. Similar results are obtained in dogs, although a critical aspect of the condition, airway
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Air-exposed mice
14 Pre
1wk
12
4wk
10
Change in Penh
Change in Penh
12
8 6 4
4wk
6 4
0
0 10
1000
1wk
8
2
30 100 300 Methacholine (mg/mL)
Pre
10
2
10
SO2-exposed mice
14
30 100 300 Methacholine (mg/mL)
1000
Fig. 8.3. Airway responsiveness to inhaled aerosolized methacholine in air- and SO2-exposed animals (10 in each group). Changes in Penh compared with saline aerosol were used as the outcome indicator. In each group, mice were studied prior to initiating exposures (Pre) and 1 week and 4 weeks after initiating exposures. Measurements were performed approximately 18 hours after the last SO2 exposure. There was no statistically significant effect of either air or SO2 exposures on airway responsiveness to methacholine. Results are expressed as mean SE.
Table 8.1. Comparison of the characteristic traits observed in human chronic bronchitis and those observed in bronchitis induced by chronic SO2 exposure in rats, dogs, and mice
Trait
Humans
Rats
Dogs
Mice
Airway epithelial changes Mucous hypersecretion Airway inflammation Airway obstruction Airway hyperresponsiveness
Yes Yes Yes Yes Yes
Yes Yes Yes Minimal Yes
Yes Yes Yes Yes No
Yes No Yes Upper airways only No
hyperresponsiveness, is not observed. The cost of acquiring and boarding dogs may also make experiments in this species prohibitively expensive. As discussed above, there are numerous advantages to working with mice. However, while the syndrome induced by chronic SO2 exposure, at least in the C57BL/6 mouse, mimics the airway obstruction and airway inflammation of the human condition, the airway obstruction is primarily due to changes in the upper airways, and neither mucus hypersecretion nor airway hyperresponsiveness is observed – although it is possible that these features would develop in other mouse strains. For these reasons, the rat model may prove to be most suitable both for investigations of the mechanisms underlying the pathophysiological events that typify the condition in humans and for pharmaceutical studies.
REFERENCES 1. Gross P, Pfitzer E, Tolker M et al. Experimental emphysema: its production with papain in normal and silicotic rats. Arch. Environ. Hlth 1965; 11:50–8.
2. Garssen J, Nijkamp FP, Van Vugt E et al. T cell-derived antigen binding molecules play a role in the induction of airway hyperresponsiveness. Am. J. Respir. Crit. Care Med. 1994; 150(6 Pt 1):1528–38. 3. Wills-Karp M, Ewart SL. The genetics of allergen-induced airway hyperresponsiveness in mice. Am. J. Respir. Crit. Care Med. 1997; 156(4 Pt 2):S89–96. 4. Gavett SH, O’Hearn DJ, Li X et al. Interleukin 12 inhibits antigeninduced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J. Exp. Med. 1995; 182:1527–36. 5. Chapoval SP, Nabozny GH, Marietta EV et al. Short ragweed allergen induces eosinophilic lung disease in HLA-DQ transgenic mice. J. Clin. Invest. 1999; 103:1707–17. 6. Tournoy KG, Kips JC, Schou C et al. Airway eosinophilia is not a requirement for allergen-induced airway hyperresponsiveness. Clin. Exp. Allergy 2000; 30:79–85. 7. Coyle AJ, Wagner K, Bertrand C et al. Central role of immunoglobulin (Ig) E in the induction of lung eosinophil infiltration and T helper 2 cell cytokine production: inhibition by a nonanaphylactogenic anti-IgE antibody. J. Exp. Med. 1996; 183:1303–10. 8. MacLean JA, Sauty A, Luster AD et al. Antigen-induced airway hyperresponsiveness, pulmonary eosinophilia, and chemokine expression in B cell-deficient mice. Am. J. Respir. Cell Mol. Biol. 1999; 20:379–87. 9. Zhang Y, Lamm WJ, Albert RK et al. Influence of the route of allergen administration and genetic background on the murine
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allergic pulmonary response. Am. J. Respir. Crit. Care Med. 1997; 155:661–9. Wilder JA, Collie DD, Wilson BS et al. Dissociation of airway hyperresponsiveness from immunoglobulin E and airway eosinophilia in a murine model of allergic asthma. Am. J. Respir. Cell Mol. Biol. 1999; 20:1326–34. Brewer JP, Kisselgof AB, Martin TR. Genetic variability in pulmonary physiological, cellular, and antibody responses to antigen in mice. Am. J. Respir. Crit. Care Med. 1999; 160:1150–6. De Sanctis GT, MacLean JA, Hamada K et al. Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma. J. Exp. Med. 1999; 189:1621–30. Hamelmann E, Tadeda K, Oshiba A et al. Role of IgE in the development of allergic airway inflammation and airway hyperresponsiveness: a murine model. Allergy 1999; 54:297–305. Drazen JM, Finn PW, De Sanctis GT. Mouse models of airway responsiveness: physiological basis of observed outcomes and analysis of selected examples using these outcome indicators. Annu. Rev. Physiol. 1999; 61:593–625. Gelfand EW. Essential role of T lymphocytes in the development of allergen-driven airway hyperresponsiveness. Allergy Asthma Proc. 1998; 19:365–9. Martin TR, Galli SJ, Katona IM et al. Role of mast cells in anaphylaxis: evidence for the importance of mast cells in the cardiopulmonary alterations and death induced by anti-IgE in mice. J. Clin. Invest. 1989; 83:1375–83. Martin TR,Takeishi T, Katz HR et al. Mast cell activation enhances airway responsiveness to methacholine in the mouse. J. Clin. Invest. 1993; 91:1176–82. Oshiba A, Hamelmann E, Takeda K et al. Passive transfer of immediate hypersensitivity and airway hyperresponsiveness by allergen-specific immunoglobulin (Ig) E and IgG1 in mice. J. Clin. Invest. 1996; 97:1398–408. Kung TT, Stelts D, Zurcher JA et al. Mast cells modulate allergic pulmonary eosinophilia in mice. Am. J. Respir. Cell Mol. Biol. 1995; 12:404–9. Kobayashi T, Miura T, Haba T et al. An essential role of mast cells in the development of airway hyperresponsiveness in a murine asthma model. J. Immunol. 2000; 164:3855–61. Takeda K, Hamelmann E, Joetham A et al. Development of eosinophilic airway inflammation and airway hyperresponsiveness in mast cell-deficient mice. J. Exp. Med. 1997; 186:449–54. Hogan SP, Mould A, Kikutani H et al. Aeroallergen-induced eosinophilic inflammation, lung damage, and airways hyperreactivity in mice can occur independently of IL-4 and allergenspecific immunoglobulins. J. Clin. Invest. 1997; 99:1329–39. Galli SJ. Complexity and redundancy in the pathogenesis of asthma: reassessing the roles of mast cells and T cells. J. Exp. Med. 1997; 186:343–7. Drazen JM, Arm JP, Austen KF. Sorting out the cytokines of asthma. J. Exp. Med. 1996; 183:1–5. Gleich GJ. The eosinophil and bronchial asthma: current understanding. J. Allergy Clin. Immunol. 1990; 85:422–36. Elbon CL, Jacoby DB, Fryer AD. Pretreatment with an antibody to interleukin-5 prevents loss of pulmonary M2 muscarinic receptor function in antigen-challenged guinea pigs. Am. J. Respir. Cell Mol. Biol. 1995; 12:320–8. Jacoby DB, Gleich GJ, Fryer AD. Human eosinophil major basic protein is an endogenous allosteric antagonist at the inhibitory muscarinic M2 receptor. J. Clin. Invest. 1993; 91:1314–18. Lee JJ, McGarry MP, Farmer SC et al. Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. J. Exp. Med. 1997; 185:2143–56. Hakonarson H, Maskeri N, Carter C et al. Autocrine interaction between IL-5 and IL-1b mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J. Clin. Invest. 1999; 104:657–67.
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30. Foster PS, Hogan SP, Ramsay AJ et al. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med. 1996; 183:195–201. 31. Hamelmann E, Takeda K, Haczku A et al. Interleukin (IL)-5 but not immunoglobulin E reconstitutes airway inflammation and airway hyperresponsiveness in IL-4-deficient mice. Am. J. Respir. Cell Mol. Biol. 2000; 23:327–34. 32. Corry DB, Folkesson HG,Warnock ML et al. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J. Exp. Med. 1996; 183:109–17. Erratum J. Exp. Med. 1997; 185:1715. 33. Hessel EM,Van Oosterhout AJ,Van Ark I et al. Development of airway hyperresponsiveness is dependent on interferon-gamma and independent of eosinophil infiltration. Am. J. Respir. Cell Mol. Biol. 1997; 16:325–34. 34. Nagai H, Yamaguchi S, Inagaki N et al. Effect of anti-IL-5 monoclonal antibody on allergic bronchial eosinophilia and airway hyperresponsiveness in mice. Life Sci. 1993; 53:L243–7. 35. Yamaguchi S, Nagai H, Tanaka H et al. Time course study for antigen-induced airway hyperreactivity and the effect of soluble IL-5 receptor. Life Sci. 1994; 54:L471–5. 36. Mullen JB, Wiggs BR, Wright JL et al. Nonspecific airway reactivity in cigarette smokers: relationship to airway pathology and baseline lung function. Am. Rev. Respir. Dis. 1986; 133:120–5. 37. Parker CWBR, Reed CE. Methacholine aerosol as a test for broncial asthma. Arch. Intern. Med. 1965; 115:452–8. 38. Wanner A, Hirsch JA, Greeneltch DE et al. Tracheal mucous velocity in beagles after chronic exposure to cigarette smoke. Arch. Environ. Hlth 1973; 27:370–1. 39. De Sanctis GT, Kelly SM, Saetta MP et al. Hyporesponsiveness to aerosolized but not to infused methacholine in cigarettesmoking dogs. Am. Rev. Respir. Dis. 1987; 135:338–44. Erratum Am. J. Respir. Crit. Care Med. 1994; 149:following 1740. 40. King M, Wight A, De Sanctis GT et al. Mucus hypersecretion and viscoelasticity changes in cigarette-smoking dogs. Exp. Lung Res. 1989; 15:375–89. Erratum Exp. Lung Res. 1994; 20:471. 41. Harkema JR, Hotchkiss JA. In vivo effects of endotoxin on intraepithelial mucosubstances in rat pulmonary airways: quantitative histochemistry. Am. J. Pathol. 1992; 141:307–17. 42. Pon DJ, van Staden CJ, Boulet L et al. Hyperplastic effects of aerosolized sodium metabisulfite on rat airway mucus-secretory epithelial cells. Can. J. Physiol. Pharmacol. 1994; 72:1025–30. 43. Pon DJ, van Staden CJ, Rodger IW. Hypertrophic and hyperplastic changes of mucus-secreting epithelial cells in rat airways: assessment using a novel, rapid, and simple technique. Am. J. Respir. Cell Mol. Biol. 1994; 10:625–34. 44. Saldiva PH, King M, Delmonte VL et al. Respiratory alterations due to urban air pollution: an experimental study in rats. Environ. Res. 1992; 57:19–33. 45. Man SF, Hulbert WC, Man G et al. Effects of SO2 exposure on canine pulmonary epithelial functions. Exp. Lung Res. 1989; 15:181–98. 46. Hulbert WC, Man SF, Rosychuk MK et al. The response phase – the first six hours after acute airway injury by SO2 inhalation: an in-vivo and in-vitro study. Scanning Microsc. 1989; 3:369–78. 47. Long NC, Abraham J, Kobzik L et al. Respiratory tract inflammation during the induction of chronic bronchitis in rats: role of Cfibres. Eur. Respir. J. 1999; 14:46–56. 48. Lamb D, Reid L. Mitotic rates, goblet cell increase and histochemical changes in mucus in rat bronchial epithelium during exposure to sulphur dioxide. J. Pathol. Bacteriol. 1968; 96:97–111. 49. Dalhamm TSL. Acute effect of sulfur dioxide on the rate of ciliary beat in the trachea of rabbit, in vivo and in vitro, with studies on the absorptional capacity of the nasal cavity. Int. J. Air Poll.Water Poll 1961; 4:154–67. 50. Frank NR,Yoder RE, Brain JD et al. SO2 (35S-labeled) absorption by the nose and mouth under conditions of varying concentration and flow. Arch. Environ. Hlth 1969; 18:315–22.
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51. Miller ML, Andringa A, Rafales L et al. Effect of exposure to 500 ppm sulfur dioxide on the lungs of the ferret. Respiration 1985; 48:346–54. 52. Vai F, Fournier MF, Lafuma JC et al. SO2-induced bronchopathy in the rat: abnormal permeability of the bronchial epithelium in vivo and in vitro after anatomic recovery. Am. Rev. Respir. Dis. 1980; 121:851–8. 53. Reid L. An experimental study of hypersecretion of mucus in the bronchial tree. Br. J. Exp. Pathol. 1963; 44:437–45. 54. Shore S, Kobzik L, Long NC et al. Increased airway responsiveness to inhaled methacholine in a rat model of chronic bronchitis. Am. J. Respir. Crit. Care Med. 1995; 151:1931–8. 55. Jany B, Gallup M, Tsuda T et al. Mucin gene expression in rat airways following infection and irritation. Biochem. Biophys. Res. Commun. 1991; 181:1–8. 56. Lightowler NM, Williams JR. Tracheal mucus flow rates in experimental bronchitis in rats. Br. J. Exp. Pathol. 1969; 50:139–49. 57. Clark JN, Dalbey WE, Stephenson KB. Effect of sulfur dioxide on the morphology and mucin biosynthesis by the rat trachea. J. Environ. Pathol.Toxicol. 1980; 4:197–207. 58. Chakrin LW, Saunders LZ. Experimental chronic bronchitis: pathology in the dog. Lab. Invest. 1974; 30:145–54. 59. Bhaskar KR, Drazen JM, O’Sullivan DD et al. Transition from normal to hypersecretory bronchial mucus in a canine model of bronchitis: changes in yield and composition. Exp. Lung Res. 1988; 14:101–20. 60. Koshino T, Bhaskar KR, Reid LM et al. Recovery of an epitope recognized by a novel monoclonal antibody from airway lavage during experimental induction of chronic bronchitis. Am. J. Respir. Cell Mol. Biol. 1990; 2:453–62. 61. Broillet A, White R, Ventrone R et al. Efficacy of fenspiride in alleviating SO2 induced chronic bronchitis in rats and allergic rhinitis in guinea pigs. Rhinol. Suppl. 1988; 4:75–83. 62. Lopata M, Barton AD, Lourenco RV. Biochemical characteristics of bronchial secretions in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1974; 110:730–9. 63. Litt M, Khan MA, Chakrin LW et al. Effect of chronic sulfur dioxide inhalation on rheological properties of tracheal mucus. Biorheology 1976; 13:107–14. 64. King M. Experimental models for studying mucociliary clearance. Eur. Respir. J. 1998; 11:222–8. 65. Breuer R, Christensen TG, Lucey EC et al. Elastase causes secretory discharge in bronchi of hamsters with elastase-induced secretory cell metaplasia. Exp. Lung Res. 1993; 19:273–82. 66. Sommerhoff CP, Nadel JA, Basbaum CB et al. Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J. Clin. Invest. 1990; 85:682–9. 67. Wilson R, Grossman R. Introduction: the role of bacterial infection in chronic bronchitis. Semin. Respir. Infect. 2000; 15:1–6. 68. Farone A, Huang S, Paulauskis J et al. Airway neutrophilia and chemokine mRNA expression in sulfur dioxide-induced bronchitis. Am. J. Respir. Cell Mol. Biol. 1995; 12:345–50. 69. Knauss HJ, Medici TC, Chodosh S et al. Cell vs noncell airway temporal response in rats exposed to sulfur dioxide. Arch. Environ. Hlth 1976; 31:241–7. 70. Shore SA, Kariya ST, Anderson K et al. Sulfur-dioxide-induced bronchitis in dogs: effects on airway responsiveness to inhaled and intravenously administered methacholine. Am. Rev. Respir. Dis. 1987; 135:840–7. 71. Seltzer J, Scanlon PD, Drazen JM et al. Morphologic correlation of physiologic changes caused by SO2-induced bronchitis in dogs: the role of inflammation. Am. Rev. Respir. Dis. 1984; 129:790–7. 72. Saetta M, Di Stefano A, Maestrelli P et al. Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am. Rev. Respir. Dis. 1993; 147:301–6.
73. Di Stefano A, Turato G, Maestrelli P et al. Airflow limitation in chronic bronchitis is associated with T-lymphocyte and macrophage infiltration of the bronchial mucosa. Am. J. Respir. Crit. Care Med. 1996; 153:629–32. 74. Martin TR, Raghu G, Maunder RJ et al. The effects of chronic bronchitis and chronic air-flow obstruction on lung cell populations recovered by bronchoalveolar lavage. Am. Rev. Respir. Dis. 1985; 132:254–60. 75. Thompson AB, Daughton D, Robbins RA et al. Intraluminal airway inflammation in chronic bronchitis: characterization and correlation with clinical parameters. Am. Rev. Respir. Dis. 1989; 140:1527–37. 76. Levrier J, Duval D, Lloyd KG. Study on the effect of oral administration of carbocysteine on ventilatory parameters in the SO2 inhalation model of bronchitis in the rat. Fundam. Clin. Pharmacol. 1992; 6:231–6. 77. Drazen JM, O’Cain CF, Ingram RH. Experimental induction of chronic bronchitis in dogs: effects on airway obstruction and responsiveness. Am. Rev. Respir. Dis. 1982; 126:75–9. 78. Long NC, Martin JG, Pantano R et al. Airway hyperresponsiveness in a rat model of chronic bronchitis: role of C fibers. Am. J. Respir. Crit. Care Med. 1997; 155:1222–9. 79. Drazen JM, Takebayashi T, Long NC et al. Animal models of asthma and chronic bronchitis. Clin. Exp. Allergy 1999; 29 (Suppl. 2):37–47. 80. Amrani Y, Panettieri RA, Frossard N et al. Activation of the TNFap55 receptor induces myocyte proliferation and modulates agonist-evoked calcium transients in cultured human tracheal smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 1996; 15:55–63. 81. Touaty E, Gerber F, Fournier M et al. SO2-induced bronchopathy decreases airway sensitization with intratracheal ovalbumin in the rat. Bull. Eur. Physiopathol. Respir. 1986; 22:329–33. 82. Moreno RH, Hogg JC, Pare PD. Mechanics of airway narrowing. Am. Rev. Respir. Dis. 1986; 133:1171–80. 83. Sweeney TD, Skornik WA, Brain JD et al. Chronic bronchitis alters the pattern of aerosol deposition in the lung. Am. J. Respir. Crit. Care Med. 1995; 151(2 Pt 1):482–8. 84. Shore SALC, Gaston B, Drazen JM. Neural networks in the lung. In: Holgate ST (ed.), Immunopharmacology of the Respiratory System, pp. 123–45. San Diego: Academic Press, 1995. 85. Jancso G, Kiraly E, Jancso-Gabor A. Pharmacologically induced selective degeneration of chemosensitive primary sensory neurones. Nature 1977; 270:741–3. 86. Killingsworth CR, Paulauskis JD, Shore SA. Substance P content and preprotachykinin gene-I mRNA expression in a rat model of chronic bronchitis. Am. J. Respir. Cell Mol. Biol. 1996; 14:334–40. 87. Tomaki M, Ichinose M, Miura M et al. Elevated substance P content in induced sputum from patients with asthma and patients with chronic bronchitis. Am. J. Respir. Crit. Care Med. 1995; 151(3 Pt 1):613–7. 88. Johnson HD, Lincoln EM, Flatt RE. Sulfur dioxide (SO2) exposure and recovery effects on mice. Proc. Soc. Exp. Biol. Med. 1972; 139:861–4. 89. Hamelmann E, Schwarze J, Takeda K et al. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 1997; 156(3 Pt 1):766–75. 90. Giddons WEFG. Effects of sulfur dioxide on the nasal mucosa of mice. Arch. Environ. Hlth 1972; 25:166–73. 91. Min YG, Rhee CS, Choo MJ et al. Histopathologic changes in the olfactory epithelium in mice after exposure to sulfur dioxide. Acta Otolaryngol. 1994; 114:447–52. 92. Ukai K. Effect of SO2 on the pathogenesis of viral upper respiratory infection in mice. Proc. Soc. Exp. Biol. Med. 1977; 154:591–6.
Mast Cells and Basophils
Chapter
9
George H. Caughey Cardiovascular Research Institute and Department of Medicine, University of California at San Francisco, USA
Mast cells and basophils first came to attention over a century ago owing to their ample stocks of intracellular granules with unusual staining characteristics. For many years their origins, normal functions, and roles in disease were obscure, and in some respects remain so. Nonetheless, knowledge of their biology increased tremendously in the 1980s and 1990s.1–5 Until recently, researchers focused on their release of histamine and eicosanoids in acute allergic events, which were considered to be a corruption of hypothesized normal function of defending against invasion by parasites such as worms and ticks. However, studies in mice now suggest that mast cells contribute to innate immune defense and responses to immunologically nonspecific injury. These roles deviate from traditional concepts of mast cell and basophil participation in adaptive responses involving antigen recognition by IgE. In asthma investigations, attention is shifting from roles of these cells in acute responses to aeroallergens to roles in promoting persistent inflammation and remodeling in chronic disease. Their roles in other obstructive lung diseases have received less attention, but they may indeed contribute to conditions apart from asthma. This chapter summarizes current thinking about roles of mast cells and basophils in obstructive airway disease.
O R I G I N A N D FAT E Mast cells and basophils have shared origins but distinct distributions and fates. Mast cells, but not basophils, are normal residents of uninflamed airways. Mature mast cells rarely appear in blood, whereas mature basophils circulate and are recruited from blood to sites of allergic inflammation. Both cell types originate from shared progenitors in bone marrow; see Li and Krilis6 for a review. Immature mast cells released from marrow circulate briefly, exit the bloodstream to multiple tissue destinations, then differentiate, adopting a phenotype determined by their microenvironment. Basophils, on the other hand, mature in the marrow, circulate, then home to sites of inflammation if recruited to
do so. Tissue mast cells are not fixed in location, for they migrate towards airway epithelium after antigen challenge and traffic to lymph nodes from sites of antigen exposure. Mast cells probably also proliferate in tissues. Conditions such as intestinal parasitosis lead to large local increases in mast cells. Both types of cell survive degranulation and can restock their secretory granules with mediators. Lifespan in vivo has not been established, but in-vitro studies predict that basophils are short-lived compared with mast cells, which survive for weeks in culture. In humans, the aggregate mast cell mass is much larger than that of basophils, which usually comprise 1% of circulating leukocytes. Among mammals, basophil numbers vary widely, ranging from numerous in guinea pigs, few in humans and mice, to nearly nonexistent in dogs, in which they are arguably unimportant. There are genetic variants of mice with almost no mast cells but none with an inherited, selective deficit of basophils. Thus, it is easier to assess involvement of mast cells than of basophils in mouse disease models; see Galli5 for a review.
DEVELOPMENT AND HETEROGENEITY Paucigranular, mast cell-committed progenitors are released from marrow expressing surface receptor tyrosine kinase c-kit and low-affinity IgG receptor (FccRII), but not highaffinity IgE receptor, FceRI. In vitro, cells with mature characteristics, including FceRI and protease-rich granules, differentiate from progenitors under the influence of IL-6 and kit ligand. Presumably, similar events occur in vivo, with kit ligand produced by endothelial, stromal, and epithelial cells being critical for mast cell survival. Mice with defective c-kit or its ligand lack mast cells. Their importance to mast cell development is underscored by gain-of-function c-kit mutations in systemic mastocytosis and mast cell malignancy, and development of generalized mastocytosis in response to exogenous kit ligand. The importance of local production of kit ligand is suggested by the finding in mice that intratracheal kit ligand provokes mast cell-dependent hyperreactivity.7
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In vitro, a variety of cytokines (especially IL-3, -6, -9, and -10, and TGF-b1) determines the phenotype of maturing mouse mast cells. In the case of IL-9 (a candidate mouse “asthma gene”), airway overexpression in transgenic mice causes eosinophilic inflammation and hyperresponsiveness with mast cell hyperplasia.8 Mast cells vary in features, such as: • • • •
proteoglycan and protease content; metachromasia; granule ultrastructure; responses to degranulating stimuli, such as substance P.
These phenotypical variations appear reversible in a given cell and changeable in cell populations in response to infection and injury. Classically, rodent mast cells are divided into “mucosal” and “connective tissue” groups, although the phenotype distribution is not strictly bimodal. Human mast cells are sorted into subsets based on content of granule proteases.9 MCT cells express tryptases but not chymase, whereas MCTC express tryptases and chymase. Occasionally, chymase-only MCC mast cells are seen. Bronchi contain a mixture of types, whereas alveolar interstitium contains predominantly MCT. Because mast cells develop and are stimulated in tissues, some variation is due to differences in maturation, activation, or recovery from degranulation. Less is known of factors influencing basophil differentiation. c-Kit appears less important than for mast cells because mature basophils normally express little or no c-kit and because levels are largely unaffected by defects in c-kit causing profound mast cell deficits in mice. Nonetheless, c-kit human basophil-like cells circulate in asthma and atopy and manifest phenotypical changes in which c-kit could play a role.10
RECRUITMENT In asthmatics, increased numbers of basophils and activated mast cells appear in sputum after allergen challenge,11 which may reflect migration from submucosal sites and the bloodstream, respectively. As noted, mast cell precursors home to tissues even without inflammation. Constitutive homing and epithelial migration may involve responses to proteins such as: • • • • • • • •
C5a; RANTES; IL-8; MIP-1a; MCP-1; VEGF; fractalkine; kit ligand.
These may orchestrate movement singly or in combination. Cultured human mast cells express a broad repertoire of
chemokine receptors, which diminishes as cells mature, thus limiting mast cell movement after differentiation at a tissue site. Kit ligand is notable in that it is specific for mast cells in comparison to other leukocytes and is produced by airway cells. Mast cell migration into tissues depends on integrins and other adhesion molecules.12 Basophils express an array of chemokine receptors. Chemokines binding to CCR3 (such as RANTES and eotaxins) may be especially important.13,14 The multiplicity of chemoattractants predicts redundant recruiting pathways. Several chemoattractants also prime or activate one or both types of cell,14,15 enhancing their role in asthma pathogenesis beyond that of recruitment alone.
A C T I VAT I O N IgE-dependent activation Classic mast cell and basophil activation involves docking of allergens to IgE via FceRI expressed as an assemblage of subunits (abc2) in the plasma membrane. FceRIa expression is strongly influenced by the serum level of IgE itself.16 Aeroallergens with repeating epitopes attach to receptor achain-bound IgE, bridging receptors. Allergen-driven crosslinking initiates intracellular signaling characterized initially by phosphorylation of intracellular immunoreceptor tyrosine-based activation motif (ITAM) domains of receptor b- and c-chains. In turn, these recruit and activate nonreceptor tyrosine kinases, especially lyn, syk, and btk, which access pathways leading to exocytosis and synthesis of eicosanoids and cytokines. The b-chain is not essential in humans, but amplifies the signal. FceRI signals are damped by inhibitory receptors, such as FccRII and gp49, which possess intracellular immunoreceptor tyrosine-based inhibition motif (ITIM) domains.17 Phosphorylated ITIMs attract phosphatases, such as SHIP, which may inhibit FceRI signaling by dephosphorylating activated proteins in the signaling pathway. FccRII’s importance is particularly compelling.18 When IgG and IgE antibodies are raised against polyvalent antigen, “heterotypic” crosslinking of FccRII and FceRI by allergen bound to IgG and IgE inhibits signaling by FceRI. This may be a means by which “blocking antibodies” reduce atopic symptoms after allergen desensitization. IgE-independent activation Mast cells are activated by multiple nonimmunological inputs (Fig. 9.1). Physiological activators include: • • • • • • •
neuropeptides (e.g. substance P); purines (adenosine and ATP); byproducts of complement activation (e.g. C3a); eosinophil toxins; bacterial products (e.g. E. coli FimH); chemokines and lymphokines (e.g. IL-4); kit ligand.
Mast Cells and Basophils
INPUT
Antigen-specific/ “ADAPTIVE”: Ag IgG Ag IgE
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Histamine OUTPUT Heparin MHC II
Antigen nonspecific/ “INNATE”: Substance P C3a C5a
Proteases: Tryptases; tPA Chymase; Cathepsin G Gelatinases A & B Carboxypeptidase A Dipeptidylpeptidase I
E.coli FimH
Cytokines: IL-4, IL-13 IL-5, IL-6 TNF-α
Kit ligand
Chemokines: IL-8, MIP-1α
NGF ATP Adenosine
CD40L
Growth factors: bFGF; VEGF NGF Eicosanoids: PGD2, LTC4
IL-4 IL-5
MAST CELL Fig. 9.1. Mast cell inputs and outputs. This contains a partial listing of factors influencing human mast cell production of mediators, with postulated roles in acute and chronic airway inflammation in asthma. Inputs are divided into those directly involving immunoglobulin-mediated “adaptive” responses and those involving immunologically nonspecific “innate/natural” immunity.
These inputs are immunologically nonspecific and provide the means by which products of activation participate in neurogenic inflammation and innate host defense.19 They also augment responses to allergen-specific mast cell activation (see below). Thus, innate and adaptive responses are not mutually exclusive. C3a, an agent of innate immunity, is an example, for C3a receptor-null mice are protected from sequelae of airway allergen challenge.20 It should be noted that human mast cell subpopulations do not respond uniformly to all stimuli. For example, lung mast cells tend to be less responsive than skin mast cells to substance P.21
allergic asthmatics are primed,24 presumably by exposure to cytokines in vivo. Priming may serve to activate cells when (and only when) necessary to protect the host; in asthmatics, dysregulated priming may contribute to the pathology of allergic inflammation. FceRI-mediated activation can also be opposed by physiological influences, including adrenergic agonists and inhibitory receptors with ITIMs, as discussed above. Inhibition of activation is the basis of emerging strategies to combat allergic disease, including use of adenosine receptor antagonists, cytokine and chemokine antagonists, and activators of ITIM-containing coreceptors.25
PRIMING AND INHIBITION
M E D I AT O R S
Priming describes the response to a substance that does not release mediators by itself, but enhances the effect of another stimulus, such as crosslinked FceRI. In cultured human mast cells, priming occurs with allergic cytokines, such as IL-4 and IL-5,22 and also with kit ligand and adenosine.23 Mechanisms of priming may be stimulus-specific and affect mediator synthesis and release in different ways. Interactions between primers are potentially complex, and, in the case of IL-4 and -5, may involve autocrine stimulation. In basophils, priming in vitro is especially impressive with IL-3, which augments release of histamine in response to MCP-4 and IL-4 in response to allergen, and is enhanced by eotaxin.15 Basophils harvested from
Eicosanoids, histamine, and proteases Stimulated mast cells and basophils release an astonishing variety of stored and newly synthesized “mediators”. These include prostanoids (Chapter 22), leukotrienes (Chapter 23), proteases (Chapter 28), chemokines (Chapter 26), lymphokines (Chapter 27), growth factors (Chapter 29), and nitric oxide (Chapter 31), the properties and pharmacology of which are considered in other cited chapters and are not reviewed extensively here. The principal eicosanoids synthesized after stimulation are PGD2 (whose importance in allergic airway inflammation is demonstrated in PGD receptor-null mice26) and LTC4, which is the major target of 5-lipoxygenase inhibitors
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and leukotriene receptor antagonists. The major granuleassociated constituents of human mast cells are histamine, serine proteases, and proteoglycans (heparin and chondroitin). Histamine’s importance is clearer in upper airway allergic disease, because antihistamines tend to be more effective in treating rhinitis than asthma. Proteases are the most abundant proteins in secretory granules,27 though this may not be true of normal basophils. As noted, human mast cells vary in expression of tryptases and chymase. In atopic and asthmatic individuals, circulating cells resembling hybrids of basophils and mast cells may express one or both types of protease.10 Human tryptases are a polymorphic family of trypsin-like proteases implicated in asthma based on in-vitro degradation of bronchodilating peptides, enhancement of bronchial contraction, promotion of airway smooth muscle and subendothelial fibroblast growth and collagen production, and proinflammatory properties.28 Studies in sheep and guinea pigs suggest that inhibitors of tryptases reduce allergeninduced airway inflammation and bronchoconstriction.29 Chymase is postulated to play roles in asthma by stimulating gland secretion and promoting airway remodeling via production of angiotensin II and activation of matrix metalloproteinases.27,30,31 Apart from helping to package and stabilize proteases,32 the role of heparin and other proteoglycans is less clear. However, because heparin delivered into airways in pharmacological doses is anti-asthmatic, heparin released from stimulated mast cells may attenuate inflammatory effects of mediators released from mast cells and other effector cells.33 There is little evidence that human basophils express mediators not also present in mast cells. However, proteins of unknown function are recognized by monoclonal antibodies and may be basophil-specific.10,34 Cytokines and chemokines Activated human mast cells express cytokines similar to those of Th2 cells, including IL-4, -5, -13, -16 and TNF-a. In airways in allergic rhinitis or asthma, mast cells are a substantial fraction of leukocytes expressing these “Th2” cytokines.35 The relative importance of mast cells and basophils versus lymphocytes as a source of these cytokines is unclear. However, mast cells differ from lymphocytes in storing cytokines in secretory granules. In the case of TNF-a, release from mast cell stores is a critical determinant of survival from peritonitis.36 Asthmatic basophils produce prodigious amounts of IL-4 and IL-13 after antigen-specific activation.37 The importance of these cytokines is strongly supported by studies in genetically modified mice, which suggest that airway overproduction causes epithelial hypertrophy, mucus metaplasia, eosinophilic inflammation, and hyperresponsiveness. Sustained overproduction of allergic cytokines by mast cells and basophils may heighten and perpetuate asthmatic inflammation. Chemokines expressed and secreted by mast cells include IL-8 and MIP-1a, which may recruit effector leukocytes to sites of inflammation.38
Growth factors Known cellular growth factors expressed by mast cells include bFGF,39 VEGF,40 and nerve growth factor.41 Lessknown growth factors are tryptases, which are mitogens for airway fibroblasts, smooth muscle, and epithelial cells,42–44 and may influence endothelial cells to form vessels, thereby promoting angiogenesis.45 Mast cell IL-4 is fibrogenic when presented in the context of cell-to-cell contact.46 These mediators suggest mechanisms by which mast cell and basophil mediators promote airway remodeling in the setting of persistent airway inflammation.
R O L E S I N H O M E O S TA S I S Basophils and mast cells are presumed to exist for reasons other than to promote sneezing, itching, and wheezing. Lacking informative animal models or natural deficiency states, investigators have few direct clues regarding normal basophil function. However, compelling evidence of roles for mast cells has emerged from studies using mast celldeficient mice, which suggest critical roles in innate as well as adaptive immune responses, including defense against bacterial peritonitis and pneumonia.36,47 In similar mouse models,5 mast cells promote a variety of immunologically nonspecific forms of inflammation, (e.g. ozone-inflicted lung injury48), providing further evidence that they are activated by IgE-independent pathways.
ROLES IN ASTHMA Animal models Several experiments in mice support a role for mast cells in asthma-like allergic inflammation, including eosinophilia, hyperresponsiveness, and epithelial remodeling;8,49–52 see Chapter 8. Other studies suggest that IgE and mast cells do not make major contributions; see Hamelmann et al.53 and Galli54 for reviews. Together, these studies reveal that IgE and mast cell dependence vary with strain of mouse, choice of antigen, mode of sensitization and challenge, and choice of physiological end-points. Mast cell dependence is easier to detect in mice sensitized and challenged locally than systemically, using lower (more physiological) amounts of antigen, without adjuvants. Overall, murine studies suggest that mast cells and IgE are not essential for development of eosinophilic inflammation but do influence kinetics and magnitude of its expression. Humans Notwithstanding some studies questioning its importance in mice, IgE’s long-suspected contributions to human asthma are supported by trials using anti-IgE antibodies, which reduce circulating IgE to nearly undetectable levels and decrease symptoms and corticosteroid use in moderate, steroid-dependent asthmatics55 and rhinitics.56 Anti-IgE joins a growing list of antiasthmatic drugs
Mast Cells and Basophils
influencing mast cells, basophils, and their products. These include: • • • • • • •
corticosteroids (which decrease mast cell numbers;57 cromones; b-adrenergic agonists; theophylline; heparin (which inhibit degranulation); IL-4 antagonists (which inhibit priming);58 leukotriene pathway inhibitors.
Others, effective in animal models, include tryptase inhibitors.29 Interestingly, mast cell desensitization to chronic bagonists used by asthmatics without corticosteroids may contribute to clinical deterioration.59 Furthermore, corticosteroids may protect mast cells from desensitization.60 Pharmacological evidence of roles for mast cells correlates with studies indicating activation in allergic airway disease.1,61 Mast cells release histamine and tryptase into bronchi following allergen challenge.62 They appear degranulated in an asthmatic airway, even in stable disease,63,64 and the percentage of mast cells expressing cytokines IL-4, IL-5, and TNF-a increases.35 Mast cell and basophil numbers rise in asthmatic airways and correlate with hyperresponsiveness to acetylcholine.65 However, fewer basophils are seen in asthmatic bronchial biopsies than mast cells or eosinophils, and they are more prominent in cutaneous than airway late-phase reactions.66 Nonetheless, their arrival coincides with development of late-phase bronchoconstriction.67 Airway basophils are thought to be the source of the late histamine release after allergen exposure because this occurs without a corresponding peak in tryptase, which is more abundant in mast cells. More basophils appear in asthmatic sputum with latephase responses to allergen than in those without such responses, and their numbers correlate with methacholine responsiveness.11 This supports the hypothesis that mast cells and basophils are important in early- and late-phase responses, respectively. The further hypothesis that these cells promote chronic, persistent asthma is speculative. However, this notion is supported by the studies summarized above suggesting that proteases, cytokines, and growth factors from chronically activated mast cells and basophils promote airway remodeling and sustain Th2-assisted IgE production and allergic inflammation.
ROLES IN CHRONIC OBSTRUCTIVE P U L M O N A RY D I S E A S E Several lines of evidence suggest connections between mast cells and COPD.68 Elevated levels of histamine and tryptase in smokers’ lavage fluid69 imply that mast cells are activated by smoke. Studies in mice suggest that mast cells promote airway injury and epithelial remodeling in response to ozone,48 which could explain some human responses to smoke. Most mast cells close to human bronchial glands
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express chymase,70 which stimulates gland cell secretion30 and may promote sputum production in bronchitis. Conceivably, mast cells contribute to emphysematous lung destruction by secreting matrix-altering proteases, such as chymase, tryptases, gelatinases, plasminogen activator, and dipeptidyl peptidase I.27 On the other hand, there is little evidence of increased mast cell numbers in COPD to match observed increases in neutrophils, macrophages, and lymphocytes. Overall, evidence of mast cell involvement in asthma is more compelling, although further investigation of connections between mast cells and COPD is warranted.
S U M M A RY Mast cells protect from certain types of infection and injury by contributing to innate and adaptive immune responses. The homeostatic roles of basophils are less clear. Both cell types participate in the pathology of atopy and asthma by deploying an arsenal of inflammatory mediators, including proteases, growth factors, chemokines, and “Th2” cytokines. Mast cells, being permanent airway residents, are more likely to encounter aeroallergens first and to participate in acute responses. Basophils, because of the time lag of recruitment, may be more important in late-phase responses. Support is mounting for the hypothesis that both types of cell magnify the pathology of persistent inflammation in chronic asthma, including stimulation of IgE production, recruitment of eosinophils, and remodeling of epithelium.
REFERENCES 1. Kaliner M. Asthma and mast cell activation. J. Allergy Clin. Immunol. 1989; 83:510–20. 2. Schulman ES. The role of mast cells in inflammatory responses in the lung. Crit. Rev. Immunol. 1993; 13:35–70. 3. Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol. Rev. 1997; 77:1033–79. 4. Dvorak AM. Cell biology of the basophil. Int. Rev. Cytol. 1998; 180:87–236. 5. Galli SJ. Mast cells and basophils. Curr. Opin. Hematol. 2000; 7:32–9. 6. Li L, Krilis SA. Mast-cell growth and differentiation. Allergy 1999; 54:306–12. 7. Campbell E, Hogaboam C, Lincoln P, Lukacs NW. Stem cell factor-induced airway hyperreactivity in allergic and normal mice. Am. J. Pathol.1999; 154:1259–65. 8. Temann UA, Geba GP, Rankin JA, Flavell RA. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J. Exp. Med. 1998; 188:1307–20. 9. Irani AA, Schechter NM, Craig SS et al. Two types of human mast cells that have distinct neutral protease compositions. Proc. Natl Acad. Sci. USA 1986; 83:4464–8. 10. Li L, Li Y, Reddel SW et al. Identification of basophilic cells that express mast cell granule proteases in the peripheral blood of asthma, allergy, and drug-reactive patients. J. Immunol. 1998; 161:5079–86.
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11. Gauvreau GM, Lee JM, Watson RM et al. Increased numbers of both airway basophils and mast cells in sputum after allergen inhalation challenge of atopic asthmatics. Am. J. Respir. Crit. Care Med. 2000; 161:1473–8. 12. Hamawy MM, Mergenhagen SE, Siraganian RP. Adhesion molecules as regulators of mast-cell and basophil function. Immunol. Today 1994; 15:62–6. 13. Uguccioni M, Mackay CR, Ochensberger B et al. High expression of the chemokine receptor CCR3 in human blood basophils: role in activation by eotaxin, MCP-4, and other chemokines. J. Clin. Invest. 1997; 100:1137–43. 14. Ochensberger B, Tassera L, Bifrare D et al. Regulation of cytokine expression and leukotriene formation in human basophils by growth factors, chemokines and chemotactic agonists. Eur. J. Immunol. 1999; 29:11–22. 15. Devouassoux G, Metcalfe DD, Prussin C. Eotaxin potentiates antigen-dependent basophil IL-4 production. J. Immunol. 1999; 163:2877–82. 16. Saini SS, Klion AD, Holland SM et al. The relationship between serum IgE and surface levels of FceR on human leukocytes in various diseases: correlation of expression with FceRI on basophils but not on monocytes or eosinophils. J. Allergy Clin. Immunol. 2000; 106:514–20. 17. Ott VL, Cambier JC. Activating and inhibitory signaling in mast cells: new opportunities for therapeutic intervention? J. Allergy Clin. Immunol. 2000; 106:429–40. 18. TakaiT, Ono M, Hikida M et al.Augmented humoral and anaphylactic responses in FccRII-deficient mice. Nature 1996; 379:346–9. 19. Galli SJ, Wershil BK. The two faces of the mast cell. Nature 1996; 381:21–2. 20. Humbles AA, Lu B, Nilsson CA et al. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 2000; 406:998–1001. 21. Church MK, Lowman MA, Robinson C et al. Interaction of neuropeptides with human mast cells. Int.Arch.Allergy Immunol. 1989; 88:70–8. 22. Ochi H, De Jesus NH, Hsieh FH et al. IL-4 and -5 prime human mast cells for different profiles of IgE-dependent cytokine production. Proc. Natl Acad. Sci. USA 2000; 97:10509–13. 23. Marquardt DL. Adenosine. In: Barnes PJ, Grunstein MM, Leff AR, Woolcock AJ (eds), Asthma, pp. 585–92. Philadelphia: Lippincott-Raven, 1997. 24. Lie WJ, Knol EF, Mul FP et al. Basophils from patients with allergic asthma show a primed phenotype. J. Allergy Clin. Immunol. 1999; 104:1000–7. 25. Bingham CO, Austen KF. Mast-cell responses in the development of asthma. J. Allergy Clin. Immunol. 2000; 105:S527–34. 26. Matsuoka T, Hirata M,Tanaka H et al. Prostaglandin D2 as a mediator of allergic asthma. Science 2000; 287:2013–17. 27. Caughey GH (ed.). Mast Cell Proteases in Immunology and Biology. New York: Marcel Dekker, 1995. 28. Caughey GH. Of mites and men: trypsin-like proteases in the lungs. Am. J. Respir. Cell Mol. Biol. 1997; 16:621–8. 29. Clark JM, Abraham WM, Fishman CE et al. Tryptase inhibitors block allergen-induced airway and inflammatory responses in allergic sheep. Am. J. Resp. Crit. Care Med. 1995; 152:2076–83. 30. Sommerhoff CP, Caughey GH, Finkbeiner WE et al. Mast cell chymase: a potent secretagogue for airway gland serous cells. J. Immunol. 1989; 142:2450–6. 31. Fang KC, Raymond WW, Blount JL, Caughey GH. Dog mast cell a-chymase activates progelatinase B by cleaving the Phe88– Phe89 and Phe91–Glu92 bonds of the catalytic domain. J. Biol. Chem. 1997; 272:25628–35. 32. Humphries DE,Wong GW, Friend DS et al. Heparin is essential for the storage of specific granule proteases in mast cells. Nature 1999; 400:769–72. 33. Ahmed T, Syriste T, Mendelssohn R et al. Heparin prevents antigen-induced airway hyperresponsiveness. J. Appl. Physiol. 1994; 76:893–901.
34. McEuen AR, Buckley MG, Compton SJ, Walls AF. Development and characterization of a monoclonal antibody specific for human basophils and the identification of a unique secretory product of basophil activation. Lab. Invest. 1999; 79:27–38. 35. Bradding P, Roberts JA, Britten KM et al. Interleukin-4, -5, and -6 and tumor necrosis factor-a in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am. J. Respir. Cell Mol. Biol. 1994; 10:471–80. 36. Echtenacher B, Männel DN, Hültner L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 1996; 381:75–7. 37. Devouassoux G, Foster B, Scott LM et al. Frequency and characterization of antigen-specific IL-4- and IL-13-producing basophils and T cells in peripheral blood of healthy and asthmatic subjects. J. Allergy Clin. Immunol. 1999; 104:811–19. 38. Moller A, Lippert U, Lissmann D et al. Human mast cells produce IL-8. J. Immunol. 1993; 151:3261–6. 39. Powers MR, Qu Z, LaGesse PC et al. Expression of basic fibroblast growth factor in nasal polyps. Ann. Otol. Rhinol. Laryngol. 1998; 107:891–7. 40. Boesiger J, Tsai M, Maurer M et al. Mast cells can secrete vascular permeability factor/vascular endothelial cell growth factor and exhibit enhanced release after IgE-dependent upregulation of FceRI expression. J. Exp. Med. 1998; 188:1135–45. 41. Nilsson G, Forsberg-Nilsson K, Xiang Z et al. Human mast cells express functional TrkA and are a source of nerve growth factor. Eur. J. Immunol. 1997; 27:2295–301. 42. Ruoss SJ, Hartmann T, Caughey GH. Mast cell tryptase is a mitogen for cultured fibroblasts. J. Clin. Invest. 1991; 88:493–9. 43. Brown JK, Tyler CL, Jones CA et al. Tryptase, the dominant secretory granular protein in humans mast cells, is a potent mitogen for cultured dog tracheal smooth muscle cells. Am. J. Resp. Cell Mol. Biol. 1995; 13:227–36. 44. Cairns JA, Walls AF. Mast cell tryptase is a mitogen for epithelial cells: stimulation of IL-8 production and intercellular adhesion molecule-1 expression. J. Immunol. 1996; 156:275–83. 45. Coussens LM, Raymond WW, Bergers G et al. Inflammatory mast cells upregulate angiogenesis during squamous epithelial carcinogenesis. Genes Develop. 1999; 13:1382–97. 46. Trautmann A, Krohne G, Brocker EB, Klein CE. Human mast cells augment fibroblast proliferation by heterotypic cell–cell adhesion and action of IL-4. J. Immunol. 1998; 160:5053–7. 47. Malaviya R, Ikeda T, Ross E, Abraham SN. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNFa. Nature 1996; 381:77–80. 48. Longphre M, Zhang LY, Harkema JR, Kleeberger SR. Mast cells contribute to O3-induced epithelial damage and proliferation in nasal and bronchial airways of mice. J. Appl. Physiol. 1996; 80:1322–30. 49. Martin TR,Takeishi T, Katz HR et al. Mast cell activation enhances airway responsiveness to methacholine in the mouse. J. Clin. Invest. 1993; 91:1176–82. 50. Kung TT, Stelts D, Zurcher JA et al. Mast cells modulate allergic pulmonary eosinophilia in mice. Am. J. Respir. Cell Mol. Biol. 1995; 12:404–9. 51. Kobayashi T, Miura T, Haba T et al. An essential role of mast cells in the development of airway hyperresponsiveness in a murine asthma model. J. Immunol. 2000; 164:3855–61. 52. Williams CM, Galli SJ. Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice. J. Exp. Med. 2000; 192:455–62. 53. Hamelmann E, Tadeda K, Oshiba A, Gelfand EW. Role of IgE in the development of allergic airway inflammation and airway hyperresponsiveness: a murine model. Allergy 1999; 54:297–305. 54. Galli SJ. Complexity and redundancy in the pathogenesis of asthma: reassessing the roles of mast cells and T cells. J. Exp. Med. 1997; 186:343–7.
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55. Milgrom H, Fick RB, Su JQ et al.Treatment of allergic asthma with monoclonal anti-IgE antibody. N. Engl. J. Med. 1999; 341:1966–73. 56. Adelroth E, Rak S, Haahtela T et al. Recombinant humanized mAb-E25, an anti-IgE mAb, in birch pollen-induced seasonal allergic rhinitis. J. Allergy Clin. Immunol. 2000; 106:253–9. 57. Djukanovic R, Wilson JW, Britten KM et al. Quantitation of mast cells and eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry. Am. Rev. Respir. Dis. 1990; 142:863–71. 58. Borish LC, Nelson HS, Lanz MJ et al. Interleukin-4 receptor in moderate atopic asthma: a phase I/II randomized, placebocontrolled trial. Am.J.Respir.Crit.Care Med. 1999; 160:1816–23. 59. Swystun VA, Gordon JR, Davis EB et al. Mast cell tryptase release and asthmatic responses to allergen increase with regular use of salbutamol. J. Allergy Clin. Immunol. 2000; 106:57–64. 60. Chong LK, Drury DEJ, Dummer JF et al. Protection by dexamethasone of the functional desensitisation to b2-adrenoceptormediated responses in human lung mast cells. Br. J. Pharmacol. 1997; 121:717–22. 61. Bousquet J, Jeffery PK, Busse WW et al. Asthma: from bronchoconstriction to airways inflammation and remodeling. Am. J. Respir. Crit. Care Med. 2000; 161:1720–45. 62. Wenzel SE, Fowler A, Schwartz LB. Activation of pulmonary mast cells by bronchoalveolar allergen challenge: in vivo release of histamine and tryptase in atopic subjects with and without asthma. Am. Rev. Respir. Dis. 1988; 137:1002–8.
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63. Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am. Rev. Respir. Dis. 1989; 139:806–17. 64. Pesci A, Foresi A, Bertorelli G et al. Histochemical characteristics and degranulation of mast cells in epithelium and lamina propria of bronchial biopsies from asthmatic and normal subjects. Am. Rev. Respir. Dis. 1993; 147:684–9. 65. Koshino T, Arai Y, Miyamoto Y et al. Airway basophil and mast cell density in patients with bronchial asthma: relationship to bronchial hyperresponsiveness. J. Asthma 1996; 33:89–95. 66. Macfarlane AJ, Kon OM, Smith SJ et al. Basophils, eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase allergic reactions in the lung and skin. J. Allergy Clin. Immunol. 2000; 105:99–107. 67. Guo CB, Liu MC, Galli SJ, Bochner BS et al. Identification of IgEbearing cells in the late-phase response to antigen in the lung as basophils. Am. J. Respir. Cell Mol. Biol. 1994; 10:384–90. 68. Pesci A, Rossi GA, Bertorelli G et al. Mast cells in the airway lumen and bronchial mucosa of patients with chronic bronchitis. Am. J. Respir. Crit. Care Med. 1994; 149:1311–16. 69. Kalenderian R, Raju L, Roth W et al. Elevated histamine and tryptase levels in smokers’ bronchoalveolar lavage fluid: do lung mast cells contribute to smokers’ emphysema? Chest 1988; 94:119–23. 70. Matin R, Tam EK, Nadel JA, Caughey GH. Distribution of chymase-containing mast cells in human bronchi. J. Histochem. Cytochem. 1992; 40:781–6.
Macrophages
Chapter
10
Galen B. Toews Division of Pulmonary and Critical Care Medicine, University of Michigan, MI, USA
Macrophages are a family of mononuclear leukocytes that are widely distributed throughout most tissues.1 They vary considerably in phenotype depending on the local microenvironment.2 Macrophages within tissues play important homeostatic roles by regulating the local and systemic milieu through diverse plasma membrane receptors and secretory products. Macrophages secrete more than 100 substances. These secreted molecules: • • • • • •
induce cell movement; induce cell growth; induce cell death; influence cell differentiation; modify connective tissue structures; regulate blood vessel growth.
These activities contribute substantially to inflammatory and immune processes. Macrophages are crucial for: • early recognition of microbes, particulates, and immunogens; • the initiation and regulation of inflammatory responses and adaptive immunity; • the ingestion and killing of invading microbes.
ORIGIN AND DISTRIBUTION Monocyte/macrophages and granulocytes originate from a common bone marrow progenitor cell.3 Interleukin-3, granulocyte–macrophage colony stimulating factor (GM-CSF), and macrophage colony stimulating factor (M-CSF) stimulate a sequence of differentiation steps important in monocyte development by binding to specific receptors on progenitor cells. Cytokines released during acute inflammatory responses also regulate macrophage differentiation. Interleukin-1 and tumor necrosis factor (TNF-a) enhance M-CSF and GM-CSF production. Inhibitory inflammatory cytokines involved in macrophage differentiation include macrophage inflammatory protein-1a (MIP-1a) and transforming growth factor b (TGF-b).4
The bone marrow transit time from the first monocytic precursor to a mature monocyte is approximately 6 days; circulating human monocytes have a half-life of approximately 3 days.5 Alveolar macrophages (AM) are derived from blood monocytes and from proliferating macrophage precursors in the interstitium of the lung. Approximately 1% of the AM population in the normal lung is proliferating at any single time.6 AM have a life span of months and perhaps years.7 Cytokine receptors and ligands that regulate monocyte traffic into the uninflammed normal lung have not been defined.
RECOGNITION OF MICROBES AND MICROBIAL PRODUCTS Macrophages are a major cellular component of the innate immune system.8 The molecular and cellular processes of the innate immune response defend the host in the first minutes or hours after exposure to microbes. The recognition of microbes is problematic because of their molecular heterogeneity and their high mutation rates. The innate immune system uses a relatively small number of proteins encoded in the germ line to recognize a vast variety of molecular structures associated with microbes. The receptors recognize a few, highly conserved structures present in large groups of micro-organisms. The receptors recognize molecular patterns rather than particular structures and accordingly have been termed “pattern-recognition receptors” (PRR). The pathogen-associated molecular patterns (PAMP) recognized by PRR are chemically quite distinct, but share certain features. PAMPs are: • produced only by microbes and not eukaryote hosts; • essential for survival or pathogenicity of the microbe; • invariant structures shared by classes of pathogens. Characteristic PAMPs include lipopolysaccharides and teichoic acids, shared by Gram-negative and Gram-positive bacteria, respectively; mannans, conserved components of
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yeast cell walls; and the unmethylated CpG motif characteristic of bacterial but not mammalian DNA. PRRs expressed on macrophages include the mannose receptor, DEC205, CD14, scavenger receptors, and integrins. Recognition of pathogens results in the activation of various types of innate immune responses.11–17 Major advances have occurred in our understanding of innate immune cell recognition of a particular bacterial cell wall product, LPS. Bacterial cell wall components such as LPS are constantly shed into the environment during bacterial life and death. Recognition of LPS is initiated when LPS is bound by a serum protein, lipopolysaccharide binding protein (LBP), that efficiently transfers LPS to cell surface receptors.18 LBP catalyzes LPS interaction with CD14 and also serves as an opsonin for LPS-bearing particles. Alveolar macrophages, tissue macrophages and monocytes recognize LPS/LBP complexes via the CD14 receptor on the cell surface.19 CD14 is anchored in the outer leaflet of the cell membrane by a glycosylphosphatidyl inositol tail that is not involved in direct CD14-dependent signaling.20 CD14 interacts with a type I transmembrane receptor of the Toll/IL-1R family to transduce a signal following recognition of microbial products. Mammalian members of this family are named Toll-like receptors (TLR) because of their homology to the Drosophila Toll gene.21 Proteins in addition to TLR and CD14 are required for recognition of LPS. Optimal signaling efficiency of TLR family members depends on association of secreted proteins MD-1 or MD-2. It is likely that lipopolysaccharide recognition in mammals involves a complex with at least three components: CD14, TLR4, and MD-2.22–26 The mammalian TLR family contains at least ten family members. Different members of the Toll family may be specialized for the recognition of different classes of pathogens. TLR4 appears to be responsible for the detection of Gramnegative bacteria. Detection is mediated in this case by the recognition of LPS, a PAMP that represents a “molecular signature” of Gram-negative bacteria.19–23 TLR2 is involved in recognition of Gram-positive bacteria through the recognition of Gram-positive bacterial PAMPs lipoteichoic acid and peptidoglycan.22,23 TLR6 cooperates with TLR2 in detecting a subset of bacterial peptidoglycan.27 TLR9 detects bacteria DNA sequences containing unmethylated cytosine–guanosine dinucleotides (CpGs).28 Specificity of the other six mammalian Toll-like receptors is unknown but is the subject of intense investigation. It is very likely that other members of the mammalian TLR family will be specific for PAMPs characteristic of other classes of pathogens such as fungi (mannan, glucan) and mycobacteria (lipoarabinomannan, muramyldipeptide). Activation ofToll-like receptors initiates signal transduction pathways that initiate and amplify inflammatory responses in the lung and modulate adaptive immune responses. Molecules induced by PAMP–PRR interactions include: • signals that generate inflammatory responses, including TNF-a, IL-1, IL-6, interferon (IFN)a/b and chemokines;
• signals that function as costimulators of T cell activation, B7.1 and B7.2; • signals that regulate the differentiation of lymphocytes, including IL-4, IL-5, IL-10, IL-12, transforming growth factor (TGF)-b and IFN-c.10,21,29 Activation of Toll-like receptors can also contribute to the induction of programmed cell death.
G E N E R AT I O N O F I N F L A M M AT O RY RESPONSES Resident alveolar macrophages can effectively ingest and kill invading microbes if the bacterial burden is low and the microbe is minimally virulent.30,31 However, the recruitment of polymorphonuclear neutrophils (PMN) is essential for the effective containment of most virulent encapsulated bacteria within the lung and for the eventual clearance of these virulent microbes from the host. The generation of inflammation in the lower respiratory tract is a dynamic process that involves the coordinated expression of both pro- and anti-inflammatory cytokines. After the introduction of microbes or microbial products, TLR-mediated signals result in the production of TNF-a and IL-1b. TNF-a and IL-1b stimulate the expression of adhesion molecules on vascular endothelial cells. L-selectin on neutrophils interacts with its receptor/ligand (P- and Eselectin) on endothelial cells, leading to rolling. ICAM-1 expression is also induced on the surface of the endothelium; interactions between neutrophils and ICAM lead to firm adhesion.33,34 CXC chemokines and CC chemokines are also rapidly produced in macrophages following microbial stimuli.35 CXC chemokines produced include IL-8, (CXCL8), GROa, (CXCL1) and ENA-78 (CXCL5), all of which are major PMN chemoattractants36 (Table 10.1). Thus, immediately after the recognition of bacterial products in the alveolar environment, PMNs begin to accumulate. Macrophages also play a major role in amplifying the inflammatory response by stimulating cytokine production by cells that do not respond directly to bacterial products. Mononuclear phagocytes, neutrophils, and endothelial cells all produce CXC chemokines in response to LPS. Alternatively, airway and alveolar epithelial cells, pulmonary fibroblasts, and pleural mesothelial cells all produce IL-8 in response to specific host-derived signals such as TNF-a or IL-1.37–42 The importance of IL-1 and TNF-a as key cytokines in the initiation of this augmented inflammatory response is emphasized by the fact that all nucleated cells possess a functional receptor for IL-1 and TNF-a. Macrophages are also potent sources of bioactive lipids, which are important in inflammatory responses. Leukotriene synthesis is dependent on three sequential enzymes: cytosolic, phospholipase A (cPLA2), 5-lipoxygenase (5LO), and 5-LO-activating protein (FLAP). All three of these proteins co-localize at a single membrane site to form a macromolecular complex termed a metabolon. There is now
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Table 10.1. The CXC chemokine/receptor family
Systematic namea
Human ligand
Mouse ligandb
Chemokine receptor(s)
CXCL1 CXCL2 CXCL3 CXCL4 CXCL5 CXCL6 CXCL7 CXCL8 CXCL9 CXCL10 CXCL11 CXCL12 CXCL13 CXCL14 (CXCL15)
GRO-a/MGSA-a GRO-b/MGSA-b GRO-c/MGSA-c PF4 ENA-78 GCP-2 NAP-2 IL-8 Mig IP-10 I-TAC SDF-1a/b BLC/BCA-1 BRAK/bolekine Unknown
GRO/KC? GRO/KC? GRO/KC? PF4 LIX? Cka-3 Unknown Unknown Mig IP-10 Unknown SDF-1 BLC/BCA-1 BRAK Lungkine
CXCR2 CXCR1 CXCR2 CXCR2 Unknown CXCR2 CXCR1, CXCR2 CXCR2 CXCR1, CXCR2 CXCR3 CXCR3 CXCR3 CXCR4 CXCR5 Unknown Unknown
a b
A systematic name in parentheses means a human homolog has not been identified. A question mark indicates that the mouse ligand homolog listed may not correspond to the human ligand.
abundant evidence documenting that the nuclear envelope is the site at which this metabolon is assembled.43,44 The leukotriene synthetic pathway is initiated when cPLA2 translocates from the cytosol to the nuclear envelope following activation signals.45,46 Arachidonate is released from nuclear envelope phospholipids and is bound by FLAP, an integral nuclear envelope protein. FLAP facilitates processing by 5-LO.47 On activation, 5-LO also translocates from its resting locale(s) in the cytosol and/or nucleoplasm to the nuclear envelope where it catalyzes the initial steps in LT synthesis.47–49 LTs, thus synthesized, are capable of either entering the nucleus or being exported out of the cell.48 Monocytes release LTB4 and LTC4 after being exposed to nonimmunological stimuli or immunological stimuli.50 AMs produce a substantial excess of LTB4 compared to LTC4 after stimulation.51 LTB4 is a potent chemotactic factor for polymorphonuclear neutrophils and a weaker chemotactic factor for eosinophils. LTB4 accounts for the majority of neutrophil chemotactic activity elaborated by AMs immediately following stimulation.51,52 LTB4 also promotes adherence of inflammatory cells to the endothelium. Leukotrienes also play a permissive role in inflammation by promoting the synthesis by macrophages of TNF-a, IL-8, (CXCL8), GROa, (CXCL1), ENA-78, (CXCL5), and IL-6.53 An important implication of the metabolon concept is that the site of macromolecular assembly has evolved in a manner to best serve the needs of the cell. The observation that the LT metabolon is located within the nuclear envelope suggests that the autocrine actions of bioactive lipid mediators, including those potentially mediated within the
nucleus, may be of more importance than those paracrine actions that have been classically recognized. 5-LO metabolites are important modulators of mitogenesis, apoptosis, and the activation of various transcription factors.54–57 A soluble nuclear receptor for LTB4 provides additional support for such interactions; interestingly, this receptor is a member of a superfamily of transcription factors and its ligation induces gene transcription. Alternatively, reactive oxygen species, which are a byproduct of arachidonate 5lipoxygenation, could exert nuclear actions by activating transcription factors or otherwise modifying nuclear constituents.58–59 Monocytes exit the blood in inflamed tissues in response to specific chemotaxins. Monocyte recruitment is critically dependent on CC chemokines.29 Twenty-seven different CC chemokine ligands (CCL) have been described.60 Chemokines that act mainly on monocytes are located on a cluster on human chromosome 17q11.2. Important monocyte chemoattractant CC chemokines include MCP-1 (CCL2), MIP-1a (CCL3), MIP-1b (CCL4), and RANTES (CCL5) (Table 10.2). CC chemokines are produced by monocytes, alveolar macrophages, lymphocytes, neutrophils, epithelial cells, fibroblasts, smooth muscle cells, and endothelial cells.These cells produce chemokines in response to a variety of factors, including cigarette smoke, viruses, bacterial products, IL-1, TNF, C5a, LTB4, and interferons.61–74 Bronchial epithelial cells release monocyte chemotaxins in response to cigarette smoke.69 TNF-a and IL-1 are among the most potent stimuli for epithelial cell cytokine production. Macrophage stimulation of epithelial cells by TNF or IL-1 likely enhances and
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Table 10.2. The CC chemokine/receptor family
Systematic namea
Human ligand
Mouse ligandb
Chemokine receptor(s)
CCL1 CCL2 CCL3 CCL4 CCL5 (CCL6) CCL7 CCL8 (CCL9/10) CCL11 (CCL12) CCL13 CCL14 CCL15 CCL16 CCL17 CCL18 CCL19 CCL20 CCL21 CCL22 CCL23 CCL24 CCL25 CCL26 CCL27
I-309 MCP-1/MCAF MIP-1a/LD78a MIP-1b RANTES Unknown MCP-3 MCP-2 Unknown Eotaxin Unknown MCP-4 HCC-1 HCC-2/Lkn-1/MIP-1d HCC-4/LEC TARC DC-CK1/PARC AMAC-1 MIP-3b/ELC/exodus-3 MIP-3a/LARC/exodus-1 6Ckine/SLC/exodus-2 MDC/STCP-1 MPIF-1 MPIF-2/eotaxin-2 TECK Eotaxin CTACK/ILC
TCA-3/P500 JE? MIP-1a MIP-1b RANTES C10/MRP-1 MARC? MCP-2? MRP-2/CCF18/MIP-1c Eotaxin MCP-5 Unknown Unknown Unknown LCC-1 TARC Unknown MIP-3b/ELC/exodus-3 MIP-3a/LARC/exodus-1 6Ckine/SLC/exodus-2/TCA-4 ABCD-1 Unknown Unknown TECK Unknown ALP/CTACK/ILC ESkine
CCR8 CCR2 CCR1/CCR5 CCR5 CCR1/CCR3/CCR5 Unknown CCR1/CCR2/CCR3 CCR3 Unknown CCR3 CCR2 CCR2/CCR3 CCR1 CCR1/CCR3 CCR1 CCR4 Unknown CCR7 CCR6 CCR7 CCR4 CCR1 CCR3 CCR9 CCR3 CCR10
a b
A systematic name in parentheses means a human homolog has not been identified. A question mark indicates that the mouse ligand homolog listed may not correspond to the human ligand.
perpetuates the initial inflammatory response. Increased epithelial expression of MCP-1 has been observed by immunohistochemistry and biopsy specimens from patients with atopic asthma, and increased levels of this chemokine are also seen in BAL fluid of allergic asthmatics when compared with normal subjects.73,74 The biological effects of chemokines are mediated by seven transmembrane-domain receptors that are a subset of the G-protein-coupled receptor superfamily. Sixteen receptors have been identified. Redundancy and binding promiscuity exists between ligands and receptors (Tables 10.1 and 10.2). A single chemokine may bind to several receptors and a single chemokine receptor can transduce signals for several chemokines.60 Monocytes also respond to formyl peptides, C5a, and elastin fragments. In a murine model of cigarette smokeinduced emphysema, CC and CXC chemokines are undetectable but chemotactic extracellular matrix fragments, particularly elastin fragments, are present.75–77
T- C E L L - I N D E P E N D E N T M A C R O P H A G E A C T I VAT I O N The early nonantigen-specific activation of macrophages is one of the first events in the innate immune response and is often very effective in eliminating microbes. Innate immune macrophage activation fills a gap between microbial entry into the host and the development of antigen-specific immunity. Innate immune macrophage activation is a cytokine-mediated macrophage–NK cell interaction.78 Macrophages release IL-12 and TNF-a following microbial recognition; these cytokines induce NK cell IFN-c which primes macrophages for microbicidal activity.79–82 IL-12 is regulated by both positive and negative feedback mechanisms. IFN-c-activated macrophages produce much higher levels of IL-12. IL-10, a product of macrophages and other cell types, is a potent inhibitor of IL-12 production.83 Expression of IL-10 is delayed compared with expression of IL-12 in vivo. IL-10 is a critical
Macrophages
component of the host’s natural defense against excessive production of IL-12 and its pathological consequences.
M A C R O P H A G E S I N T H E I N I T I AT I O N O F IMMUNE RESPONSES The activation of T lymphocytes is a complex biological function that requires the participation of an antigenpresenting cell (APC). Most cell types cannot perform these functions; “professional antigen-presenting cells” (macrophages, dendritic cells, and B cells) are required. Antigen presentation involves the display of an antigenic epitope in association with an MHC molecule. Three additional molecular interactions are crucial to the interaction between an APC and a T lymphocyte: • adhesion molecules that promote the physical interaction between APC and T cells; • costimulatory molecules which are membrane-bound growth/differentiation molecules that produce T cell activation; • soluble molecules such as TNF-a and IL-1.84,85 Alveolar macrophages are ineffective in presenting antigen to T cells.86–88 AMs are less effective than monocytes in inducing proliferation of blood T lymphocytes to soluble recall antigens. AMs can, however, restimulate recently activated T cells effectively. AMs fail to activate CD4 T cells because of defective expression of B7 costimulatory cell surface molecules. AMs activated with IFN-c fail to express B7-1 or B7-2 antigens.89 Resident pulmonary AM actively suppresses T cell proliferation induced by antigens.86 Compelling evidence for the presence of active alveolar macrophage suppression in vivo exists. Although the potential value of such a steady-state downregulatory control mechanism within the lungs is self-evident, this suppressive activity is reversible in the face of a microbial antigen. Alveolar macrophage suppressive activity can be reversed via GM-CSF. Thus, microbial products (LPS) lessen the downregulatory tone of AMs by inducing GM-CSF production by macrophages and/or alveolar and airway epithelial cells.90 The mechanisms whereby particulate antigens and microbial agents induce T cell responses are poorly defined. The relative contribution to this process of macrophages and dendritic cells is uncertain. Dendritic cells are present in the airways and in the interstitium of the lower respiratory tract.91 Dendritic cells are clearly crucial for activating naive T cells for proliferation and clonal expansion. Monocytes are also stimulatory to T cell activation. Thus, inflammatory stimuli that recruit fresh monocytes to the lung might theoretically dilute the resident alveolar macrophage population with recruited monocytes and convert a normally immunosuppressive tissue milieu into one that is supportive of T cell activation.
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I N N AT E I M M U N E C O N T R O L O F ADAPTIVE IMMUNE RESPONSES Naive T lymphocytes can differentiate along different pathways to become distinct effector cells. The tissue microenvironment in which the specific immune response is generated crucially regulates this differentiation process via the secretion of specific cytokine signals (Fig. 10.1). IL-12 produced by macrophages during the early innate immune response and IFN-c induced by IL-12 create an environment in which antigen-specific CD4 and CD8 T cells are preferentially induced to differentiate into T1 cells that produce even higher levels of IFN-c.92–94 IL-4 is crucial to the development of T2 responses during the priming of naive T cells.95 The crucial cellular source of early IL-4 production is uncertain. Basophils, mast cells, cd cells, T2 lymphocytes, and an NK 1.1 CD4 CD8 T lymphocyte have all been reported to produce IL-4.96 The type of APC that presents the antigen may also be crucial. Dendritic cells (DC) preferentially activate T2 cells in certain circumstances.97 The mechanisms by which DCs favor the expression of T2 cells remains uncertain, but it may be related to the ability of DCs to secrete IL-1, a costimulator for T2 cells but not T1 cells, and to the absence of IFN-c production by dendritic cells which would inhibit the development of T2 cells. Differential expression of costimulatory molecules may also be crucial to this polarization process. B7.2 is constitutively expressed on dendritic cells and macrophages, whereas B7.1 is not.The outcome of B7.1 and B7.2 co-stimulation is different. B7.2 costimulates the production of IL-4 as well as IL-2 and IFN-c. Thus, after B7.2 costimulation an initial source of IL-4 is available. However, B7.2 costimulation provides only a moderate signal for T2 cell differentiation; additional signals are almost surely required to achieve high levels of IL-4 production.98,99 B7 costimulatory signals can be delivered by bystander APC in vitro with the same efficiency as the APC engaging the T cell receptor. Accordingly,T cell activation in vivo may occur with MHC-TCR engagement being provided by one APC, whereas costimulation is delivered by a second bystander APC-type.100 The tissue microenvironment in which the immune response is generated is crucial in determining the type and intensity of T lymphocyte responses. Cytokines secreted in the tissues where the antigen is deposited are also crucial for the maintenance and/or regulation of immune responses.
MACROPHAGE-DERIVED GROWTH FA C T O R S I N T I S S U E R E M O D E L I N G A N D R E PA I R Fibrotic changes occur in airways and the lower respiratory tract following certain injuries. Macrophages produce numerous growth factors for fibroblasts, including plateletderived growth factor (PDGF), transforming growth factors a and b (TGF-a,TGF-b), and insulin-like growth factor.101–106
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IL-10 Th1 cell
Macrophage IL-12 IFN-γ Bacteria Fungi Protozoa Viruses Helminths Allergens Superantigens
APC
NK cell
Bystander APC Costimulation
B7 CD28
Naive T-helper cell
γδ T cell
MHC/Peptide/TCR Density Antigen focusing Affinity B7.1, B7.2 TCR CD28
MHC B7-1,B7-2
Costimulation B7-2 IL-4 Dendritic cell DC subset State of differentiation
IL-4
Antigen focusing Basophil/mast cell Th2 cell
+ NK 1.1 CD4, CD8 T cells
Fig. 10.1. Innate immune control of adaptive immune response. The tissue microenvironment regulates adaptive immune responses. Dendritic cell (DC) migration and DC cell functional differentiation state are crucial determinants of immune priming. IgE on the surface of DCs may focus uptake and processing of other antigens. Density and affinity of antigens regulates differential signals following T cell receptor engagement. Costimulatory molecules influence T cell differentiation. Innate immune cell cytokines are the major regulators of T cell differentiation. Solid arrows indicate stimulators; broken arrows indicate inhibitor.
• PDGF induces fibroblast proliferation and collagen production. • The wound healing effects of PDGF are macrophagedependent in most models.106 • TGF-a stimulates the closure of wounds induced in cultures of type II alveolar epithelial cells in vitro. TGF-a also likely plays a role in epithelial cell repair of the lungs following injury.104,105 • TGF-b has important effects on the turnover of matrix proteins and the proliferation of fibroblasts.107 TGF-b activates genes that favor the production of matrix proteins. TGF-b also downregulates production of matrix metalloproteinases derived from PMNs and macrophages that digest matrix in the interstitium and alveolar spaces. In aggregate, these effects shift the balance in favor of matrix accumulation. GM-CSF has a protective effect on repair processes following bleomycin. This protective effect is mediated, in part, by GM-CSF induced production of PGE2 by pulmonary macrophages.108 PGE2 has crucial downregulatory effects on fibroblasts, including decreasing fibroblast proliferation and decreasing matrix produced by fibroblasts. Macrophages may also play critical roles in regulating angiogenesis, which is a central biological event in repair and remodeling. CXC chemokines such as IL-8 or ENA-78 that contain the sequence Glu-Leu-Arg (ELR motif) are potent angiogenic factors. In contrast, CXC chemokines that lack the ELR motif (platelet factor 4, IFN-c inducible
protein 10) behave as potent angiostatic factors. Non-ELRcontaining chemokines can inhibit angiogenic activity of both ELR-CXC chemokines and structurally unrelated macrophage-derived angiogenic factor bFGF.109
MACROPHAGES AND CHRONIC O B S T R U C T I V E P U L M O N A RY D I S E A S E A marked increase in the number of macrophages and neutrophils in the airways of both humans and experimental animals is the most consistent, early effect of exposure to cigarette smoke.110,111 Histological studies of bronchial biopsies and lung parenchyma obtained from cigarette smokers demonstrates a predominance of macrophages and CD8 T cells at sites of parenchymal destruction.112–114 The paucity of neutrophils in lung parenchyma and airway biopsies suggests neutrophils traffic rapidly from the blood into the airway lumen.112,113 The inflammatory process, once initiated, persists in ex-smokers.115,116 Surprisingly, the inflammatory responses persists in end-stage emphysema. Increased numbers of macrophages, CD8 and CD4 T lymphocytes, and neutrophils are noted in lungs from patients undergoing lung volume reduction surgery. Macrophages are likely to play an important role in initiating the neutrophilic inflammatory response in cigarette smokers. Macrophages may be activated by cigarette smoke and other inhaled particulates. Elevated levels of the CXC chemokines IL-8, (CXCL8), and GROa (CXCL1) are
Macrophages
noted in cigarette smokers. IL-8 (CXCL8) levels in sputum correlate with the magnitude of neutrophilic inflammation and with percentage predicted FEV1.117,118 LTB4 is increased in the sputum of patients with COPD; this potent neutrophilic chemoattractant likely participates in the generation of the neutrophilic inflammatory response.119 The inflammatory response in COPD has several distinguishing features: • Resident alveolar macrophages are activated upon exposure to cigarette smoke. • Neutrophils are rapidly recruited almost immediately after cigarette smoke exposure in response to macrophage and epithelial cell-derived chemokines and leukotrienes. • Macrophages and CD8 and CD4 T lymphocytes accumulate within days to weeks and continue to accumulate with time. • The abnormal accumulation of inflammatory cells persists throughout the disease process, even when the exciting agent, cigarette smoke, is removed.
MACROPHAGE PROTEINASES AND COPD Early changes of emphysema include subtle disruption of elastic fibers, bronchiolar and alveolar distortion, and the appearance of fenestrae. Destruction of the elastic framework leads to loss of the intra-alveolar septae and macroscopic appearance of spaces of more than one millimeter in diameter.120,121 This destructive process is accompanied by an increase in the mass of collagen, suggesting that active alveolar wall fibrosis occurs in the tissues which remain in otherwise emphysematous lungs.122,123 The dominant, working hypothesis to explain the pathogenesis of emphysema has postulated an imbalance between proteolytic enzymes and proteinase inhibitors in the lung, favoring an excess of proteinases, particularly elastases. This hypothesis postulates that cigarette smoke, macrophages, chemoattractants, neutrophils, elastases, and proteinase inhibitors interact with lung connective tissue, primarily elastin, to cause repeated destruction and synthesis of pulmonary matrix. Pulmonary macrophages may play an important role in this proteolytic process by releasing neutrophil chemotactic factors, which recruit neutrophils to the respiratory tract. Neutrophil elastase is believed to play an important role in COPD. Neutrophil elastase is one of the most potent elastases in the lung. Instillation of neutrophil elastase and proteinase 3 causes emphysema in animals.124–127 Neutrophils are recruited into the lungs of animals and generate detectable elastin fragments following exposure to cigarette smoke. Neutrophil elastase is also a potent mucus secretagogue.128,129 Macrophages also secrete potent proteinases. Human alveolar macrophages produce the cysteine (thiol) pro-
105
teinases, cathepsins B, H, L, and S.130 Cathepsins L and S have relatively indiscriminate substrate specificities that include elastin and other matrix components. Cysteine proteinases are involved in lung destruction in IL-13 and IFN-c transgenic mice.131,132 Pulmonary macrophages also produce matrix metalloproteinases (MMP). Studies of human emphysematous lung tissue have demonstrated the presence of several MMPs. A correlation between MMP-1 and MMP-9 and emphysema was noted when smokers with emphysema were compared to smokers without emphysema.133 Studies using transgenic and gene-targeted mice also lend support for the role of MMPs in emphysema. Transgenic mice overexpressing human MMP-1 in the lung develop airspace enlargement.134 Studies of MMP-12 knockout mice provide specific loss-offunction data that MMP-12 is importantly involved in the development of emphysema in response to cigarette smoke. Exposure of MMP-12 / mice to long-term cigarette smoke led to inflammatory cell recruitment followed by alveolar space enlargement similar to that seen in humans with emphysema. Mice deficient in MMP-12 (MMP-12 /) were protected from development of emphysema despite long-term smoke exposure.75 Interestingly, MMP-12 / mice failed to recruit monocytes into the lung in response to cigarette smoke. MMP-12 / monocytes could egress from the pulmonary vasculature in response to MCP-1 instillation. However, even in the presence of MMP-12 / macrophages, the lungs of mice exposed to cigarette smoke had no changes in the mean linear intercept in alveolar duct areas when compared to mice not exposed to smoke. These findings suggest that MMP-12 is expressed by resident alveolar macrophages after exposure to cigarette smoke. MMP-12 generates monocyte chemotaxins, likely fragments of elastin, which are responsible for the monocyte recruitment in response to smoke. Macrophage-mediated lung destruction after exposure to cigarette smoke is, at least in part, directly related to the presence of MMP-12, which is most likely required for direct degradation of lung tissue. The generation of chemotactic elastin fragments provides a positive feedback loop perpetuating macrophage accumulation in lung destruction.
MACROPHAGES IN ASTHMA Initiation of antigen-specific T2 immune responses Resident pulmonary alveolar macrophages actively suppress T cell proliferation induced by antigen or polyclonal stimuli.86 Changes occur within the local inductive milieu of the lung in patients with asthma. Alveolar macrophage suppression is reduced after exposure to allergens.135–137 Monocyte accumulation is a hallmark of post-challenge bronchial biopsies from asthmatics. The tissue microenvironment is a crucial regulator of specific immune response generation (Fig. 10.1). The presence of IgE on antigen-presenting cells likely promotes
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the uptake and processing of allergens and their eventual presentation to naive T cells. Dendritic cells express both FceRI and FceRII. These two receptors could function to capture allergen bound to allergen-specific IgE and thus focus the immune response through facilitated antigen presentation.138 Antigens also deliver signals via quantitative variation in ligand density on APC. Peptide/MHC class II complexes that interact strongly with the TCR favor T1 responses, whereas weak interactions result in the priming of T2 responses. The overall binding affinity can be varied by modifying the peptide, which results in different signals. The mechanisms by which signals delivered via the TCR control differentiation is uncertain; differential TCR aggregation may result in differential intracellular signals that favor distinct cytokine gene expression, or certain MHC/TCR interactions may favor differential coreceptor expression.139–140 Costimulatory molecules may direct the polarization of T cells into T1 or T2 cells. B7.2 provides only a moderate signal for T2 cell differentiation. Co-stimulatory signals may be delivered either by the APC that presents the antigen or by a bystander APC. Thus, macrophages may serve as bystander APC and influence DC-induced T cell proliferation.141 Soluble cytokines produced by cells of the innate immune response are likely the major regulators of T cell differentiation (see the section on innate immune control of adaptive immune responses). Macrophages in the effector phages of immune responses in asthma Macrophages are likely sources of cell-specific chemoattractants in patients with asthma. RANTES, (CCL5), and MIP1a, (CCL3) are chemotactic for macrophages, eosinophils, and basophils. MCP-1 (CCL1) is chemotactic for macrophages and basophils. IL-8 (CXCL8) is chemotactic for neutrophils, basophils, and to a lesser extent, eosinophils. Additionally, macrophage-released early cytokines likely induce epithelial cells and fibroblasts to release chemoattractants and growth factors (GM-CSF, IL8 (CXCL8), MCP-1 (CCL1), MCP-3 (CCL7), MCP-4 (CCL13), MIP-1a (CCL3), and RANTES (CCL9)) in patients with asthma.142–146 Leukotrienes are perhaps the best studied macrophageproduced mediators involved in the pathogenesis of asthma. The role of macrophage-derived leukotrienes remains uncertain. Cysteinyl leukotrienes (LTC4, D4, and E4) are minor products of AMs when compared with LTB4 production.51,147 This metabolic profile argues against a role for AMs in leukotriene overproduction in the lung. Alternatively, several features favor a role for AMs in leukotriene production. The cells are located on the airway surface, express plasma membrane IgE receptors, and secrete substantially more LTC4 than do PMNs. Cysteinyl leukotrienes are known to promote mucus hypersecretion, airway inflammation, and marked, prolonged contraction of smooth muscles in airways.
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graphically localized phospholipid hydrolysis. Biochem. J. 1996; 318:797–803. Woods J, Evans J, Ethier D et al. 5-lipoxygenase and 5-lipoxygenase activating protein are localized in the nuclear envelope of activated human leukocytes. J. Exp. Med. 1993; 178:1935–46. Woods J, Coffey M, Brock TG et al. 5-lipoxygenase is located in the euchromatin of the nucleus in resting human alveolar macrophages and translocated to the nuclear envelope upon cell activation. J. Clin. Invest. 1995; 95:2035–40. Brock TG, McNish RW, Peters-Golden M. Translocation and leukotriene synthetic capacity of nuclear 5-lipoxygenase in rat basophilic leukemia cells and alveolar macrophages. J. Biol. Chem. 1995; 270:21652–8. Ferreri NR, Howland WC, Spiegelberg HL. Release of leukotrienes C4 and B4 and prostaglandin E2 from human monocytes stimulated with aggregated IgG, IgA, and IgE. J. Immunol. 1986; 136:4188–93. Martin TR, Raugi G, Merritt TH et al. Relative contribution of leukotriene B4 to the neutrophil chemotactic activity produced by the resident human alveolar macrophage. J. Clin. Invest. 1987; 80:1114–24. Martin TR, Pistorese B, Chi E et al. Effect of leukotriene B4 in the human lung: recruitment of neutrophils into the alveolar spaces without a change in protein permeability. J. Clin. Invest. 1989; 84:1609–19. Phan S, McGarry B, Loeffler K et al. Regulation of macrophagederived fibroblast growth factor release by arachidonate metabolites. J. Leuk. Biol. 1987; 42(2):106–13. Beno D, Mullen J, Davis B. Lipoxygenase inhibitors block PDGFinduced mitogenesis: a MAPK-independent mechanism that blocks Fos and Egr. Am. J. Physiol. 1995; 268:C604–10. Avis I, Jett M, Boyle T et al. Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling. J. Clin. Invest. 1996; 97:806–13. Bonizzi G, Piette J, Merville M-P et al. Distinct signal transduction pathways mediate nuclear factors jb induction by IL-1b in epithelial and lymphoid cells. J. Immunol. 1997; 159:5264–72. Lee S, Felts K, Parry G et al. Inhibition of 5-lipoxygenase blocks IL-1b-induced vascular adhesion molecule-1 gene expression in human endothelial cells. J. Immunol. 1997; 158:3401–7. Los M, Schenk H, Hexel K et al. IL-2 gene expession and NF-jb activation through CD28 requires reactive oxygen production by 5-lipoxygenase. EMBO J. 1995; 14:3731–40. Devchand P, Keller H, Peters J et al. The PPRRa-leukotriene B4 pathway to inflammation control. Nature Lond. 1996; 384:39–43. Zlotnik A, Yoshi O. Chemokines: a new classification system and their role in immunity. Immunity 2000; 12:121–7. Christensen PJ, Rolfe MW, Standiford TJ et al. Characterization of the production of monocyte chemoattractant protein-1 (MCP1) and interleukin-8 (IL-8) in an allogeneic immune response. J. Immunol. 1993; 151:1205–13. Liebler JM, Kunkel SL, Burdick MD et al. The production of IL-8 and MCP-1 by peripheral blood monocytes: disparate responses to PHA and LPS. J. Immunol. 1994; 152:241–9. Standiford TJ, Kunkel SL, Lieber JM.The gene expression of MIP1a from human blood monocytes and alveolar macrophages is inhibited by IL-4. Am. J. Respir. Cell Mol. Biol. 1993; 9:192–8. Schall TJ, Jongstra J, Dyer BJ et al. A human T cell-specific molecule is a member of a new gene family. J. Immunol. 1988; 141:1018–25. Miller MD, Hata S, deWaal Malefyt R, Krangel MS. A novel polypeptide secreted by activated human T lymphocytes. J. Immunol. 1989; 143:2907–16. Kasama T, Strieter RM, Standiford TJ et al. Expression and regulation of human neutrophil-derived macrophages by inflammatory protein-1a. J. Exp. Med. 1993; 178:63–72. Paine R, Rolfe MW, Standiford TJ et al. MCP-1 expression by rat type II alveolar epithelial cells in primary culture. J. Immunol. 1993; 150:4561–70.
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68. Standiford TJ, Kunkel SL, Phan SH et al. Alveolar macrophagederived cytokines induce monocyte chemoattractant protein-1 expression from human pulmonary type II like epithelial cells. J. Biol. Chem. 1991; 266:9912–18. 69. Koyama S, Rennard SI, Leikauf GD et al. Bronchial epithelial cells release monocyte chemotactic activity in response to smoke and endotoxin. J. Immunol. 1991; 147:972–9. 70. Strieter RM, Wiggins R, Phan SH et al. Monocyte chemotactic protein gene expression by cytokine-treated human fibroblasts and endothelial cells. Biochem. Biophys. Res. Commun. 1989; 162:694–700. 71. Rolfe MW, Kunkel SL, Standiford TJ et al. Expression and regulation of human pulmonary fibroblast-derived monocyte chemotactic peptide (MCP-1). Am. J. Physiol. 1992; 263:L536–45. 72. Brown Z, Gerritsen ME, Carley WW et al. Chemokine gene expression and secretion by cytokine-activated human microvascular endothelial cells: differential regulation of MCP-1 and IL-8 in response to interferon-gamma. Am J. Pathol. 1994; 145:913–21. 73. Sousa AR, Lane SJ, Nakhosteen JA et al. Increased expression of the monocyte chemoattractant protein-1 in bronchial tissue from asthmatic subjects. Am. J. Respir. Cell Mol. Biol. 1994; 10:142–7. 74. Alan R, York T, Boyars M et al. Increased MCP-1, RANTES and MIP-1a in bronchoalveolar lavage fluid of asthmatic patients. Am. J. Respir. Crit. Care Med. 1996; 153:1398–404. 75. Hautamaki RD, Kobayashi DK, Senior RM et al. Macrophage elastase is required for cigarette smoke-induced emphysema in mice. Science 1997; 277:2002–4. 76. Senior RM, Griffin GL, Mecham RP. Chemotactic activity of elastin-derived peptides. J. Clin. Invest. 1980; 66:859–62. 77. Hunninghake GW, Davidson JM, Rennard S et al. Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema. Science 1981; 212:925–7. 78. Scott P, Trinchieri G. The role of natural killer cells in host parasite interactions. Curr. Opin. Immunol. 1995; 7:34–40. 79. D’Andrea A, Rengaraju M, Valiante NM et al. Production of natural killer cell stimulatory factor (NKSF/IL-12) by peripheral blood mononuclear cells. J. Exp. Med. 1992; 176:1387–98. 80. Macatonia SE, Hosken NA, Litton M et al. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4 T cells. J. Immunol. 1995; 154:5071–9. 81. Cleveland MG, Gorham JD, Murphy TL et al. Lipoteichoic acid preparations of Gram-positive bacteria induce interleukin-12 through a CD 14-independent pathway. J. Infect. Immun. 1996; 64:1906–12. 82. Klinman DM, Yi AK, Beaucage SL et al. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin-6, interleukin-12 and interferon gamma. Proc. Natl Acad. Sci. USA 1996; 93:2879–83. 83. D’ Andrea A, Aste-Amezaga M, Valiante NM et al. Interleukin-10 inhibits human lymphocyte IFN-c production by suppressing natural killer cell stimulatory factor/interleukin-12 synthesis in accessory cells. J. Exp. Med. 1993; 178:1041–8. 84. Allison JP. Interactions in T cell activation. Curr. Opin. Immunol. 1994; 6:414–9. 85. Thompson CB. Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell differentiation. Cell 1995; 81:979–82. 86. Toews GB, Vial WC, Dunn MM et al. The accessory cell function of human AMs in specific T cell proliferation. J. Immunol. 1984; 132:181–6. 87. Lipscomb MF, Lyons CR, Nunez G et al. Human AMs: HLA-DRpositive macrophages that are poor stimulators of a primary mixed leukocyte reaction. J. Immunol. 1986; 136:497–504. 88. Lyons CR, Ball EJ, Toews GB et al. Inability of human AMs to stimulate resting T cells correlates with decreased antigenspecific T cell–macrophage binding. J. Immunol. 1986; 137:1173–80.
89. Chelen CJ, Fang Y, Freeman GJ et al. Human AMs present antigen ineffectively due to defective expression of B7 costimulatory cell surface molecule. J. Clin. Invest. 1995; 95:1415–21. 90. Bilyk N, Holt PG. Inhibition of the immunosuppressive activity of resident pulmonary AMs by granulocyte macrophage colonystimulating factors. J. Exp. Med. 1993; 177:1773–7. 91. Toews GB. Pulmonary dendritic cells: sentinels of lung-associated lymphoid tissues. Am. J. Respir. Cell Mol. Biol. 1991; 4:204–5. 92. Trinchieri G. Interleukin-12: a pro-inflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu. Rev. Immunol. 1995; 13:251–76. 93. Trinchieri G, Gerosa F. Immunoregulation by interleukin-12. J. Leuk. Biol. 1996; 59:505–11. 94. Trinchieri G. Interleukin 12: a cytokine produced by antigenpresenting cells with immunoregulatory functions in the generation of T helper cells type 1 and cytotoxic lymphocytes. Blood 1994; 84:4008–27. 95. Harriman W, Volk H, Defraroux N et al. Immunoglobulin class switch recombination. Annu. Rev. Immunol. 1993; 11:361–84. 96. Seder RA, Mosmann TA. Differentiation of effector phenotypes of CD4 and CD8 T cells. In: Paul WE (ed.), Fundamental Immunology, pp. 879–908. Philadelphia: Lippencott Raven, 1999. 97. Hauser C, Snapper CM, O’Hara J et al. T helper cells grown with hapten-modified cultured Langerhans cells produce interleukin4 and stimulate IgE production by B cells. Eur. J. Immunol. 1989; 19:245–51. 98. Freeman GJ, Boussiotis VA, Anumanthan A et al. B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity 1995; 2:523–32. 99. Bluestone JA. New perspective of CD28-B7-mediated T cell costimulation. Immunity 1995; 2:555–9. 100. Ding L, Shevach EM. Activation of CD4 T cells by delivery of the B7 costimulatory signal on bystander antigenpresenting cells (trans-costimulation). Eur. J. Immunol. 1994; 24:859–66. 101. Mornex JF, Martinet Y,Yamauchi K et al. Spontaneous expression of the c-sis gene and release of a platelet-derived growth factorlike molecule by human alveolar macrophages. J. Clin. Invest. 1986; 78:61–6. 102. Assoian RK, Fleudelys GE, Stevensen HC et al. Expression and secretion of type beta transforming growth factor by activated human macrophages. Cell 1988; 53:285–93. 103. Henke C, Marineili W, Jessurn J et al. Macrophage production of basic fibroblast growth factor in the fibroproliferative disorder of alveolar fibrosis after lung injury. Am. J. Pathol. 1993; 143:1189–99. 104. Madtes DK, Klima LD, Rubenfeld G et al. Elevated transforming growth factor-alpha levels in bronchoalveolar lavage fluid in patients with acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 1998; 158:424–30. 105. Kheradmand F, Folkesson HG, Shum L et al. Transforming growth factor-alpha enhances alveolar epithelial cell repair in a new in vitro model. Am. J. Physiol. 1994; 267:L728–38. 106. Rose R, Raines EW, Bowen-Pope DF. The biology of plateletderived growth factor. Cell 1986; 46:155–69. 107. Moses HL, Yang EL, Pietenpol JA. TGFb stimulation and inhibition of cell proliferation: new mechanistic insights. Cell 1990; 63:245–7. 108. Moore BB, Coffey MJ, Christensen PJ et al. GM-CSF regulates bleomycin-induced pulmonary fibrosis via a prostaglandindependent mechanism. J. Immunol. 2000; 165:4032–9. 109. Strieter RM, Polverini PJ, Kunkel SL et al. The functional role of the ELR motif in CXC chemokine mediated angiogenesis. J. Biol. Chem. 1995; 270:27348–57. 110. Reynolds HY. Bronchoalveolar lavage. Am. Rev. Respir. Dis. 1987; 135:250–63.
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111. Mitchell RS, Sanford RE, Johnson JM et al. The morphologic features of the bronchi, bronchioles and alveoli in chronic airway obstruction: a clinicopathologic study. Am. Rev. Respir. Dis. 1976; 114:137–45. 112. Jeffrey PK. Structural and inflammatory changes in COPD: a comparison with asthma. Thorax 1998; 53:129–36. 113. Seatta M, Di Stefano A, Maestrelli P et al. Activated Tlymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am. Rev. Respir. Dis. 1993; 147: 301–6. 114. Seatta M, Di Stefano A, Turato G et al. CD8 T lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 157:822–6. 115. Turato G, Di Stefano A, Maestrelli P et al. Effect of smoking cessation on airway inflammation in chronic bronchitis. Am. J. Respir. Crit. Care Med. 1995; 152:1666–72. 116. Hogg JC. Pathology of COPD. Eur. J. Respir. Med. 2001; in press. 117. Keatings VM, Collins PD, Scott DM et al. Differences in interleukin-8 and tumor necrosis factor-a induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Respir. Crit. Care Med. 1996; 153:530–4. 118. Yamamoto C, Yoneda T, Yoshikawa M et al. Airway inflammation in COPD assessed by sputum levels of interleukin-8. Chest 1997; 112:505–10. 119. Barnes PJ. Mechanisms in COPD: differences from asthma. Chest 2000; 117:105–45. 120. Gilooly M, Lamb D. Microscopic emphysema in relation to age and smoking habit. Thorax 1993; 48:491–5. 121. Lamb D, McLean A, Gilooly M et al. Relation between distal airspace size, bronchial attachments, and lung function. Thorax 1993; 48:1012–17. 122. Lang MR, Fiaux GW, Gilooly M et al. Collagen content of alveolar wall tissue in emphysematous and non-emphysematous lungs. Thorax 1994; 49:319–26. 123. Wright JL. Emphysema: concepts under change – a pathologists’ perspective. Mod. Pathol. 1995; 8:873–80. 124. Damiano VV, Tsang A, Kucich U et al. Immunolocalization of elastase in human emphysematous lungs. J. Clin. Invest. 1986; 78:482–93. 125. Senior RM, Tegner H, Kuhn C et al. The induction of pulmonary emphysema induced with human leukocyte elastase. Am. Rev. Respir. Dis. 1977; 116:469–77. 126. Snider G, Lucey EC, Christiansen TG et al. Emphysema and bronchial secretory cell metaplasia induced in hamsters by human neutrophil products. Am. Rev. Respir. Dis. 1984; 129:155–60. 127. Kao RC, Wehner NG, Skubitz KM et al. Proteinase 3: a distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters. J. Clin. Invest. 1988; 82:1693. 128. Voynow JA, Rosenthal-Young L, Wang Y et al. Neutrophil elastase increases MUC5AC mRNA and protein expression in respiratory epithelial cells. Am. J. Physiol 1999; 276:L835–43. 129. Nadel JA. Role of neutrophil elastase in hypersecretion during COPD exacerbations, and proposed therapies. Chest 2000; 17:386S–9S. 130. Chapman HA, Munger JS, Shi G-P. The role of thiol proteases in tissue injury and remodeling. Am. J. Respir. Crit. Care Med. 1994; 150:S155–60.
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131. Wang Z, Zheng T, Zhu Z et al. Interferon gamma induction of pulmonary emphysema in the adult murine lung. J. Exp. Med. 2000; 192:1587–600. 132. Zheng T, Zhu Z, Wang Z et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinases and cathepsindependent emphysema. J. Clin. Invest. 2000; 106:1081–93. 133. Finlay GA, O’Driscoll LR, Russel KJ et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am. J. Respir. Crit. Care Med. 1997; 156:240–7. 134. D’Armiento J, Dalal SS, Okada Y et al. Collagenase expression in the lung of transgenic mice causes pulmonary emphysema. Cell 1992; 71:955–61. 135. Aubus P, Cosso B, Godard P et al. Decreased suppressor cell activity of AMs in bronchial asthma. Am. Rev. Respir. Dis. 1984; 130:875–8. 136. Spiteri MA, Knight RA, Jeremy JY et al. Alveolar macrophageinduced suppression of T cell hyperresponsiveness in asthma is reversed following allergen exposure in vitro. Eur. Respir. J. 1994; 7:1431–8. 137. Fischer HG, Frosch S, Reske K et al. Granulocyte-macrophage colony-stimulating factor activates macrophages derived from bone marrow cultures to synthesis of MHC class II molecules and to augment antigen presentation function. J. Immunol. 1988; 141:3882–8. 138. Van der Heijden FL, Van Neerven RJI, Van Katwijk et al. SerumIgE-facilitated allergen presentation in atopic disease. J. Immunol. 1993; 150:3643–50. 139. Racioppi L, Ronchese F, Matis LA et al. Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligandrelated differences in T cell receptor-dependent intracellular signaling. J. Exp. Med. 1993; 177:1047–60. 140. Pfeiffer C, Stein J, Southwood S et al. Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J. Exp. Med. 1995; 181:1569–74. 141. Ding L, Shevach EM. Activation of CD4 T cells by delivery of the B7 costimulatory signal on bystander antigen-presenting cells (transcostimulation). Eur. J. Immunol. 1994; 24:859–66. 142. Lamkhioued B et al. Monocyte chemoattractant protein (MCP)-4 expression in the airways of patients with asthma: induction in epithelial cells and mononuclear cells by proinflammatory cytokines. Am. J. Respir. Crit. Care Med. 2000; 165:2205–13. 143. Ying S et al. Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokines receptor 3 expression in bronchial biopsies from atopic and non-atopic (intrinsic) asthmatics. J. Immunol. 1999; 163:6321–9. 144. Gonzalo JA et al.The coordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness. J. Exp. Med. 1998; 188:157–67. 145. Elsner J et al. The CC chemokine antagonist Met-RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3. Eur. J. Immunol. 1997; 27:2892–8. 146. Dabbagh K et al. Local blockage of allergic airway hyperreactivity and inflammation by the poxvirus-derived pan-CC-chemokine inhibitor vCCI. J. Immunol. 2000; 165:3418–22. 147. Fels AO, Pawlowski NA, Cramer EB et al. Human AMs produce leukotriene B4. Proc. Natl Acad. Sci. USA 1982; 79:7866–70.
Chapter
Eosinophils
11
W. Bruce Davis Pulmonary and Critical Care Medicine, Medical College of Georgia, Augusta, GA, USA
Eosinophilic inflammation of the airways is common in patients with asthma. Increased eosinophils have been identified in the blood, sputum, BAL fluid, and bronchial wall of asthma patients, and their presence has been correlated with airways obstruction and bronchial hyperresponsiveness. Eosinophil effector functions, especially the release of toxic granule proteins and leukotrienes, are considered fundamental to the pathogenesis of asthma. Recent studies have focused on the complex cellular and molecular mechanisms that regulate the recruitment of eosinophils from the blood to the site of inflammation in the airways. In contrast to asthma, the eosinophil appears much less important in chronic obstructive pulmonary disease (COPD) and has received relatively little attention. This chapter provides a brief review of eosinophil structure and function and discusses the mounting evidence that eosinophils contribute to the pathogenesis of asthma.
MORPHOLOGY The human eosinophil is slightly larger than the neutrophil and has a mean diameter of 12–17 lm on blood smears.The cell is easily recognized by light microscopy owing to its bilobed nucleus and large intracytoplasmic eosin-staining granules. The electron microscopic appearance of the eosinophil is also unique owing to the geometric shape and staining properties of these granules (Fig. 11.1). Two other granule populations have been described. As eosinophils become activated and migrate into tissues, they can become harder to recognize by light microscopy. Such cells may have multiple nuclear lobes, and cytoplasmic vacuoles may develop as cells undergo degranulation.1
and the T lymphocyte products IL-3, IL-5, and granulocytemacrophage colony stimulating factor (GM-CSF).2 IL-9 is also important in the production of eosinophils.3 IL-5 (also called eosinophil differentiation factor) is the most specific of these cytokines and is responsible for the terminal differentiation of immature eosinophils. Overproduction of IL-5 in transgenic mice causes profound eosinophilia, and deletion of the IL-5 gene causes a marked decrease in eosinophils in blood and lungs after antigen challenge.4 Elevated levels of serum IL-5 are present in patients with blood eosinophilia, and elevations in IL-5 have been shown to precede the eosinophilia.5 IL-5 production is in turn regulated by other cytokines such as IL-2. The T-helper (CD4) lymphocytes which produce IL-3, IL-5, and GM-CSF are grouped into two subclasses, the Th1 and Th2 cells. These subclasses are relevant to the pathogenesis of eosinophilic diseases since certain diseases are associated with selective Th1 activation and others with Th2 activation, or a combination of Th1 and Th2 activation. There is extensive evidence that asthma results at least in part from Th2-mediated mechanisms.6 Following production in the bone marrow, IL-5 stimulates the release of eosinophils into the peripheral blood
EOSINOPHIL PRODUCTION AND LIFE CYCLE The eosinophil is a polymorphonuclear leukocyte produced in the bone marrow from totipotent stem cells. Eosinophil production is largely under the control of T lymphocytes
Fig. 11.1. Electron photomicrograph of a guinea pig eosinophil. Secondary granules (arrows) have an outer matrix surrounding a dense, geometric core. Scale bar 1 m. Reproduced from reference 22, with permission.
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where they normally comprise about 1–3% of blood leukocytes (fewer than 350 cells/mm3). Eosinophils remain in the peripheral circulation for an average of 8–18 hours, although their survival is prolonged in disease states.1 IL-3, IL-5, and GM-CSF prolong eosinophil survival by causing a delay in programmed cell death, or apoptosis.3 In contrast, adrenal corticosteroids decrease the number of circulating eosinophils by several mechanisms. Corticosteroids hasten apoptosis by overcoming the anti-apoptotic effect of IL-3, IL-5, and GM-CSF.7 Corticosteroids also suppress the transcription of genes for inflammatory mediators, including the genes for IL-3, IL-4, IL-5, GM-CSF, and chemokines.6 Adrenergic agents also decrease circulating eosinophils by a mechanism independent of corticosteroids.8 Following a short time in the peripheral circulation, eosinophils migrate into tissues throughout the body. Thus the eosinophil is primarily a tissue cell, not a blood cell, and the ratio of tissue to blood eosinophils in man has been estimated to be at least 100:1. Eosinophils tend to accumulate in tissues exposed to the environment, including gastrointestinal tract, lungs, and skin.9 The lifespan of eosinophils in the tissues is probably several days to weeks and can be prolonged by IL-3, IL-5, and GM-CSF. Eosinophils can also regulate their own survival through an autocrine pathway in which they produce these same cytokines.4 Tissue eosinophils eventually undergo apoptosis and ingestion as intact cells by macrophages.10
PROCESSES AND MECHANISMS Membrane receptors Receptors for several mediators are expressed by resting eosinophils, and additional membrane receptors are expressed following cell activation. Eosinophils express IgG receptors, principally FccRII receptors. Eosinophils also express receptors for IgA, IgE, and complement components. Adhesion molecules expressed on eosinophils include L-selectin, CD18, and very late activation antigen-4 (VLA4). Other membrane receptors include those for IL-2, HLADR, CD4, IL-3, GM-CSF, IL-5, chemokines, leukotriene B4, platelet activating factor, estrogen, and glucocorticoids.2 Migration The eosinophil migrates from the circulation into tissues by a series of interactions involving adhesion molecules and counter-ligands on eosinophils and endothelial cells. Although the process is similar for all leukocytes, adhesion molecules differ for each type of leukocyte. The cell first undergoes margination, whereby it moves from the center to the periphery of the blood vessel. Initial adherence by rolling of eosinophils along the endothelium is mediated by L-selectin on the eosinophil and its corresponding endothelial ligand and by P-selectin on endothelium and its ligand on the eosinophil. Adhesion is mediated by both b1 and b2 integrins on the surface of eosinophils. Eosinophils express a4b1 integrin (very late antigen 4, or
VLA4), which binds to vascular-cell adhesion molecule 1 (VCAM-1) on endothelium. Eosinophils also express the b2 integrins (CD18 family), which bind to intercellular adhesion molecule 1 (ICAM-1) on endothelium. There is constitutive expression of b1 and b2 integrins on the surface of resting eosinophils, and the level of expression can be increased by various chemoattractants. Likewise, ICAM-1 is induced by mediators, including IL1 and TNF-a, and VCAM-1 is induced by IL-4. Finally, upon exposure to chemoattractants, eosinophils undergo diapedesis between endothelial cells and migrate into the tissues.4 Chemotaxis Eosinophil chemotaxis is complex and is regulated by many mediators at different levels. Several substances possess true chemotactic activity, whereas others mainly prime eosinophil responses to chemoattractants. Many mediators attract eosinophils but are not selective. Chemotaxis is defined as the directed migration of cells towards an increasing gradient of chemoattractant molecules. The specific receptor expressed on the eosinophil determines which chemoattractants regulate movement and to what extent migration can be induced. Chemotactic factors for eosinophils include lipid mediators (PAF and LTB4), complement (C5a), bacterial-derived peptide (fMLP), histamine, and chemokines.4 Chemokines are lowmolecular-weight chemotactic cytokines (8–15 kDa) that regulate leukocyte migration (Table 11.1). The chemokines eotaxin-1 and eotaxin-2 are relatively specific chemoattractants for eosinophils.4 Most chemokines that attract eosinophils bind with the CCR-3 receptor on eosinophils,11 and several have been shown to be important in recruiting eosinophils to the airways in asthma. These include eotaxin1 and -2, regulated on activation, normal T expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1a, and monocyte chemotactic protein (MCP)-3. These chemokines are produced by epithelium, endothelium, macrophages, lymphocytes, and eosinophils, and have been shown to be present in cells and airway tissue in asthmatics.6 In contrast to the above chemoattractants, IL-5, IL-3, and GM-CSF prime eosinophil responses to chemoattractants.12 Table 11.1. Chemokines For human eosinophils
Eotaxin-1 Eotaxin-2 MCP-2 MCP-3 MCP-4
MDC RANTES MIP-1a
MCP, macrophage chemotactic protein; MDC, macrophagederived chemokine; RANTES, regulated on activation, normal T expressed and secreted; MIP, macrophage inflammatory protein
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Similar priming of eosinophils has been shown for neuropeptides, including substance P and neurokinin A. Priming results in an increase in chemokinetic or nondirectional movement, which can be distinguished in vitro from classical chemotaxis, or directed migration. IL-3, IL-5, and GMCSF prime eosinophils for enhanced chemotaxis in response to suboptimal concentrations of PAF, LTB4, C5a, and fMLP. IL-5 also primes eosinophils for enhanced response to chemokines (eotaxin, RANTES, and MCP-3). Possible mechanisms by which priming agents increase cellular responses to chemoattractants include promotion of receptor aggregation and colocalization of downstream signaling mediators.12 Eosinophil migration depends on the cooperative action of chemotactic and priming (chemokinetic) signals. The cooperation between IL-5 and eotaxin has been widely studied. Unlike most agents that affect eosinophil migration, only IL-5 and eotaxin are specific for eosinophils. Studies in animal models indicate that these agents act in synergy to control eosinophil migration under basal conditions and during allergy.12 Although IL-5 alone is probably not sufficient to induce eosinophilic infiltration, its importance has been repeatedly shown in clinical studies. For example, recombinant IL-5 given intranasally to normal volunteers is a potent inducer of nasal eosinophil infiltration.13 In
addition, direct instillation of IL-5 in human airways results in eosinophil recruitment and an increase in bronchial responsiveness.14 The late-phase response In asthmatics, inhaled allergens produce cross-linking of mast cell-bound IgE, triggering the immediate release of histamine and leukotrienes from mast cells. The resultant airway obstruction of this early-phase reaction usually resolves within an hour. The late-phase response begins in 3–4 hours, peaks at about 8 hours, and subsides in several days. Eosinophils are a prominent and essential component of the recruited inflammatory cells in the late-phase response. Moreover, chronic exposure to allergen (e.g., house dust mites) leads to chronic airway inflammation with eosinophils.4 Eosinophil recruitment to the airways in the late-phase response is thought to occur by two nonmutually exclusive pathways involving mast cells and helper T lymphocytes (Fig. 11.2). As a part of the early-phase reaction, the first pathway involves the cross-linking of IgE receptors on mast cells, leading to the generation of proinflammatory cytokines, including IL-1 and TNF-a. These cytokines direct epithelial cells and endothelial cells to produce eosinophil-directed cytokines (e.g. GM-CSF) and chemokines (e.g. eotaxin).
Transmigration
Eotaxins MCP 3, 4 RANTES
Adherence IL-5
IL-1β TNF-α IL-5 IL-4
ALLERGEN
Eotaxins MAST CELL
Endothelium
Allergen
Th2 cell
IL-5 IL-3 GM-CSF
Dendritic cell IL-4 Eosinophil IgE, VCAM-1 Degranulation
Fig. 11.2. Mechanism of eosinophilia during the late-phase asthmatic response. Allergen exposure activates two nonmutually exclusive pathways that lead to the influx of eosinophils into the airways. In the first pathway involving mast cells, allergen exposure causes crosslinking of IgE receptors leading to release of inflammatory mediators (e.g. histamine) and proinflammatory cytokines (IL-1b and TNF-a). These cytokines induce respiratory epithelial and endothelial cells to produce eosinophil-directed cytokines (IL-3, IL-5, and GM-CSF) and chemokines (e.g. eotaxin). In the second pathway, allergen is recognized by dendritic cells and presented to Th2 lymphocytes. Th2 cells produce IL-5 as well as IL-4, which induces IgE and vascular-cell adhesion molecule 1 (VCAM-1).
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Mast cells also produce IL-4 and IL-5. There is substantial evidence that the pathway involving mast cells is not required for the late-phase response. In contrast, the second pathway involving helper T lymphocytes is essential. Allergen is recognized and processed by antigen-presenting cells in the airways and then presented to Th2 cells. Th2 cells then release IL-5, IL-4, and IL-13. The latter two cytokines regulate IgE and VCAM-1 production. IL-5 provides the key signal for mobilization of eosinophils from the bone marrow and amplifies the chemoattractant potential of chemokines in the tissues. Once eosinophils are recruited to the tissues, eosinophils can amplify and perpetuate the inflammatory cascade by producing their own cytokines and chemokines.4 Degranulation and activation The eosinophil is only a weakly phagocytic cell. In contrast, exocytosis of granule contents like major basic protein on to the surface of antibody-coated targets appears to be a fundamental step in the killing of helminthic organisms.15 IgG, IgA, and IgE can cause degranulation of eosinophils.15 A variety of other mediators can cause degranulation, including IL-3, IL-5, GM-CSF, IL-1b, and platelet activating factor.5 Granule release is selective in that some stimuli cause release of certain granule products but not others. Eosinophil granule release can also be triggered by pharmacological agents, including calcium ionophore A23187, concanavalin A, phytohemaglutinin, levamisole, and compound 48/80.16 Eosinophil activation is frequently associated with degranulation. Blood and tissue eosinophils from patients with diseases like asthma are activated by several criteria when compared to resting eosinophils. Activated eosinophils show morphological changes, including increased number of nuclear lobes, vacuolization with loss of granules, and loss of electron density in the cores of the specific granules.5 The loss of granule contents probably explains the light density, or “hypodense” nature, of these cells which sediment to a different level on density gradient centrifugation compared with normal eosinophils. Whereas the blood from normal humans contains fewer than 10% eosinophils with density less than 1.082, patients with eosinophilia have marked increases in light-density eosinophils. In addition, numbers of light-density eosinophils directly correlate with the degree of peripheral blood eosinophilia.17 Compared with normal eosinophils, hypodense eosinophils express more IgG and complement receptors, produce more superoxide (O2), exhibit more killing of parasites, and generate more leukotriene C4 in response to stimuli.2 In addition to density gradient methods, activated eosinophils can be recognized by certain monoclonal antibodies. EG1 and EG2 are monoclonal antibodies to eosinophil cationic protein (ECP) that recognize granule (total) and secreted ECP, respectively. These antibodies are commonly used to recognize total and activated eosinophils in blood and tissue samples.18
Many substances can activate eosinophils, including TNF, PAF, and C5a. In addition, the same cytokines that stimulate eosinophil production (IL-3, IL-5, and GM-CSF) can produce activated, hypodense eosinophils.2 These cytokines in the presence of endothelial cells and fibroblasts can also prolong eosinophil survival and enhance effector functions. The movement of the eosinophil into tissues in disease states means that the cell has been acted upon by multiple mediators at different steps in its life cycle. For example, IL5, the most important and specific cytokine for eosinophils, is active in proliferation, chemotaxis, adhesion, degranulation, activation, and enhanced survival.2 Granule proteins Once the eosinophil arrives in the tissues in an activated state, it possesses several effector functions capable of inflicting injury to host tissues (Fig. 11.3). The ability to release granule proteins on to biologically relevant targets is of fundamental importance.19 The most important and wellstudied granule proteins are localized to the secondary (“specific”) granules. These proteins are highly charged and basic, which explains the avidity of the cell for acid, or eosin, stains. The four proteins are major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil derived neurotoxin (EDN), and eosinophil peroxidase (EPO). All four proteins have been isolated, sequenced, and cloned. MBP is a single polypeptide chain of 118 amino acid residues. It is arginine-rich and has a molecular weight of about 14,000 kDa. By electron microscopy, MBP is localized
Granule proteins MBP ECP EPO
Lipid mediators LTC4 PAF
Cytokines Chemokines
O2 radicals O2 H2O2 HOBr
Fig. 11.3. Effector functions of the eosinophil. Eosinophils release major basic protein from the granule core and eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase from the granule matrix. Lipid mediators include platelet activating factor (PAF) and leukotriene C4 (LTC4). Eosinophils produce reactive oxygen species (H2O2, hypohalous acids) and several cytokines and chemokines.
Eosinophils
to the core of the secondary granule. MBP is toxic to helminths, tumor cells, and mammalian cells. Moreover, the concentration of MBP required for toxicity is achieved in body fluids such as serum and sputum. MBP induces degranulation and histamine release from mast cells and basophils. MBP also neutralizes heparin.15 Eosinophil cationic protein (ECP) has a molecular weight of 21,000 kDa and is localized to the matrix of the secondary granules. It is a more potent toxin for helminthic organisms than MBP. It is also a neurotoxin and causes histamine release from mast cells. ECP binds heparin and neutralizes its anticoagulant activity. ECP also has weak ribonuclease activity.15 ECP damages target cells by causing voltageinsensitive, ion-nonselective toxic pores.4 ECP shares partial sequence homology with eosinophil-derived neurotoxin (EDN), a protein also localized to the matrix of the secondary granule. Compared with ECP, EDN is a much more potent ribonuclease.15 As its name implies, it is also a potent neurotoxin. Unlike ECP, EDN, even at high concentrations, does not damage airway epithelium.20 Eosinophil peroxidase (EPO) is distinct from neutrophil myeloperoxidase and is localized to the matrix of the secondary granule. It is extremely basic with an isoelectric point of about 10.8. EPO alone kills helminth larvae and causes damage to mammalian target cells. A much more potent system occurs when EPO is able to react with H2O2 and halide producing hypochlorous acid (HOCl) and hypobromous acid (HOBr). The complete enzyme system has been shown to kill micro-organisms, airway epithelial cells, and tumor cells and to cause histamine release from mast cells. It also regulates the levels of leukotrienes at sites of inflammation.15 In addition to the secondary granules, eosinophils contain two other types of granule.2 Primary granules are round, electron-dense structures seen early in eosinophil maturation. Charcot Leyden Crystal (CLC) protein, a lysophospholipase, is localized to primary granules that persist during cell maturation.21 A second type of granule contains arylsulfatase and acid phosphatase. Mediators In addition to granule proteins, eosinophils produce arachidonic acid products, especially LTC4 and PAF.5 The eosinophil is a metabolically active cell that produces reactive oxygen species under resting conditions and in response to stimuli. The cell undergoes respiratory burst activity producing superoxide (O2), H2O2, HOBr and HOCl, species capable of inflicting oxidant damage to micro-organisms, parasites, and host tissues.22 Eosinophils produce a variety of cytokines, including transforming growth factor (TGF) alpha and beta, tumor necrosis (TNF) alpha, IL-1, IL-3, IL-5, IL-6, and GM-CSF.5 Chemokines produced by eosinophils include eotaxin, macrophage inflammatory protein (MIP)-1a, and RANTES.11 Other mediators produced by eosinophils include collagenase, matrix metalloproteinases, elastase, histaminase, phospholipase D, and nonspecific esterase.5
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EOSINOPHILS IN ASTHMA There is a large body of information showing that eosinophils are an important component of the inflammatory response in asthma. Peripheral blood and sputum eosinophilia have long been associated with both allergic and nonallergic asthma. Autopsy studies have clearly identified eosinophils in the bronchial mucosa of patients dying of asthma. BAL studies in many types of asthma patients have documented the presence of increased BAL eosinophils. Finally, bronchial biopsy studies in asthma patients have confirmed the presence of airway eosinophils, including cells that appear to be activated, implying that eosinophils play a direct role in the pathogenesis of asthma. Thus, the presence of eosinophils has been amply documented in the blood, sputum, bronchial tissue at autopsy, BAL, and bronchial biopsies of asthmatic patients.23 Eosinophil granule proteins in the pathogenesis of asthma The evidence supporting a pathogenetic role for major basic protein (MBP) in asthma is compelling and is supported by several key observations.20 MBP induces the release of histamine from mast cells and basophils. MBP has been shown to cause desquamation and damage to airway epithelial cells in a variety of model systems. The epithelial damage is similar to the changes seen in autopsy studies of asthma patients, and MBP has been localized to the sites of the bronchial epithelial damage. MBP is present in the sputum of asthmatic patients, and the levels decline with treatment as patients show improvement in airway function. Moreover, the concentrations of MBP in asthmatic sputum samples are in the range required for cytotoxicity for airway epithelium. The mechanism by which MBP produces airway epithelial damage is thought to be direct membrane damage by MBP due to its charge properties. At sublethal concentrations, MBP also inhibits the ciliary activity of respiratory epithelial cells by causing a loss of axonemal ATPase and changes in chloride and water secretion. MBP has been shown to directly increase airway smooth muscle reactivity by causing dysfunction of vagal muscarinic receptors. MBP instilled into monkey lungs produces a transient bronchoconstriction. Finally, human and animal studies have shown that MBP increases bronchial reactivity by its action on respiratory epithelium.19,20 Although MBP is the most important granule protein in the pathogenesis of asthma, both eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) also appear to play important roles.20 ECP causes direct damage to airway epithelium and induces the release of histamine from mast cells. EPO alone is cytotoxic to airway epithelium and produces transient bronchoconstriction when instilled into the airway. The complete enzyme system (EPO + H2O2 + halide) produces greater damage to airway epithelial cells and induces histamine release from mast cells.
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Eosinophil mediators in the pathogenesis of asthma Eosinophils produce relatively large amounts of LTC4, which can cause airway smooth muscle contraction and increases in vascular permeability and mucus secretion. In addition, eosinophils produce PAF, which can cause smooth muscle contraction, increased vascular permeability, and further eosinophil recruitment.2 Other eosinophil mediators important in the pathogenesis of asthma include substance P, calcitonin-gene-related peptide, and neurokinin A.3 As the eosinophil is attracted to the airways, it is capable of producing a variety of cytokines and chemokines that can amplify the inflammatory response and lead to further eosinophil recruitment. Finally, the eosinophil may play an important role in airways remodeling in asthma by its production of fibrogenic growth factors, elastase, and metalloproteinases.24 Peripheral blood eosinophils Peripheral blood eosinophils undergo marked changes in numbers and state of activation as the asthmatic process evolves. Eosinophil counts tend to increase as asthma becomes more clinically manifest.25 The dynamic nature of peripheral blood eosinophil counts has been shown in bronchial provocation studies. For example, following allergen challenge, there may be a transient decrease in eosinophils at 6 hours post-challenge followed by a progressive eosinophilia up to 24 hours postchallenge. The eosinopenia is probably explained by recruitment of eosinophils into the airways. The post-challenge eosinophilia occurs only in those patients who manifest a late-phase asthmatic response and correlates with the magnitude of this response as well as the basal level of airway responsiveness.26 Not surprisingly, hypodense eosinophils are present in the blood of asthma patients,17 and these hypodense eosinophils have been shown to produce greater amounts of LTC4 than normodense eosinophils. Moreover, bronchial provocation with antigens increases the percentage of hypodense eosinophils in the peripheral blood of asthmatics who develop both an early and late asthmatic response.27 Increases in serum levels of ECP in asthma have been shown in response to exacerbations during the pollen season and in response to bronchial provocation, implying that blood eosinophils undergo degranulation in response to these allergens.26 Finally, important clinical observations have been made concerning the relationship between blood eosinophil numbers and markers of asthma disease activity. For example, total eosinophil counts in the blood of asthmatic patients show an inverse correlation with indices of airways function; i.e. higher eosinophil counts correlate with worsening airways obstruction.25 Subsequent studies in asthma patients have shown a direct correlation between peripheral blood eosinophil counts and bronchial hyperreactivity.20 Bronchoalveolar lavage (BAL) studies Compared with blood studies, BAL provides a more direct method for studying the role of eosinophils in asthma. A
large number of studies have documented the presence of increased BAL eosinophils in both allergic and nonallergic asthmatic patients compared with normal controls.28 These BAL studies have also provided insights into the pathogenetic role of eosinophils in asthma. BAL eosinophil counts have been shown to correlate with symptoms, decreases in FEV1, and increased bronchial hyperreactivity.28 In late-phase asthmatic reactions induced by bronchial provocation, BAL eosinophils have been shown to remain elevated up to 96 hours post-challenge. In late-phase asthmatic reactions, BAL eosinophils have been associated with elevated ECP/albumin ratios and with ultrastructural evidence for loss of core material from eosinophils.20 These studies suggest that eosinophils degranulate during the latephase asthmatic response. Additional studies of the late-phase asthmatic response have shown correlations between: • BAL eosinophils and histamine levels; • BAL eosinophils and sloughing of airway epithelial cells; • BAL eosinophils and vascular permeability as assessed by BAL albumin.20 BAL fluid concentrations of MBP are higher in asthmatic patients who are symptomatic, and the MBP concentrations correlate with indices of airway responsiveness and with numbers of epithelial cells recovered in the BAL fluid.29 Further evidence for eosinophil degranulation is provided by studies that show increases in BAL fluid ECP and EDN.28 BAL fluid ECP levels have been shown to correlate with clinical scores of asthma severity.23 Eosinophil-directed cytokines and chemokines have been measured in the BAL fluid of asthmatic patients.30 For example, BAL concentrations of IL-5 are higher in asthma patients than in patients with other types of lung disease not associated with eosinophils.31 Segmental challenge of airways with allergen increases the BAL concentration of IL-5, which correlates directly with the degree of airway eosinophilia.32 BAL cells from asthma patients have increased levels of mRNA for IL-3, IL-4, 1L-5, and GMCSF compared to cells from normal controls.33 Finally, increased levels of RANTES, MIP-1a, and MCP-1 have been measured in the BAL fluid of asthmatics 4 hours after airway challenge with antigen. At 4 hours, there was a positive correlation between RANTES concentration and numbers of BAL eosinophils.34 Bronchial biopsy studies of airway eosinophils Bronchial biopsy studies have provided an improved understanding of airway inflammation that is not possible with BAL alone. It is possible to monitor the recruitment and function of inflammatory cells, production of mediators and cytokines, and expression of genes that control synthesis of proinflammatory proteins or influence the remodeling process. Several studies have shown that eosinophils are a prominent component of the inflammatory changes seen in
Eosinophils
bronchial biopsy specimens of asthmatics, even in patients with mild asthma.24 Eosinophils, including activated cells, are seen both in the epithelium and in the submucosa.23 Eosinophil numbers measured by bronchial biopsy correlate with disease severity and with bronchial hyperresponsiveness and are an important means of assessing the response to various asthma treatments.24 Several studies have measured the cytokine and chemokine profile in bronchial biopsies. In general, these studies have documented the presence of cytokines and chemokines that promote eosinophil recruitment. For example, there is an increased expression of IL-4 and IL-13 (cytokines that direct the vascular adhesion of eosinophils) in both atopic and nonatopic asthmatics.35 Other bronchial biopsy studies have shown that epithelial cells, endothelial cells, and macrophages are the primary sources of eotaxin1, eotaxin-2, RANTES, and monocyte chemotactic proteins 3 and 4. Moreover, significant correlations were shown between the degree of eosinophil staining for EG2 and the concentration of eotaxin.6
E O S I N O P H I L S A N D T H E PAT H O G E N E S I S OF COPD The airways in chronic bronchitis and COPD are markedly inflammed. BAL studies usually show increased macrophages and neutrophils. Bronchial biopsy studies of these patients show a predominant mononuclear cell infiltrate consisting of lymphocytes (especially CD8+ cells), plasma cells, and macrophages. Neutrophils are usually scant in the absence of infection.36 In contrast to asthma, eosinophils seem to be a minor component of the inflammatory response in chronic bronchitis and COPD. There are, however, notable exceptions to this general observation. For example, one study reported increased eosinophils in bronchial biopsies of subjects with chronic bronchitis without evidence of respiratory tract infection.37 The airway eosinophils in these patients were not degranulated. In another study of nonatopic patients with chronic bronchitis, eosinophils were increased 30-fold in patients during exacerbation compared with subjects examined under baseline conditions. Activated eosinophils (EG2+ cells) in the bronchial biopsy samples and increased sputum eosinophils were found in the chronic bronchitis patients with exacerbation.38 It is not clear what role eosinophils play in these selected patients, and most BAL and bronchial biopsy studies of COPD patients do not report significant increases in eosinophils.36
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mediators, including the genes for IL-3, IL-5, GM-CSF, and various chemokines. They also inhibit the cytokinedependent survival of eosinophils. Despite their proven efficacy in asthma, glucocorticoids have long-term side-effects and do not consistently control eosinophilic inflammation in the airways.39 Other asthma medications currently in use also have effects on eosinophils.4 The 5-lipoxygenase inhibitors block the synthesis of leukotrienes B4, C4, D4, and E4. These drugs decrease the recruitment of eosinophils in the late-phase asthmatic response. The leukotriene receptor antagonists (e.g. zafirlukast) inhibit smooth muscle contraction and vascular permeability in the airways and have been shown to improve lung function in asthmatics. Cromolyn and nedocromil inhibit eosinophil effector functions, including antibody-dependent cellular cytotoxicity. Phosphodiesterase inhibitors increase intracellular cAMP, thereby inhibiting cell signaling and activation of eosinophils. Chronic eosinophilic inflammation in the airways should be controlled by targeting IL-5. This review has emphasized the pivotal role of this cytokine in eosinophil function and eosinophilic recruitment to the airways. A recent study in patients with mild asthma showed that a monoclonal antibody to IL-5 was effective in decreasing eosinophils in blood and sputum in response to inhaled allergen. Despite the inhibition of eosinophils, the study showed no effect on the allergen-induced late-phase asthmatic response or on bronchial hyperresponsiveness.40 The study is surprising and suggests that this obvious therapeutic strategy may not be effective. The findings also provide a strong challenge to the importance of eosinophils in asthma. Treatment with a recombinant humanized monoclonal antibody against IgE (rhuMAB-E25) has been shown to be effective in patients with moderate to severe allergic asthma.41 This agent attenuates the early-phase and late-phase asthmatic responses and suppresses the influx of eosinophils into the airways as assessed by sputum analysis.42 Several other therapeutic agents currently in development have the potential to improve asthma, at least in part, by their effects on eosinophils.4 Inhibition of eosinophil chemotaxis by inhibitors and antagonists of chemokine receptor 3 (CCR-3) would seem to be very promising. Another approach is the inhibition of eosinophil adhesion by agents that block selectins, the CD18-ICAM pathway, or the VLA4-VCAM-1 pathway. Other proposed strategies that may affect eosinophil function in asthma include:
THERAPY OF EOSINOPHILIC I N F L A M M AT I O N I N A S T H M A
• inhibition of IL-4 by soluble IL-4 receptor; • use of DNA vaccines to downregulate Th2-mediated responses; • the use of IL-12 to shift to Th1 immunity.
Glucocorticoids, oral or inhaled, are the most effective agents for reducing eosinophils in the airways.4 They suppress the transcription of several genes for inflammatory
Finally, other agents under development include lidocaine, sulfonylurea-receptor inhibitors, and phosphodiesterase IV inhibitors.
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REFERENCES 1. Spry CJF. Eosinophils: A Comprehensive Review, and Guide to the Scientific and Medical Literature. Oxford: Oxford University Press, 1988. 2. Weller PF. The immunobiology of eosinophils. N. Engl. J. Med. 1991; 324:1110–18. 3. Kay AB. Allergy and allergic diseases [first of two parts]. N. Engl. J. Med. 2001; 344:30–7. 4. Rothenberg ME. Eosinophilia. N. Engl. J. Med. 1998; 338:1592–600. 5. Allen JN, Davis WB. Eosinophils. In: Crystal RG, West JB (eds), The Lung: Scientific Foundations, 2nd edn, pp. 905–15. Philadelphia: Raven, 1997. 6. Busse WW, Lemanske R. Advances in immunology: asthma. N. Engl. J. Med. 2001; 344:350–62. 7. Wallen N, Kita H, Weiler D, Gleich GJ. Glucocorticoids inhibit cytokine-mediated eosinophil survival. J. Immunol. 1991; 147:3490–5. 8. Beeson PB, Bass DA. The eosinophil. In: Major Problems in Internal Medicine. Philadelphia: WB Saunders, 1977. 9. Slifman NR, Adolphson CR, Gleich GJ. Eosinophils: biochemical and cellular aspects. In: Middleton E, Reed CE, Ellis EF, Adkinson NF, Yunginger JW (eds), Allergy: Principles and Practice, pp. 179–205. St Louis: CV Mosby, 1988. 10. Stern M, Meagher L, Savill J, Haslett C. Apoptosis in human eosinophils: programmed cell death in the eosinophil leads to phagocytosis by macrophages and is modulated by IL-5. J. Immunol. 1992; 148:3543–9. 11. Nickel R, Beck LA, Stellato C, Schleimer RP. Chemokines and allergic disease. J. Allergy Clin. Immunol. 1999; 104:723–42. 12. Simson L, Foster PS. Chemokine and cytokine cooperativity: eosinophil migration in the asthmatic response. Immunol. Cell. Biol. 2000; 78:415–22. 13. Terada N, Konno A,Tada H et al.The effect of recombinant human interleukin-5 on eosinophil accumulation in human nasal mucosa. J. Allergy Clin. Immunol. 1992; 90:160–8. 14. Shi H-Z, Xiao C-Q, Zhong D. Effect of inhaled interleukin-5 on airway hyperreactivity and eosinophilia in asthmatics. Am. J. Respir. Crit. Care Med. 1998; 157:204–9. 15. Gleich GJ, Adolphson CR. Eosinophils. In: Crystal RG, West JB (eds), The Lung: Scientific Foundations, pp. 581–90. New York: Raven, 1991. 16. Gleich GJ, Adolphson CR. The eosinophilic leukocyte: structure and function. Adv. Immunol. 1986; 39:177–253. 17. Fukuda T, Dunnette SL, Reed CE et al. Increased numbers of hypodense eosinophils in the blood of patients with bronchial asthma. Am. Rev. Respir. Dis. 1985; 132:981–5. 18. Jeffery PK, Laitinen A, Venge P. Biopsy markers of airway inflammation and remodelling. Respir. Med. 2000; 94:S9–15. 19. Gleich GJ, Adolphson CR, Leiferman KM. The biology of the eosinophilic leukocyte. Annu. Rev. Med. 1993; 44:85–101. 20. Gleich GJ. The eosinophil and bronchial asthma: current understanding. J. Allergy Clin. Immunol. 1990; 85:422–36. 21. Dvorak AM, Letourneau L, Login GR, Weller PF, Ackerman SJ. Ultrastructural localization of the Charcot–Leyden crystal protein (lysophospholipase) to a distinct crystalloid-free granule population in mature human eosinophils. Blood 1988; 72:150–8. 22. Davis WB, Husney RM, Mohammed BS et al. Activation and deactivation of guinea pig peritoneal eosinophils during chronic polymyxin B stimulation. J. Leuk. Biol. 1989; 45:147–54. 23. Bousquet J, Chanez P, Lacoste JY et al. Eosinophilic inflammation in asthma. N. Engl. J. Med. 1990; 323:1033–9.
24. Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM. Asthma: From bronchoconstriction to airways inflammation and remodeling. Am. J. Respir. Crit. Care Med. 2000; 161:1720–45. 25. Horn BR, Robin ED, Theodore J, Van Kessel A. Total eosinophil counts in the management of bronchial asthma. N. Engl. J. Med. 1975; 292:1152–5. 26. Djukanovic R, Roche WR, Wilson JW et al. Mucosal inflammation in asthma. Am. Rev. Respir. Dis. 1990; 142:434–57. 27. Frick WE, Sedgwick JB, Busse WW. The appearance of hypodense eosinophils in antigen-dependent late phase asthma. Am. Rev. Respir. Dis. 1989; 139:1401–6. 28. Smith DL, Deshazo RD. Bronchoalveolar lavage in asthma: an update and perspective. Am. Rev. Respir. Dis. 1993; 148:523–32. 29. Wardlaw AJ, Dunnette S, Gleich GJ, Collins JV, Kay AB. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Am. Rev. Respir. Dis. 1988; 137:62–9. 30. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54:825–57. 31. Walker C, Bauer W, Braun RK et al. Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia. Am. J. Respir. Crit. Care Med. 1994; 150:1038–48. 32. Sedgwick JB, Calhoun WJ, Gleich GJ et al. Immediate and late airway response of allergic rhinitis patients to segmental antigen challenge: characterization of eosinophil and mast cell mediators. Am. Rev. Respir. Dis. 1991; 144:1274–81. 33. Robinson DS, Hamid Q, Ying S et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 1992; 326:298–304. 34. Holgate ST, Body KS, Janezic A et al. Release of RANTES, MIP1 alpha, and MCP-1 into asthmatic airways following endobronchial allergen challenge. Am. J. Respir. Crit. Care Med. 1997; 156:1377–83. 35. Humbert M, Durham SR, Kimmit P et al. Elevated expression of messenger ribonucleic acid encoding IL-13 in the bronchial mucosa of atopic and nonatopic subjects with asthma. J. Allergy Clin. Immunol. 1997; 99:657–65. 36. Jeffery PK. Structural and inflammatory changes in COPD: a comparison with asthma. Thorax 1998; 53:129–36. 37. Lacoste J, Bousquet J, Chanez P et al. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 1993; 92:537–48. 38. Saetta M, Stefano AD, Maestrelli P et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am. J. Respir. Crit. Care Med. 1994; 150:1646–52. 39. Louis R, Lau LCK, Bron AO et al. The relationship between airways inflammation and asthma severity. Am. J. Respir. Crit. Care Med. 2000; 161:9–16. 40. Leckie MJ, ten Brinke A, Khan J et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet 2000; 356:2144–8. 41. Milgrom H, Fick RB, Su JQ et al.Treatment of allergic asthma with monoclonal anti-IgE antibody. N. Engl. J. Med. 1999; 341:1966–73. 42. Fahy JV, Fleming HE, Wong HH et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am. J. Respir. Crit. Care Med. 1997; 155:1828–34.
Chapter
Lymphocytes
12
Carlo Agostini, Marina Saetta, and Gianpietro Semenzato Department of Clinical and Experimental Medicine, University of Padova, Padua, Italy
It is essential that the pulmonary immune system, which is constantly exposed to pathogens within inhaled air, can correctly determine whether an antigenic molecule represents a hazard. This is of crucial importance since, under normal conditions, most infectious agents or foreign antigenic materials do not signal to the host and may be processed without requiring an inflammatory response. Only if the infectious or antigenic burden becomes dangerous, will pulmonary accessory cells process and expose the antigen to T lymphocytes. These release chemokines and cytokines and hence trigger the generation of antigenspecific B and T cells in the secondary lymphoid tissues or within the alveolar spaces.1 Antigen-specific lung lymphocytes have evolved a number of effector mechanisms to respond to foreign antigens, ranging from direct cytotoxicity mechanisms to secretion of lymphokines that have the ability to activate themselves or other pulmonary immunocompetent cells. This chapter reviews current concepts on the recruitment, homing, and activity of lymphocytes in the lower respiratory tract, paying particular attention to the activity pattern shown by lung T cells in response to immunological challenge. Much information on the role of lymphocytes in the lung derives from study of the interstitial lung diseases and will be referenced. The relevant abnormalities detected in B, T and natural killer cells in asthma and COPD are discussed in the final section of the chapter.
T H E B R O N C H U S - A S S O C I AT E D LY M P H O I D T I S S U E Human lymphocytes are functionally compartmentalized in the lung according to their specific properties and discrete functions. The great majority of organized lymphoid tissue is represented by the so-called bronchus-associated lymphoid tissue (BALT) and lymph nodes that receive drainage from the nose or lung.2 Lymphoid follicles are located throughout the bronchial tree as far down as the small bronchioles and consist of B cell germinal centers surrounded by T cells, macrophages, and dendritic cells. In pulmonary
follicles, naive B and T cells continuously traffic until they respond to their cognate antigen and differentiate into memory and effector lymphocytes. In this respect, contiguity is crucial between the respiratory epithelium and lymphoid follicles because it allows antigens to pass across the epithelial barrier and to contact cells with antigen-presenting capacity. Unwanted antigens induce clonal expansion of intraalveolar precursor effector cells and migration of memory lymphocytes, leading to a local accumulation and differentiation of antigen-specific T and B cells with effector specializations (immunoglobulin secretion, cytotoxic activity, delayed-type hypersensitivity response, immunoregulatory activity, etc.). We can assume that lymphocytes traffic continuously throughout the two functionally distinct lymphoid compartments of the lung: BALT tissue where antigens first enter the system and initiate an immune response, and the remainder of the lung parenchyma where differentiated memory T and B cells, that have developed in the secondary follicles, travel to interact with inciting antigens. The increase in pulmonary memory T cells after antigen challenge can be the consequence of either local proliferation or migration from BALT and lymph nodes draining the pulmonary parenchyma. It is likely that both these functions are mediated by the interaction of lymphocytes with accessory cells, including dendritic cells.3 In fact, pulmonary intraepithelial and interstitial T cells can recognize antigens with high efficiency when presented by “professional” major histocompatibility complex (MHC) class II dendritic cells (see later). As observed in other epithelial systems, pulmonary dendritic cells can capture and transfer antigens from the airway epithelium to BALT and draining lymph nodes. Here, after antigen presentation and activation, resting T cells can proliferate, and the repertoire of adhesive and homing receptors necessary for their migration to lung parenchyma is up-modulated.
T A N D N AT U R A L K I L L E R C E L L S T cells account for the great majority of lung lymphocytes that can be retrieved in the respiratory tract of normal
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individuals.4 They are located within the airways, alveolar epithelium, and interstitium. Fewer than 1 106 lymphocytes are usually recovered from normal bronchoalveolar lavage (BAL); they are generally CD45R0 T “memory” cells which coexpress the a/b T-cell receptor (TCR). By contrast, only a few normal lung cells (about 5%) stain with the monoclonal antibody TCRd1 that recognizes a common epitope of the d chain apparently expressed by all TCR c/d cells. In healthy non-smoking individuals, both CD4 helper-related and CD8 cytotoxic/suppressor-related cells are present in approximately the same proportions as in the peripheral blood.5 As in the other tissues, pulmonary CD4 and CD8 molecules are functionally associated with the TCR and represent the structures that are involved in cell–cell adhesion and in signal transduction during T cell activation. Most functions shown by lung T cells are mediated by the in-situ release of biological response modifiers.6 After antigenic activation, pulmonary CD4 lymphocytes acquire the capacity to produce a broad repertoire of cytokines (see below). These molecules act as critical mediators of cell functions and cell to cell communication by influencing many physiological cell properties. These include proliferation, differentiation, and activation of other immunocompetent cells, chemotaxis and connective tissue metabolism. As in other organs, lymphokine-producing CD4 Thelper (Th) cells can be subdivided into two types, called Th1 and Th2, based on the lymphokine production pattern. Th1 cells secrete IL-2, IFN-c and TNF-b; Th2 lymphocytes produce IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, and IL-17. Both cell types produce GM-CSF and IL-3. The two subpopulations differ from one another in their function. In fact, Th1 lymphocytes elicit a delayed-type hypersensitivity reaction and help in IgG synthesis, but they inhibit cytokine release by Th2 lymphocytes and IgE synthesis through the release of IFN-c. In contrast, Th2 cells release IL-10 that inhibits the proliferative activity of Th1 lymphocytes. The respiratory mucosa is also equipped with CD8 cells that can undergo activation whenever challenged by foreign antigens. In particular, during conditions resembling host invasion, the pulmonary microenvironment may be infiltrated by cytotoxic T lymphocytes (CTL) that recognize target cells via the CD3–Ti complex and require the expression of major histocompatibility complex (MHC)-gene products on targets. There are also unrestricted cytotoxic T cells that may lyse certain tumor and viral infected targets without prior sensitization. CTLs resident in the respiratory mucosa play a central role in antiviral immunity and are also essential for the defense mechanism against tumors. While the majority of peripheral blood cytotoxic cells are large granular lymphocytes with natural killer (NK) activity that bear CD16 and lack expression of the CD3/TCR, few CD3/CD16 cells are present in the pulmonary microenvironment. The number and the functional activity of CD3/CD16 NK cells may increase during some viral infections of the pulmonary microenvironment with the introduction of locally released cytokines, including IL-2 and IL-15.
Under normal conditions, the majority of lung T cells are relatively hyporesponsive and become functional only after undergoing an activation process.5 However, T cells may proliferate in response to mitogens, such as phytohemoagglutinin and concanavalin A, and in a mixed lymphocyte reaction. In pathological conditions they strictly cooperate with pulmonary accessory cells in the process of antigenic recognition. Following activation, several accessory and adhesion molecules are expressed on the surface of pulmonary T lymphocytes.7 Antigen-dependent activation increases the expression of CD2, CD18, CD29, CD38, CD44, CD45RO, CD54, and CD58, class II MHC antigens, and VLA determinants on the cell surface of pulmonary T cells. These structures have been involved in nonantigen-specific homing of primed T cells to the secondary lymphoid tissues, in the process of T cell activation and in the localization of T cells to the sites of inflammation. The compartmentalization of T cells involves the interaction of homing receptors on the surface of “virgin” lymphocytes (CD44, LFA-1, and very late activation (VLA) antigens) to organ-specific endothelial molecules (known as vascular adressin) of the secondary lung lymphoid tissues. The conversion of naive CD45RA T cells to memory pulmonary CD45RO T cells coincides with the increase in the surface expression of adhesion structures (2- to 5-fold). In turn, CD45RO T cells express high levels of accessory molecules (CD2, LFA-1, LFA-3, VLA, and CD44) and acquire the ability to selectively localize within the pulmonary parenchyma via the expression of activated T-cell-specific chemokine receptors (CXCR3).8
C Y T O K I N E S M A I N LY P R O D U C E D B Y T LY M P H O C Y T E S The effectiveness of the lung immune system is dependent on the ordered differentiation of the lymphocyte subpopulations that acquire functional capabilities under antigenic challenge. Furthermore, networks of interacting cytokines are responsible for controlling the state of activation of all local immunocompetent cells. This section focuses on the pattern of cytokines produced by T cells within the respiratory tract (see also Chapter 28). Interleukin-2 Actively released by pulmonary Th1 cells, the role of IL-2 in the pulmonary immune system is to expand activated T cell populations; its receptor is formed by three different chains: a (CD25), b (CD122), and c (CD132). IL-2 acts as a local growth factor for T lymphocytes infiltrating lung tissues of patients exhibiting hypersensitivity reactions. This Th1 cytokine is also involved in the regulation of immunoglobulin production and in the enhancement of the potential capabilities of pulmonary cytotoxic T lymphocytes (CTL). The range of lung cells that IL-2 targets is broader than was originally appreciated. Since some alveolar macrophages (AM) normally express b/c IL-2R at low density,
Lymphocytes
and considering that the addition of IL-2 to activated AMs increases GM-CSF expression, it is believed that IL-2 may play a role in the activation of some functional capabilities of activated AMs. The presence of binding sites for IL-2 is also demonstrated on human lung fibroblasts. Addition of IL-2 to fibroblasts leads to an enhanced expression of the gene coding for the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2), which is involved in fibrosis through the regulation of profibrotic cytokine generation and extracellular matrix. IL-2 may thus serve to integrate fibroblasts and tissue macrophages into a coordinated response initiated by Th1 lymphocytes. Interleukin-4 This lymphokine, released by most cell types (including Th2 cells, eosinophils, and mast cells), is a cofactor for the proliferation of fibroblasts.9 Inducing the expression of class II major histocompatibility complex antigens on the surface membrane of accessory cells, it acts in synergism with IL-2 in stimulating the growth of T cells. The IL-4/IL-13 axis is also involved in the triggering and maintaining of the recruitment, homing, and activation of inflammatory cells during remodeling of the airways.10 Finally, IL-4 induces the release of chemokines from human bronchial epithelial cell, including IL-8/CXCL8. This effect is thought to be of particular importance in attracting neutrophils and monocytes to sites of inflammation. Interleukin-9 This is a multifunctional cytokine produced by activated Th2 cells in vitro and during Th2-like T cell responses in vivo. Data obtained in an animal model indicate that IL-9 promotes inflammation and airway hyperresponsiveness.11 Lung expression of IL-9 in transgenic mice causes massive airway inflammation with eosinophils and lymphocytes as the predominant infiltrating cell types. An additional striking finding is the presence of increased numbers of mast cells within the airway epithelium. Other impressive pathological changes in the airways are epithelial cell hypertrophy associated with the accumulation of mucus-like material within nonciliated cells, and increased subepithelial deposition of collagen. Since human fibroblasts express the IL-9 receptor, it is believed that this cytokine is involved in fibroproliferative responses. Interleukin-10 This has anti-inflammatory and immunoregulatory properties. It inhibits proinflammatory cytokine and chemokine production in addition to blocking T cell responses to specific antigens.12 It acts primarily through inhibition of costimulatory properties of macrophages. Activated Th2 cells may represent a source for this molecule in the pulmonary microenvironment. Nonetheless, Th0 CD4 T cells, CD8 T cells, LPS-activated macrophages, and mast cells may also produce IL-10.13 This cytokine shows inhibitory activity on the release of IFN-c and IL-2 by lung Th1 cells, stimulates mast cell growth, and regulates
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the accessory function of antigen-presenting cells resident in the pulmonary microenvironment. In the lung, IL-10 has inhibitory activity on local immune response, via its capability for inhibiting dendritic T cell interactions. IL-10 can reduce the production of biologically active IL-12 in lung dendritic cells. Furthermore, since IL10 may induce differentiation of naive Th cells into Th2 cells, this cytokine has been implicated in the pathogenesis of pulmonary allergic disorders. There are also data on the involvement of IL-10 in the regulation of fibroproliferative responses in the lung. This cytokine also partially inhibits Tcell-mediated immune responses taking place during some hypersensitivity reactions.14 Interleukin-13 IL-13 is expressed in activated Th0 cells, Th1-like cells, Th2-like cells, and T-cells expressing CD8.15 This molecule strongly inhibits cytokine secretion induced by LPS in monocyte–macrophages. In particular, the pulmonary release of IL-1, IL-6,TNF-a, and IL-8 may be influenced by the local release of IL-13. IL-13 is also a monocyte chemoattractant. IL-13 is believed to be involved in the regulation of pulmonary inflammatory responses. During lung inflammation, endogenous IL-13 regulates nuclear factor (NF)-jB activation and related cytokine/chemokine generation, determining the intensity of the inflammatory response. IL13 also has effects on fibrogenesis, it increases adhesion molecule and inflammatory cytokine expression in human lung fibroblasts and is critical for recruitment of inflammatory cells. IL-13 serves as an important mediator of Th2mediated inflammation in the lung,16 in particular in allergic asthma where dysregulation of IL-13 production has been found to be a key factor.17 The pulmonary expression of IL-13 in transgenic mice causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, airway fibrosis, eotaxin/CCL15 production, airways obstruction, and nonspecific airways hyperresponsiveness. Interleukin-17 This cytokine is produced by CD4 T cells. It can induce expression of IL-6 and IL-8 on target cells. It enhances the surface expression of ICAM-1 on fibroblasts. Recent evidence also indicates that IL-17 can link the activation of certain T-lymphocytes to recruitment and activation of airway neutrophils.18 IL-17-induced neutrophil recruitment is mediated via induced CXC chemokine release through steroid-sensitive mechanisms and is modulated by the release of endogenous tachykinins. These effects of IL-17 are potentiated by other proinflammatory cytokines such as IL-1b and TNF-a. Taken together, these findings suggest the potential role of this cytokine in T-cell-driven lung inflammation. Interferon-c This typical Th1 cytokine is a key factor in the events that favor local immune responses in the lung.19 IFN-c enhances
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the accessory function of AMs, increases the cytotoxic function of lung macrophages and lymphocytes, and regulates the secretion of an array of lymphokines, cytokines, and chemokines into the surrounding microenvironment. In addition, this Th1 cytokine activates pulmonary macrophages to phagocytose intracellular pathogens. IFN-c is typically expressed by T cells infiltrating the lung during most interstitial lung diseases, including sarcoidosis, hypersensitivity pneumonitis, tuberculosis, and HIV infection. There are data suggesting that monocyte–macrophages may represent a cell source of IFN-c in the lungs, but the data are not accepted fully. Through its pleiotropic effects on cytokine production, IFN-c modulates mucosal immune responses in interstitial lung disease.20 IFN-c upregulates the expression of costimulatory molecules on pulmonary accessory cells, including CD80 and CD86.21 It influences cell-mediated mechanisms of cytotoxicity and modulates T cell growth and functional differentiation. However, by inducing non-ERL chemokines (MIG/CXCL9, IP-10/CXCL10, ITAC/CXCL11), this
Antigenpresenting cell
IL-12
IFN-γ
cytokine plays a major role in the recruitment of activated CXCR3 T cells into inflamed tissues of patients with interstial lung disease (see later). IFN-c also has crucial antifibrotic effects – it inhibits the proliferation of endothelial cells and the synthesis of collagens by fibroblasts. The Th1/Th2 model The pattern of Th1 and Th2 cytokine production in the lung can be summarized in the context of the Th1/Th2 paradigm.22 By releasing Th1 and Th2 cytokines, pulmonary T-helper cells regulate local host defense mechanisms (Fig. 12.1). A Th1 CD4 or Tc1 T-cell profile predominates during the formation of typical T-cell-mediated alveolitis. Th1 cells producing IFN-c or IL-2 are responsible for initiating the alveolitis in the lung of patients with most interstitial lung diseases. Conversely, the Th2-type pattern is associated with local activation of allergic mechanisms, with fibroproliferative responses, or with a reduced resistance to intracellular pathogens. In fact, a switch to Th2 cells with concomitant release of IL-10, IL-6, and IL-4 is involved in
NK cell
LAK cell
Precursor CTL
Effector CTL
IL-2 Oxygen intermediates
Th1 IL-3 GM-CSF
Neutrophil Proinflammatory cytokines
Uncommitted lung CD4 T cell
GM-CSF
Macrophage
IL-3
Th2
IL-13 IL-5
IL-4 IL-10 IL-6
B cell
Plasma cell
Mast cell
Mediator release
Eosinophil Fig. 12.1. Th1 and Th2 cells keenly regulate pulmonary immune responses. The prevalance of Th1-type T cells favors the activation and compartmentalization of cytotoxic lymphocytes (CTL and activated NK cells) and the triggering of proinflammatory capabilities of macrophages and neutrophils. By contrast, lung Th2 cells are involved in the regulation of antibody production and in the activation of lung eosinophils and mast cells. However, the concomitant release of IL-10 may downregulate functional activities of alveolar macrophages. LAK cell, lymphokine-activated killer cell; NK, natural killer.
Lymphocytes
the pathogenesis of pulmonary hypersensitivity diseases characterized by eosinophilic pneumonia, (including asthma, allergic bronchopulmonary aspergillosis, Löffler’s syndrome, for example) as well as in patients with an interstitial lung disease evolving toward pulmonary fibrosis.23 In the lungs of patients with HIV infection, the Th1/Th2 shift may favor the development of pulmonary opportunistic infections. The clinical outcome of most diffuse lung diseases may also be influenced by the Th1/Th2 pattern of cytokine production. The net effect of the Th1 response is the development of a hypersensitivity reaction, such as in sarcoidosis, or an antigen-specific immune response, as in the case of hypersensitive pneumonitis or allograft rejection. In general terms, inhibition of fibrogenetic processes may be observed in this phase. However, depending on the host susceptibility, a switch to Th2 cells may occur in patients developing lung fibrosis with a concomitant release of cytokines, including IL-4, that stimulate the production of extracellular matrix proteins, and chemoattractants for fibroblasts.
P U L M O N A RY B C E L L S A N D T H E HUMORAL RESPONSE As in other secondary lymphoid tissues, highly differentiated B cells largely predominate in the germinal centers of bronchus-associated lymphoid tissue (BALT) follicular aggregates. Conversely, within alveolar spaces and in the diffuse pulmonary parenchyma, fewer than 5% of the lymphocytes are B cells. The distribution of B cell subpopulations in the lung is similar to that in the blood. The majority of pulmonary B cells are CD19- and CD20-positive, showing the phenotype of mature B cells and bearing surface immunoglobulins and, in a small number of cases, plasma cells with intracytoplasmic immunoglobulins. The primary role of B cells in the lung is to produce immunoglobulins important for local defense against microbial pathogens. Each type of antibody (IgG, IgA, IgM, IgD, IgE) can be produced in the lung as a circulating or stationary molecule. The latter functions as the B cell receptor for lung B cells. IgA is the predominant immunoglobulin isotype detectable in the upper respiratory tract (where the ratio of IgA to IgG is approximately 2.5:1). IgG represents the predominant immunoglobulin isotype in the alveolar spaces. IgA immunoglobulins are found principally in their secretory form and are involved in the clearance of micro-organisms from the respiratory tract. IgG opsonsins specific for bacteria together with complement factor (C3b) facilitate the phagocytosis by alveolar macrophages. However, specific IgGs are mandatory for the killing of Gram-negative micro-organisms, such as P. aeruginosa or E. coli. It is also possible that IgG may induce antibody-dependent cellular cytotoxicity against micro-organisms and tumors. This activity is mediated by multiple cell types having on their surface membrane the Fc receptors for IgG as a common denominator. They include granular lymphocytes with natural
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killer activity, some T cells, macrophages, and neutrophils. IgM may present in the lavage fluid. It derives from active secretion by IgM-expressing B lymphocytes present in the bronchial mucosa, or from the transport of IgM across epithelial cells into the airway lumen. Levels of BAL IgE and cells with intracytoplasmic IgE are detected only in atopic individuals, and no detectable IgD have been found in normal individuals.
C E L L S R E G U L AT I N G LY M P H O C Y T E FUNCTIONS IN THE LUNG Under normal conditions, alveolar macrophages (AM) are functionally quiescent and poor antigen-presenting cells to T cells.24 The reduced capacity of normal AMs to initiate Tcell immune response is linked to the fact that normal AMs do not bear or bear low levels of costimulatory molecules at resting conditions.25 The accessory function of AMs depends on the expression of members of the B7 family (CD80 and CD86), CD40, and the CD5 coligand CD72. Only in pathological conditions characterized by a dangerous antigenic burden may AMs express high levels of these coligands and function as effective antigen-presenting cells.26 In this case the antigen is ingested by endocytosis and degraded. Part of the molecule comprising the relevant epitope is transported to the cell membrane and bound to the class II MHC molecule (HLA-DR); i.e. the structure expressed on the surface membrane of AMs that physically presents the antigen to T cells. Following the interaction of the T cell receptor with the bimolecular complex Ag/HLADR, T cells become activated and release a series of immunomodulatory substances including IFN-c. In particular, the interaction between IFN-c and its receptor triggers AMs to become “primed”. This activation state of AMs is indicated by an increased metabolic activity and by an enhanced secretion of immunomodulatory molecules, such as proinflammatory cytokines, chemokines, and other cytokines that are specified below. The lung has also a substantial population of dendritic cells. While normal AMs are unresponsive and have poor antigen-presenting cells, human lung dendritic cells are considerably more potent in inducing T-cell immune responses.27 They carry molecules, including CD54 (ICAM-1), CD58 (LFA-3), and B7 members (CD80/CD86) that can enhance the interaction of antigen-presenting cells with T cells and deliver a second proliferative signal. The local network of dendritic cells extends from the basement membrane up to the tight junctions between the apical side of the epithelial cells and is involved in the clearance of antigens.28 Once dendritic cells have captured the antigen, they migrate to lymph nodes where they interact with naive T and B cells. Primed, antigen-specific T cells may in turn migrate to the lung parenchyma where they release Th1 cytokines, such as IFN-c. These further activate dendritic cells and alveolar macrophages, thus potentiating local immune responses.
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C Y T O K I N E S R E G U L AT I N G LY M P H O C Y T E A C T I VAT I O N I N T H E L U N G A milieu of cytokines is released by pulmonary accessory cells in healthy and disease states. In the following paragraphs only cytokines that regulate lymphocyte proliferation and activity in the lung will be taken into consideration. Interleukin-1 Lung macrophages are capable of producing detectable amounts of IL-1a and 1b as well as IL-1ra, a receptor-like molecule which functions as an antagonist of IL-1, in response to several inflammatory stimuli. IL-1 provides accessory growth factor activity for inflammatory lung T cells.29 In particular, the main biological activity of IL-1 is the stimulation of T-helper cells that are induced to secrete IL-2 and to express IL-2 receptors. Promoting the adhesion of neutrophils, monocytes, and T cells by enhancing the expression of adhesion molecules such as ICAM-1/CD54 (intercellular adhesion molecule) and CD62E/ELAM (endothelial leukocyte adhesion molecule), IL-1 also regulates the development of the alveolar inflammation. Interleukin-12 In the lung this cytokine is mainly produced by macrophages and dendritic cells.30 IL-12 is involved in Th1 immune responses and stimulates the proliferation and the lytic activity of activated lung T cells. Specifically, IL-12 induces the Th0–Th1 shift and stimulates proliferation and the lytic activity of activated T cells and natural killer cells. In synergy with IL-15, IL-12 favors the contact between activated T cells and antigen-presenting cells. By interacting with specific receptors (IL-12Rb) expressed by accumulating lymphocytes, the cytokine acts in the lung during most Th1-driven diffuse lung diseases. Interleukin-15 This pleiotropic lymphokine shares biological activities and components of its receptor with IL-2 (b/c IL-2R). In the lung, IL-15 is mainly produced by alveolar macrophages and dendritic cells. IL-15 supports the growth and chemotaxis of T cells, favoring the development of T cell alveolitis. It is also involved: • as a costimulatory factor for the production of other cytokines and chemokines (IL-17, CXCL8/IL-8, CCL2/MCP-1, GM-CSF, IFN-c, and TNF-a); • in the expression of molecules involved in the antigenpresenting capability of resident accessory cells (CD80/CD86); • as a down-modulator of the apoptosis rate of lung T cells. The latter could imply that IL-15 is a possible inhibitor of death-inducing effects of physiological apoptotic stimuli. Interleukin-18 Previously known as IFN-c-inducing factor (IGIF), IL-18 has activity roughly similar to, though distinct from, that of
IL-1. Mainly produced by monocytes, macrophages, and lung epithelial cells,31 it induces the expression of IFN-c and inhibits production of IL-10. In addition to stimulating IFN-c synthesis, IL-18 also possesses inflammatory effects by inducing synthesis of the proinflammatory cytokines TNF and IL-1b and the chemokines IL-8 and macrophage inflammatory protein-1a (MIP-1a). Interestingly, IL-18 and IL-12 act on Th1 cells synergistically to induce IFN-c, cooperating in the development of Th1-type immune responses. Tumor necrosis factor and other molecules belonging to the TNF-ligand superfamily TNF-a is a member of a large family of soluble molecules having several complex immunoregulatory properties that interact with specific receptors (TNF-R). TNF-a and other ligands of the TNF superfamily (TNF-L) have a role in modulating apoptotic mechanisms at sites of inflammation, including the lung. There are data suggesting that the chronic overexpression of TNF-a and IFN-c and the dysregulation of TNF-R/TNF-L set the stage for the persistence of lymphocyte accumulation during some inflammatory pulmonary diseases. In some circumstances, alterations of the TNF-R/TNF-L balance favor the chronic recruitment of lymphocytes that assemble granulomatous structures in the inflamed tissue.
C H E M O K I N E S R E G U L AT I N G LY M P H O C Y T E H O M I N G AT S I T E S O F P U L M O N A RY I N F L A M M AT I O N The superfamily of chemokines consists of an array of chemoattractant proteins. This has been divided into four branches (C, CC, CXC, CXXXC), according to variations in a shared cysteine32–34 (see also Chapter 27). The current roster approaches 50 related proteins. Structural variations of chemokines have been demonstrated to be associated with differences in their ability to regulate the trafficking of immune cells during inflammation. The chemokines that have been demonstrated to be involved in lymphocytes homing into the lung are now being considered (Table 12.1). CC chemokines Most molecules of this chemokine branch are expressed extensively in the lung during inflammatory responses.35 Monocyte chemoattractant protein 1 (MCP-1/CCL2), monocyte inflammatory protein-1a (MIP-1a/CCL3), MIP-1b/CCL4, RANTES/CCL5, and Eotaxin/CCL11 cooperate to mobilize several leukocyte subpopulations into perivascular foci of inflammation. MCP-1/CCL2 and RANTES/CCL5 interacting with CCR1/CCR2 or CCR1/CCR3/CCR5, respectively, may be the chemoattractants for different cell targets, including T lymphocytes, that have been involved in the pathogenesis of most lung diseases.
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Lymphocytes
Table 12.1. Inflammatory and homeostatic chemokines regulating lymphocyte traffic
Type
Receptor
Cell targets
CXCR3 CXCR6 CCR1 CCR2
Effector Effector Effector Effector
T T T T
cells (Th1) cells cells cells
CCR3 CCR5 CCR8 CX3CR1
Effector Effector Effector Effector
T T T T
cells (Th2) cells (Th1) cells (Th2) cells
SDF-1/CXCL12
CXCR4
BCA-1/CXCL13 SLC/CCL21, ELC/CCL19
CXCR5 CCR7
TECK/CCL25
CCR9
CTACK/CCL27, MEC/CCL28
CCR10
Naive and memory T cells B cells Thymocytes T cells, B cells Naive and memory T cells B cells Thymocytes Memory T cells B cells Thymocytes Memory T cells
Inflammatory or inducible chemokines Mig/CXCL9, IP10/CXCL10, I-TAC/CXCL11 CXCL16 RANTES/CCL5, MIP-1a/CCL3, MCP-2/CCL8, MCP-3/CCL7 MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13 RANTES/CCL5, MCP-3/CCL7, MCP-2/CCL8, Eotaxin-1/CCL11, MCP-4/CCL13, Eotaxin-2/CCL24, Eotaxin-3/CCL26, MEC/CCL28 MIP-1a/CCL3, MIP-1b/CCL4, RANTES/CCL5, MCP-2/CCL8 I-309/CCL1 Fractalchina/CX3CL1 Homeostatic or constitutive chemokines
Chemokines belonging to both subfamilies MDC/CCL22, TARC/CCL17
CCR4
LARC/CCL20
CCR6
CXC chemokines Three lymphocyte-specific CXC chemokines, which are produced in response to IFN-c (i.e. IP-10/CXCL10, Mig/CXCL9, and I-TAC/CXCL11) play an important role in the recruitment of activated T cells into the pulmonary micoenvironment.8,20 Signaling mediated by these non-ERL CXC-chemokines – CXC chemokines without the Glu-LeuArg (ERL) motif before the CXC motif – are mostly directed to pulmonary activatedT lymphocytes.Alveolar macrophages are the main cell source for these molecules; they release high amounts of CXCL10 and CXCL9 that interact with specific receptors expressed by Th1 and Tc1 cells (CXCR3), so that the migration and accumulation of pulmonary T is induced.36,37 Activated bronchial epithelium is another important source of CXCL9, CXCL10, and CXCL11. IL-8(CXCL8), a chemokine that favors T cell and neutrophil recruitment, is also actively released into the airways and lungs exhibiting different diffuse lung diseases associated with lung damage.38
Effector T cells (Th1, Th2) Memory T cells Thymocytes Effector T and B cells Memory T cells
Other molecules chemotactic for lung lymphocytes Interleukin-16 is a proinflammatory cytokine produced by CD8 T cells, CD4 T cells, eosinophils, mast cells, and bronchial epithelial cells. This cytokine induces the migratory response of CD4 cells, increases intracellular Ca and inositol 1,4,5-triphosphate levels, and induces the production of proinflammatory cytokines. This cytokine is involved in the pathogenesis of hypersensitivity reactions and plays a role in directing lymphocyte emigration from the circulation into sites of inflammation and tissue injury.39 IL-16 shares chemoattractant activity for eosinophils and CD4 T cells. Large amounts can be detected in the lung at sites of inflammatory process where a perivascular accumulation of lymphocytes may be demonstrated. IL-15 is also able to favor the chemotaxis of T cells.40 It induces migration of lung T cells bearing an effective IL-15 receptor (formed by three chains, IL-15Ra, IL-2Rb, and IL-2Rc).
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LY M P H O C Y T E S I N A S T H M A Asthma has three characteristic features: reversible airway obstruction, bronchial hyperresponsiveness, and airway inflammation. Although each of these components is recognized as an important part of the asthmatic phenotype, the primary underlying abnormality in this disease is thought to be the unique form of airway inflammation that gives rise to reversible obstruction and hyperresponsiveness.41 Traditionally, asthma has been categorized as atopic – i.e. associated with environmental inducing antigens and specific IgE antibodies – or nonatopic, with no environmental inducing factors identified. Although occupational asthma is often considered as a further type of asthma, the adjective “occupational” merely recognizes that a specific workrelated antigen has been identified. Atopic, nonatopic, and occupational asthma are similar in most respects, including the type of inflammatory response which, in all these forms of asthma, is characterized by a prominent eosinophilia associated with an increased number of T lymphocytes and mast cells. T lymphocytes have been suggested to play a key role in orchestrating the interaction of the participating cells, since they are able to release an array of cytokines which can attract, prime, and activate other cell types.42 Direct evidence for T lymphocyte infiltration in asthma comes from a variety of studies. Postmortem examination of airways of asthmatic patients has revealed a large number of lymphocytes.43–45 Moreover, immunohistochemical studies have shown that T cells are the most abundant inflammatory cell in bronchial biopsies taken during life in subjects with mild asthma.46 In both bronchoalveolar lavage and bronchial mucosa, T lymphocytes are in an increased state of activation, with a greater proportion of cells expressing surface activation markers interleukin-2 receptor (IL-2R), very late activation antigen-1 (VLA-1) and class II histocompatibility antigen (HLA-DR).46–48 Recent reports demonstrated that activated T lymphocytes are predominantly CD4,46,48 and that they correlate with asthma symptoms and bronchial hyperresponsiveness as well as with eosinophil number and activation.49 CD4 T lymphocytes are present not only in the airways but also in the lung parenchyma of subjects with asthma. In particular, studies on transbronchial biopsies of patients with nocturnal asthma have shown that the overnight decrease in lung function in these patients correlates with the increased number of CD4 T lymphocytes and eosinophils in the alveolar walls, supporting the role of parenchymal inflammation in the acute worsening of the condition.50,51 CD4 T cells are likely to play a role in controlling chronic inflammation in asthma by the release of Th2 cytokines. Asthmatic subjects have an increased expression of both IL-4 and IL-5 mRNA and protein products in bronchoalveolar lavage and bronchial biopsy specimens.52,53 Using double immunohistochemistry/in-situ hybridization, T cells appear to be the major source of mRNA for these
cytokines.54 Notably, IL-4 and IL-5 mRNA colocalizes predominantly to CD4 cells, but was also noted to be present in CD8 cells.55 In addition, the expression of IL-5 protein and IL-5 mRNA has been shown to correlate with disease severity.56 Airway pathology in atopic, nonatopic, and occupational asthma is remarkably similar,57,58 with T lymphocytes orchestrating the inflammatory response in the three forms of the disease. Furthermore, recent data have shown an increased number of cells expressing IL-4 and IL-5 mRNA and protein products as well as high-affinity IgE receptor (FceRI)-bearing cells in bronchial biopsies from both atopic and nonatopic asthma, suggesting an immunological basis for both these conditions.59 The immunological mechanism underlying the different forms of asthma was explored by cloning lymphocytes from bronchial biopsies.60,61 The results showed that, in atopic asthma (characterized by airway eosinophilia and an increase in circulating specific IgE), the majority of T cell clones were CD4 and produced a Th2 pattern of cytokines; i.e. IL-4 and IL-5.61 In occupational asthma induced by toluene diisocyanate (characterized by airway eosinophilia and a lack of circulating specific IgE), the majority of T cell clones were CD8 and were capable of producing IL-5 but not IL-4.60 Since IL-4 stimulates B lymphocytes to produce IgE, while IL-5 promotes the differentiation, adhesion, and survival of eosinophils, it can be hypothesized that T lymphocytes, because of their pattern of cytokine production, may play a central role in determining the nature of the response in the different types of asthma. In atopic asthma, CD4 Th2-like cells may induce both bronchial eosinophilia (via IL-5) and allergen-specific IgE production (via IL-4). In occupational asthma, CD8 T cells may cause bronchial eosinophilia (via IL-5) but not specific IgE production (absence of IL-4). One of the advantages of examining occupational asthma is that there is a well-defined and specific agent responsible for the sensitization. This allows an evaluation of the reversibility of the inflammatory response after cessation of exposure to the sensitizing agent. Such an evaluation is more difficult in atopic asthma, where the avoidance of the sensitizing agent can be problematic, and even more problematic in nonatopic asthma, where the agent is unknown. Longitudinal studies of bronchial biopsies from patients with occupational asthma induced by toluene diisocyanate have established that cessation of exposure to the offending agent for one year is associated with a reduction of T lymphocytes, mast cells, and fibroblasts and with a decreased thickness of the reticular basement membrane, despite the persistence of bronchial hyperresponsiveness and of eosinophil infiltration.62,63 Both lymphocytes and mast cells: • have the capacity to produce IL-4 (which is a cofactor for proliferation of fibroblasts); • may induce fibroblast chemotaxis; • stimulate synthesis of matrix proteins such as collagen I, III and fibronectin.64,65
Lymphocytes
Therefore, the reduction in number of lymphocytes and mast cells may represent a mechanism for the reduction of fibroblast numbers and therefore of collagen deposition. The fact that the number of eosinophils did not change significantly after cessation of exposure to toluene diisocyanate suggests a role for these cells in the persistence of nonspecific bronchial hyperresponsiveness in the majority of asthmatic subjects, even several months after cessation of exposure to the sensitizing agent.
LY M P H O C Y T E S I N C H R O N I C O B S T R U C T I V E P U L M O N A RY D I S E A S E Chronic obstructive pulmonary disease has been defined recently as a disease state characterized by poorly reversible airflow limitation that is usually progressive and associated with an abnormal inflammatory response of the lung.66 COPD is not a disease entity, but rather a complex of conditions that contribute to airflow limitation. These conditions include chronic bronchitis and emphysema. Whilst in asthma the lung inflammatory process is characterized by T lymphocytes in association with eosinophils and mast cells, in COPD the lung inflammatory process consists predominantly of T lymphocytes associated with macrophages and neutrophils.67,68 Neutrophils are the predominant cells in the airway lumen, while T lymphocytes and macrophages are the predominant cells in the airway wall. These cells are not only increased in number in smokers with COPD, but also exhibit signs of activation as shown by the greater proportion of cells expressing surface activation markers IL-2R and VLA-1.67 In-vitro studies have shown that the IL-2 receptor appears on T cells 24 hours after stimulation and disappears after 2 days, whereas VLA1 antigen appears on the same cells at least 15 days after stimulation.69 If this is the case in vivo, the simultaneous presence of both activation markers indicates the presence of lymphocytes at different stages of activation in COPD patient airways, suggesting the presence of an immunological response in these people. Recently, it has been demonstrated that it is the CD8 T lymphocyte subset that increases in number in COPD and becomes the predominant T cell subset in this disease.70–73 This contrasts with the predominance of the CD4 T cell subset that characterizes asthma. The CD8 inflammatory process appears to be extensively distributed in the lung. Indeed, CD8 T lymphocytes infiltrate the central airways,70 the peripheral airways,71,73 and the lung parenchyma,72 suggesting a consistent inflammatory process along the entire tracheobronchial tree in smokers with COPD. Interestingly, CD8 T lymphocytes not only are increased in number in all these lung compartments, but also show a significant correlation with the degree of airflow limitation, suggesting a role for these cells in the progression of the disease.70–72 Traditionally, the major activity of CD8 T lymphocytes has been considered to be the rapid resolution of acute viral
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infections; viral infections are a frequent occurrence in patients with COPD. The observation that people with frequent respiratory infections in childhood are more prone to develop COPD supports the role of viral infections in this disease.74 It is conceivable that, in response to repeated viral infections, an excessive recruitment of CD8 T lymphocytes may occur and damage the lung in susceptible smokers, possibly through the release of perforins and TNF-a.75 On the other hand, it is also possible that CD8 T lymphocytes are able to damage the lung even in the absence of a stimulus such as a viral infection, as shown by Enelow and coworkers.76 They clearly demonstrated that recognition of a lung “autoantigen” by a T cytotoxic cell may directly produce a marked lung injury. Taking into account these findings, it can be hypothesized that the cytotoxic T cell accumulation observed in COPD could be a response to an “autoantigenic” stimulus originating in the lung and induced by cigarette smoking. The observation that CD8 T lymphocytes are increased not only in the airways, but also in the lung parenchyma, of smokers with COPD invites speculation that these cells, because of their location within the alveolar walls, may contribute to the development of parenchymal destruction that characterizes emphysema. A current paradigm in immunology is that the nature of an immune response to an antigenic stimulus is determined largely by the pattern of cytokines produced by activated CD4 and CD8 T cells. Whereas several studies have shown a prevalent type-2 response in asthma, little is known about the pattern of cytokine response in COPD, even though preliminary data suggest a prevalent type-1 response in this disease.77 B lymphocyte infiltration has been documented in COPD, particularly in peripheral airway adventitia; i.e. in the airway wall external to smooth muscle. This preponderance of B cells may be interesting in the light of a previously reported association between cigarette smoking, elevated levels of serum IgE, and airway obstruction.78 As airflow limitation progressively worsens, natural killer lymphocytes in the airway wall increase, and their number is associated with an increased epithelial expression of macrophage inflammatory protein (MIP)-1a.79 Since NK lymphocytes have specialized cytotoxic functions and act as a first line of defense against virus-infected cells, their excessive recruitment, upregulated by MIP-1a, may occur in response to the repeated viral infections that characterize the natural history of COPD. Although it is well accepted that eosinophilia is a characteristic feature of asthma, recent studies have reported a prominent airway eosinophilia in COPD, in particular during an acute exacerbation of the disease.80 It has been demonstrated that, in contrast to asthma, the tissue eosinophilia found in COPD is not associated with an increased expression of IL-5, suggesting that different mechanisms inducing eosinophilia are involved in the two diseases.81 A relevant question related to T lymphocyte infiltration in COPD is whether it is reversible upon cessation of cigarette
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smoking. This was investigated in bronchial biopsies by comparing a group of current smokers and a group of exsmokers, who had stopped smoking at least 1 year (on average 13 years) before the study and still had symptoms of chronic bronchitis.82 The number of inflammatory cells, including T lymphocytes, and the expression of their activation markers IL-2R (recent activation) and VLA-1 (late activation) were not significantly different between current and ex-smokers. These data indicate that the inflammatory process may persist in COPD subjects who still have cough and sputum production despite smoking cessation, suggesting that, when the disease is established, the pathology is not reversible with the avoidance of smoking. The persistence of the activation markers IL-2R and VLA-1 in the airways of subjects who had stopped smoking at least 1 year before the study suggests that continuous exogenous stimulation by cigarette smoking is not required to maintain lymphocyte activation.
S U M M A RY A N D C O N C L U S I O N S • There is evidence of airway and parenchymal inflammation in both asthma and COPD, but there are marked differences in terms of the predominant cell phenotype. • The involvement of activated T lymphocytes seems to be a common theme in both conditions, yet the marked tissue eosinophilia of patients with asthma does not appear in those with COPD, until there is an exacerbation of the disease. • The predominant T lymphocyte subsets in asthma and COPD appear to be distinct; i.e. CD4 and CD8, respectively. Although it is well accepted that the cytokines produced by CD4T lymphocytes in asthma have a type2 pattern, further studies are needed to understand the cytokines produced by CD8 T lymphocytes in COPD.
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8. Loetscher M, Gerber B, Loetscher P et al. Chemokine receptor specific for IP-10 and Mig: structure, function and expression in activated T-lymphocytes. J. Exp. Med. 1996; 184:963–9. 9. Choi P, Reiser H. IL-4: role in disease and regulation of production. Clin. Exp. Immunol. 1998; 113:317–19. 10. Striz I, Mio T, Adachi Y et al. IL-4 and IL-13 stimulate human bronchial epithelial cells to release IL-8. Inflammation 1999; 23:545–55. 11. Temann UA, Geba GP, Rankin JA, Flavell RA. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J. Exp. Med. 1998; 188:1307–20. 12. Spits H, de Waal Malefyt R. Functional characterization of human IL-10. Int. Arch. Allergy Immunol. 1992; 99:8–15. 13. Pretolani M, Goldman M. IL-10: a potential therapy for allergic inflammation? Immunol.Today 1997; 18:277–80. 14. Tinkle SS, Kittle LA, Newman LS. Partial IL-10 inhibition of the cell-mediated immune response in chronic beryllium disease. J. Immunol. 1999; 163:2747–53. 15. de Vries JE. The role of IL-13 and its receptor in allergy and inflammatory responses. J. Allergy Clin. Immunol. 1998; 102:165–9. 16. Chiaramonte MG, Schopf LR, Neben TY et al. IL-13 is a key regulatory cytokine for Th2 cell-mediated pulmonary granuloma formation and IgE responses induced by Schistosoma mansoni eggs. J. Immunol. 1999; 162:920–30. 17. Wills-Karp M. IL-12/IL-13 axis in allergic asthma. J. Allergy Clin. Immunol. 2001; 107:9–18. 18. Linden A, Hoshino H, Laan M. Airway neutrophils and interleukin-17. Eur. Respir. J. 2000; 15:973–7. 19. Agostini C, Semenzato G. Cytokines in sarcoidosis. Semin. Respir. Infect. 1998; 13:184–96. 20. Farber JM. Mig and IP-10: CXC chemokines that target lymphocytes. J. Leukoc. Biol. 1997; 61:246–57. 21. Agostini C, Trentin L, Perin A et al. Regulation of alveolar macrophage–T cell interactions during Th1-type sarcoid inflammatory process. Am. J. Physiol. 1999; 277:L240–50. 22. Romagnani S. The Th1/Th2 paradigm. Immunol. Today 1997; 18:263–6. 23. Romagnani S. T-cell subsets (Th1 versus Th2). Ann. Allergy Asthma Immunol. 2000; 85:9–18. 24. Lyons CR, Ball EJ, Toews GB et al. Inability of human alveolar macrophages to stimulate resting T cells correlates with decreased antigen-specific T cell-macrophage binding. J. Immunol. 1986; 137:1173–80. 25. Chelen CJ, Fang Y, Freeman GJ et al. Human alveolar macrophages present antigen ineffectively due to defective expression of B7 costimulatory cell surface molecules. J. Clin. Invest. 1995; 95:1415–21. 26. Tager AM, Luster AD, Leary CP et al. Accessory cells with immunophenotypic and functional features of monocytederived dendritic cells are recruited to the lung during pulmonary inflammation. J. Leukoc. Biol. 1999; 66:901–8. 27. Reynolds HY. Advances in understanding pulmonary host defense mechanisms: dendritic cell function and immunomodulation. Curr. Opin. Pulm. Med. 2000; 6:209–16. 28. Lambrecht BN, Pauwels RA, Bullock GR. The dendritic cell: its potent role in the respiratory immune response. Cell Biol. Int. 1996; 20:111–20. 29. Rosenwasser LJ. Biologic activities of IL-1 and its role in human disease. J. Allergy Clin. Immunol. 1998; 102:344–50. 30. Scott P,Trinchieri G. IL-12 as an adjuvant for cell-mediated immunity. Semin. Immunol. 1997; 9:285–91. 31. Cameron LA, Taha RA, Tsicopoulos A et al. Airway epithelium expresses interleukin-18. Eur. Respir. J. 1999; 14:553–9. 32. Baggiolini M. Chemokines and leukocyte traffic. Nature 1998; 392:565–8. 33. Luster A. Chemokines: chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 1998; 228:436–45.
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34. Kim CH, Broxmeyer HE. Chemokines: signal lamps for trafficking of T and B cells for development and effector function. J. Leukoc. Biol. 1999; 65:6–15. 35. Kunkel SL, Lukacs NW, Strieter RM, Chensue SW. The role of chemokines in the immunopathology of pulmonary disease. Forum Genova 1999; 9:339–55. 36. Agostini C, Cassatella M, Zambello R et al. Involvement of the IP10 chemokine in sarcoid granulomatous reactions. J. Immunol. 1998; 161:6413–20. 37. Agostini C, Siviero M, Facco M et al. CXC chemokines IP-10 and Mig expression and direct migration of pulmonary CD8/CXCR3 T cells in the lung of patients with HIV infection and T-cell alveolitis. Am. J. Respir. Crit. Care Med. 2000; 162:1466–72. 38. Baggiolini M, Moser B, Clark-Lewis I. Interleukin-8 and related chemotactic cytokines. The Giles Filley Lecture. Chest 1994; 105:95S–8S. 39. Yoshimoto T, Wang CR, Yoneto T et al. Role of IL-16 in delayedtype hypersensitivity reaction. Blood 2000; 95:2869–74. 40. Waldmann T, Tagaya Y, Bamford R. Interleukin-2, interleukin-15, and their receptors. Int. Rev. Immunol. 1998; 16:205–26. 41. Haley KJ, Drazen JM. Inflammation and airway function in asthma: what you see is not necessarily what you get. Am. J. Respir. Crit. Care Med. 1998; 157:1–3. 42. Krug N, Tschernig T, Holgate S, Pabst R. How do lymphocytes get into the asthmatic airways? Lymphocyte traffic into and within the lung in asthma. Clin. Exp. Allergy 1998; 28:10–18. 43. Dunnill MS, Massarella GR, Anderson JA. A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis, and in emphysema. Thorax 1969; 24:176–9. 44. Saetta M, Di Stefano A, Rosina C, Thiene G, Fabbri LM. Quantitative structural analysis of peripheral airways and arteries in sudden fatal asthma. Am. Rev. Respir. Dis. 1991; 143:138–43. 45. Carroll N, Cooke C, James A. The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics. Eur. Respir. J. 1997; 10:292–300. 46. Bradley BL, Azzawi M, Jacobson M et al. Eosinophils, T-lymphocytes, mast cells, neutrophils, and macrophages in bronchial biopsy specimens from atopic subjects with asthma: comparison with biopsy specimens from atopic subjects without asthma and normal control subjects and relationship to bronchial hyperresponsiveness. J. Allergy Clin. Immunol. 1991; 88:661–74. 47. Azzawi M, Bradley B, Jeffery PK et al. Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am. Rev. Respir. Dis. 1990; 142:1407–13. 48. Maestrelli P, Saetta M, Di Stefano A et al. Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage. Am. J. Respir. Crit. Care Med. 1995; 152:1926–31. 49. Robinson DS, Bentley AM, Hartnell A, Kay AB, Durham SR. Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness. Thorax 1993; 48:26–32. 50. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am. J. Respir. Crit. Care Med. 1996; 154:1505–10. 51. Kraft M, Martin RJ, Wilson S, Djukanovic R, Holgate ST. Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am. J. Respir. Crit. Care Med. 1999; 159:228–34. 52. Walker C, Bode E, Boer L et al. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am. Rev. Respir. Dis. 1992; 146:109–15. 53. Robinson DS, Hamid Q,Ying S et al. Predominant Th2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 1992; 326:298–304. 54. Ying S, Durham SR, Corrigan CJ, Hamid Q, Kay AB. Phenotype of cells expressing mRNA for Th2-type (interleukin 4 and inter-
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leukin 5) and Th1-type (interleukin 2 and interferon gamma) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic and normal control subjects. Am. J. Respir. Cell Mol. Biol. 1995; 12:477–87. Ying S, Humbert M, Barkans J et al. Expression of IL-4 and IL-5 mRNA and protein product by CD4 and CD8 T cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and nonatopic (intrinsic) asthmatics. J. Immunol. 1997; 158:3539–44. Humbert M, Ying S, Corrigan C et al. Bronchial mucosal expression of the genes encoding chemokines RANTES and MCP-3 in symptomatic atopic and nonatopic asthmatics: relationship to the eosinophil-active cytokines interleukin (IL)-5, granulocyte macrophage-colony-stimulating factor, and IL-3. Am. J. Respir. Cell Mol. Biol. 1997; 16:1–8. Bentley AM, Kay AB, Durham SR. Human late asthmatic reactions. Clin. Exp. Allergy 1997; 27(Suppl. 1):71–86. Humbert M, Durham SR, Ying S et al. IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity. Am. J. Respir. Crit. Care Med. 1996; 154:1497–504. Humbert M, Grant JA, Taborda-Barata L et al. High-affinity IgE receptor (FcepsilonRI)-bearing cells in bronchial biopsies from atopic and nonatopic asthma. Am. J. Respir. Crit. Care Med. 1996; 153:1931–7. Maestrelli P, Del Prete GF, De Carli M et al. CD8 T-cell clones producing interleukin-5 and interferon-gamma in bronchial mucosa of patients with asthma induced by toluene diisocyanate. Scand. J.Work Environ. Hlth 1994; 20:376–81. Del Prete GF, De Carli M, D’Elios MM et al. Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients with allergic respiratory disorders. Eur. J. Immunol. 1993; 23:1445–9. Saetta M, Maestrelli P, Turato G et al. Airway wall remodeling after cessation of exposure to isocyanates in sensitized asthmatic subjects. Am. J. Respir. Crit. Care Med. 1995; 151:489–94. Saetta M, Di Stefano A, Maestrelli P et al. Airway mucosal inflammation in occupational asthma induced by toluene diisocyanate. Am. Rev. Respir. Dis. 1992; 145:160–8. Postlethwaite AE, Seyer JM. Fibroblast chemotaxis induction by human recombinant interleukin-4: identification by synthetic peptide analysis of two chemotactic domains residing in amino acid sequences 70–88 and 89–122. J. Clin. Invest. 1991; 87:2147–52. Postlethwaite AE, Holness MA, Katai H, Raghow R. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J. Clin. Invest. 1992; 90:1479–85. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am. J. Respir. Crit. Care Med. 2001; 163:1256–76. Saetta M, Di Stefano A, Maestrelli P et al. Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am. Rev. Respir. Dis. 1993; 147:301–6. Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Respir. Crit. Care Med. 1996; 153:530–4. Hemler ME, Glass D, Coblyn JS, Jacobson JG. Very late activation antigens on rheumatoid synovial fluid T lymphocytes: association with stages of T cell activation. J. Clin. Invest. 1986; 78:696–702. O’Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8 T lymphocytes with FEV1. Am. J. Respir. Crit. Care Med. 1997; 155:852–7.
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71. Saetta M, Di Stefano A, Turato G et al. CD8 T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 157:822–6. 72. Saetta M, Baraldo S, Corbino L et al. CD8ve cells in the lungs of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:711–17. 73. Saetta M, Turato G, Baraldo S et al. Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am. J. Respir. Crit. Care Med. 2000; 161:1016–21. 74. Paoletti P, Prediletto R, Carrozzi L et al. Effects of childhood and adolescence–adulthood respiratory infections in a general population. Eur. Respir. J. 1989; 2:428–36. 75. Liu AN, Mohammed AZ, Rice WR et al. Perforin-independent CD8() T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-alpha: relative insensitivity to Fas ligand. Am. J. Respir. Cell Mol. Biol. 1999; 20:849–58. 76. Enelow RI, Mohammed AZ, Stoler MH et al. Structural and functional consequences of alveolar cell recognition by CD8() T lymphocytes in experimental lung disease. J. Clin. Invest. 1998; 102:1653–61.
77. Saetta M, Turato G, Maestrelli P, Mapp CE, Fabbri LM. Cellular and structural bases of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 163:1304–9. 78. Bosken CH, Hards J, Gatter K, Hogg JC. Characterization of the inflammatory reaction in the peripheral airways of cigarette smokers using immunocytochemistry. Am. Rev. Respir. Dis. 1992; 145:911–17. 79. Di Stefano A, Capelli A, Lusuardi M et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am. J. Respir. Crit. Care Med. 1998; 158:1277–85. 80. Saetta M, Di Stefano A, Maestrelli P et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am. J. Respir. Crit. Care Med. 1994; 150:1646–52. 81. Saetta M, Di Stefano A, Maestrelli P et al. Airway eosinophilia and expression of interleukin-5 protein in asthma and in exacerbations of chronic bronchitis. Clin. Exp. Allergy 1996; 26:766–74. 82. Turato G, Di Stefano A, Maestrelli P et al. Effect of smoking cessation on airway inflammation in chronic bronchitis. Am. J. Respir. Crit. Care Med. 1995; 152:1262–7.
Chapter
Neutrophils
13
Ellen M. Drost and William MacNee Department of Medical and Radiological Sciences, University of Edinburgh, ELEGI/WLT Laboratories, UK
Obstruction of normal airflow is the manifestation of two major lung diseases, asthma and chronic obstructive pulmonary disease (COPD), but they are very distinct diseases. Asthma is characterized by airway hyperresponsiveness and the airways obstruction is reversible, whereas in COPD the airways obstruction, due to chronic obstructive bronchitis or emphysema, is largely irreversible. Both diseases are also characterized by chronic inflammation, although initiated by different stimuli: environmental and occupational allergens in asthma, and largely tobacco smoking in COPD. The development of persistent inflammation is likely to be the cause of disease progression. The presence of neutrophils in the airways has been shown in both conditions. However, as will become evident in this chapter, there are differences in the mechanism and location of neutrophil trafficking in the lungs for asthma and COPD, which may relate to their distinct pathologies.
T H E I N F L A M M AT O RY R E S P O N S E Inhalation of cigarette smoke can repeatedly activate resident lung cells to elicit an inflammatory response in the lungs in COPD. Similarly, in extrinsic asthma, repeated exposure to allergens initiates airway inflammation. Hence, as the first cellular response to inflammation, an airway neutrophilia would not be unexpected. Much recent work has examined the inflammatory cellular infiltrate in the large airways of the lungs of patients with asthma and COPD using biopsy, bronchoalveolar lavage, and sputum samples. These studies have revealed that the nature of the inflammatory infiltrate appears to be different for asthma and COPD, and the distribution throughout the lungs may also differ. In COPD patients, the airway wall inflammatory infiltrate, as observed in biopsy studies, appears to be mainly lymphocytes, predominantly CD8, with eosinophils present in only some individuals particularly during exacerbations.1 Although inhalation of cigarette smoke can cause an increase in neutrophil numbers in the submucosa2 and airway epithelium3,4 these cells predominate in the airway lumen, as determined by brochoalveolar
lavage (BAL) and sputum sampling. That neutrophils are transitory and migrate into the airways of the lungs may explain why neutrophils are not normally seen in the airway walls in COPD. As COPD progresses, however, neutrophils become more prominent.5 The involvement of neutrophils in the development of airways obstruction in COPD has been suggested by the strong correlations between neutrophil numbers and FEV1, as a measure of airways obstruction. Several studies with smokers have reported a significant inverse relationship between peripheral blood neutrophil numbers and FEV1,6,7 and between the change in peripheral blood count and the annual rate of decline in FEV1.6 Although components of cigarette smoke (e.g. nicotine) are themselves chemotactic for neutrophils, it is likely that activation of lung macrophages and bronchial and alveolar epithelium by cigarette smoke causes the release of chemokines that mediate the neutrophil influx. Elevated levels of the leukotriene B4 (LTB4), interleukin-8 (IL-8), and tumor necrosis factor a (TNF-a), all strong neutrophil chemokines, have been measured in BAL and sputum of COPD patients7,8 (Table 13.1). Interestingly, a study of ex-smokers showed that, once initiated, the inflammation was ongoing even after the stimulus (cigarette smoke) was removed,9 suggesting that the established inflammation was self-perpetuating. Also, a report comparing airway inflammation in patients with chronic bronchitis who had never smoked, and nonsmoking healthy subjects, found an increase in airway neutrophil numbers (but not superoxide anion generation or free elastolytic activity) which correlated significantly with percentage predicted FEV1, as a measure of airflow obstruction.10 This study demonstrates that lung inflammation initiated by Table 13.1. Neutrophil chemotactic factors
COPD
Asthma
IL-8, TNF-a, LTB4, GRO-a, GM-CSF
PAF, LTB4, GM-CSF, IL-8, ENA-78, MIP-1a, C5a
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stimuli other than cigarette smoke can also result in airway obstruction. However, what is not clear is why, in some cases, the cycle is perpetuated, resulting in COPD, whereas for others removal of the initial stimulant allows the inflammation to resolve. Experimental studies in humans have found that an influx of neutrophils into the airways occurs in asthmatics in response to allergen challenge. Although eosinophils, CD4 lymphocytes, and mast cells predominate in the airway walls in asthma,11,12 the presence of high numbers of airway neutrophils, as well as eosinophils, has been identified in both chronic asthma and during exacerbations.13,14 Neutrophils appear first in asthmatic reactions to inhaled allergens, but are transient, whereas the other leucocytes persist for longer.15 Likewise, lavage and sputum samples from patients with acute exacerbations of asthma show increased neutrophil numbers, whether associated with infection or not.15,16 Inhaled allergens15,17,18 or nonallergic triggers such as the air pollutants ozone and nitrogen dioxide in asthma,19,20 like cigarette smoke in COPD, could potentially cause neutrophil activation and emigration. Most likely, however, inhaled allergens activate resident lung cells, such as the macrophage and airway epithelial cells, to release proinflammatory mediators which cause neutrophil activation and diapedesis. Of the mediators involved in asthma, those that have chemotactic activity for neutrophils are: C5a (by activation of the complement pathways and cleavage of plasma or tissue C5); platelet activating factor (PAF); granulocytemacrophage colony stimulating factor (GM-CSF); LTB4.21 (See Table 13.1) Also, the cytokines IL-4 and IL-13, which are present in increased amounts in asthma, increase neutrophil production of LTB4, which would attract more neutrophils.22 Additionally, in acute exacerbations of asthma, increased levels of IL-8 have been detected.13 Exacerbations of disease The inflammation which occurs during an exacerbation of either disease is clearly different from that of the chronic state. Exacerbations in both asthma and COPD are most often secondary to bacterial or viral infection in the lungs. As an inflammatory response to infection, the presence of neutrophils in increased numbers would be normal. In both diseases there are reports of an increase in the levels of IL8, a strong chemoattractant and stimulator of neutrophils, in the airways,7,23 which could explain the further increase in neutrophil numbers reported for exacerbations. Enhanced neutrophil sequestration in the pulmonary microcirculation was found for exacerbations of COPD, which was due to reduced cell deformability.24 Increased evidence of neutrophil activation has also been reported for both diseases.25–29 Animal models Asthma Animal models of asthma suggest that acute bronchoconstriction and airway hyperresponsiveness are mediated by
eosinophils.30,31 However, some models have also shown a rapid, but transient influx of neutrophils into the airways following inhalation of stimuli such as ozone.32,33 Indeed, increased neutrophil numbers in the airways, in these studies, were associated with bronchial hyperresponsiveness, and depletion of neutrophils protected against the development of airway hyperresponsiveness.34 Also, in one study by Lukacs and colleagues,35 bronchial hyperresponsiveness in the lungs of mice following allergen challenge was assessed at intervals over 48 hours. In their study, the neutrophil influx showed a strong correlation with airway reactivity, whereas eosinophils appeared only when airway responsiveness was diminished. Likewise, dogs exposed to ozone showed increased airway hyperresponsiveness to acetylcholine challenge associated with a neutrophil influx into the airways.32,36 These studies in animals highlight that the presence of increased neutrophil numbers in the airways should be considered as a potential contributing factor to the development of asthma. COPD In animal models of COPD, neutrophils appear to be the key cell in the oxidant/antioxidant and protease/antiprotease imbalance, which is thought to be central to the pathogenesis of this condition, as a result of the release of their toxic oxygen radicals and proteases. Early studies, which led to the development of the protease/antiprotease theory of emphysema, found that installation of a proteolytic enzyme resulted in alveolar tissue destruction.37 Subsequently studies identified neutrophil elastase as the major proteolytic enzyme responsible with increased levels of elastase being detected in plasma and lavage of smokers, which was further increased during acute smoking.25,38,39 As cigarette smoke is a major factor implicated in the development of emphysema, cigarette smoke or its derivatives have been used in animal models.40–43 Li and colleagues40,42 found depletion of reduced glutathione in rat lung following installation with cigarette smoke condensate. Likewise, increased activity of the enzymes superoxide dismutase and glutathione peroxidase in rat lung in response to cigarette smoke exposure was reported.44 Such models have implicated oxygen radicals, and proposed the oxidant/ antioxidant imbalance theory, as a mechanism involved in the tissue destruction resulting in emphysema.
TRAFFICKING OF NEUTROPHILS IN THE LUNGS It is evident from the studies described above that chronic inflammation is present in both asthma and, particularly, in COPD. There are, however, differences in the type and location of the inflammatory response that occurs in each condition, which may relate to the development of these distinct lung diseases. Such differences can be attributed to the stimuli initiating the inflammation, but may also be influ-
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enced by the manner of neutrophil trafficking within, and emigration from, the circulatory beds in the proximal and distal airways. Circulating and marginating leucocyte pools The lung, as an organ, is unique in that it contains two distinct circulations, pulmonary and bronchial. Because of its function in gas exchange, the pulmonary circulation is structurally very different from the bronchial (systemic) circulation. The pulmonary microvasculature is composed of short interconnecting segments, which accommodate the large drop in blood pressure necessary for blood flow through vessels of minimal wall thickness to allow for gas exchange. The bronchial circulation, as for all the systemic circulation, supplies the nutrients required by the tissues, in this case to the lungs. To perform their role as phagocytes, neutrophils must be recruited from the circulation to the site of infection in the tissues. Such recruitment comprises a sequence of events, which differ for the bronchial and pulmonary circulations owing to the distinct structure and dimensions of their microvascular beds. Neutrophil margination and sequestration The location of neutrophils in the margins of postcapillary venules of the systemic circulation has been termed “margination”. As blood flow along the vessel wall is slower than the central axial stream, the cells displaced to this region move more slowly. Their slowed transit allows for adhesive interactions to occur between the leucocytes and the endothelium, which would further retard the cells’ transit.45 A similar delayed transit of leucocytes also occurs in the pulmonary vasculature, but occurs in the capillary bed and is due to the restrictions caused by the smaller vascular dimensions relative to that of the neutrophil.46 Thus, the total blood pool of leucocytes can be divided into the circulating and marginated or sequestered pools, with a continual flux occurring between the two.47 It is from the noncirculating (marginated or sequestered) pool that neutrophils can be mobilized in times of stress to return to the circulation, or in response to infection in the tissues to migrate out of the circulation. The distribution of the inflammatory infiltrate throughout the lungs differs for asthma and COPD (see below), so the location where activation of recruited and resident inflammatory cells occurs may be important in their different pathologies. Asthma is mainly a large-airways disease, whereas the pathological changes in COPD occur in both the central and small airways.The recruitment of neutrophils from the pulmonary microcirculation into the alveolar spaces,46 as established in COPD, is thought to play a major role in the tissue destruction of emphysema. By the very nature of the pulmonary circulation, the first contact neutrophils have with inhaled cigarette smoke, and thus their possible activation, is in the center of the acinus where emphysema is predominant in smokers.47 Whether neutrophil activation occurs whilst the cells are sequestered within the microvasculature, during transit from the circula-
tion to the lungs, or once in the airspaces has not definitively been established. Indeed, it is likely that activation can occur at all three sites. The normal delayed passage of neutrophils through the pulmonary capillary bed, relative to the passage of erythrocytes, is further delayed when the cells are exposed to inhaled cigarette smoke.48 Cigarette smoke also causes the release of neutrophils from bone marrow, which preferentially sequester in the pulmonary microvasculature as these immature neutrophils are less deformable.49 Likewise, inflammatory mediators released by alveolar macophages and epithelium activated by cigarette smoke can transiently reduce neutrophil deformability, causing their sequestration in capillaries.50 Neutrophil emigration The process of neutrophil migration from the pulmonary capillary bed is different from the sequence of events necessary for emigration from the systemic circulation (Fig. 13.1). In the systemic circulation, marginated neutrophils are captured from the flowing blood by a rolling adhesive interaction with the endothelium mediated mainly by the selectins (Table 13.2). The neutrophil may then respond to activating agents on the endothelium and firm adhesion takes place, which facilitates subsequent emigration into the tissues.45 This sequence differs for recruitment from the pulmonary capillaries, as cell sequestration is initiated by the cells’ ability to deform, which is necessary as the neutrophil is, on average, larger than the lumen of the
(a) 1. Tethering/rolling
2.Activation/ firm adhesion
3. Transendotheal migration
(b) Airspace 3. Transendotheal migration
Interstitium
Capillary 1.Deformation
2.Activation/firm adhesion
Fig. 13.1. Schematic of the different mechanisms of neutrophil capture and delayed transit in, and emigration from, (a) the systemic postcapillary venules, and (b) the pulmonary capillaries.
134 Table 13.2.
Asthma and Chronic Obstructive Pulmonary Disease
Neutrophil–endothelial cell adhesion molecules
Neutrophil
Endothelium
Rolling adhesion
L-selectin
E- and P-selectin
Firm adhesion
CD11/18
ICAM-1 and 2, VCAM-1
Migration
CD11/18, PECAM-1
ICAM-1 and 2, VCAM-1, PECAM-1
capillaries, through which they must traverse during each circulation of the body.24 Subsequently, adhesive molecules on both neutrophils and on the endothelium prolong the cells’ retention in the capillaries, and mediate extravasation.51 In the pulmonary circulation, both CD11/CD18dependent and -independent migration has been observed, depending on the initial activating agent.52 As the bronchial capillaries are larger than the pulmonary capillaries, and the (driving) blood pressure is greater, cell deformability will play less of a role in neutrophil sequestration in the bronchial circulation. Neutrophil kinetics through the pulmonary microvasculature has received considerable attention in the past. However, only recently has neutrophil kinetics in the bronchial circulation been addressed. Baile and colleagues53 found that 50–60% of neutrophils were retained in their transit of the bronchial circulation, relative to erythrocyte transit. Although neutrophils were delayed less (20–30%) in their transit of the bronchial circulation when compared with the first transit of neutrophils in the pulmonary vasculature, this normal sequestration in the bronchial microvasculature would still provide a considerable pool of neutrophils which could respond to inhaled irritants either directly, or indirectly, to proinflammatory mediators released by the presence of inhaled irritants in the lungs.
ROLE OF THE NEUTROPHIL IN LUNG I N F L A M M AT I O N A N D I N J U RY I N A I R WAY S D I S E A S E S The neutrophil, in its immunological role in combating infection, is armed with a toxic arsenal comprising: • reactive oxygen species (superoxide anion, hydrogen peroxide, hydroxyl radical, hypochlorous acid); • proteases (elastase, matrix metalloproteases, cathepsins); • defensins. The major role of this cell in the inflammatory processes in the lungs is to remove the invading pathogens through a tightly controlled process involving phagocytosis of the foreign organism into a lysosome for destruction by
proteolytic enzymes stored in the cytoplasmic granules, and oxygen free radicals generated from lysosome and plasma membranes. However, the neutrophil may cause host tissue damage, when malfunction of the normal response occurs by: • inappropriate activation; • excessive production of these toxic oxygen radicals and proteases released into the cells’ environment; • reduction of the protective mechanisms. These factors have, to some extent, been observed in asthma and COPD. Activation of the increased numbers of neutrophils recruited into the lungs may be enough to overwhelm the airway antioxidant and antiprotease defense mechanisms, particularly when these innate mechanisms are also reduced by the oxidant burden of cigarette smoke inhalation, by inactivating antiproteases, or by dietary antioxidant deficiency.54 Also, several studies have reported increased functional activity for both peripheral blood and airway neutrophils in patients with COPD and asthma, as measured by increased superoxide anion release and free proteolytic activity (see below). Evidence of enhanced reactive oxygen species production The spontaneous, as well as PMA-stimulated, O2 generation by peripheral blood neutrophils is significantly increased for patients with acute exacerbations compared with healthy control subjects.27 The enhanced O2 release was found to return to levels equivalent to controls by the end of treatment of the exacerbation. Moreover, exacerbations of COPD are also associated with a depleted plasma antioxidant potential in the blood, demonstrating the presence of a systemic oxidant stress.27 A significant correlation was also found for PMAstimulated superoxide anion release by peripheral blood neutrophils and bronchial hyperreactivity in both smokers and ex-smokers with chronic airflow obstruction.55 Furthermore, considering that neutrophils may be delayed in the microcirculation of the lung for some time, several studies have shown that the neutrophils in the sequestered pool released increased amounts of reactive oxygen metabolites compared with circulating cells.21,56,57 Additionally, leucocytes that had migrated into the airways of smokers, obtained by broncholaveloar lavage (BAL), had increased free radical production compared with nonsmokers.58 Likewise, increased production of reactive oxidants was observed for peripheral blood neutrophils from asthmatics.59 Greater levels of reactive oxygen species generation were observed for neutrophils from stable asthmatics compared with control subjects, with even higher levels detected in unstable asthmatics.28 Superoxide anion production by neutrophils in asthmatics likewise correlated with airflow obstruction (FEV1),26 suggesting a role for these oxygen metabolites in the development of airway obstruction.
Neutrophils
Another potent oxidant, nitric oxide, which is present in high levels in exhaled breath from asthmatics, can combine with O2 generated by neutrophils to form the highly reactive peroxynitrite. Additionally, increased levels of the enzyme myeloperoxidase (MPO) were detected in BAL obtained from both allergic and nonallergic asthma patients when stable, compared with control subjects.14 MPO levels in the airways demonstrate the presence of neutrophils, and also represent an increased oxidant burden. This oxidant burden results when neutrophil-derived hydrogen peroxide (H2O2), which is detected in increased levels in breath condensate from asthmatics, interacts with MPO to form hypochlorous acid (HOCl). Increased MPO levels have also been reported in BAL from COPD patients, which correlated significantly with neutrophil numbers and IL-8 levels.60 Thus, neutrophil-derived oxidants are increased and may potentially mediate tissue damage in both asthma and COPD. Evidence for increased protease release As well as the damaging effects of oxidants, one hypothesis for alveolar destruction in COPD is parenchymal digestion through proteases released by neutrophils and macrophages.61 Neutrophil elastase is probably the major candidate, although several matrix metalloproteases (MMP) may also be involved.62 Normally the presence locally of an abundance of antiproteases would protect host tissue from degradation by any proteases which are released. However, reactive oxidants generated by neutrophils, as well as the oxidants in cigarette smoke, are capable of inactivating proteinase inhibitors, resulting in a local protease/antiprotease imbalance.63 Increased neutrophil elastase activity has been measured in both blood and lavage from patients with emphysema64 and in smokers, compared with nonsmokers.39,65 Moreover, further augmenting tissue destruction, cigarette smoke also inhibits elastin cross-linking, which would serve to slow the repair process.66 In asthma, free proteolytic activity in the lungs has been associated with smooth muscle cell proliferation and airway fibrosis, which would cause the airway narrowing characteristic of chronic asthma.67–70 Additionally, increased elastolytic activity and neutrophil-derived oxidants can also increase mucus secretion from submucosal glands, airway goblet cells,71 and epithelial cells,72 which could hinder the phagocytosis process as well as contribute to the airflow obstruction in both asthma and COPD.
R E S O L U T I O N O F I N F L A M M AT I O N The process involved in the resolution of inflammation may also be affected in these airway diseases. The role of programmed cell death, or apoptosis, of the inflammatory infiltrate has been demonstrated in the acute lung disease, adult respiratory distress syndrome (ARDS).73 The
135
chronic inflammation observed in asthma and particularly COPD may, in part, be due to an imbalance between proinflammatory factors initiating and maintaining inflammation, and the resolution of the inflammatory process caused by ineffective clearance of inflammatory cells. Much work is ongoing in examining the mechanism and control of apoptosis in different cell types. It has been established that eosinophils and neutrophils respond differently, and frequently in a contrasting manner, to initiators and inhibitors of the apoptotic pathway.74 The finding that increased eosinophil apoptosis in asthmatics treated with corticosteroids was associated with improved airway function demonstrates the importance of apoptosis in this inflammatory lung disease.75 Moreover, treatment with corticosteroids enhances neutrophil survival,76 which would serve to enhance neutrophil numbers in the airways. A repeated insult of the airways, as well as repeatedly initiating an inflammatory process, with cigarette smoke (as occurs in smokers), or environmental or occupational allergens in asthmatics, may also repeatedly switch off the clearance pathway.
CONSEQUENCES OF ABNORMAL NEUTROPHIL FUNCTION The consequences of abnormal neutrophil function resulting in diseases such as asthma and COPD have been discussed throughout this chapter. Although neutrophil numbers are increased in the airways of patients with chronic asthma and in exacerbations of asthma, the pathogenic role of neutrophils is not proven in either disorder. The presence of increased numbers of neutrophils in both diseases means a greater potential for damage by release of the neutrophils’ toxic components (oxygen radicals, proteases, defensins). It is clear that neutrophil-derived oxidants can cause direct tissue injury. Increased oxygen radical production can also inactivate the antiproteases of the lung, such as a1-proteinase inhibitor and secretory leukoprotease inhibitor,25,77 required to counteract neutrophil and macrophage proteases. In addition to injury, oxidant-mediated signaling events can also result in smooth muscle cell proliferation in asthma and increased mucin production in both asthma and COPD.72 Moreover, oxidants are known to be involved in the activation of transcription factors such as NF-jB and AP-1, which initiate the transcription of proinflammatory genes such as IL-8 and TNF-a.78,79 These in turn can activate neutrophils, as well as the other phagocytes and epithelial cells, to release oxygen radicals, thus setting a vicious cycle in process. From the many papers discussed in this chapter, it is evident that neutrophils are prevalent in the airways of patients with COPD and asthma; and, by virtue of their toxic metabolites, appear to play a role in the pathogenesis of both asthma and COPD.
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21. Williams TJ, Das A, von Uexkull C, Nourshargh S. Neutrophils in asthma. Ann. NY Acad. Sci. 1991; 629:73–81. 22. Zaitsu M, Hamasaki Y, Matsuo M et al. New induction of leukotriene A(4) hydrolase by interleukin-4 and interleukin-13 in human polymorphonuclear leukocytes. Blood 2000; 96:601–9. 23. Mills PR, Davies RJ, Devalia JL. Airway epithelial cells, cytokines, and pollutants. Am. J. Respir. Crit. Care Med. 1999; 160: S38–S43. 24. Selby C, Drost E, Wraith PK, MacNee W. In vivo neutrophil sequestration within lungs of humans is determined by in vitro “filterability”. J. Appl. Physiol. 1991; 71:1996–2003. 25. Janoff A, Raju L, Dearing R. Levels of elastase activity in bronchoalveolar lavage fluids of healthy smokers and nonsmokers. Am. Rev. Respir. Dis. 1983; 127:540–4. 26. Kanazawa H, Kurihara N, Hirata K, Takeda T. The role of free radicals in airway obstruction in asthmatic patients. Chest 1991; 100:1319–22. 27. Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in asthma, COPD, and smokers. Am. J. Respir. Crit. Care Med. 1996; 154:1055–60. 28. Vachier I, Chanez P, Le Doucen C et al. Enhancement of reactive oxygen species formation in stable and unstable asthmatic patients. Eur. Respir. J. 1994; 7:1585–92. 29. Vignola AM, Bonanno A, Mirabella A et al. Increased levels of elastase and alpha1-antitrypsin in sputum of asthmatic patients. Am. J. Respir. Crit. Care Med. 1998; 157:505–11. 30. Sampson AP. The role of eosinophils and neutrophils in inflammation. Clin. Exp. Allergy 2000; 30(Suppl. 1):22–7. 31. Wardlaw AJ. Molecular basis for selective eosinophil trafficking in asthma: a multistep paradigm. J Allergy Clin Immunol 1999; 104:917–26. 32. Fabbri LM, Aizawa H, Alpert SE et al. Airway hyperresponsiveness and changes in cell counts in bronchoalveolar lavage after ozone exposure in dogs. Am. Rev. Respir. Dis. 1984; 129:288–91. 33. Matsumoto K, Aizawa H, Inoue H et al. Role of neutrophil elastase in ozone-induced airway responses in guinea-pigs. Eur. Respir. J. 1999; 14:1088–94. 34. Murlas C, Roum JH. Bronchial hyperreactivity occurs in steroidtreated guinea pigs depleted of leukocytes by cyclophosphamide. J. Appl. Physiol. 1985; 58:1630–7. 35. Lukacs NW, Lamm WJ, Strieter RM, Albert RK. Airway hyperreactivity is associated with specific leukocyte subset infiltration in a mouse model of allergic airway inflammation. Pathobiology 1996; 64:308–13. 36. O’Byrne PM, Walters EH, Gold BD et al. Neutrophil depletion inhibits airway hyperresponsiveness induced by ozone exposure. Am. Rev. Respir. Dis. 1984; 130: 214–19. 37. Gross P, DeTreville RT, Babyak MA, Kaschak M, Tolker EB. Experimental emphysema: effect of chronic nitrogen dioxide exposure and papain on normal and pneumoconiotic lungs. Arch. Environ. Hlth 1968; 16:51–8. 38. Snider GL, Lucey EC, Stone PJ. Animal models of emphysema. Am. Rev. Respir. Dis. 1986; 133:149–69. 39. Weitz JI, Crowley KA, Landman SL, Lipman BI, Yu J. Increased neutrophil elastase activity in cigarette smokers. Ann. Intern. Med. 1987; 107:680–2. 40. Chitano P, Hosselet JJ, Mapp CE, Fabbri LM. Effect of oxidant air pollutants on the respiratory system: insights from experimental animal research. Eur. Respir. J. 1995; 8:1357–71. 41. Gairola CG. Free lung cell response of mice and rats to mainstream cigarette smoke exposure. Toxicol. Appl. Pharmacol. 1986; 84:567–75. 42. Li XY, Donaldson K, Rahman I, MacNee W. An investigation of the role of glutathione in increased epithelial permeability induced by cigarette smoke in vivo and in vitro. Am. J. Respir. Crit. Care Med. 1994; 149: 1518–25. 43. Wright JL, Churg A. Cigarette smoke causes physiologic and morphologic changes of emphysema in the guinea pig. Am. Rev. Respir. Dis. 1990; 142:1422–8.
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44. York GK, Peirce TH, Schwartz LW, Cross CE. Stimulation by cigarette smoke of glutathione peroxidase system enzyme activities in rat lung. Arch. Environ. Hlth 1976; 31:286–90. 45. Von Andrian UH, Hansell P, Chambers JD et al. L-selectin function is required for beta 2-integrin-mediated neutrophil adhesion at physiological shear rates in vivo. Am. J. Physiol. 1992; 263:H1034–44. 46. Downey GP, Worthen GS, Henson PM, Hyde DM. Neutrophil sequestration and migration in localized pulmonary inflammation. Capillary localization and migration across the interalveolar septum. Am. Rev. Respir. Dis. 1993; 147:168–76. 47. Hogg JC. Neutrophil kinetics and lung injury. Physiol. Rev. 1987; 67:1249–95. 48. MacNee W,Wiggs B, Belzberg AS, Hogg JC. The effect of cigarette smoking on neutrophil kinetics in human lungs. N. Engl. J. Med. 1989; 321:924–8. 49. Terashima T, Klut ME, English D et al. Cigarette smoking causes sequestration of polymorphonuclear leukocytes released from the bone marrow in lung microvessels. Am. J. Respir. Cell Mol. Biol. 1999; 20:171–7. 50. Drost EM, MacNee W. Differential effects of inflammatory mediators on PMN deformability and adhesion. Thorax 1997; 52:S118. 51. Kubo H, Doyle NA, Graham L et al. L- and P-selectin and CD11/CD18 in intracapillary neutrophil sequestration in rabbit lungs. Am. J. Respir. Crit. Care Med. 1999; 159:267–74. 52. Doerschuk CM, Tasaka S, Wang Q. CD11/CD18-dependent and -independent neutrophil emigration in the lungs: how do neutrophils know which route to take? Am. J. Respir. Cell Mol. Biol. 2000; 23:133–6. 53. Baile EM, Pare PD, Ernest D, Dodek PM. Distribution of blood flow and neutrophil kinetics in bronchial vasculature of sheep. J. Appl. Physiol. 1997; 82:1466–71. 54. Hatch GE. Asthma, inhaled oxidants, and dietary antioxidants. Am. J. Clin. Nutr. 1995; 61:625S–30S. 55. Postma DS, Renkema TE, Noordhoek JA et al. Association between nonspecific bronchial hyperreactivity and superoxide anion production by polymorphonuclear leukocytes in chronic air-flow obstruction. Am Rev. Respir Dis. 1988; 137:57–61. 56. Brown DM, Drost E, Donaldson K, MacNee W. Deformability and CD11/CD18 expression of sequestered neutrophils in normal and inflamed lungs. Am. J. Respir. Cell Mol. Biol. 1995; 13:531–9. 57. Ludwig PW, Hoidal JR. Alterations in leukocyte oxidative metabolism in cigarette smokers. Am. Rev. Respir. Dis. 1982; 126:977–80. 58. Morrison D, Rahman I, Lannan S, MacNee W. Epithelial permeability, inflammation, and oxidant stress in the air spaces of smokers. Am. J. Respir. Crit. Care Med. 1999; 159:473–9. 59. Meltzer S, Goldberg B, Lad P, Easton J. Superoxide generation and its modulation by adenosine in the neutrophils of subjects with asthma. J. Allergy Clin. Immunol. 1989; 83:960–6. 60. Pesci A, Balbi B, Majori M et al. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur. Respir. J. 1998; 12:380–6.
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61. Snider GL. Experimental studies on emphysema and chronic bronchial injury. Eur. J. Respir. Dis. Suppl. 1986; 146:17–35. 62. Finlay GA, Russell KJ, McMahon KJ et al. Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients. Thorax 1997; 52:502–6. 63. Janoff A. Elastase in tissue injury. Annu. Rev. Med. 1985; 36:207–16. 64. Yoshioka A, Betsuyaku T, Nishimura M et al. Excessive neutrophil elastase in bronchoalveolar lavage fluid in subclinical emphysema. Am. J. Respir. Crit. Care Med. 1995; 152:2127–32. 65. Abboud RT, Fera T, Johal S, Richter A, Gibson N. Effect of smoking on plasma neutrophil elastase levels. J. Lab. Clin. Med. 1986; 108:294–300. 66. Laurent P, Janoff A, Kagan HM. Cigarette smoke blocks crosslinking of elastin in vitro. Am. Rev. Respir. Dis. 1983; 127:189–92. 67. Hogg JC. The pathology of asthma. Clin. Chest Med. 1984; 5:567–71. 68. Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity. Am. Rev. Respir. Dis. 1989; 140:1745–53. 69. Jeffery PK. Histological features of the airways in asthma and COPD. Respiration 1992; 59 (Suppl. 1):13–16. 70. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989; i:520–4. 71. Laitinen LA, Laitinen A, Haahtela T. Airway mucosal inflammation even in patients with newly diagnosed asthma. Am. Rev. Respir. Dis. 1993; 147:697–704. 72. Fischer B, Voynow J. Neutrophil elastase induces MUC5AC messenger RNA expression by an oxidant-dependent mechanism. Chest 2000; 117:317S–20S. 73. Matute-Bello G, Liles WC, Radella F et al. Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit. Care Med. 2000; 28:1–7. 74. Haslett C. Granulocyte apoptosis and its role in the resolution and control of lung inflammation. Am. J. Respir. Crit. Care Med. 1999; 160:S5–11. 75. Woolley KL, Gibson PG, Carty K et al. Eosinophil apoptosis and the resolution of airway inflammation in asthma. Am. J. Respir. Crit. Care Med. 1996; 154:237–43. 76. Cox G. Glucocorticoid treatment inhibits apoptosis in human neutrophils: separation of survival and activation outcomes. J. Immunol. 1995; 154:4719–25. 77. Vogelmeier C, Biedermann T, Maier K et al. Comparative loss of activity of recombinant secretory leukoprotease inhibitor and alpha 1-protease inhibitor caused by different forms of oxidative stress. Eur. Respir. J. 1997; 10:2114–19. 78. Barnes PJ, Adcock IM. Transcription factors and asthma. Eur. Respir. J. 1998; 12:221–34. 79. Rahman I, MacNee W. Role of transcription factors in inflammatory lung diseases. Thorax 1998; 53:601–12.
Chapter
Fibroblasts
14
Robin J. McAnulty and Geoffrey J. Laurent Royal Free and University College Medical School, London, UK
Fibroblasts/myofibroblasts are the most abundant cells in the lung and are primarily responsible for producing the extracellular matrix proteins which maintain the structure of the airways and lung parenchyma.In asthma and chronic obstructive pulmonary disease (COPD) there are changes in the deposition, location, and organization of these proteins together with changes in the number and phenotype of fibroblasts. These changes may play a critical role in the loss of airway and lung function associated with these diseases. There are both similarities and differences in the bronchiolar and peribronchiolar changes in extracellular matrix between the diseases. The mechanisms responsible for these changes are incompletely understood and merit further investigation since current treatments have little effect on this aspect of the pathology.
FIBROBLASTS AND THE E X T R A C E L L U L A R M AT R I X Asthma Subepithelial thickening of asthmatic bronchi and bronchioli has been recognized for many years,1 but it is only relatively recently that this has begun to be characterized. There is a 2–3 fold increase in the thickness of the lamina reticularis between the epithelial basement membrane and the smooth muscle layer.2–6 There is also evidence of thickening of the outer wall or adventitia of the airway.5 However it is uncertain whether this is due to edema, increased deposition of extracellular matrix proteins, or both. In contrast, the thickened lamina reticularis has been shown to contain a variety of extracellular matrix proteins. These include: • collagen types I, III and V;3,6,7 • elastin;8 • fibronectin.3 For a more detailed review of the constituents of the airway extracellular matrix, see Akers et al.,9 and Chapter 22. The increase in the thickness of the lamina reticularis has been correlated with an increase in fibroblast/myofibroblast
numbers,4,8,10 airway hyperresponsiveness,11,12 and reduced lung function.13 Fibroblasts have been localized to the lamina reticularis and form a sheath surrounding the airways.14 Myofibroblasts are also found in the lamina reticularis appearing as multicellular strands.4,15,16 They are similar to fibroblasts but are morphologically larger with a greater proportion of cytoplasm and express a-smooth muscle actin.4,17 COPD COPD represents a combination of conditions: chronic obstructive bronchiolitis, mucus hypersecretion and plugging, and emphysema. In contrast to asthma there is much less information on the changes that occur in the airways of patients with COPD. In COPD most of the extracellular matrix changes occur in the peripheral airways and surrounding parenchyma. As in asthma there is an increase in the thickness of the inner (lamina reticularis) and outer (adventitia) walls of the airways. However, this thickening occurs to a lesser extent than that seen in asthma, with increases of about 20–30%.5,18 Little is known of the composition of individual extracellular matrix proteins associated with this thickening, or of the changes in fibroblast number or phenotype. In addition to changes in the airway wall, emphysematous lesions of the surrounding parenchyma lead to the destruction of alveolar connections to the outer bronchial wall, causing further obstruction of the airways.19,20
R E G U L AT I O N O F F I B R O B L A S T M I G R AT I O N , P R O L I F E R AT I O N , D I F F E R E N T I AT I O N A N D E X T R A C E L L U L A R M AT R I X P R O T E I N SYNTHESIS Fibroblasts are highly active cells which can be induced to migrate, proliferate, differentiate, and alter their extracellular matrix production and deposition. They respond to many different mediators which they release, or which are produced by other resident or inflammatory cells, as well as mediators derived from the circulation (Fig. 14.1).
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Fibroblasts Epithelial cells EGF, ET-1, FGF2, fibronectin, GM-CSF, IGF-1, IL-1, IL-6, IL-8, PDGF, PGE2, PGF2α, PGI2, TGF-β
ET-1, FGF2, GM-CSF, fibronectin, IGF-1, IL-1, IL-6, IL-8, MCP-1, PDGF, PGE2, PGI2, TGF-β
Macrophages ET-1, fibronectin, GM-CSF, IGF-1, IL-1, IL-6, IL-8, LTB4, PAF, PDGF, PGE2, PGF2α, TGF-β-TNF-α
Lymphocytes GM-CSF, IFN-γ, IL-1, IL-4, IL-6, IL-10, IL-13, TNF-α
Migration
Neutrophils
Differentiation
IL-1, IL-8, LTB4
Fibroblasts Vasculature and endothelium bradykinin, ET-1, FGF2, IL-1, IL-6, PDGF, TGF-β, thrombin
Sensory nerves Proliferation
ECM synthesis
Eosinophils
Smooth muscle cells FGF2, IGF-1, PGE2, TGF-β
bombesin, CGRP, neurokinin A, substance P
Mast cells histamine, IL-1, IL-4, IL-6, PGD2, leukotrienes, TGF-β, TNF-α, tryptase
ECP, GM-CSF, leukotrienes, PAF, PDGF, prostaglandins, TGF-α, TGF-β, TNF-α
Fig. 14.1. Regulation of fibroblast function. Major functions of fibroblasts including migration, differentiation between fibroblast and myofibroblast phenotypes, proliferation, and extracellular matrix (ECM) synthesis can be modulated by many cells and mediators. This diagram highlights mediators which are likely to be up- or downregulated in the airways of individuals with asthma or COPD and which have direct effects on one or more fibroblast functions. The precise role of these mediators in the regulation of fibroblast function and airway remodeling associated with asthma and COPD has yet to be fully characterized.
In addition, these cells may release mediators which, although not having direct effects on fibroblasts, may stimulate other cells to release mediators having direct effects on fibroblasts. For example, eotaxin produced by fibroblasts can attract eosinophils which are capable of releasing mediators that have direct effects on all fibroblast functions. Furthermore, fibroblasts synthesize matrix metalloproteinases (MMP) and their inhibitors, tissue inhibitors of metalloproteinase (TIMP), which regulate degradation of extracellular matrix proteins and could modulate fibroblast function via altered cell–matrix interactions (see Chapter 29). The synthesis and ratios of MMPs and TIMPs are known to be altered in asthma and COPD. In addition to endogenous mediators, inhaled toxicants may also affect fibroblast function. For example, the major risk factor for the development of COPD is cigarette smoking, and cigarette smoke can directly and indirectly affect fibroblasts. Apart from modulating release of inflammatory mediators, smoke can directly inhibit fibroblast functions, including migration, proliferation, and matrix production and remodeling.21,22 Thus the ultimate response of a fibroblast depends on a complex balance of stimulatory and inhibitory mediators acting upon it, as well as cell–cell and
cell–matrix interactions which can modulate fibroblast function. There is still relatively little information on the regulation of fibroblast function in relation to asthma and COPD. However, the evidence suggests that in both asthma and COPD an environment exists in the airway which adversely affects fibroblast migration, proliferation, differentiation, and extracellular matrix deposition. The following sections review the evidence for a role for stimulatory and inhibitory mediators of fibroblast function in these diseases.
S T I M U L AT O RY M E D I AT O R S Transforming growth factor-b Transforming growth factor-b (TGF-b) is one of the most extensively studied mediators in relation to airway remodeling in asthma and COPD (see Chapter 30). It is capable of stimulating fibroblast migration, differentiation of fibroblasts to myofibroblasts, modulates fibroblast proliferation, and is one of the most potent stimulants of extracellular matrix protein synthesis and deposition. In the normal airways, TGF-b is localized predominantly to the bronchial epithelium.23,24
Fibroblasts
In the airways of asthmatics and chronic bronchitics, TGF-b expression is increased and it is localized predominantly to submucosal and inflammatory cells, including fibroblasts and eosinophils, and the connective tissue of the airway wall, with expression in epithelial cells appearing to be variable.10, 13, 24–28 In addition, levels of TGF-b are greater in bronchoalveolar lavage from asthmatics than controls and increase further following allergen exposure.29 It has also been demonstrated that allergen challenge increases fibroblast activation and the appearance of increased numbers of myofibroblasts assessed at light and electron microscopic levels.16 Expression of TGF-b has also been shown to correlate with fibroblast number and subepithelial thickening of the airway in biopsies obtained from asthmatics and chronic bronchitics,10,27 and has been correlated with severity of asthma.13 Together the evidence suggests that TGF-b plays an important role in the pathogenesis of these diseases and that approaches to reduce the expression or activity of TGF-b may be of potential benefit in the treatment of asthma and COPD. Endothelin-1 Endothelin-1 (ET-1) has also been studied extensively in the context of asthma, although primarily because of its bronchoconstrictor and inflammatory effects (see Chapter 31). However, it is also capable of stimulating fibroblast migration, differentiation, proliferation, and extracellular matrix protein synthesis, and it inhibits extracellular matrix protein degradation. In normal airways there is limited expression of ET-1 mRNA and protein staining in airway epithelium and vascular endothelium.30,31 In asthmatic airways, prepro ET-1 gene expression and staining for mature active ET-1 is increased and again localized predominantly to the airway epithelium and vascular endothelium.30,31 Levels of ET-1 have also been shown to be increased in bronchoalveolar lavage fluid of asthmatics.32,33 In addition, bronchial epithelial cells cultured from asthmatic airways can modulate fibroblast/myofibroblast differentiation and proliferation via mechanisms involving ET-1.34,35 Treatment of asthmatics or bronchial epithelial cells derived from asthmatic airways with corticosteroids reduces the production of ET-1.32,33,36 In contrast to asthma, ET-1 mRNA and protein are not generally increased in patients with chronic bronchitis,31,32 although an increase in sputum ET-1 has been reported in patients with stable COPD.37 Thus the development of ET-1 inhibitors such as endothelin receptor antagonists may have potential applications in the treatment of airway remodeling as well as bronchoconstriction and inflammation associated with asthma. Interleukin-4 Interleukin-4 (IL-4), a cytokine produced predominantly by Th2 lymphocytes and mast cells, stimulates fibroblast proliferation and synthesis of extracellular matrix proteins
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including collagens and proteoglycans (see Chapter 28). In addition, IL-4 stimulates fibroblasts to release eotaxin, providing a further indirect mechanism of fibroblast activation. In asthma there is increased expression of IL-4 mRNA and protein associated with T lymphocytes, mast cells, and eosinophils in both the large and small airways.38,39 IL-4 production by T lymphocytes, obtained from asthmatic bronchoalveolar lavage,is upregulated by allergen challenge.40 There is little information on the expression and effects of IL-4 in COPD, although, in contrast to asthma, in peripheral blood from patients with COPD there is a decreased proportion of T lymphocytes expressing IL-4 compared with controls.41 Thus the effects of increased amounts of IL-4 on fibroblasts in the airways of asthmatics may contribute to the thickening of the lamina reticularis in this disease. The apparent differences in IL-4 expression between asthma and COPD may at least partly explain the differences in airway remodeling between these two conditions. Treatment of asthma with corticosteroids has been shown to reduce IL-4 expression,42 suggesting that treatment with corticosteroids or more selective inhibitors of IL-4 may restrict fibroblast activation and airway remodeling. Platelet derived growth factor Platelet derived growth factor (PDGF) is a potent stimulant of fibroblast migration and proliferation (see Chapter 30). The PDGF-B isoform is expressed in the lung, but the majority of studies suggest there is no difference in expression in asthmatics compared with controls.10,43–45 However, one study has shown an increase in PDGF-B expression associated with eosinophils in severe asthmatics,46 and there may even be a decrease in PDGF-B expression in COPD.43 There is less information on the PDGF-A isoform, but again there appears to be no difference between asthmatics and controls.45 Thrombin Thrombin, thrombin–antithrombin complex, and tissue factor levels have been shown to be increased in induced sputum from asthmatics compared with controls, and there is also evidence for increased thrombin formation in patients with COPD.47,48 In addition to its role in blood coagulation, thrombin is also capable of stimulating fibroblast migration, proliferation, and extracellular matrix synthesis via activation of cell surface protease activated receptors (PAR), indicating an additional potential role in airway remodeling. Epidermal growth factor Epidermal growth factor (EGF) stimulates fibroblast proliferation and synergizes with other fibroblast mitogens (see Chapter 30). Immunohistochemical staining demonstrates increased EGF in the airway epithelium and submucosa in asthma and chronic bronchitis, and increased EGF receptor staining in asthmatics which correlated with subepithelial thickening.27,49,50
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Neuropeptides In human airways, peptide-containing sensory nerves have been localized to the submucosa, often in close apposition to subepithelial fibroblasts. These nerves contain neuropeptides such as substance P and neurokinin A, and there is evidence for an increase in substance P immunoreactive nerve fibers in severe asthmatics51,52 (see Chapter 34). In addition to their effects on bronchoconstriction, airway microvascular leakage, and mucus secretion, these neuropeptides also stimulate fibroblast migration and proliferation, suggesting a potential role in airway remodeling.53,54
I N H I B I T O RY M E D I AT O R S Interferon-c Fibroblast activation can also result from a lack of inhibitory mediators. The Th1 lymphokine, interferon-c (IFN-c), inhibits fibroblast proliferation and extracellular matrix protein synthesis (see Chapter 28). In addition, IFN-c is also capable of stimulating differentiation of myofibroblasts towards a fibroblast phenotype and stimulating extracellular matrix degradation. Lymphocytes from peripheral blood or bronchoalveolar lavage from asthmatics generally show a predominant Th2 pattern of cytokine release with low levels of IFN-c production compared with controls.40,55 Treatment with steroids appears to promote changes towards a Th1 pattern of cytokine production with an increase in the proportion of cells expressing IFN-c.42,56,57 In contrast, there is little information on COPD. One study suggests a predominant Th1 cytokine profile in peripheral blood CD4 cells with a greater proportion of cells producing IFN-c compared with controls.41 The lack of upregulation of IFN-c in asthma in the presence of increased levels of stimulatory mediators described above could play an important role in the remodeling of the airways in this disease. Prostaglandin E2 PGE2 is produced by a number of cells in the lung, including fibroblasts, smooth muscle cells, epithelial cells, and macrophages. It is thought to have bronchoprotective effects in the lung, inhibiting mast cell degranulation, smooth muscle contraction, and eosinophil activation. It can inhibit the early and late response to allergen challenge. In addition, it is a potent inhibitor of fibroblast proliferation and collagen synthesis. Therefore decreased levels of PGE2 in the presence of increased levels of stimulatory mediators of fibroblast function, as has been observed in interstitial pulmonary fibrosis,58 could contribute to fibroblast hyperproliferation and extracellular matrix deposition associated with airway remodeling. There is little information on PGE2 levels in asthma or COPD. It has been suggested that a relative decrease in PGE2 may play a role in the pathogenesis of asthma, and blood levels of PGE2 are lower in asthmatics than in controls.59,60
S U M M A RY There is extensive evidence that mediators released by cells or sequestered in the airways can affect fibroblast function. However, there is little direct proof of a role for any of these mediators in the development of airway remodeling associated with asthma, and even less in COPD. Furthermore, many studies have been conducted with samples from stable asthmatics and may not reflect the changes that occur following exposure to allergens or during exacerbations. Future studies need to be focused on determining the relative importance of different mediators and the timing of expression in initiating and maintaining fibroblast activation, as well as confirming the importance of the fibroblast in airway remodeling and the importance of airway remodeling in the pathogenesis of asthma and COPD. A number of novel strategies are being developed to inhibit mediators and their effects on fibroblast function, including pharmacological inhibitors, antibodies, soluble receptors, and gene therapy.9,61,62 The application of these strategies may provide additional and potentially improved treatments for asthma and COPD.
REFERENCES 1. Huber HL, Koessler KK.The pathology of bronchial asthma. Arch. Intern. Med. 1922; 30:689–760. 2. Jeffery PK, Wardlaw AJ, Nelson FC et al. Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am. Rev. Respir. Dis. 1989; 140:1745–53. 3. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989; i:520–4. 4. Brewster CE, Howarth PH, Djukanovic R. Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am. J. Respir. Cell Mol. Biol. 1990; 3:507–11. 5. Kuwano K, Bosken CH, Pare PD et al. Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1993; 148:1220–5. 6. Wilson JW, Li X. The measurement of reticular basement membrane and submucosal collagen in the asthmatic airway. Clin. Exp. Allergy 1997; 27:363–71. 7. Chakir J, Laviolette M, Boutet M et al. Lower airways remodeling in nonasthmatic subjects with allergic rhinitis. Lab. Invest. 1996; 75:735–44. 8. Gabbrielli S, Di-Lollo S, Stanflin N, Romagnoli P. Myofibroblast and elastic and collagen fiber hyperplasia in the bronchial mucosa: a possible basis for the progressive irreversibility of airway obstruction in chronic asthma. Pathologica 1994; 86(2):157–60. 9. Akers IA, McAnulty RJ, Laurent GJ. In: Page CP, Banner KH, Spina D (eds), Cellular Mechanisms in Airways Inflammation, pp. 159–98. Switzerland: Birkhauser-Verlag, 2000. 10. Hoshino M, Nakamura Y, Sim JJ. Expression of growth factors and remodelling of the airway wall in bronchial asthma. Thorax 1998; 53(1):21–7. 11. Boulet L-P, Belanger M, Carrier G. Airway responsiveness and bronchial-wall thickness in asthma with or without fixed airflow obstruction. Am. J. Respir. Crit. Care Med. 1995; 152:865–71. 12. Chetta A, Foresi A, Del Donno M et al. Bronchial responsiveness to distilled water and methacholine and its relationship to
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inflammation and remodeling of the airways in asthma. Am. J. Respir. Crit. Care Med. 1996; 153:910–17. Minshall EM, Leung DY, Martin RJ et al. Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am. J. Respir. Cell Mol. Biol. 1997; 17:326–33. Evans MJ, Guha SC, Cox RA, Moller PC. Attenuated fibroblast sheath around the basement membrane zone in the trachea. Am. J. Respir. Cell Mol. Biol. 1993; 8:188–92. Ryan GB, Cliff WJ, Gabbiani G et al. Myofibroblasts in human granulation tissue. Hum. Pathol. 1974; 5(1):55–67. Gizycki MJ, Adelroth E, Rogers AV et al. Myofibroblast involvement in the allergen-induced late response in mild atopic asthma. Am. J. Respir. Cell Mol. Biol. 1997; 16:664–73. Sappino AP, Schurch W, Gabbiani G. Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of phenotypic modulations. Lab. Invest. 1990; 63:144–61. Bosken CH, Wiggs BR, Pare PD, Hogg JC. Small airway dimensions in smokers with obstruction to airflow. Am. Rev. Respir. Dis. 1990; 142:563–70. Jeffery PK. Structural and inflammatory changes in COPD; a comparison with asthma. Thorax 1998; 53:129–36. Barnes PJ. Chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343:269–80. Nakamura Y, Romberger DJ, Tate L et al. Cigarette smoke inhibits lung fibroblast proliferation and chemotaxis. Am. J. Respir. Crit. Care Med. 1995; 151:1497–503. Carnevali S, Nakamura Y, Mio T et al. Cigarette smoke extract inhibits fibroblast-mediated collagen gel contraction. Am. J. Physiol. 1998; 274(4 Part 1):L591–8. Coker RK, Laurent GJ, Shahzeidi S et al. Diverse cellular TGFbeta 1 and TGF-beta 3 gene expression in normal human and murine lung. Eur. Respir. J. 1996; 9:2501–7. Magnan A, Retornaz F, Tsicopoulos A et al. Altered compartmentalization of transforming growth factor-beta in asthmatic airways. Clin. Exp. Allergy 1997; 27:389–95. Aubert JD, Dalal BI, Bai TR et al. Transforming growth factor beta 1 gene expression in human airways. Thorax 1994; 49(3):225–32. Ohno I, Nitta Y,Yamauchi K et al. Transforming growth factor beta 1 gene expression by eosinophils in asthmatic airway inflammation. Am. J. Respir. Cell Mol. Biol. 1996; 15:404–9. Vignola AM, Chanez P, Chiappara G et al. Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med. 1997; 156(2 Part 1):591–9. de-Boer WI, van Schadeewijk A, Sont JK et al. Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 158:1951–7. Redington AE, Madden J, Frew AJ et al. Transforming growth factor-beta 1 in asthma: measurement in bronchoalveolar lavage fluid. Am. J. Respir. Crit. Care Med. 1997; 156(2 Part 1):642–7. Springall DR, Howarth PH, Counihan H et al. Endothelin immunoreactivity of airway epithelium in asthmatic patients. Lancet 1991; 337:697–701. Vittori E, Marini M, Fasoli A, de Franchis R, Mattoli S. Increased expression of endothelin in bronchial epithelial cells of asthmatic patients and effect of corticosteroids. Am. Rev. Respir. Dis. 1992; 146(5 Part 1):1320–5. Mattoli S, Soloperto M, Marini M, Fasoli A. Levels of endothelin in the bronchoalveolar lavage fluid of patients with symptomatic asthma and reversible airflow obstruction. J. Allergy Clin. Immunol. 1991; 88(3 Part 1):376–84. Redington AE, Springall DR, Ghatei MA et al. Endothelin in bronchoalveolar lavage fluid and its relation to airflow obstruction in asthma. Am. J. Respir. Crit. Care Med. 1995; 151:1034–9. Sun G, Stacey MA, Bellini A, Marini M, Mattoli S. Endothelin-1 induces bronchial myofibroblast differentiation. Peptides 1997; 18:1449–51.
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35. Zhang S, Smartt H, Holgate ST, Roche WR. Growth factors secreted by bronchial epithelial cells control myofibroblast proliferation: an in vitro co-culture model of airway remodeling in asthma. Lab. Invest. 1999; 79:395–405. 36. Redington AE, Springall DR, Meng QH et al. Immunoreactive endothelin in bronchial biopsy specimens: increased expression in asthma and modulation by corticosteroid therapy. J. Allergy Clin. Immunol. 1997; 100:544–52. 37. Chalmers GW, Macleod KJ, Sriram S et al. Sputum endothelin-1 is increased in cystic fibrosis and chronic obstructive pulmonary disease. Eur. Respir. J. 1999; 13:1288–92. 38. Ying S, Humbert M, Barkans J et al. Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and CD8+ T cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and nonatopic (intrinsic) asthmatics. J. Immunol. 1997; 158:3539–44. 39. Minshall EM, Hogg JC, Hamid QA. Cytokine mRNA expression in asthma is not restricted to the large airways. J. Allergy Clin. Immunol. 1998; 101:386–90. 40. Bodey KJ, Semper AE, Redington AE et al. Cytokine profiles of BAL T cells and T-cell clones obtained from human asthmatic airways after local allergen challenge. Allergy 1999; 54:1083–93. 41. Majori M, Corradi M, Caminati A et al. Predominant Th1 cytokine pattern in peripheral blood from subjects with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 1999; 103(3 Part 1):458–62. 42. Robinson D, Hamid Q, Ying S et al. Prednisolone treatment in asthma is associated with modulation of bronchoalveolar lavage cell interleukin-4, interleukin-5, and interferon-gamma cytokine gene expression. Am. Rev. Respir. Dis. 1993; 148:401–6. 43. Aubert JD, Hayashi S, Hards J et al. Platelet-derived growth factor and its receptor in lungs from patients with asthma and chronic airflow obstruction. Am. J. Physiol. 1994; 266(6 Part 1):L655–63. 44. Taylor IK, Sorooshian M, Wangoo A et al. Platelet-derived growth factor-beta mRNA in human alveolar macrophages in vivo in asthma. Eur. Respir. J. 1994; 7:1966–72. 45. Chanez P, Vignola M, Stenger R et al. Platelet-derived growth factor in asthma. Allergy 1995; 50:878–83. 46. Ohno I, Nitta Y,Yamauchi K et al. Eosinophils as a potential source of platelet-derived growth factor B-chain (PDGF-B) in nasal polyposis and bronchial asthma. New Engl. J. Med. 1992; 326:298–304 47. Alessandri C, Basili S, Violi F et al. Hypercoagulability state in patients with chronic obstructive pulmonary disease. Chronic Obstructive Bronchitis and Haemostasis Group. Thromb. Haemost. 1994; 72(3):343-6. 48. Gabazza EC,Taguchi O,Tamaki S et al.Thrombin in the airways of asthmatic patients. Lung 1999; 177:253–62. 49. Amishimi M, Munakata M, Nasuhara Y et al. Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway. Am. J. Respir. Crit. Care Med. 1998;157(6 Part 1):1907–12. 50. Puddicombe SM, Polosa R, Richer A et al. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J. 2000; 14:1362–74. 51. Ollerenshaw SL, Jarvis D, Sullivan CE, Woolcock AJ. Substance P immunoreactive nerves in airways from asthmatics and nonasthmatics. Eur. Respir. J. 1991; 4:673–82. 52. Joos GF, Kips JC, Peleman RA, Pauwels RA. Tachykinin antagonists and the airways. Arch. Int. Pharmacodyn. Ther. 1995; 329:205–19. 53. Kahler CM, Sitte BA, Reinisch N, Wiedermann CJ. Stimulation of the chemotactic migration of human fibroblasts by substance P. Eur. J. Pharmacol. 1993; 249(3):281–6. 54. Harrison NK, Dawes KE, Kwon OJ et al. Effects of neuropeptides on human lung fibroblast proliferation and chemotaxis. Am. J. Physiol. 1995; 268(2 Part 1):L278–83.
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55. Robinson DS, Hamid Q,Ying S et al. Predominant Th2-like bronchoalveolar T-Lymphocyte population in atopic asthma. New Engl. J. Med. 1992; 326:298–304. 56. Leung DY, Martin RJ, Szefler SJ et al. Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J. Exp. Med. 1995; 181:33–40. 57. Bentley AM, Hamid Q, Robinson DS. Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. Am. J. Respir. Crit. Care Med. 1996; 153:551–6. 58. Keerthisingam CB, Jenkins RG, Harrison NK et al. Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative
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response to transforming growth factor-beta in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice. Am. J. Pathol. 2001; 158:1411–22. Pavord ID, Wong CS, Williams J, Tattersfield AE. Effect of inhaled prostaglandin E2 on allergen-induced asthma. Am. Rev. Respir. Dis. 1993; 148:87–90. Kunkel G, Nigam S, Herold D et al. Arachidonic acid metabolites and their circadian rhythm in patients with allergic bronchial asthma. Chronobiol. Int. 1988; 5(4):387–94. McAnulty RJ, Laurent GJ. Pathogenesis of lung fibrosis and potential new therapeutic strategies. Exp. Nephrol. 1995; 3(2):96–107. Jenkins RG, Herrick SE, Meng Q-H et al. An integrin-targeted non-viral vector for pulmonary gene therapy. Gene Ther. 2000; 7(5):393–400.
Chapter
Epithelial Cells
15
John R. Spurzem Omaha VA Medical Center and University of Nebraska Medical Center, Omaha, NE, USA
Stephen I. Rennard Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA There are a number of reasons to discuss epithelial cells and their roles in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Damage to epithelial cells is a prominent feature of asthma and is also seen in chronic bronchitis. It has been suggested that inadequate repair of airway epithelium is an important mechanism which contributes to airway hyperresponsiveness and chronic inflammation. Epithelial cells are capable of contributing to inflammatory processes in many ways. Epithelial cells are involved in repair and remodeling of the airways after injury and inflammation. This chapter addresses these topics as they relate to the pathogenesis of asthma and COPD.
E P I T H E L I A L I N J U RY Damage to epithelia is a major pathological finding in asthma and COPD. Epithelial shedding and denudation of the basement membrane can be seen in asthma.1 In studies of chronic bronchitis and smokers, loss of epithelial cells has been described2,3 as well as squamous metaplasia.4,5 There are a number of mechanisms by which the epithelial cells are injured: • Activated eosinophils release a considerable armamentarium of proteases, oxidants, and toxic molecules. The major constituent of eosinophil granules, major basic protein, is toxic to epithelial cells in culture.6,7 • Neutrophils release neutrophil elastase, which is capable of causing epithelial cell detachment from the underlying matrix in in-vitro assays.8 • Acute inflammation is also associated with vasodilatation, leakage of fluid, and possible increases in hydrostatic forces, which can damage epithelium.9,10 Epithelial enzymes Damaged epithelium is thought to contribute to the pathogenesis of asthma, in that the absence of normal
metabolism by epithelial cells may contribute to prolonged inflammation and hyperresponsiveness. Epithelial cells contain several enzymes that inactivate inflammatory mediators. Airway epithelial cells may be particularly important for the metabolism and inactivation of neuropeptides such as bradykinin, substance P, and neurokinin A. Airway epithelial cells express several peptidases including membrane-associated neutral endopeptidase, previously called enkephalinase, and angiotensin-converting enzyme. The use of neutral endopeptidase inhibitors has shown augmentation of airway responsiveness in several animal models.11 The loss of neutral endopeptidase activity when epithelium is shed has been hypothesized as a major mechanism of airway hyperresponsiveness and neurogenic inflammation in asthma. Angiotensin-converting enzyme also inactivates bradykinin and substance P. Angiotensin-converting enzyme inhibitors have been known to cause cough and airway hyperreactivity in some patients, and it has been suggested that the effect is mediated by a reduction in the metabolism of neuropeptides.12 Airway epithelial cells are thought to play important roles in the metabolism of xenobiotics. The cells are capable of phase I metabolism by means of the cytochromes P-45013 and phase II or conjugative metabolism by enzymes such as glutathione transferases and sulfotransferases.14 The exact role of these metabolic pathways in allergic diseases has not been defined but there are several possibilities. For example, sulfation is a predominant mechanism for the inactivation of catecholamines. Airway epithelial cells may be responsible in part for the metabolism of inhaled catecholamines. Studies by Beckmann et al.14 demonstrated greatest expression of phenol sulfotransferases in the nonciliated secretory epithelial cells of the bronchioles with lower levels of expression in the larger airways. It is not yet known whether phenol sulfotransferase expression is regulated in airway epithelial cells. If sulfotransferase activity is modulated, however, this might have consequences for the fate of inhaled catecholamines.
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Thus, the absence of intact epithelium is thought to prolong neurogenic inflammation and be a major mechanism of airway hyperresponsiveness through the loss of normal metabolic processes. Effects on airway smooth muscle An intact epithelium is thought to have effects on airway tone. The influence of intact epithelium on airway responsiveness has been studied in models of smooth muscle contraction in multiple species.The subject has been extensively reviewed by Farmer and Hay.15 The original observation was that removal of the airway epithelium caused a significant leftward shift of the concentration–effect curve for several bronchoconstrictors. It was hypothesized that the epithelium was capable of providing an “epithelium-derived inhibitory factor” that reduced responsiveness to various bronchoconstrictors. A clear-cut identification of the inhibitory factor has not been achieved and several factors are likely to account for the inhibitory activity. Some of the activity is probably PGE2.16 It is tempting to hypothesize that NO is the inhibitory activity as it has already been identified as the endotheliumderived relaxing factor and NO has some relaxing activity on airway smooth muscle. Careful studies by Gao and Vanhoutte have shown that endogenous NO is produced during acetylcholine-induced contractions.17 However, endogenous NO did not appear to be the major factor involved in epithelium-derived inhibition of contractions.
E P I T H E L I A L C E L L S A N D I N F L A M M AT I O N It is now well accepted that epithelial cells play important roles in the pathogenesis of asthma and COPD through participation in inflammatory and immune processes. The first way in which epithelial cells may do this is through the production of inflammatory mediators and being part of an inflammatory cascade. The second way is through direct interactions with inflammatory cells via cell–cell adhesion molecules. Mediator privation It has been proposed that epithelial cells are key initiators of inflammation and are “sentinels” for the immune system.18–20 Epithelial cells are likely to be the first cells to release mediators after encountering environmental agents. Koyama et al.21 have shown that cultured bovine bronchial epithelial cells release arachidonate metabolites including LTB4 within 1 hour of exposure to endotoxin. Other chemotactic activities for neutrophils and monocytes were released at later time points. The release of arachidonate metabolites may be a rather general, early response of airway epithelial cells to injury as many stimuli will elicit LTB4 release from bovine bronchial epithelial cells in primary culture. Viral infection is known to cause rapid release of mediators.22 Thus, epithelial cells would seem to play an important role in viral infection in asthma.
Exacerbations of asthma have been related to viral infections in some clinical settings.23 Viral infections detected by sensitive techniques, polymerase chain reaction (PCR), are associated with inflammatory mediators in the nasal secretions of children with exacerbations of asthma.24 Important to the pathogenesis of COPD is the observation that epithelial cells release inflammatory mediators in response to air pollutants. Nitrogen dioxide, ozone, and diesel exhaust particles have been studied.25 The magnitude of response of epithelial cells may be modified in COPD such that there is some downregulation of the inflammatory response. Epithelial cells also produce mediators that are involved in more chronic inflammatory processes. Some hours after stimulation, airway epithelial cells release very potent chemotactic factors for neutrophils that are likely to have roles in the chronic attraction of leucocytes. The cytokine with perhaps the most potent chemotactic activity for neutrophils is IL-8.26 IL-8 is thought to have a relatively long half-life. It is now known to be one member of a family of similarly sized (8–10 kDa) chemokines called the CXC chemokines. Another family of closely related chemokines is the CC family, which includes RANTES, MCP-1, and MIP-1.27 These chemokines have more activity on macrophages. Epithelial cells release RANTES, MCP-1, and eotaxin in response to mediators such as TNF-a and c-IFN.28 Relevant to the pathogenesis of COPD is the observation by Wyatt et al.29 that cigarette smoke enhances the release of IL-8. It has been suggested that the sequence of events leading to mucus hypersecretion is dependent on IL-8 recruitment of neutrophils, which then stimulate goblet cell hyperplasia and degranulation.30 Epithelial cells also release mediators that are involved in the maturation and activation of leucocytes. Airway cells release GM-CSF in vitro, which is capable of promoting survival and activation of eosinophils, stimulating neutrophils, and stimulating macrophage proliferation. Ohtoshi et al.31 have demonstrated that GM-CSF released by human upper airway epithelial cells induces histamine-containing cell differentiation of progenitor cells. The same group has also shown that epithelial cells from inflamed tissue release more GM-CSF than do cells from normal tissues. Thus, epithelial cells from inflamed tissues release factors that recruit, activate, and differentiate leucocytes. It has been proposed that epithelial cells release mediators such as IL-8 in response to other stimuli in a way that effects a cascade of inflammation. In addition to the mediators described above that are proinflammatory, epithelial cells are also capable of producing mediators which downregulate inflammatory processes. Mediators that have been described in this regard are PGE2, IL-6, and TGF-b: • PGE2 reduces neutrophil migration, for example.32 • IL-6 is capable of reducing inflammation in several models of inflammation, including an in-vivo model of pulmonary inflammation.33
Epithelial Cells
• TGF-b is present in the epithelial lining fluid of the lung34 and is present in the epithelium of damaged lung.35 It has also been demonstrated in the airways of subjects with COPD.36 TGF-b inhibits cytokine production by mononuclear cells.37 As described above, epithelial cells are likely to have an important role in the cascade effect, especially in reference to IL-8 and MCP-1. It is thought that TGF-b released from macrophages followed by IL-8 and MCP-1 release constitutes an important cytokine network effect in the lung.38 Recent work has shown that Th2 cytokines also influence airway epithelial cell production of cytokines.39,40 IL-4 and IL-13 both can increase IL-8 secretion.IL-4 but not IL-13 augments the effects ofTGF-b on IL-8 secretion. IL-4 and IL-13 inhibit the TGF-b induced secretion of IL-6. Thus, epithelial cells participate in cycles of cytokine cascades that can accelerate, perpetuate, or inhibit inflammatory processes that may be key to controlling the airway inflammation of asthma. Cell adhesion molecules Once inflammatory cells are recruited to the airways they necessarily must interact with structural cells in order to migrate and attach. Epithelial cells express adhesion molecules for leucocytes and are capable of binding such cells. The exact role of these interactions is not well worked out but it would seem to be complementary to the ability of epithelial cells to produce cytokines that promote leucocyte recruitment and survival. A number of investigations have emphasized the importance of the expression of intercellular adhesion molecule-1 (ICAM-1) by epithelial cells.41–43 ICAM-1 is the ligand for LFA-1 on leucocytes.The interaction of ICAM-1 with LFA-1 is thought to strengthen the cell–cell adhesion mechanisms during activities such as antigen presentation and target recognition. The expression of ICAM-1 is enhanced on airway epithelial cells by proinflammatory cytokines.42,44,45 IL-1b, TGF-b, c-IFN, and IL-4 are cytokines that are implicated in the expression-enhancing activity. The expression and function of adhesion molecules such as ICAM-1 is also modulated by viral infection.41,46 The ability of the cells to express ICAM1 in the setting of a viral infection may be an important component of the defense mechanism to clear such infections. The importance of ICAM-1 expression has been explored in a primate model of asthma.42 Eosinophils infiltrating into the epithelium were found in association with ICAM-1 expressing epithelial cells. Epithelial expression of ICAM-1 correlates with asthma severity.47,48 Eosinophil interaction with ICAM-1 on epithelial cells augments eosinophil activation.49 ICAM-1 expression is also increased in chronic bronchitis47 where activation and adhesion of eosinophils and neutrophils is also important. The adhesive interaction between inflammatory cells and epithelial cells may augment inflammatory injury of the epithelium.50 The regulation of ICAM-1 expression on epithelial cells is a potentially important target for pharmacological intervention in inflammatory processes.
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E P I T H E L I A L R E PA I R Considering the many important roles of epithelial cells in metabolism, airway tone, and inflammation it would seem that repair and restitution of a normal epithelium would be very consequential in the pathogenesis of asthma and COPD. It has been suggested by several authors that airway disease can be viewed as the result of inadequate and disordered repair mechanisms that promote continued inflammation and abnormal airway remodeling.51,52 Restoration of denuded epithelium has been extensively described at both the light and electron microscopic level in both in-vitro and in-vivo models of repair. In models of intestinal, epidermal, or airway repair, cells at the edge of the wound migrate into the provisional matrix that forms in the wound.53–58 The process can be very rapid. Once the epithelium is intact, the cells differentiate into the mature cell types. Interestingly, there are conflicting data on which of the cells of the normal bronchial airway are responsible for the migration into the wound. It appears that the basal cells are not necessarily the progenitors of all of the other cell types. Secretory cells or an intermediate cell may flatten out at the edge of a wound and start the migration process.59 However, Shimizu and colleagues60 have shown that nearly every cell present in the early phases after airway injury expresses a basal cell marker, cytokeratin 14. Cytokeratin 14 expression is lost over the next 2 weeks, during which columnar cells increasingly express markers associated with normal epithelial columnar cells. A schematic drawing of epithelial repair is shown in Fig. 15.1. Matrix proteins The provisional matrix that forms in wounds includes fibrin, fibronectin, vitronectin, collagens, various proteoglycans, and possibly remnants of the basement membrane such as type IV collagen and laminin.57 Exudation of plasma proteins occurs on to the airway surface.57 Adjacent epithelial cells and underlying fibroblasts appear to be able to contribute matrix proteins and proteoglycans to the mix. Bronchial epithelial cells are also capable of producing fibronectin.61,62 Epithelial-derived fibronectin may represent a special form of the protein produced by either differential splicing of the gene or by post-translational modifications which results in some biological differences compared with plasma-derived fibronectin.63 The cell-derived form of fibronectin is a more potent chemoattractant than is the plasma-derived form for fibroblasts.64 The structural organization of the fibronectin gene and protein has been reviewed by Morla et al.63 Alternative splicing of three different regions can occur. The first two regions are called extra domains ED-A and ED-B (also known as EIII-A and EIII-B). Each of them can undergo cassette splicing of entire exons.The third region, CS-III, has several splice donor and acceptor sites within the exon.Tissue specific splice variants have been described. Bronchial epithelial cells are also likely able to produce type IV collagen,62 but the extent of
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(a)
Wound
Columnar cells
Provisional matrix (derived from plasma proteins)
Basal cells
Basement membrane Mesenchymal cells (b) 1 2
Epithelial cell migration 3 4
5
Basement membrane
Mesenchymal cell accumulation
(c)
Epithelial cell proliferation
(d)
Epithelial cell differentiation
Fig. 15.1. Schematic of airway repair. (a) Wounding causes portions of the basement membrane to become stripped of cells. A provisional matrix derived from plasma proteins including fibrin and fibronectin accumulates rapidly. (b) Epithelial cells participate in the wound repair process in a number of ways: (1) Basal cells remaining in the wound can release cytokines, which can function as autocrine or paracrine factors driving the inflammatory response. (2) Epithelial cells can respond to these paracrine factors, leading to the production of additional mediators (e.g. TGF-b produced by airway epithelial cells can drive epithelial cell production of fibronectin). (3) Mediators derived from epithelial cells and potentially other sources induce dedifferentiation of epithelial cells present at the wound margins. (4) Epithelial cells migrate across the provisional matrix, restoring epithelial integrity. (5) Mediators produced by epithelial cells can also lead to activation of mesenchymal cells. (c) After recruitment, epithelial cells undergo accumulation through proliferation. This results in accumulation of a dedifferentiated epithelium. Mesenchymal cells may accumulate concurrently. (d) Over the course of days to weeks, the newly recruited epithelial cells can differentiate and have the potential to restore epithelial architecture.
Epithelial Cells
matrix proteins produced by normal bronchial epithelial cells has not been fully evaluated. Similarly, fibroblasts underlying wounds are thought to be important sources of collagens, fibronectin and proteoglycans after injury.65 Production of matrix after injury is modulated by at least several mediators. TGF-b is an important mediator of wound repair and has been the subject of recent reviews.66,67 One of the major effects of TGF-b is the accumulation of collagen and increasing wound strength.68 TGF-b also modulates the alternative splicing of fibronectin in some cells.69 Production of fibronectin by bronchial epithelial cells is also increased by TGF-b.61 When bronchial epithelial cells were examined for ability to produce factors, which subsequently modulated matrix production, by fibroblasts in vitro, both stimulatory and inhibitory factors were found.70–72 The stimulatory factor is composed in part of TGF-b. The inhibitory activity produced by bronchial epithelial cells appeared to be PGE2, capable of inhibiting collagen production by fibroblasts.Thus, mediator “networking” is likely to be operating in the control of matrix production in epithelia. Other mediators of relevance to matrix production in the lung include PDGF, bFGF, IGF-1, TNF-a, IL-1, and IL-6.69 Migration The migration of epithelial cells in wounds has been described in several animal models. Similar to what has been described for keratinocytes, bronchial epithelial cells flatten out and migrate to rapidly cover small wounds.53,54,58 A number of potential attractants are likely to be present in wounds (Fig. 15.1). The matrix components themselves are capable of stimulating epithelial cell migration in both chemotaxis and haptotaxis assays. Fibronectin and collagens are potent stimulators of bronchial epithelial cell migration in modified Boyden chamber assays.73 Laminin is less potent as an attractant. In order for migrating cells to interact with and attach to the underlying matrix, specific receptors are used. Most of the cell surface receptors for matrix proteins that have been described are members of the integrin family of receptors. Migrating cells use specific receptors to attach to matrix and can form focal contacts.74 Focal contacts are contact points where integrins interact with several cytoplasmic proteins and the actin cytoskeleton.75 The formation of the focal contacts is essential for the anchoring of the matrix to the cytoskeleton. Control of the expression and function of integrins is an active area of research. TGF-b can alter the spectrum of integrins expressed on many cell types.76,77 TGF-b increases the attachment of bronchial epithelial cells to matrix-coated dishes and is associated with increased expression of fibronectin receptors.78 Interestingly, the increase in adhesion was associated with decreased migration. The balance between adhesion and mobility is delicate and decreased attachment strength may be necessary for maximal migration.79
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Role of matrix proteins Some matrix proteins may be more important than others in supporting epithelial cell migration and survival during repair processes. Fibronectin, in contrast to collagen or laminin, has unique effects on epithelial cells.80,81 Attachment of bronchial epithelial cells to collagen initiated signaling events and cell attachment only when additional growth factors were present in the medium. Fibronectin is able to support cell spreading, focal adhesion assembly and subsequent cell survival, even without growth factors in the medium. A 120-kDa fragment of fibronectin that contains the classical cell-binding domain (for the a5b1 integrin) appeared to be enough to support integrin clustering and subsequent F-actin accumulation, without additional growth factors. Thus, bronchial epithelial cell attachment to fibronectin through the a5b1 integrin is capable of initiating signaling events that other matrix components do not initiate. The unique activity of a5b1 integrin may reside in the cytoplasmic domain of the a5 chain.82 Others have suggested that attachment of cells to fibronectin through a5b1 integrin can initiate PKC activation.83 This work is consistent with the concept that epithelial cell–matrix adhesion with the formation of focal adhesions promotes cell survival and inhibits apoptosis. Growth factors In addition to matrix proteins themselves, other stimuli for epithelial and mesenchymal cell migration have been described. TGF-b has been described as a chemoattractant for fibroblasts and bronchial epithelial cells.78,84 This effect may be in contrast to the in-vitro effects of TGF-b on epithelial cells described above.The effect of TGF-b in in-vivo models is thought to be one of cellular accumulation, particularly the accumulation of fibroblasts.85 Epithelial cells appear to play a role in localizing the effects of TGF-b at sites of injury. Epithelial cells express the avb6 integrin, which has been shown to bind and activate latent TGF-b.86 This may result in decreased inflammation and increased cellular accumulation at sites of injury. The effects of TGF-b may then be multiphasic, with initial effects on increasing cell accumulation in wounds, followed by later effects that alter morphology of the cells and increase cell attachment and wound strength. Bronchial epithelial cells also respond to other growth factors such as insulin, IGF-1, and EGF.87,88 EGF might also affect sheet migration of epithelial cells through effects on cell proliferation. Signaling through the EGF receptor can regulate mucin expression in epithelial cells and may help regulate epithelial cell differentiation (see also below). The EGF receptor can be activated by both ligand-dependent and ligand-independent mechanisms including inflammatory stimuli.89,90 It is likely, therefore, that epithelial cell repair is modulated by the local inflammatory milieu.
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Cytokines There are a number of additional lines of evidence to suggest that inflammatory cytokines and mediators can modulate the process of epithelial cell migration in wound healing. Certainly, leucocyte migration is modulated by inflammatory mediators and pharmacological agents,91 and it appears that some of the same mechanisms of activation of migration may also act on epithelial cells. Agents which modulate leucocyte migration that might also be active on epithelial cells include tumor necrosis factor-a (TNF-a), IL-1b, c-IFN, PGE2, and phorbol esters.92,93 The subject of cell mobility and possible mechanisms of activation have been reviewed by Stossel94 and Caterina and Devreotes.95 Stimuli that interact with receptors that activate the inositol phospholipid pathway appear to switch on actin assembly. While epithelial and mesenchymal cells are less well studied with regards to activation of motility, TNF-a is also able to stimulate bronchial epithelial cell motility and the effects are PKC mediated.92,93 Other inflammatory mediators, which have been shown to enhance bronchial epithelial cell migration, are tachykinins, bombesin analogs, and the above-mentioned growth factors.96,97
A I R WAY R E M O D E L I N G Epithelial cells are known to release factors which can drive fibroblast recruitment, proliferation, matrix production, and matrix remodeling64,70,72,98,99 (see Chapter 7). In-vitro studies of bronchial epithelial cells have shown that bronchial epithelial cell-conditioned medium stimulates fibroblast proliferation. The growth regulatory activity in the conditioned medium is heterogeneous, including peptides, eicosanoids, and TGF-b.70 Some of the mediators that drive epithelial repair also drive fibroblast accumulation. Fibronectin was mentioned above as a wound component that attracts and supports epithelial cell survival. Fibronectin is also an attractant for fibroblasts.64 Epithelial cells may also influence peribronchial tissue through fibroblast-mediated contraction of collagenous matrix. Bronchial epithelial cells release mediators that enhance collagen gel contraction by fibroblasts in vitro.99 Thus, epithelial cells may influence the accumulation and activity of fibroblasts in the peribronchial tissue.
E P I T H E L I A L C E L L D I F F E R E N T I AT I O N Once epithelial cells are recruited to re-epithelialize a wound area, they undergo a recapitulation of development and differentiate into mature columnar cells. Studies in other cell systems would suggest that the underlying matrix proteins play crucial roles in directing this process.100 There is a two-way exchange of information in this process. Epithelial cells express matrix metalloproteinases
that modulate matrix proteins, and modulation of matrix proteins subsequently influences apoptosis and differentiation of epithelial cells.101,102 Recent studies have begun to address the roles of matrix metalloproteinases in COPD.103–105 It appears that expression of certain metalloproteinases is increased in airway disease. Agents which modulate the function of metalloproteinases would be just one of many possible therapeutic approaches for peribronchial fibrosis. Cilia The state of differentiation of airway epithelial cells affects a number of important functions. Mucociliary clearance mechanisms are dependent on a functioning epithelium. The clearance of secretions is dependent on two mechanisms, ciliary beating and cough. Ciliated cells make up approximately 50% of the cells of the human trachea and the percentage falls off in more peripheral airways.106 The structure of cilia comprises the well-described array of microtubules called the axoneme.107,108 The axoneme is made up of nine microtubular doublets that have two rows of dynein arms. Sliding movements of the microtubules that are powered by adenosine triphosphate (ATP) generate the movement of cilia. A number of signaling systems can influence ciliary beat frequency.109–112 Activation of cAMP-dependent protein kinase (PKA), cGMP-dependent protein kinase (PKG), and PKC have all been associated with increases in ciliary beat frequency. Thus, any number of inflammatory mediators can potentially modulate ciliary function. A functional ciliary transport system is required for normal lung maintenance; cough alone is not enough. This is inferred from the observation that genetic abnormalities of ciliary function are associated with chronic lung disease.108 Mucus secretion Secretions within the lumen of the airways are themselves complex structures. Proximal to the luminal cell surface is an aqueous layer, which permits the organized beating of the cilia. On the aqueous layer rests the mucus layer comprised of secretions produced by epithelial cells and mucous glands. With normal functioning of the mucociliary escalator, the luminal contents are propelled proximally where they are cleared. As the secretions move proximally, however, their composition changes. The mechanisms which regulate the secretion and absorption of ions and fluid along the axis of the airway are incompletely understood, but a number of mediators, including purinergic agonists, have been suggested to play important roles.113 The fundamental abnormality in cystic fibrosis is a defect in a regulator of epithelial ion transport.114 Defects in the cystic fibrosis transmembrane conductance regulator (CFTR) have also been described in COPD, although their clinical significance is uncertain.115 It is likely, however, that
Epithelial Cells
abnormalities in epithelial ion transport contribute to the abnormal secretions which characterize both asthma and COPD. Mucociliary clearance in COPD A number of pathological findings suggest that mucociliary clearance is impaired in smokers and chronic bronchitics. Ciliated cells are damaged in chronic bronchitis and COPD. The cilia themselves are shortened116 and there are fewer ciliated cells.117 Enlargement of the bronchial glands, increases in gland mass, and hyperplasia of mucus-secreting goblet cells are important pathological hallmarks of chronic bronchitis.118 In small airways it has been shown that clara cells are replaced by mucus-producing cells in smokers.119,120 Excess mucus production in the setting of damaged ciliary transport is likely to contribute to mucus plugging of airways.
S U M M A RY It is hoped that this chapter has conveyed the concept that epithelial cells are not simple structural cells of the lung but have important roles in airways disease. Epithelial cells are capable of contributing to many of the inflammatory processes thought to be central to the pathogenesis of asthma and COPD. Restitution of a normal epithelium may be key to the resolution of airway inflammation and bronchial hyperresponsiveness. These concepts would put epithelial cells at the center of new hypotheses for intervention and treatment of these disorders.
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31. Ohtoshi T, Tsuda T, Vancheri C et al. Human upper airway epithelial cell-derived granulocyte-macrophage colony-stimulating factor induces histamine-containing cell differentiation of human progenitor cells. Int. Arch. Allergy Appl. Immunol. 1991; 95:376–84. 32. Christman JW, Christman BW, Shepherd VL, Rinaldo JE. Regulation of alveolar macrophage production of chemoattractants by leukotrine B4 and prostaglandin E2. Am. J. Respir. Cell Mol. Biol. 1991; 5:297–304. 33. Ulich TR, Yin S, Guo K et al. Intratracheal injection of endotoxin and cytokines. II: Interleukin-6 and transforming growth factoralpha inhibit acute inflammation. Am. J. Pathol. 1991; 138:1097–101. 34. Yamauchi K, Martinet Y, Basset P, Fells GA, Crystal RG. High levels of transforming growth factor-beta are present in the epithelial lining fluid of the normal human lower respiratory tract. Am. Rev. Respir. Dis. 1988; 137:1360–3. 35. Khalil N, O’Connor RN, Unruh HW et al. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 1991; 5:155–62. 36. Rahman I, van Schadewijk AA, Hiemstra PS et al. Localization of gamma-glutamylcysteine synthetase messenger RNA expression in lungs of smokers and patients with chronic obstructive pulmonary disease. Free Radic. Biol. Med. 2000; 28:920–5. 37. Espevik T, Figari IS, Shalaby MR et al. Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J. Exp. Med. 1987; 166:571–6. 38. Standiford TJ, Kunkel SL, Basha MA et al. Interleukin-8 gene expression by a pulmonary epithelial cell line: a model for cytokine networks in the lung. J. Clin. Invest. 1990; 86:1945–53. 39. Striz I, Mio T, Adachi Y et al. IL-4 and IL-13 stimulate human bronchial epithelial cells to release IL-8. Inflammation 1999; 23:545–55. 40. Striz I, Mio T, Adachi Y, Romberger DJ, Rennard SI. Th2-type cytokines modulate IL-6 release by human bronchial epithelial cells. Immunol. Lett. 1999; 70:83–8. 41. Tosi MF, Stark JM, Hamedani A et al. Intercellular adhesion molecule-1 (ICAM-1)-dependent and ICAM-1-independent adhesive interactions between polymorphonuclear leukocytes and human airway epithelial cells infected with parainfluenza virus type 2. J. Immunol. 1992; 149:3345–9. 42. Wegner CD, Gundel RH, Reilly P et al. Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma. Science 1990; 2:456–9. 43. Rothlein R, Czajkowski M, O’Neill MM et al. Induction of intercellular adhesion molecule 1 on primary and continuous cell lines by pro-inflammatory cytokines. J. Immunol. 1988; 141:1665–9. 44. Tosi MF, Stark JM, Hamedani A et al. Induction of ICAM-1 expression on human airway epithelial cells by inflammatory cytokines: effects on neutrophil-epithelial cell adhesion. Am. J. Respir. Cell Mol. Biol. 1992; 7:214–21. 45. Striz I, Mio T, Adachi Y et al. IL-4 induces ICAM-1 expression in human bronchial epithelial cells and potentiates TNF-alpha. Am. J. Physiol. 1999; 277(1 Pt 1):L58–64. 46. Bianco A, Spiteri MA. A biological model to explain the association between human rhinovirus respiratory infections and bronchial asthma. Monaldi Arch. Chest Dis. 1998; 53:83–7. 47. Vignola AM, Campbell AM, Chanez P et al. HLA-DR and ICAM1 expression on bronchial epithelial cells in asthma and chronic bronchitis. Am. Rev. Respir. Dis. 1993; 148:689–94. 48. Canonica GW, Ciprandi G, Pesce GP et al. ICAM-1 on epithelial cells in allergic subjects: a hallmark of allergic inflammation. Int. Arch. Allergy Immunol. 1995; 107(1/3):99–102. 49. Nagata M, Sedgwick JB, Kita H, Busse WW. Granulocyte macrophage colony-stimulating factor augments ICAM-1 and VCAM-1 activation of eosinophil function. Am. J. Respir. Cell Mol. Biol. 1998; 19:158–66.
50. DeRose V, Robbins RA, Snider RM et al. Substance P increases neutrophil adhesion to bronchial epithelial cells. J. Immunol. 1994; 152:1339–46. 51. Niewoehner D. Anatomic and pathophysiological correlations in COPD. In: Baum G, Crapo J, Celli B, Karlinsky J (eds), Textbook of Pulmonary Diseases, pp. 823–42. Philadelphia: LippincottRaven, 1998. 52. Rennard SI. Inflammation and repair processes in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160(5 Pt 2):S12–16. 53. Lane BP, Gordon R. Regeneration of rat tracheal epithelium after mechanical injury. Proc. Soc. Exp. Biol. Med. 1974; 145:1139–44. 54. McDowell EM, Ben T, Newkirk C, Chang S, DeLuca LM. Differentiation of tracheal mucociliary epithelium in primary cell culture recapitulates normal fetal development and regeneration following injury in hamsters. Am. J. Pathol. 1987; 129:511–22. 55. Rutten MJ, Ito S. Morphology and electrophysiology of guinea pig gastric mucosal repair in vitro. Am. J. Physiol. 1983; 244G:171–82. 56. Moore R, Carlson S, Madara JL. Rapid barrier restitution in an invitro model of intestinal epithelial injury. Lab. Invest. 1989; 60:237–44. 57. Erjefalt JS, Erjefalt I, Sundler F, Persson CG. Microcirculationderived factors in airway epithelial repair in vivo. Microvasc. Res. 1994; 48:161–78. 58. Erjefalt JS, Erjefalt I, Sundler F, Persson CG. In-vivo restitution of airway epithelium. Cell Tissue Res. 1995; 281:305–16. 59. Keenan KP, Wilson TS, McDowell EM. Regeneration of hamster tracheal epithelium after mechanical injury. IV: Histochemical, immunocytochemical and ultrastructural studies. Virchows Arch. Cell Pathol. 1983; 43:213–40. 60. Shimizu T, Nishihara M, Kawaguchi S, Sakakura Y. Expression of phenotypic markers during regeneration of rat tracheal epithelium following mechanical injury. Am. J. Respir. Cell Mol. Biol. 1994; 11:85–94. 61. Romberger DJ, Beckmann JD, Claassen L, Ertl RF, Rennard SI. Modulation of fibronectin production of bovine bronchial epithelial cells by transforming growth factor-beta. Am. J. Respir. Cell Mol. Biol. 1992; 7:149–55. 62. Stoner GD, Katoh Y, Foidart JM et al. Cultured human bronchial epithelial cells: blood group antigens, keratin, collagens, and fibronectin. In Vitro 1981; 17:577–87. 63. Morla A, Zhang Z, Ruoslahti E. Superfibronectin is a functionally distinct form of fibronectin. Nature 1994; 367:193–6. 64. Shoji S, Rickard KA, Ertl RF et al. Bronchial epithelial cells produce lung fibroblast chemotactic factor: fibronectin. Am. J. Respir. Cell Mol. Biol. 1989; 1:13–20. 65. Goldstein RH, Polgar P. The effect and interaction of bradykinin and prostaglandins on protein and collagen production by lung fibroblasts. J. Biol. Chem. 1982; 257:8630–3. 66. Padgett RW. TGF-beta signaling pathways and human diseases. Cancer Metast. Rev. 1999; 18:247–59. 67. Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N. Engl. J. Med. 2000; 342:1350–8. 68. Mustoe TA, Pierce GF, Thomason A et al. Accelerated healing of incisional wounds in rats induced by transforming growth factor-beta. Science 1987; 237:1333–6. 69. McGowan SE. Extracellular matrix and the regulation of lung development and repair. FASEB J. 1992; 6:2895–904. 70. Nakamura Y, Tate L, Ertl RF et al. Bronchial epithelial cells regulate fibroblast proliferation. Am. J. Physiol. 1995; 269(3 Pt 1):L377–87. 71. Nakamura Y, Romberger DJ, Tate L et al. Cigarette smoke inhibits lung fibroblast proliferation and chemotaxis. Am. J. Respir. Crit. Care Med. 1995; 151:1497–503. 72. Kawamoto M, Romberger DJ, Nakamura Y et al. Modulation of fibroblast type I collagen and fibronectin production by bovine
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93. Wyatt TA, Ito H, Veys TJ, Spurzem JR. Stimulation of protein kinase C activity by tumor necrosis factor-alpha in bovine bronchial epithelial cells. Am. J. Physiol. 1997; 273(5 Pt 1):L1007–12. 94. Stossel TP, Hartwig JH, Janmey PA, Kwiatkowski DJ. Cell crawling two decades after Abercrombie. Biochem. Soc. Symp. 1999; 65:267–80. 95. Caterina MJ, Devreotes PN. Molecular insights into eukaryotic chemotaxis. FASEB J. 1991; 5:3078–85. 96. Kim JS, McKinnis VS, White SR. Migration of guinea pig airway epithelial cells in response to bombesin analogues. Am. J. Respir. Cell Mol. Biol. 1997; 16:259–66. 97. Kim JS, Rabe KF, Magnussen H, Green JM, White SR. Migration and proliferation of guinea pig and human airway epithelial cells in response to tachykinins. Am. J. Physiol. 1995; 269(1 Pt 1):L119–26. 98. Kawamoto M, Matsunami T, Ertl RF et al. Selective migration of alpha-smooth muscle actin-positive myofibroblasts toward fibronectin in the Boyden’s blindwell chamber. Clin. Sci. (Colch.) 1997; 93:355–62. 99. Mio T, Liu XD, Adachi Y et al. Human bronchial epithelial cells modulate collagen gel contraction by fibroblasts. Am. J. Physiol. 1998; 274(1 Pt 1):L119–26. 100. Boudreau N, Bissell MJ. Extracellular matrix signaling: integration of form and function in normal and malignant cells. Curr. Opin. Cell Biol. 1998; 10:640–6. 101. Schmeichel KL, Weaver VM, Bissell MJ. Structural cues from the tissue microenvironment are essential determinants of the human mammary epithelial cell phenotype. J. Mammary Gland. Biol. Neoplas. 1998; 3:201–13. 102. Lelievre SA, Weaver VM, Nickerson JA et al. Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus. Proc. Natl Acad. Sci. USA 1998; 95:14711–16. 103. Segura-Valdez L, Pardo A, Gaxiola M et al. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 2000; 117:684–94. 104. Yao PM, Lemjabbar H, D’Ortho MP et al. Balance between MMP-9 and TIMP-1 expressed by human bronchial epithelial cells: relevance to asthma. Ann. NY Acad. Sci. 1999; 878:512–14. 105. Hoshino M, Nakamura Y, Sim J, Shimojo J, Isogai S. Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. J. Allergy Clin. Immunol. 1998; 102:783–8. 106. Serafini SM, Michaelson ED. Length and distribution of cilia in human and canine airways. Bull. Eur. Physiopathol. Respir. 1977; 13:551–9. 107. Sleigh MA, Blake JR, Liron N. The propulsion of mucus by cilia. Am. Rev. Respir. Dis. 1988; 137:726–41. 108. Lee R, Forrest J. Structure and function of cilia. In: Crystal R, West J (eds), The Lung: Scientific Foundations, 2nd edn. Philadelphia: Lippincott-Raven, 1997. 109. Sisson JH, May K, Wyatt TA. Nitric oxide-dependent ethanol stimulation of ciliary motility is linked to cAMP-dependent protein kinase (PKA) activation in bovine bronchial epithelium. Alcohol Clin. Exp. Res. 1999; 23:1528–33. 110. Wyatt TA, Spurzem JR, May K, Sisson JH. Regulation of ciliary beat frequency by both PKA and PKG in bovine airway epithelial cells. Am. J. Physiol. 1998; 275(4 Pt 1):L827–35. 111. Eljamal M, Wong LB, Yeates DB. Capsaicin-activated bronchialand alveolar-initiated pathways regulating tracheal ciliary beat frequency. J. Appl. Physiol. 1994; 77:1239–45. 112. Wong LB, Park CL, Yeates DB. Neuropeptide Y inhibits ciliary beat frequency in human ciliated cells via nPKC, independently of PKA. Am. J. Physiol. 1998; 275(2 Pt 1):C440–8. 113. Paradiso AM, Ribeiro CM, Boucher RC. Polarized signaling via purinoceptors in normal and cystic fibrosis airway epithelia. J. Gen. Physiol. 2001; 117:53–67.
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114. Larson JE, Cohen JC. Cystic fibrosis revisited. Mol. Genet. Metab. 2000; 71:470–7. 115. Sandford AJ, Paré PD. Genetic risk factors for chronic obstructive pulmonary disease. Clin. Chest Med. 2000; 21:633–43. 116. Ailsby RL, Ghadially FN. Atypical cilia in human bronchial mucosa. J. Pathol. 1973; 109:75–8. 117. Wanner A. Clinical aspects of mucociliary transport. Am. Rev. Respir. Dis. 1977; 116:73–125.
118. Reid L. Pathology of chronic bronchitis. Lancet 1954; i:275–9. 119. Ebert RV, Hanks PB. Mucus secretion by the epithelium of the bronchioles of cigarette smokers. Br. J. Dis. Chest 1981; 75:277–82. 120. Ebert RV, Terracio MJ. The bronchiolar epithelium in cigarette smokers: observations with the scanning electron microscope. Am. Rev. Respir. Dis. 1975; 111:4–11.
Mucus and Mucin-Secreting Cells
Chapter
16
Pierre-Regis Burgel and Jay A. Nadel Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, CA, USA
In humans, secretion of a thin layer of mucus spreads as a gel on the luminal surface of the airways. It helps in the hydration of the airway epithelium and in assisting in mucociliary clearance of foreign materials such as particles and micro-organisms. However, excessive mucus production can be deleterious and may contribute to the pathophysiology of asthma1 and chronic obstructive pulmonary disease (COPD).2
MUCUS AND MUCIN-SECRETING CELLS Properties of airway mucus Airway mucus is a complex mixture of proteins, lipids, and a sol phase composed of water and electrolytes.3,4 Mucus components derive mainly from surface epithelial (goblet) cells and submucosal gland serous and mucous cells. Composition of airway mucus is reviewed elsewhere.5 Among proteins contained in mucus are mucins, which are highly glycosylated proteins synthesized in airways by goblet cells and by gland mucous cells.6 In airways, seven mucin genes (1, 2, 4, 5AC, 5B, 7, 8) have been reported in secretory cells;7–11 two mucin genes (MUC2 and MUC5AC) appear to be particularly important.12,13 Mucin production Cell multiplication versus differentiation Present evidence indicates that goblet cells develop from precursor cells already present in the epithelium. This evidence includes the following: • Sendai virus infection induces goblet cell production in rats without increased incorporation of [3H]-thymidine, so cell multiplication does not occur.14 • Endotoxin-induced goblet cell metaplasia in rat nasal septum is not prevented by colchicine (which causes metaphase blockade). The mitotic rate and total number of epithelial cells was unchanged, showing that mucincontaining cells are produced by direct conversion of nongranulated secretory cells.15
• In pathogen-free rats, TNF-a induced EGFR expression, and consequent stimulation with EGFR ligands increased the number of goblet cells and decreased the number of nongranulated secretory cells, with no change in the total number of epithelial cells,16 implicating a differentiation process. Stimuli and mechanisms of mucin production Many stimuli cause goblet cell metaplasia and upregulation of mucin production. They include: • • • • • •
allergens;17 cigarette smoking;18,19 oxidative stress and activated neutrophils;20 mechanical wounding of the airway;21–24 bacterial and viral infections;15,25,26 molecules such as PAF,27 elastase,28 and acrolein.29
Pseudomonas aeruginosa activates a c-Src-Ras-MEK signaling pathway that leads to activation of NF-jB, which in turn induces MUC2 mucin transcription.30 In 1999, a novel pathway of mucin production involving activation of the epidermal growth factor receptor (EGFR) was described.16 Because multiple stimuli cause mucin upregulation via an EGFR “cascade”, this pathway will be discussed in detail. Role of epidermal growth factor (EGF) Cohen discovered the epidermal growth factor (EGF), and his group extended our knowledge of EGF and its receptor (EGFR).31 EGFR is a 170-kDa membrane glycoprotein. It is activated by its ligands (EGF, transforming growth factor (TGF)-a, heparin binding EGF, amphiregulin, betacellulin, and epiregulin), which are synthesized as transmembrane precursors and cleaved by metalloproteases to release the mature growth factor.32 EGFR was recently found to be involved in the production of goblet cells by cell differentiation.16 In the control state, the epithelium was low cuboidal, contained few goblet cells, and EGFR expression was absent. Stimulation with tumor necrosis factor (TNF)-a caused expression of EGFR
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in basal cells, which lengthened to produce nongranulated secretory cells.Then, stimulation with EGFR ligands caused EGFR phosphorylation and subsequent mucin MUC5AC expression. Selective inhibitors of EGFR tyrosine kinase phosphorylation (e.g. BIBX1522) inhibited MUC5AC expression, implicating EGFR activation in mucin production (Fig. 16.1). This report was followed by a series of studies implicating EGFR activation in mucin upregulation by various stimuli: • Ovalbumin (OVA) challenge causes goblet cell metaplasia in sensitized rats, an effect that was prevented by pretreatment with EGFR inhibitors.16 • Th2 cytokines (IL-4 and IL-13) induce goblet cell metaplasia in vivo,33–35 but not in vitro.36 IL-13-induced goblet cell metaplasia is dependent on an EGFR cascade involving neutrophils37 (see later). • Mechanical wounding of the airway causes mucus hypersecretion.21–24 Irritation-induced goblet cell metaplasia in rat airways is abolished by EGFR inhibitors.24 • Oxygen free radicals activate EGFR via a ligandindependent mechanism,38 and H2O2 upregulates MUC5AC expression, effects that are prevented by selective EGFR inhibitors.20 Furthermore, human neutrophils activated by cytokines induced ligandindependent EGFR activation (and subsequent mucin synthesis) via the release of oxygen free radicals20 (see later).
• Cigarette smoke induces mucin production in vitro and in vivo via a mechanism involving EGFR expression and activation (see cigarette smoking section).19 • In asthmatics, EGFR expression is increased in submucosal glands and surface epithelium39,40 and is correlated with the amount of mucin staining.40 Mucin secretion When mucins are formed, they are packed and stored in cytoplasmic granules.41 Mucin secretion is a regulated process involving exocytosis of preformed mucus granules in response to extracellular stimuli.5,41 Stimuli that trigger secretory cell degranulation include neural and inflammatory mediators and products of inflammatory cells.5 Vagal42 and adrenergic43 stimulation lead to mucus secretion. Neuropeptides (e.g. substance P, neurokinins A and B) and vasoactive intestinal peptide also stimulate mucus secretion. Similarly, cyclooxygenase and lipooxygenase products, adenosine triphosphate (ATP), reactive oxygen species, platelet activating factor, mast cell chymase, neutrophil proteases (e.g. elastase, cathepsin G and proteinase 3) stimulate secretion.5 Allergen-induced mucus secretion in OVA-sensitized guinea pigs depends on neutrophil recruitment.44 Furthermore, an antibody to intracellular adhesion molecule-1 (ICAM-1) prevents neutrophil recruitment and goblet cell degranulation. Pretreatment with a selective elastase inhibitor prevents allergen-induced goblet cell degranulation.
Ligand
EGFR Cell Membrane
Storage in Granules
Reactive Oxygen Species
Tyrosine kinase Phosphorylation
Downstream Messengers
MUC5AC Protein Synthesis
MUC5AC Gene Transcription
Nucleus
Fig. 16.1. Schematic of mucin production via EGFR activation: Binding of ligand to EGFR leads to EGFR tyrosine kinase phosphorylation (solid circles) and downstream messengers, which cause MUC5AC mucin gene expression. Subsequent production of MUC5AC protein (black squares) is followed by incorporation into granules (circles surrounding squares), which are stored in the cytoplasm until activated by an extracellular stimulus to cause secretion. Reactive oxygen species (and other stimuli) activate EGFR phosphorylation intracellularly and cause mucin production via a ligandindependent pathway.
Mucus and Mucin-Secreting Cells
Neutrophil-dependent goblet cell degranulation in human and guinea pig bronchial explants in vitro involves close contact between neutrophils and goblet cells via adhesion molecules including intercellular adhesion molecule-1 (ICAM-1).45 The Th2 cytokine IL-4 increases ICAM-1 expression in human bronchial epithelial cells in vitro.46 Neutrophilic inflammation occurs in acute asthma,47,48 and ICAM-1 expression is increased in asthma,49,50 suggesting that adherent neutrophils may play an important role in mucus secretion in asthma. Mucus clearance In the airway lumen, accumulated secretions are propelled forward by a mucociliary transport system composed of: • ciliary beating, which provides the driving force propelling the overlying mucus; • a periciliary layer that provides the medium through which the cilia move and facilitates the coupling of the ciliary tips and the overlying viscoelastic mucus; • mucus, which has the special characteristic of becoming more fluid when a shearing force (e.g., ciliary tips) is applied. It is this unusual “thixotropic” characteristic of mucus that allows it to spread and to be propelled during mucociliary transport. When exocytosis occurs, mucins mix with airway fluid and become hydrated rapidly. Inadequate hydration of mucin, by reduction of the volume of periciliary liquid, may prevent the spreading of mucus and thus impair mucociliary clearance.51 Cough is also an important mechanism of clearance. Cough receptors are located in the large conducting airways,52 concentrated at bifurcations where the openings of gland ducts are also localized. During cough, expiratory effort causes dynamic compression of the airways.53 The high linear velocity of air traveling through compressed airways results in shearing of mucus, and effective clearance normally results.54 Physiological effects of mucus secretions in conducting and peripheral airways In hypersecretory diseases, goblet cell metaplasia occurs both in central and in peripheral airways. In large conducting airways, goblet cell metaplasia is less likely to cause airway obstruction because of the large airway volume in relation to the volume of the goblet cells. However, large amounts of secretion could plug even large airways. Hypersecretion here can cause cough, and expectoration of sputum is noticed by the patient. In airways of small diameter, degranulation of goblet cells and the subsequent hydration of the mucus could increase the volume of mucus and could occlude these small airways completely. Moreover, peripheral airway obstruction may not cause symptoms early because cough receptors are not present peripherally and because complete obstruction of a
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peripheral airway causes an insignificant increase in the work of breathing. Furthermore, individual peripheral airways contribute little to airflow resistance, so spirometric tests of airflow obstruction can be predicted to be relatively insensitive to peripheral airway plugging.
M U C U S R E G U L AT I O N I N A S T H M A Clinical relevance of hypersecretion in asthma Asthma incidence is increasing worldwide.55 In the United States, rates of asthma mortality have increased from 8.2 deaths per million in 1975 to 17.9 deaths per million in 1995.56 Postmortem studies in people dying of asthma show mucus plugging in airways.57–59 Goblet cell hyperplasia was reported in the airway epithelium of people dying of acute asthma,60 and submucosal gland enlargement61,62 and dilated gland ducts filled with mucus63 have been described. Therefore, mucus plugging, resulting in asphyxia, may be a consequence of both goblet cell and submucosal gland cell degranulation. Representative sections of airways from a patient who died of acute asthma, suggesting roles for both gland and goblet cell hypersecretion in fatal asthma, are shown in Fig. 16.2. Mucus hypersecretion also occurs in chronic asthma: In a large cohort of asthmatics, chronic excessive sputum production was found in more than half of the patients and was independently associated with an accelerated rate of decline in maximal expiratory airflow.64 In stable asthmatics, goblet cell hyperplasia was reported in bronchial biopsies,40,65 and mucin-like glycoproteins were increased in induced sputum.66 Increased sputum production was also reported during asthma exacerbations.67,68
Fig. 16.2. (a) Alcian blue (AB)/PAS staining for mucous glycoconjugates in a proximal airway section in a patient with fatal asthma. The airway lumen is plugged with mucus. The epithelium shows marked goblet cell metaplasia. The submucosal gland (GLAND) has intense staining for mucous glycoconjugates and releases its contents into a gland duct (DUCT) that is filled with AB/PAS-stained material. (b) Another section of airway epithelium in the same patient, stained with AB/PAS. Although goblet cells are still intact, mucous can be seen streaming from the luminal tips of the goblet cells into the lumen. The lumen is filled with AB/PAS-stained mucous material. Both scale bars 50 lm.
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Because mucus hypersecretion contributes to the mortality and morbidity of asthma, an understanding of the mechanisms that regulate mucus production and release and development of new drugs to prevent mucus hypersecretion remain important challenges. Properties of mucus in asthma In asthma, studies show not only a quantitative increase in mucus production but also modifications in its physical characteristics.1 High concentrations of mucins are reported to be the major determinant of the modification of mucus in asthmatics.69 MUC5AC has been reported consistently in asthmatic airways: MUC5AC protein was identified in a mucous plug in fatal asthma,13 and MUC5AC expression was upregulated in bronchial biopsies of asthmatic patients.40,65 MUC5B protein was also identified in a mucous plug in fatal asthma70 and was expressed in epithelial goblet cells in stable asthmatic patients, but its expression was not increased.65 MUC2 mRNA was increased in bronchial biopsies from asthmatics,65 but MUC2 protein was not assessed. Therefore, MUC5AC plays an important role in excessive mucus production in asthma, but the contributions of MUC5B and MUC2 are less clear. Mechanisms of increased mucin production in asthma To understand basic mechanisms of excessive mucus production, investigators have performed animal studies in rodents. Rodents have few submucosal glands,71 so most studies have focused on mucus production by epithelial goblet cells; the regulation of mucin production by submucosal gland cells remains unknown. In rodents, allergic sensitization followed by intratracheal challenge with OVA results in recruitment of inflammatory cells (e.g. neutrophils, eosinophils, lymphocytes, and macrophages) in airways and results in the rapid development of epithelial changes mimicking asthma.17 Among these are goblet cell metaplasia17 and degranulation.44 Allergen-induced goblet cell metaplasia in mice is dependent on T lymphocytes,72 which produce Th2 cytokines.73 Blockade of the IL-4 receptor (IL-4Ra)33 or STAT6 deficiency74 prevents allergen-induced goblet cell metaplasia in mice, implicating the IL4Ra-STAT6 pathway. Overexpression75 or intratracheal instillation76 of IL-4 in rodents results in goblet cell metaplasia and upregulation of MUC5AC expression. However, Th2 cell-induced goblet cell metaplasia is independent of IL-4.77 IL-13 shares a receptor component with IL-4, and blockade of IL-13 in vivo prevents OVA-induced goblet cell metaplasia.34,35 Because expression of IL-13 in the airway epithelium leads to goblet cell metaplasia,78 IL-13 is considered important in allergen-induced goblet cell metaplasia. Recently, IL-9 was reported to induce mucin transcription in vitro79 and goblet cell metaplasia in vivo;80 the significance of these findings requires further study.81 Because neither IL-4 nor IL-13 induces mucin gene expression in airway epithelial cells in vitro,36,79 it was sug-
gested that their effect on mucin expression is indirect and could be mediated via the action of other, perhaps recruited, cells. IL-4 and IL-13 stimulate eosinophil recruitment in mouse airways.34 An interaction between eosinophils and epithelial cells was suspected to play a role in allergeninduced goblet cell metaplasia, but Th2 cell-induced goblet cell metaplasia occurs independently of eosinophilic inflammation in mice.82 However, mouse and human eosinophils show different characteristics in vitro and in vivo.83,84 Thus, activated human eosinophils induce mucin MUC5AC expression in human airway epithelial cells.85 Therefore, a role for eosinophils in allergen-induced goblet cell metaplasia in human diseases cannot be excluded. Because activated neutrophils cause MUC5AC production in airway epithelial cells via EGFR activation,20 the role of neutrophils and EGFR in Th2-induced mucin production was studied: Instillation of IL-13 in rat airways induced EGFR expression and goblet cell metaplasia in airway epithelium; a selective EGFR tyrosine kinase inhibitor prevented IL-13-induced goblet cell metaplasia.37 IL-13 induced IL-8 expression and neutrophil recruitment in the epithelium, and cyclophosphamide (an inhibitor of leucocytes), or an antibody to IL-8 prevented both neutrophil recruitment and IL-13-induced goblet cell metaplasia.37 These results suggest that IL-13 induces goblet cell metaplasia via neutrophil recruitment and consequent EGFR activation. EGFR expression is increased in asthmatic airways39,40,86 and neutrophils are recruited in asthma exacerbations48 and in severe asthma.47 Therefore, neutrophilic inflammation could play an important role in excess mucus production in human asthma.
M U C U S R E G U L AT I O N I N C O P D Clinical relevance of hypersecretion in COPD Inflammatory diseases generally associated with cigarette smoking encompass different pathological processes, including chronic bronchitis, COPD, and emphysema (not discussed further here). Because approximately 13.8 million men and women have chronic bronchitis,2 and because mucus hypersecretion contributes to the morbidity and mortality of COPD,2 this section discusses the role of mucus hypersecretion in these diseases. Role of submucosal glands Glands are located in the conducting airways only; they contain serous demilunes and mucous tubules (which express mucins constitutively). Secreted mucins are transported via secretory ducts (which also produce mucins) to the airway lumen. The duct openings are concentrated at airway bifurcations adjacent to cough receptors.Thus, chronic bronchitis (defined as chronic cough and mucus secretion) is likely to be derived in large part from hypersecreting glands. Hypersecretion is associated with enlargement of glandular elements;87 but goblet cells are also increased.88 Stimuli causing gland enlargement are unknown.
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Serous cells are clustered at the end of mucous tubules; they produce watery secretions43 that hydrate the mucous secretions. Some studies report enlargement selectively of mucous cells in COPD.6 Inadequate hydration of glandular secretions (e.g. by inadequate production of fluid by serous cells) could lead to the production of mucous “plugs” that cannot be cleared by ciliary action. These plugs may be aspirated retrograde (together with bacteria from the upper respiratory tract), especially during sleep. Aspiration of mucus plugs could play a role in exacerbations of COPD. Stimuli inducing mucin production related to COPD Cigarette smoking Chronic bronchitis and COPD are strongly associated with cigarette smoking.2 In smokers, peripheral airways contain an increased number of goblet cells.88,89 Smoking also increases production of mucins and goblet cell hyperplasia in several species.18,90 Because EGFR activation results in mucin synthesis,16 and because EGFR expression is increased in airways of smokers,91 Takeyama et al.19 examined the role of the EGFR cascade in smoke-induced mucin synthesis: Exposure to cigarette smoke upregulated the expression of EGFR mRNA and induced EGFR-specific tyrosine phosphorylation resulting in upregulation of mucin synthesis in vitro and in rat airways. Goblet cell metaplasia
was prevented completely by selective EGFR tyrosine kinase inhibitors. About half of cigarette smoke-induced mucin synthesis was inhibited by antioxidants, implicating a role for oxygen free radicals in the EGFR cascade.19 The remainder could involve other stimuli such as acrolein29 and the cyclooxygenase pathway.92 Neutrophils and oxidative stress The association of neutrophils with chronic bronchitis, even in the stable state,93 and the finding of neutrophils in association with airway submucosal glands in COPD94 suggest that neutrophils play a role in mucin regulation in this disease. When neutrophils are recruited into the airways by chemoattractants, they produce TNF-a, which upregulates EGFR expression in airway epithelium.16 Stimulated neutrophils also release oxygen free radicals, which activate EGFR.20 Thus, neutrophils recruited to the epithelium have the potential of causing epithelial differentiation into mucus-producing cells. In addition, during neutrophil recruitment, elastase moves to the surface, where it can interact with the airway epithelium.45 Elastase, in addition to its action as a potent secretagogue,45,95 is capable of causing goblet cell metaplasia in airways.28,96 Thus, neutrophils can play major roles in both mucin synthesis and degranulation (Fig. 16.3).
Neutrophil
NEUTROPHIL ACTIONS
TNF-α
O2 Free radicals
Elastase
Cathepsin G Proteinase 3
EGFR expression
EGFR activation
mRNA stabilization Mucin secretion Mucin production P
EGFR
P
EPITHELIAL CELLS Basal cell
Nongranulated secretory cell
P
P
Inflammation
Goblet cell
Fig. 16.3. Schematic depicting effects of neutrophils on mucin production and secretion. Release of TNF-a from neutrophils induces EGFR expression in basal cells, which elongate to produce nongranulated secretory cells. Release of oxygen (O2) free radicals from neutrophils activates EGFR phosphorylation (P) to produce mucin containing goblet cells. Neutrophil elastase also stimulates mucin production (via stabilization of mucin mRNA). Downregulation of EGFR occurs in quiescent goblet cells. Neutrophil enzymes (elastase, cathepsin G, proteinase 3) cause mucin secretion and recruited neutrophils reactivate the EGFR cascade.
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Airway infections Airway infections, especially by Gram-negative bacteria, play an important role in hypersecretion and deterioration in COPD,2 and in cystic fibrosis.97 Endotoxin from Gramnegative bacteria increases epithelial mucosubstances.26 Kohri et al.98 reported that Pseudomonas aeruginosa induces mucin synthesis in airway epithelial cells via EGFR activation; the downstream pathway involves the c-Src-Ras-MEK signaling pathway.30 In vivo, the effect on mucus production could be increased by the recruitment of neutrophils by the bacteria.99,100 Differentiation of airway epithelial cells into goblet cells is complete in approximately 72 hours24 and degranulation of goblet cells begins within minutes.44 Thus, in exacerbations of COPD, bacteria-induced mucus hypersecretion may play a major role in the patient’s deterioration.
T R E AT M E N T O F M U C U S HYPERSECRETION Current therapies A recent review of COPD2 states: [There] is little available in the way of specific therapy . . . the most successful means of controlling airway mucous secretion is avoidance of inhaled irritants . . . mucolytic agents are not used in the United States . . . Thus, treatment of hypersecretion is not presently available. Several drugs currently used have been evaluated for their possible effect on mucus hypersecretion. Some reviews suggest that corticosteroids have a limited beneficial effect on mucus hypersecretion.101,102 However, Blyth et al.17 found that in animals sensitized with OVA, challenged intratracheally with OVA for 3 days, and pretreated with high doses of dexamethasone 1 mg/kg daily before each challenge, goblet cell metaplasia still occurred. Longer treatment showed some inhibitory effect.103 In other studies, high doses of corticosteroids had only a limited effect on mucus production and secretion in vitro.104,105 In humans, asthmatics treated with inhaled steroids for three months were reported to have increased numbers of ciliated compared to goblet cells;106 in another study107 there was no change in the content of mucin-like glycoproteins in induced sputum after a month of inhaled steroids. Thus, the effect of corticosteroids on mucus hypersecretion is questionable, especially in therapeutic concentrations. Cysteinyl leukotrienes have been shown to induce mucus secretion,108 and it is conceivable that leukotriene inhibitors could have an inhibitory effect on mucus secretion in asthmatics. Suplatast tosilate decreases the production of Th2 cytokines and inhibits allergen-induced goblet cell metaplasia in mice;109 clinical studies in asthmatics are under way.110 Platelet activating factor (PAF) is a mucus secretagogue111 and induces goblet cell metaplasia in vivo.27 Clinical trials with PAF antagonists have shown disappointing results in
the treatment of chronic asthma;112 their effects on mucus hypersecretion in humans have not been evaluated. Future therapies Mucus hypersecretion could be prevented by blocking secretory cell differentiation or degranulation: Because EGFR inhibitors have been shown to prevent goblet cell differentiation in various animal models,19,24,37 inhibition of EGFR provides a promising approach for the treatment of hypersecretory diseases.113 Selective EGFR tyrosine kinase inhibitors currently exist, and are being examined for cancer therapy.114,115 Clinical trials will be necessary to confirm the role of the EGFR cascade in mucus hypersecretion in humans. Phosphodiesterase 4 (PDE4) inhibitors were effective in blocking allergen-induced goblet cell metaplasia in mice.116 The mechanisms by which these drugs prevent goblet cell metaplasia remain unknown; it is speculated that their effect on neutrophil activation could be involved. For secretory cells already formed, preventing degranulation could prevent mucus secretion and mucous plugging. Because proteases such as neutrophil elastase, cathepsin G, and mast cell tryptase are potent secretagogues,95,117 they provide interesting targets for therapeutic intervention. Elastase inhibitors are of special interest because neutrophil elastase also induces mucin synthesis ascribed to mRNA stabilization96 and goblet cell metaplasia.28 Tryptase inhibitors have been shown to prevent allergen-induced inflammatory responses in sheep, but mucus was not assessed.118 Tryptase inhibitors are in clinical development,102 and their efficacy should be evaluated in mucus hypersecretion.
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76. Dabbagh K, Takeyama K, Lee H-M et al. IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J. Immunol. 1999; 162:6233–7. 77. Cohn L, Homer RJ, Marinov A et al. Induction of airway mucus production by T-helper 2 (Th2) cells: a critical role for interleukin 4 in cell recruitment but not in mucus production. J. Exp. Med. 1997; 186:1737–47. 78. Zhu Z, Homer RJ, Wang Z et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 1999; 103:779–88. 79. Longphre M, Li D, Gallup M et al. Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells. J. Clin. Invest. 1999; 104:1375–82. 80. Louhaed J, Toda M, Jen J et al. IL-9 upregulates mucus expression in the airways. Am. J. Respir. Cell Mol. Biol. 2000; 22:649–56. 81. Wills-Karp M. Trophic slime, allergic slime. Am. J. Respir. Cell Mol. Biol. 2000; 22:637–9. 82. Cohn L, Homer RJ, MacLeod H et al. Th2-induced airway mucus production is dependent on IL-4R alpha, but not on eosinophils. J. Immunol. 1999; 162:6178–83. 83. Malm-Erjefalt M, Persson CGA, Erjefalt JS. Degranulation status of airway tissue eosinophils in mouse models of allergic airway inflammation. Am. J. Respir. Cell Mol. Biol. 2001; 24:352–9. 84. Denzler KL, Farmer SC, Crosby JR et al. Eosinophil major basic protein-1 does not contribute to allergen-induced airway pathologies in mouse models of asthma. J. Immunol. 2000; 165:5509–17. 85. Burgel P-R, Lazarus SC, Tam DC et al. Human eosinophils induce mucin production in airway epithelial cells via epidermal growth factor receptor activation. J. Immunol. 2001 (in press). 86. Puddicombe SM, Polosa R, Richter A et al. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J 2000; 14:1362–74. 87. Scott KWM. An autopsy study of bronchial mucous gland hypertrophy in Glasgow. Am. Rev. Respir. Dis. 1973; 107:239–45. 88. Saetta M, Turato G, Baraldo S et al. Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am. J. Respir. Crit. Care Med. 2000; 161:1016–21. 89. Cosio MG, Hale KA, Niewoehner DE. Morphologic and morphometric effects of prolonged cigarette smoking on the small airways. Am. Rev. Respir. Dis. 1980; 122:265–71. 90. Lamb D, Reid LM. Goblet cell increase in rat bronchial epithelium after exposure to cigarette and cigar tobacco smoke. Br. Med. J. 1969; i:33–5. 91. Kurie JH, Shin HJ, Lee JS et al. Increased epidermal growth factor expression in metaplastic bronchial epithelium. Clin. Cancer Res. 1996; 2:1787–93. 92. Rogers DF, Jeffery PK. Inhibition of cigarette smoke-induced airway secretory cell hyperplasia by indomethacin, dexamethasone, prednisolone, or hydrocortisone in the rat. Exp. Lung Res. 1986; 10:285–98. 93. Hill AT, Bayley D, Stockley RA. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am. J. Respir. Crit. Care Med. 1999; 160:893–8. 94. Saetta M, Turato G, Facchini FM et al. Inflammatory cells in the bronchial glands of smokers with chronic bronchitis. Am. J. Respir. Crit. Care Med. 1997; 156:1633–9. 95. Sommerhoff CP, Nadel JA, Basbaum CB et al. Neutrophil elastase and cathepsin G stimulate secretion of cultured bovine airway gland serous cells. J. Clin. Invest. 1990; 85:682–9. 96. Voynow JA, Rosenthal Young L, Wang Y et al. Neutrophil elastase increases MUC5AC mRNA and protein expression in respiratory epithelial cells. Am. J. Physiol. 1999; 276:L835–43. 97. Boucher RC, Knowles MR, Yankaskas J. Cystic Fibrosis. In: Murray JF, Nadel JA (eds), Textbook of Respiratory Medicine, pp. 1291–323. Philadelphia: WB Saunders, 2000.
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98. Kohri K, Ueki IF, Shim JJ et al. Pseudomonas aeruginosa (PA) exoproducts induce mucin MUC5AC production via expression and activation of epidermal growth factor receptor (EGFR). Am. J. Respir. Crit. Care Med. 2001; 163:A995. 99. Massion PP, Hebert CA, Leong S et al. Staphylococcus aureus stimulates neutrophil recruitment by stimulating interleukin-8 production in dog trachea. Am. J. Physiol. 1995; 268:L85–94. 100. Inoue H, Massion PP, Ueki IF et al. Pseudomonas stimulates interleukin-8 mRNA expression in airway epithelium, in gland ducts and in recruited neutrophils. Am. J. Respir. Cell Mol. Biol. 1994; 11:651–63. 101. Horiuchi T, Castro M. The pathobiologic implications for treatment: old and new strategies in the treatment of chronic asthma. Clin. Chest Med. 2000; 21:381–95. 102. Barnes PJ. Airway pharmacology. In: Murray JF, Nadel JA (eds), Textbook of Respiratory Medicine, pp 267–96. Philadelphia: WB Saunders, 2000. 103. Blyth DI, Pedrick MS, Savage TJ et al. Induction, duration, and resolution of airway goblet cell hyperplasia in a murine model of atopic asthma: effect of concurrent infection with respiratory syncytial virus and response to dexamethasone. Am. J. Respir. Cell Mol. Biol. 1998; 19:38–54. 104. Shimura S, Sasaki T, Ikeda K et al. Direct inhibitory action of glucocorticoids on glycoconjugate secretion from airway submucosal glands. Am. Rev. Respir. Dis. 1990; 141:1044–9. 105. Kai H,Yoshitake K, Hisatsune A et al. Dexamethasone suppresses mucus production and MUC2 and MUC5AC gene expression by NCI-H292 cells. Am. J. Physiol. 1996; 271:L484–8. 106. Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta-2 agonist in newly diagnosed asthma: a randomized, doubleblind, parallel-group controlled trial. J. Allergy Clin. Immunol. 1992; 90:32–42. 107. Fahy JV, Boushey HA. Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation. Eur. Respir. J. 1998; 11:1240–7.
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108. Marom Z, Shelhamer JH, Bach MK et al. Slow-reacting substances (leukotrienes C4 and D4) increase the release of mucus from human airways in vitro. Am. Rev. Respir. Dis. 1982; 126:449–51. 109. Shim JJ, Dabbagh K, Takeyama K et al. Suplatast tosilate inhibits goblet-cell metaplasia of airway epithelium in sensitized mice. J. Allergy Clin. Immunol. 2000; 105:739–45. 110. Tamaoki J, Kondo M, Sakai N et al. Effect of suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a doubleblind randomised study. Lancet 2000; 356:273–8. 111. Hotchkiss JA, Stam MA, Harkema JR. Platelet activating factor stimulates rapid mucin secretion in rat nasal airways in vivo. Exp. Lung Res. 1993; 19:545–57. 112. Tavakkoli A, John Rees P. Drug treatment of asthma in the 1990s: achievements and new strategies. Drugs 1999; 57:1–8. 113. Nadel JA. Role of epidermal growth factor receptor activation in regulating mucin synthesis. Respir. Res. 2001; 2:85–9. 114. Noonberg SB, Benz CC.Tyrosine kinase inhibitors targeted to the epidermal growth factor subfamily: role as anticancer agents. Drugs 2000; 59:753–67. 115. Raymond E, Faivre S, Armand JP. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs 2000; 60(Suppl. 1):15–23. 116. Kanehiro A, Ikemura T, Makela MJ et al. Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. Am. J. Respir. Crit. Care Med. 2001; 163:173–84. 117. Sommerhoff CP, Caughey GH, Finkbeiner WE et al. Mast cell chymase: a potent secretagogue for airway gland serous cells. J. Immunol. 1989; 142:2450–6. 118. Clark JM, Abraham WM, Fishman CE et al. Tryptase inhibitors block allergen-induced airway and inflammatory responses in allergic sheep. Am. J. Respir. Crit. Care Med. 1995; 152:2076–83.
Airway Smooth Muscle
Chapter
17
Yassine Amrani, Vera P. Krymskaya, Aili L. Lazaar, and Reynold A. Panettieri, Jr Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, PA, USA
Airway smooth muscle (ASM) functions as the primary effector cell that regulates bronchomotor tone. In asthma and chronic obstructive pulmonary disease (COPD), bronchoconstriction evoked by smooth muscle shortening promotes airway obstruction, a hallmark of asthma and COPD. Recent evidence also suggests that ASM may undergo hypertrophy and/or hyperplasia and modulate inflammatory responses by secreting chemokines and cytokines. This chapter reviews current studies focusing on excitation–contraction coupling, signaling pathways modulating ASM growth, and cytokine-induced effects on ASM synthetic responses.
R E G U L AT I O N O F C A L C I U M S I G N A L I N G I N A I R WAY S M O O T H M U S C L E Because increases in cytosolic calcium directly regulate the initiation and development of ASM contraction, changes in calcium homeostasis may promote bronchial hyperresponsiveness in asthma. Evidence suggests that various mediators and cytokines important in the pathogenesis of asthma, which augment agonist-induced contractile function, also directly alter calcium signaling. This section reviews (1) the critical calcium-dependent mechanisms involved in the regulation of ASM contraction, and (2) the potential molecular mechanisms that regulate calcium signaling. Calcium responses induced by bronchoconstrictor agents Using the fluorescent dye Fura-2, studies performed on ASM cells have shown that agonist-induced elevation of the cytosolic free calcium ([Ca2]i) concentration is biphasic. The initial rapid and transient phase of [Ca2]i elevation results from the depletion of inositol-1,4,5 trisphosphates (IP3)-sensitive calcium stores; see the review by Amrani and Panettieri.1 This transient increase in intracellular calcium initiates the contraction process through activation of a calcium–calmodulin dependent myosin light-chain kinase and subsequent phosphorylation of the 20 kDa myosin light
chain, the central regulatory mechanism of ASM contraction; see the review by Gienbycz and Raeburn.2 The subsequent sustained elevation of intracellular [Ca2]i is regulated by the activation of a calcium influx across the plasma membrane since depletion of extracellular calcium or the use of calcium channel inhibitors prevents this sustained phase.3,4 The role of the calcium influx in ASM cells after agonist stimulation is not completely understood, but evidence suggests that calcium entry plays an important role in maintaining the plateau phase of ASM contraction via a PKCdependent mechanism.2 Pathways regulating [Ca2]i influx Although agonist-mediated increases in [Ca2]i have been extensively characterized, much less is known about the cellular mechanisms linking the transient and the sustained phase. In 1986, Putney proposed the concept of storedependent calcium entry (called also the capacitative model) where depletion of intracellular stores directly regulates calcium entry at the plasma membrane via storeoperated calcium channels (SOCC). This calcium influx contributes to the refilling of the internal stores.5 The existence of capacitative calcium entry in excitable cells such as smooth muscle cells was demonstrated using drugs such as thapsigargin that cause depletion of sarco-endoplasmic reticulum (SER) by directly inhibiting the activity of the SER-associated calcium-ATPases (SERCA).6 In human ASM cells, although thapsigargin-sensitive SERCA2a and 2b isoforms exist, SERCA2b is the predominant isoform. In these cells, depletion of intracellular calcium stores in response to thapsigargin activates a calcium influx with a magnitude that is dependent upon the duration of stimulation with thapsigargin.1 These data suggest that pathways that activate calcium influx in ASM are linked to the filling state of SERCA2b-associated internal calcium stores. Release of calcium from SER also regulates calciumdependent chloride and nonselective cation channels, leading to membrane depolarization and opening of voltage-dependent channels; see the review by Janssen.7 Pretreatment of human ASM cells with thapsigargin also
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abrogates the calcium responses induced by bradykinin, histamine, or carbachol, suggesting that thapsigarginsensitive calcium stores involve, at least in part, those activated by the contractile agonists.4 By mobilizing the same calcium stores, it is plausible that both thapsigargin and agonists activate similar SOCCdependent calcium influx pathways in ASM. This is supported by the fact that the amplitude of the sustained increase in [Ca2]i is dependent on the amplitude of the initial transient phase.4 Whether additional mechanisms are involved, such as concomitant activation of receptoroperated calcium channels (ROCC) previously described in ASM,3,4 or involvement of a released soluble mediator controlling calcium influx,8 remains unknown. Collectively, these data show that the thapsigarginsensitive intracellular calcium stores in ASM not only serve as a source of calcium to initiate the transient response to
agonists, but also participate in the regulation of calcium influx in ASM cells as proposed by the capacitative model. Fig. 17.1 summarizes the potential sources of calcium mobilized by contractile agonists to regulate ASM contraction. Calcium homeostasis in airway smooth muscle: a possible target for proinflammatory agents Amplification of contractile receptor-coupled calcium signaling The observation that cultured ASM cells derived from hyperresponsive Fisher rats have an enhanced calcium signal to serotonin suggests the existence of altered calcium metabolism in a model of airway hyperresponsiveness.9 The underlying mechanism is unknown, but evidence shows that proinflammatory factors may play an important role in regulating calcium metabolism in ASM. Recent studies demonstrate that TNF-a and IL-1b enhance bovine smooth muscle
ROCCs
SOCCs
Contractile receptor
G -protein
Calcium channels
γ
α β
PLC
IP3 Ca2 Internal stores
2
Ca
Calmodulin
SERCA MLCK
PKC
Thapsigargin MLC-P
Initial phase
Sustained phase
Contraction
Fig. 17.1. Sources of calcium involved in the regulation of agonist-induced ASM contraction. Contractile agonists activate G-protein-coupled receptors that stimulate phospholipase C (PLC) and evoke contraction via the mobilization of calcium from inositol trisphosphate (IP3)-sensitive internal stores. The increase in [Ca2+]i activates calcium-/calmodulin-sensitive myosin light-chain kinase (MLCK), with subsequent phosphorylation of the 20-kDa myosin light chain (MLC) and initiation of the cross-bridge cycling between actin and myosin. The sustained phase of contraction is thought to involve calcium entry through both receptor-operated calcium channels (ROCC) and store-operated calcium channels (SOCC). In contrast to ROCCs that remain opened as long as the contractile agonist is present, SOCCs are triggered by the filling state of sarco-endoplasmic reticulum calcium ATPases (SERCA)-associated internal stores.
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contractility to acetylcholine and other contractile agonists by involving an increased mobilization of intracellular [Ca2]i.10 Accordingly, proinflammatory cytokines may “prime” ASM cells for a nonspecific increase in calcium responsiveness, an effect that appears not to involve a change in the receptor affinity for its ligand.11,12 The fact that TNF-a potentiates increases in calcium induced by thapsigargin, which depletes SER calcium stores, suggests a possible modulatory effect of TNF-a on SER-associated regulatory proteins such as SERCA. In addition,TNF-a and IL-1b also augment agonist-evoked phosphoinositide turnover, suggesting that cytokines may modulate receptorcoupled phospholipase C activity; see the review by Amrani et al.12 In support of this hypothesis, TNF-a also enhanced calcium signals in response to NaF,1 an agent that directly activates G-proteins in ASM cells, and upregulated expression of Gq and Gi proteins in human ASM cells.13 Together, these data suggest that TNF-a can induce a “hyperresponsive” phenotype by enhancing signaling pathways downstream from G-protein coupled receptor (GPCR) activation. Other reports have also described that proinflammatory stimuli modulate GPCR/PLC signaling pathways in cultured ASM cells (Table 17.1). Pretreatment of bovine ASM cells with either eosinophil-derived polycationic proteins or myelin basic protein increased bradykinin-induced transients as well as sustained elevations of [Ca2]i.14 Incubation with either the aldehyde pollutant acrolein or the proinflammatory enzyme PLA2 significantly increased the intensity as well as the frequency of calcium transients in response to acetylcholine.15,16 Finally, other experimental conditions such as chronic hypoxia or mechanical strain also modulate calcium signaling induced by agonists in ASM
cells. Belouchi et al.17 reported that the amplitude of calcium transients in response to low concentrations of acetylcholine were significantly higher in freshly isolated tracheal smooth muscle cells from hypoxic rats than in those obtained from normoxic animals. Investigators also showed that mechanical strain augmented carbachol-induced IP3 turnover through the regulation of G-protein and/or phospholipase C activities.18 Alteration in the density of contractile receptors Exposure of cultured ASM to various proinflammatory mediators also modulates the density of contractile agonist receptors. ASM cells exposed to TNF-a have a dramatic decrease in muscarinic receptor density.4,13 In contrast, levels of the bradykinin B2 receptor are rapidly increased in human bronchial smooth muscle exposed to IL-1b via a prostanoid-dependent regulation of gene transcription.11 Surprisingly, fenoterol, a b2-agonist, as well as other cAMPelevating agents, significantly upregulates the expression of histamine H1 receptor in bovine ASM cells, an effect that involves both increased gene expression and mRNA stability.19 This increase in H1 receptor expression was associated with an increase in ASM responsiveness to histamine in contraction studies. This may be important since fenoterol may lead to the worsening asthma by modulating, at least in part, bronchial hyperresponsiveness; see the review by Bearley et al.20 Fig. 17.2 summarizes the potential mechanisms involved in the modulation of agonist-evoked calcium signaling in response to various stimuli. Increase in the calcium sensitivity of the contractile apparatus Increase in the sensitivity of myofilaments to calcium also represents a mechanism by which the contractile function of
Table 17.1. Potential modulators of calcium metabolism in ASM cells
Modulation of receptorcoupled signal transduction
Factors
Effect
Species
References
IL-1b, TNF-a
↑ Ca2 transient, IP3 turnover ↑ Ca2 transient and frequency oscillations ↑ Ca2 transient and plateau ↑ IP3 turnover ↑ Ca2 signals ↑ Ca2 signals, ↓ IP3 5-phosphatase ↑ Ca2 frequency oscillations, receptor affinity for agonist
Human
11, 12
Rat
15
Bovine Bovine Bovine Rat
14 18 16 9
Rat
17
↑ Histamine H1 receptor ↑ Bradykinin B2 receptor ↓ Muscarinic receptor
Bovine Human Human
19 11 1, 13
Acrolein Major basic protein Mechanical strain PLA2 Allergen challenge Chronic hypoxia Modulation of receptor density
Feneterol IL-1b TNF-a
Legend: (↑) increase, (↓) decrease, (IP3) inositol 1,4,5 trisphosphate
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?
Allergen challenge
β2-agonist
Inflammatory mediators
Pollutant
Chronic hypoxia
Abnormal mechanical strain
Receptor
G -protein
γ
α β
PLC
IP3
Ca2
Internal stores SERCA2b
Amplification of Ca2 signals
Fig. 17.2. Potential modulators of contractile receptor-coupled calcium signaling in ASM. A variety of stimuli may induce a “hyperresponsive” phenotype, which modulates G-protein-coupled receptor activation in response to agonists. (?) indicates the possible role played by inflammatory mediators in allergen-induced changes in calcium responsiveness to contractile agonist. The potential intracellular targets underlying the increase in calcium responsiveness induced by these various stimuli are shown with a bold star. IP3, inositol-1,3,5 trisphosphate; PLC, phospholipase C; [Ca2+]i, intracellular calcium.
ASM can be enhanced.Abnormal calcium sensitivity has been described in ASM derived from allergen-sensitized animals or from passively sensitized tissues; see the review by Schmidt and Rabe.21The role played by pro-inflammatory agents in the impairment of calcium sensitivity has been suggested in vitro. Nakatani et al.,22 by simultaneously measuring [Ca2]i and isometric tensions in response to acetylcholine, showed that brief exposure to TNF-a enhanced the calcium sensitivity of contractile elements in bovine tracheal smooth muscle. Surprisingly, TNF-a did not affect the calcium signals induced by acetylcholine. In guinea pig tracheal smooth muscle, short-term treatment with TNF-a also increased calcium sensitivity of the contractile apparatus.23 Together, these studies suggest that, in addition to the
modulation of receptor-coupled signal transduction, increase in calcium sensitization of contractile elements represent another downstream target potentially modulated by proinflammatory agents. Because ASM is an essential effector cell modulating bronchoconstriction, changes in ASM properties can be regarded as a potential mechanism contributing to the increased ASM contractility associated with asthma. A variety of stimuli present in asthmatic airways may induce hyperresponsiveness by modulating calcium signaling in response to contractile agonists as summarized in Fig. 17.3. Whether this amplification of calcium signaling contributes to the increased contractility in asthmatic patients remains to be investigated.
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Airway Smooth Muscle
Normal
Asthma/COPD
Acute
Chronic
Epithelium Features Basement membrane
T cells
Mast cells Mediators
Cell–cell interaction via CD40, ICAM-1, CD44 Enhanced signaling PI3K, NF-lB pathways
Smooth muscle
Increased Ca2 signals
Increased Ca2 signals Increased cell number Increased cytokine/chemokine release
Modulation of ASM function Fig. 17.3. Factors affecting ASM function in acute and chronic state of asthma/COPD. During the acute inflammation, a variety of mediators, such as cytokines, can modulate ASM contractile function by enhancing calcium signaling to agonists. These mediators regulate the recruitment and activation of eosinophils and T lymphocytes in the airway mucosa, a characteristic histopathological feature of the chronic disease. The persistence of airway inflammation via the production of cytokines and chemokines by both inflammatory as well as structural cells has the potential to directly stimulate ASM proliferation or indirectly as a result of T cell–ASM interaction mediated by cell surface expression of various CAM proteins such as ICAM-1, CD40, and CD44. Enhanced activation of PI3K or the transcription factor NF-jB in ASM may also stimulate mitogenic and synthetic functions.
A I R WAY S M O O T H M U S C L E C E L L P R O L I F E R AT I O N Increased ASM mass is a characteristic histopathological finding in the airways of chronic severe asthmatics and of COPD patients. Although increased ASM mass is, in part, due to ASM cell proliferation, the mechanisms that regulate ASM cell growth remain unclear. Many studies have characterized the stimulation of airway smooth muscle growth in response to mitogenic agents such as polypeptide growth factors, inflammatory mediators, and cytokines. The observation that contractile agonists induce smooth muscle cell proliferation may be a critical link between the chronic stimulation of muscle contraction and myocyte proliferation.24 Although the mechanisms by which agonists induce cell proliferation are unknown, similarities exist between signal transduction processes activated by these agents and those of known growth factors, which can also stimulate smooth muscle contraction. The complex interaction between signaling pathways that induce myocyte proliferation and those that inhibit cell growth by stimulation of apoptosis may promote airway remodeling as seen
in the bronchi of patients with asthma, bronchiolitis obliterans, or chronic bronchitis. Smooth muscle cell proliferation is stimulated by mitogens that fall into two broad categories: • those that activate receptors with intrinsic tyrosine kinase activity (RTK); • those that mediate their effects through receptors coupled to heterotrimeric GTP binding proteins (G proteins) and activate nonreceptor-linked tyrosine kinases found in the cytoplasm. Although both pathways increase cytosolic calcium through activation of phospholipase C (PLC), different PLC isoenzymes appear to be involved. Activated PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2) to inositol trisphosphate (IP3) and diacylglycerol (DAG). These second messengers activate other cytosolic tyrosine kinases as well as serine and threonine kinases (protein kinase C, G, and N) that have pleiotropic effects including the activation of proto-oncogenes, which are a family of cellular genes (c-onc) that control normal cellular growth and differentiation.
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Recent reviews attempted to summarize current progress in our understanding of cellular mechanisms leading to smooth muscle cell proliferation.25–28 This section will focus on the role of phospholipase C activation and the phosphatidylinositol 3-kinase signaling pathway in smooth muscle cell mitogenesis. Phospholipase C (PLC) activation Receptors with intrinsic tyrosine kinase activity and those coupled to G proteins both activate specific PLC isoforms. These PLCs are the critical regulatory enzymes in the activation of the PI pathway. The c family of phospholipase C contains src-homology SH2 and SH3 domains and is regulated by tyrosine phosphorylation. In ASM cells, some growth factors which activate receptors with intrinsic tyrosine kinases have been identified. PDGF and EGF in human ASM cells29–31 and IGF-1 in bovine and rabbit ASM cells32–34 have been shown to induce myocyte proliferation. However, the role of PLC-c1 activation in modulating ASM cell growth remains unknown. Other PLC isoforms are controlled by G proteins and/or calcium. Although the role of PLC activation in mediating G protein-dependent cell growth is complex, G protein activation appears critically important in transducing contractile agonist-induced cell growth. G proteins are composed of three distinct subunits, a, b, c, the latter two existing as a tightly associated complex.35 Although a-subunits were considered the functional components important in downstream signaling events, recent evidence suggests that bc-subunits also play a critical role in modulating cell function.36 Advances in single-cell microinjection techniques in combination with the development of neutralizing antibodies to specific Ga subunits have enabled investigators to characterize the role of G protein activation in cell proliferation. Using these techniques, studies with 3T3 fibroblasts have determined that, while both thrombin and bradykinin required Gq activation to mobilize cytosolic calcium, to generate IP3 and to induce mitogenesis, thrombin, but not bradykinin, induces cell growth by stimulating Gi2.37 These studies determined that a single mitogen may require functional coupling to distinct subtypes of G proteins in order to stimulate cell growth. Collectively, these data also provide a mechanism to explain why some, but not all, agonists induce cell proliferation while mobilizing comparable levels of cytosolic calcium. Recently, the role of PLC activation and inositol trisphosphate in mediating contractile agonist-induced ASM cell growth has been explored. Several contractile agonists, which mediate their effects through G protein-coupled receptors, induce ASM cell proliferation. Studies have determined that histamine38 and serotonin induce canine and porcine ASM cell proliferation. Endothelin-1, leukotriene D4 and U-46619, a thromboxane A2 mimetic, induce rabbit ASM cell growth,39 and thrombin induces mitogenesis in human ASM cells.31 Although the mechanisms that mediate these effects are unknown, agonist-
induced cell growth probably is modulated by activation of G proteins in a manner similar to that described in vascular smooth muscle. Using human ASM cells, Panettieri et al.31 examined whether contractile agonist-induced human ASM cell growth was dependent on PLC activation and inositol trisphosphate formation. These investigators examined the relative effects of bradykinin and thrombin on myocyte proliferation and PI turnover. Thrombin, but not bradykinin, stimulated ASM cell proliferation despite a 5-fold greater increase in [3H]-inositol phosphate formation in cells treated with bradykinin as compared with those treated with thrombin. Inhibition of PLC activation with U-73122 had no effect on thrombin- or EGF-induced myocyte proliferation. In addition, pertussis toxin completely inhibited thrombin-induced ASM cell growth but had no effect on PI turnover induced by either thrombin or bradykinin.31 Taken together, these studies suggest that thrombin induced human ASM cell growth by activation of a pathway that was pertussis toxin-sensitive and independent of phospholipase C activation or PI turnover. Compared to RTK-dependent growth factors, contractile agonists, with the exception of thrombin and sphingosine-1phosphate, appear to be less effective human ASM mitogens.40 In cultured human ASM cells, 100 lmol/L histamine or serotonin induces 2–3 fold increases in [3H]-thymidine incorporation as compared with that obtained from unstimulated cells. EGF, serum, or phorbol esters, which directly activate protein kinase C, induce 20–30 fold increases in [3H]-thymidine incorporation.41 In rabbit ASM cells, endothelin-1 induces cell proliferation by activating phospholipase A2, and by generating thromboxane A2 and LTD4.39,42 In human ASM cells, however, endothelin-1, thromboxane A2 and LTD4 appear to have little effect on ASM cell proliferation despite these agonists inducing increases in cytosolic calcium.31,43,44 Clearly, interspecies variability exists with regard to contractile agonist-induced cell proliferation. These models, however, may prove useful in dissecting downstream signaling events that modulate the differential effects of contractile agonists on ASM cell proliferation. Phosphatidylinositol 3-kinase (PI3K) signaling pathway In many cell types, activation of PI3K coordinates a variety of cellular functions including cell proliferation, differentiation, transformation, cell motility, and apoptosis. PI3Ks are a subfamily of lipid kinases that catalyze the addition of phosphate molecules specifically to the 3-position of the inositol ring of phosphoinositides.45 PTEN, a tumor suppressor, appears to negatively control the PI3K signaling pathway by dephosphorylating the 3-position of inositol ring.46 PI3K lipid products are not substrates for the PIspecific PLC enzymes that cleave inositol phospholipids into membrane-bound diacylglycerol and soluble inositol phosphates. The 3-phosphoinositides function as second messengers and activate downstream effector molecules
Airway Smooth Muscle
such as PDK1, p70s6k, protein kinase Cf and Akt.45,47 The ability of PI3K to regulate diverse functions may be due to the existence of multiple isoforms that have specific substrate specificities and that reside in unique cytoplasmic locations within the cell.48 Krymskaya et al.49 demonstrated that human ASM cells express most PI3K isoforms but appear to be lacking the Class IB p110c isoform. Studies support a role for PI3K in airway and vascular smooth muscle (VSM) cell proliferation. Wortmannin and LY294002, two potent inhibitors of PI3K, inhibit DNA synthesis in bovine ASM, porcine and rat VSM cells stimulated with PDGF, basic fibroblast growth factor, angiotensin II, or serum.50–53 Stimulation of a1 adrenergic receptors with noradrenaline activated mitogenesis, Ras, MAPK and PI3K in human VSM cells in a wortmanninsensitive manner.54 In rat thoracic aorta VSM cells, wortmannin completely blocked angiotensin II-induced Ras activation but had no effect on MAPK activation or protein synthesis.55 Thrombin, which induces human ASM cell growth by activating a receptor presumably coupled to both Gi and Gq proteins,31 requires PI3K activation to mediate its growth effects.56 In bovine ASM, the mitogenic effects of PDGF or endothelin-1 (ET-1) have been attributed to their ability to stimulate PI3K or pp70S6k.50 These data suggest that in both airway and vascular smooth muscle cells PI3K is involved in mitogenic signaling induced by numerous agents. In order to determine whether PI3K activation is necessary or sufficient to stimulate human ASM DNA synthesis, Krymskaya et al.49 used transfected cells with a chimeric model of class IA PI3K in which the inter-SH2 region of p85 regulatory subunit was covalently linked to its binding site at the p110 N-terminal region of the catalytic subunit.57 Transient expression of constitutively active p110* was sufficient to induce DNA synthesis in ASM cells in the absence of mitogens.49 Interestingly, in human ASM cells the level of p110*-induced DNA synthesis was markedly lower than that induced by EGF, thrombin, or serum; and thus, although PI3K activation is sufficient to induce DNA synthesis in ASM cells, other signaling pathways that act in parallel or that are more effective inducers of PI3K may play a role in modulating mitogen-induced DNA synthesis in these cells. In numerous cell types, PI3K has been shown to be an important mediator of pp70S6k activation in response to serum and growth factors.58 pp70S6k is a critical enzyme for mitogen-induced cell cycle progression through the G1 phase and translational control of mRNA transcripts that contain a polypyrimidine tract at their transcriptional start site.59 EGF and thrombin significantly stimulate pp70S6k, and wortmannin, LY294002, and rapamycin completely block this activation in ASM cells.56 Moreover, transient expression of constitutively active p110* PI3K activates pp70S6k in the absence of stimulation with mitogens, while overexpression of a dominant negative Dp85 PI3K abolished EGFand thrombin-induced pp70S6k activation.56 Thus, EGF and
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thrombin induce activation of pp70S6k in human ASM cells and mitogen-induced activation of pp70S6k appears PI3Kdependent. A recent study demonstrated that GPCR activation by inflammatory and contractile agents can synergize with RTK activation to augment human ASM growth. In EGFstimulated cells, GPCR-mediated potentiation does not appear mechanistically linked to increased EGFR or p42/p44 MAPK activation but is associated with sustained activation of p70 S6 kinase for several hours after the initial early phase of activation. These findings not only provide insight into mechanisms by which inflammation contributes to ASM hyperplasia/hypertrophy in diseases such as asthma and COPD, but also suggest a general mechanism by which GPCRs and RTKs interact to promote cell growth.60
A I R WAY S M O O T H M U S C L E : A N I M M U N O M O D U L AT O RY C E L L Asthma is a disease characterized, in part, by reversible airflow obstruction, hyperresponsiveness, and inflammation. COPD, which includes chronic bronchitis, emphysema, and bronchiectasis, is defined as predominantly irreversible airflow obstruction associated with neutrophilic airway inflammation. Traditional concepts concerning airway inflammation have focused on trafficking leucocytes and on the effects of inflammatory mediators, cytokines, and chemokines secreted by these cells. Airway smooth muscle, the major effector cell responsible for bronchomotor tone, has been viewed as a passive tissue responding to neurohumoral control and inflammatory mediators. New evidence, however, suggests that airway smooth muscle may secrete cytokines and chemokines and express cell adhesion molecules that are important in modulating submucosal airway inflammation. The cellular and molecular mechanisms that regulate the immunomodulatory functions of airway smooth muscle may offer new and important therapeutic targets in treating these common lung diseases. Chemokine and cytokine release by airway smooth muscle cells The various cell types that infiltrate the inflamed submucosa present the potential for many important cell–cell interactions. Eosinophils, macrophages, neutrophils, and lymphocytes initiate and perpetuate airway inflammation by producing proinflammatory mediators. Evidence also suggests that exposure of ASM to cytokines or growth factors alters contractility and calcium homeostasis1 and induces SMC hypertrophy and hyperplasia; see the review by Lazaar et al.61 Studies now show that ASM cells secrete a number of cytokines and chemoattractants. Studies of bronchial biopsies in mild asthmatics reveal constitutive staining for RANTES, a CC chemokine, in ASM62; in vitro, RANTES secretion is induced by TNF-a and IFN-c.63–65 Similarly, the CXC
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chemokine IL-8 is also secreted by ASM in response to TNF-a, IL-1b, and bradykinin, a contractile agonist.66,67 Other chemokines that are secreted by ASM cells include eotaxin, an eosinophil chemoattractant, and monocyte chemotactic proteins (MCP)-1, MCP-2, MCP-3.64,68,69 In asthma and COPD, b-adrenergic agonists, by elevating [cAMP]i, promote bronchodilation. Studies have investigated whether cAMP pathways also modulate chemokine secretion by ASM cells. In TNF-a-stimulated ASM cells, eotaxin and RANTES expression was potently and effectively inhibited by isoproterenol, PGE2, dibutyl-cAMP, or phosphodiesterase inhibitors, rolipram and cilomast.65,70 TNF-a-induced IL-8 secretion was inhibited by the combination of cAMP-mobilizing agents and corticosteroids.71 Similarly, sphingosine-1-phosphate, which activates a Gs protein coupled receptor and increases [cAMP]i, abrogated TNF-a-induced RANTES secretion in ASM cells.72 Current evidence suggests that chemokine secretion induced by inflammatory mediators is inhibited by dexamethasone in human ASM cells. Cytokine-induced secretion of RANTES,63–65 MCP,64 eotaxin,70 and GM-CSF73 was abrogated with corticosteroids. In most of these studies, corticosteroid and cAMP-mobilizing agents also acted additively to inhibit chemokine secretion. IL-6, a pleiotropic cytokine, induces smooth muscle cell hyperplasia,74 but also modulates B and T cell proliferation and immunoglobulin secretion. IL-6 secretion by ASM cells is inducible by multiple stimuli, including IL-1b, TNF-a, TGF-b and sphingosine-1-phosphate, a recently described mediator in asthma.65,72,75,76 Although corticosteroids are potent inhibitors of IL-6 secretion,76 agents that elevate [cAMP]i actually increase IL-6 secretion.65 This suggests an intriguing role for IL-6 in regulating airway hyperreactivity and is in agreement with murine models in which IL-6 overexpression promotes airway hyporesponsiveness.77 Finally, additional cytokines that are secreted by human ASM cells include IL-1b and other IL-6 family cytokines, such as leukemia inhibitory factor and IL-11.75,78,79 ASM cells may also play a role in promoting both the recruitment and survival of eosinophils by secretion of GM-CSF and IL-5.73,78,80 Receptors involved in cell adhesion Cell adhesion molecules (CAMs) mediate leucocyte– endothelial cell interactions during the process of cell recruitment and homing81 (Chapter 21).The expression and activation of a cascade of CAMs that include selectins, integrins, and members of the immunoglobulin superfamily, as well as the local production of chemoattractants, leads to leucocyte adhesion and transmigration into lymph nodes and sites of inflammation involving nonlymphoid tissues. In addition to mediating leucocyte extravasation and transendothelial migration, CAMs promote submucosal or subendothelial contact with cellular and extracellular matrix components. New evidence suggests that CAMs mediate inflammatory cell–stromal cell interactions that may contribute to airway inflammation. ASM cells express ICAM-1
and VCAM-1, which are inducible by a wide range of inflammatory mediators. Contractile agonists such as bradykinin and histamine, in contrast, have little effect on ASM CAM expression.82 ASM cells also constitutively express CD44, the primary receptor of the matrix protein hyaluronan.82 Activated T lymphocytes adhere via LFA-1 and VLA-4 to cytokine-induced ICAM-1 and VCAM-1 on cultured human airway smooth muscle cells. Moreover, an integrin-independent component of lymphocyte–smooth muscle cell adhesion appeared to be mediated by CD44–hyaluronan interactions.82 Current hypotheses suggest that steroids may directly inhibit gene expression, such as CAMs, by altering gene promoter activity and/or by abrogating critical signaling events such as NF-jB or AP-1 activation that then modulate gene expression as shown in Fig. 17.4. Interestingly, dexamethasone had no effect on TNF-a- or IL-1b-induced NF-jB activation in human ASM cells.83 Further, cytokineinduced ICAM-1 expression in ASM cells, which is completely dependent on NF-jB activation, was not affected by dexamethasone, whereas IL-1b-induced cyclooxygenase-2 expression was abrogated.83–85 In contrast, cytokine-induced CAM expression is sensitive to cAMP-mobilizing agents.86 Receptors involved in leucocyte activation and immune modulation CAMs can function as accessory molecules for leucocyte activation.81,87,88 Whether CAMs expressed on smooth muscle serve this function remains controversial. ASM cells do express MHC class II and CD40 following stimulation with IFN-c.89,90 Recent studies also suggest that human ASM cells express low levels of CD80 (B7.1) and CD86 (B7.2).91 The physiological relevance of these findings remains unknown since ASM cells cannot present alloantigen to CD4 T cells, despite the expression of MHC class II and costimulatory molecules.89 Functionally, however, adhesion of stimulated CD4 T cells can induce smooth muscle cell DNA synthesis.82 This appears to require direct cell–cell contact and cannot be mimicked by treatment of the cells with T cell conditioned medium. In addition, ligation of CD40 on ASM increases intracellular calcium as well as IL-6 secretion, while cross-linking VCAM-1 cells activates phosphatidylinositol 3-kinase and augments growth factor-induced ASM cell proliferation.90,92 These studies highlight the fact that direct interactions between leucocytes and smooth muscle cells via immune receptors such as CD40 or adhesion receptors such as ICAM-1 or VCAM-1 contribute to the modulation of the local milieu resulting in smooth muscle cell activation. Increased amounts of nitric oxide (NO) have been detected in patients with asthma; see the review by Gaston et al.,23 and Chapter 32. Nitric oxide appears to have a selective suppressive effect on the Th1 subset of T-helper cells, suggesting that increased levels of nitric oxide may therefore lead to the predominantly Th2-type response associated with asthma. Nitric oxide synthase has been demonstrated
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Albuterol, PGE2 Salmeterol Formeterol
Steroid TNF-α, IL-1β
Gs
Adenylyl cyclase Cilomast rolipram
p38, ERK1/2, JNK NF-κB
cAMP PDE
?
? AP-1 5-AMP
GR
A kinase
Nucleus CRE
Gene
Steroid-insensitive genes •ICAM-1
GRE
Steroid-sensitive genes •IL-6, IL-8 •RANTES, eotaxin, GM-CSF •COX2
Fig. 17.4. Putative signaling pathways that regulate cytokine-induced synthetic responses in airway smooth muscle cells. [cAMP]i mobilizing agents inhibit cytokine-induced chemokine and cell adhesion molecule expression. IL-6 secretion, however, is augmented by agents that increase [cAMP]i. Cytokine-induced NF-jB activation in human airway smooth muscle is corticosteroid-insensitive. A-kinase, cAMP-dependent protein kinase A; NF-jB, nuclear factor jB; CRE, cAMP response element; GRE, glucocorticoid response element; GR, glucocorticoid receptor; Gs, guanine-nucleotide binding protein; PDE, phosphodiesterase; JNK, jun kinase; ERK, extracellular signal-regulated kinase.
in airway smooth muscle cells where it results in an inhibition of ASM cell proliferation.94,95 Thus the role of ASMderived NO needs to be further defined, as it may have both beneficial and deleterious effects in the airway. ASM cells produce large amounts of PGE2, and to a lesser extent other prostanoids, following stimulation with proinflammatory cytokines.84 Although PGE2 is a potent bronchodilator, it also has significant immunological effects. For example, PGE2 can decrease expression of CD23 (FccRII), which has been shown to be expressed on human ASM cells,96 and synergize with IL-4 to induce IgE synthesis.97 Release of PGE2 by ASM cells may also be important in modulating the inflammatory milieu by inhibiting smooth muscle cell secretion of chemokines.98
that may be important in the pathogenesis of asthma and COPD. ASM, which secretes chemokines and cytokines, may participate or even perpetuate the mucosal inflammatory changes via activation and the recruitment of inflammatory cells. Further, cytokine-induced alterations in calcium homeostasis renders the ASM hyperresponsive to contractile agonists. In chronic severe asthma and COPD, ASM hypertrophy and hyperplasia may potentially render the asthmatic airway irreversibly obstructed. Further elucidation of the cellular and molecular mechanisms that regulate ASM function in asthma and COPD will offer new therapeutic targets in the treatment of asthma, chronic bronchitis and emphysema.
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Tracheobronchial Circulation
Chapter
18
Gabor Horvath Department of Pulmonology, Semmelweis University, Budapest, Hungary
Adam Wanner Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine, Miami, FL, USA
Inflammation is considered to have a pivotal role in the pathogenesis of bronchial asthma and chronic obstructive pulmonary disease (COPD). Since the blood circulation typically participates in the inflammatory responses at the tissue level, the vasculature of the tracheobronchial tree can be expected to undergo functional and structural changes in these diseases. Based on observations made in other systemic vascular beds, the changes may include hyperemia, hyperpermeability, edema, and new vessel formation. This chapter reviews the pathophysiological role of the tracheobronchial circulation in asthma and COPD and the vascular effects of pharmacological interventions.
N
T R A C H E O B R O N C H I A L VA S C U L AT U R E The tracheobronchial vasculature, which derives its blood from the systemic circulation, is the principal vascular supply to the airway wall (Fig. 18.1).1 Bronchial arteries usually arise from the aorta or intercostal arteries and form a peribronchial plexus surrounding the bronchial wall.Branches penetrate the muscular layer to form a subepithelial plexus.The two interconnected plexuses follow airways as far as the terminal bronchiole. Although bronchial capillaries anastomose freely with the pulmonary circulation along the airways and anastomoses have been demonstrated at pre-, post-, and capillary levels,2 venous blood from the intraparenchymal bronchial vasculature mainly drains through postcapillary pulmonary vessels3 to the left heart.4 Venous blood from the trachea and major bronchi drains through the vena azygos and superior vena cava to the right heart.The anatomy of the tracheobronchial vasculature, including vessel origin, distribution, and density, greatly varies from species to species.2 Some species have a capacitance vessel system (sinuses) under the subepithelial plexus; the significance of these sinuses is not known. Subepithelial (mucosal) blood flow Under physiological conditions, total airway blood flow comprises 0.5–1% of cardiac output.The major part of blood flow
Fig. 18.1. Section of sheep bronchus (glutaraldehyde fixed at 100 mmHg aortic pressure, paraffin embedded, hematoxylin-eosin stained, x200). A, artery; C, capillaries; V, venule; SG, submucosal gland; N, nerve; L, airway lumen. Section kindly provided by A. Mariassy. Reproduced in colour between pages 56 and 57.
is distributed to the subepithelial tissues where the microvasculature comprises 10–20% of tissue volume.5 Subepithelial blood flow has been reported to range from 30 to 95 mL/min per 100 g wet tissue in different species including man.6,7 Its main function presumably is to nourish the epithelium that has one of the highest metabolic rates in the body.The airway circulation has been studied in considerable detail, but the available information is limited because: • tracheobronchial blood flow is technically difficult to measure, as indicated by the large number of techniques that have been used;7 • most of the available information has been derived from animal models and isolated vessel preparations, which may have uncertain relevance to man; • most investigations have focused on the airway circulation as a whole, and less is known about the circulation of the subepithelial tissue that is an important site of airway inflammation.
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Table 18.1. Vasoconstrictors and vasodilators in the tracheobronchial vasculature
Vasodilators
Vasoconstrictors
b-adrenergic agonists
a-adrenergic agonists Neuropeptide Y LTC4, LTD4 TNF-a ET-1 Glucocorticosteroids (indirect?)
Cholinergic agonists VIP, PHI, PHM NO SP, NKA, CGRP Histamine, bradykinin, PAF, 5-HT PGE1, PGF2, PGD2a
VIP, vasoactive intestinal polypeptide; PHI, polypeptide histidine isoleucine; PHM, polypeptide histidine methionine; NO, nitric oxide; SP, substance P; NKA, neurokinin A; CGRP, calcitonin gene related peptide; PAF, platelet activating factor; 5-HT, serotonine; PG, prostaglandin; NPY, neuropeptide Y; LT, leukotrien; TNF-a, tumor necrosis factor-a; ET-1, endothelin-1.
Regulation of blood flow Tracheobronchial blood flow is influenced by a variety of factors (Table 18.1). Although adrenergic and cholinergic nerves have been demonstrated in the airway wall,8,9 physiological and pharmacological studies suggest that the main nervous control of the airway circulation is by the sympathetic nervous system.8 In different animal models, sympathetic nerve stimulation,10 close-arterial injection of adrenergic agonists,11 and inhalation of selective aadrenergic agonist12 have been shown to induce vasoconstriction. Selective b2-adrenergic agonist increases bronchial blood flow in sheep,6,8 a finding subsequently confirmed in humans.13 Parasympathetic nerve stimulation and intravascular administration of cholinergic agonists cause vasodilatation in several animal models,8 whereas aerosolized acetylcholine has only minimal effects.14 Nonadrenergic, noncholinergic mechanisms have also been described. Vasoactive intestinal polypeptide (VIP), polypeptide histidine isoleucine (PHI), or polypeptide histidine methionine (PHM) released by parasympathetic nerves are vasodilators, whereas neuropeptide Y (NPY) released by sympathetic nerves is a vasoconstrictor in the tracheobronchial circulation.10,11 Sensory neuropeptides, as substance P (SP), neurokinin A (NKA), and calcitonin gene related peptide (CGRP) released by unmyelinated sensory afferents, induce vasodilation.8 Nitrergic mechanisms have recently been reported to regulate bronchovascular tone and partially mediate b-adrenergic vasodilator responses.12,15,16 Physicochemical stresses including hydrostatic pressure, temperature, humidity, deviations from normal osmolarity, hypoxia, and acid–base relations have all been reported to influence airway blood flow.17
A C U T E VA S C U L A R R E S P O N S E S I N ASTHMA Allergic and nonallergic acute inflammation is considered a major factor in asthma-associated acute vascular responses. Inflammatory mechanisms include the complex actions of inflammatory cells and mediators, neurotransmitters, and neuropeptides on vascular endothelial and smooth muscle cells. The main vascular manifestations are hyperemia, hyperpermeability, and edema formation. Increased blood flow Allergic and non-allergic airway inflammation has been shown to be associated with an increase in airway blood flow.6,11 This is also the case in subjects with stable asthma.18 Increased airway blood flow is generally thought to result from dilatation of resistance arteries. Numerous inflammatory mediators have vasodilator effect.8 Histamine has a triphasic effect characterized by an initial vasodilation, followed by vasoconstriction and then a longlasting vasodilation.8 Sensory neuropeptides released from afferent nerves are also strong vasodilators. Reflex bronchial vasodilation is largely mediated by cholinergic and noncholinergic parasympathetic vagal pathways.19 Not all hemodynamically active inflammatory mediators are vasodilators. For example, endothelin-1, a potent vasoconstrictor, is increased in the airway of asthmatics.20 Its release may be induced by proinflammatory cytokines such as tumor necrosis factor-a.21 However, the net effect of inflammatory mediators is vasodilation. Microvascular hyperpermeability: edema and luminal liquid Asthma-associated leakage of macromolecules from the microvasculature occurs through endothelial pores and vesicles or through the formation of intercellular gaps in postcapillary venules. Inflammatory mediators and sensory autonomic nerve stimulation have been shown to increase microvascular permeability by producing intercellular gaps8 and induce interstitial edema formation. In addition, plasma components can collect in the airway lumen by passing through paracellular gaps between epithelial cells, thereby contributing to excessive airway secretions. Vasodilation and hyperperfusion-related microvascular congestion have been shown to potentiate microvascular hyperpermeability.22 In this regard, blood flow is related to edema formation.
C H R O N I C VA S C U L A R R E S P O N S E S Persistent inflammatory changes of the airway circulation are more likely to be associated with structural changes than the above described transient bronchovascular responses. The functional correlates of these morphological changes and their significance are not well understood, nor have the mechanisms responsible for the altered structure been elucidated.
Tracheobronchial Circulation
Asthma: new vessel formation It has been recognized for many years that asthmatics have an increased cross-sectional submucosal vascular area,23 and increased size and number of vessels in their airway wall24 (see Chapter 6). This can be considered the vascular component of airway wall remodeling.The stimulus for new vessel formation in asthma is unclear, although various endothelial growth factors, inflammatory cytokines, and other putative angiogenic factors have been proposed.25 Chronic bronchitis and emphysema: regional variability Morphological studies of the tracheobronchial vasculature have yielded conflicting results in COPD. In chronic bronchitis, enlarged bronchial arteries, hypertrophy of the bronchial venous circulation, and prominent bronchopulmonary anastomoses have been reported.26 Decreased bronchial vasculature has been demonstrated in emphysema. These findings can support the theory that the bronchial vessels atrophy in the emphysematous lesions and hypertrophy in the uninvolved regions. This suggests nonuniform distribution of airway blood flow, but this has thus far not been confirmed with physiological measurements.
FUNCTIONAL CONSEQUENCES The pathophysiological consequences of altered tracheobronchial blood flow could participate in the physiological and clinical manifestations of asthma and COPD; however, this is still a matter of debate. Mucosal thickness As vessels are known to occupy a significant portion of the inner airway wall, it is possible that the vascular component of inflammation increases mucosal thickness enough to increase airflow resistance. Airway vascular engorgement, submucosal edema, and luminal fluid accumulation have all been proposed to contribute to the excessive airway narrowing and enhanced airway responsiveness in asthma. Several animal and human studies have examined this experimentally; the results have been conflicting with the respect to the effects of vascular congestion on airway caliber.27–31 Observation that rapid infusion of intravenous fluids causes airway obstruction in humans supports this theory.29 However, another study has not been able to confirm this finding.30,31 There is less controversy on the effect of airway edema on airway caliber: edema of the inner wall internal to the smooth muscle does at least contribute to airway hyperresponsiveness as the same degree of muscle shortening causes greater luminal narrowing than in the normal airway.32 Drug, mediator, and cell transport Inflammation-associated blood flow, permeability, and interstitial barrier changes could alter transport functions of
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the airway vasculature as suggested by previous studies. Desmopressin uptake of nasal mucosa was enhanced when blood flow was increased,33 whereas inhaled histamine34 and antigen challenge-induced35 bronchoconstriction were prolonged when bronchial blood flow was decreased.Therefore one might speculate that the inflammatory increase in airway blood flow would enhance the clearance of locally released inflammatory substances (e.g. spasmogens) and decrease the magnitude and duration of the effect of inhaled bronchoactive drugs. In addition, increased airway blood flow could favor the distribution of systemically administered drugs to the airways and the accumulation of inflammatory cells in the airway wall. Thus, the inflammatory increase in airway blood flow appears to have clinically beneficial as well as undesirable effects on inflammation and its drug treatment. Heat and water exchange Exercise-induced bronchoconstriction is a common condition in asthmatics. Reactive hyperemia in response to airway cooling and increased airway liquid and interstitial osmolarity caused by water loss have been proposed to have a critical role.36,37 The former may narrow the airway while the latter may promote mediator release from inflammatory cells. To what extent exercise-associated airway hyperperfusion contributes to bronchoconstriction is not known. Mucociliary clearance The role of airway blood flow in supporting the mucociliary apparatus is incompletely understood. Mucociliary clearance was impaired in the immediate postoperative period after lung transplantation,38 and clearance of inhaled particles was significantly impaired when bronchial blood flow was stopped in sheep.39 The effect of increased airway blood flow on mucociliary clearance in asthma has not been examined.
THERAPEUTIC APPROACHES In COPD, the dearth of physiological data on the pathogenetic role of the airway circulation precludes the formulation of meaningful therapeutic recommendations. In asthma, the goal of vascular therapy probably should be to reverse the increased airway blood flow. The beneficial consequences are: • decongestion and decreased exsudation of the airway mucosa; • improved distribution of systemic bronchoactive drugs to the airway. To date, only sympathomimetics and glucocorticosteroids have been investigated. The available data demonstrate that both inhaled a-adrenergic agonists and inhaled glucocorticosteroids decrease airway blood flow in asthma.
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(a)
(b) 15 Methoxamine/healthy Methoxamine/asthmatic
*
5 0 5
*
10
*
*
10
Qaw (µL/min per mL)
10
Qaw (µL/min per mL)
* 15
*
5 0 5 Albuterol/healthy Albuterol/asthmatic
10
*
15
15 0.0
0.4
0.8 1.2 1.6 Drug dose (mg)
2.0
2.4
0.0
0.2
0.4 0.6 0.8 Drug dose (mg)
1.0
1.2
˙ aw) in 11 asthmatic subjects and 11 healthy subjects. Fig. 18.2. Effects of inhaled (a) methoxamine and (b) albuterol on airway mucosal blood flow (Q Mean values SE. *P < 0.05 versus baseline. Reproduced from reference 40, with permission.
Glucocorticosteroids There is increasing evidence that glucocorticosteroids have profound effects on the tracheobronchial vasculature. Among other actions, such as reduction of microvascular hyperpermeability, glucocorticosteroids decrease airway blood flow by two distinct mechanisms: a nongenomic rapid and transient vasoconstriction mediated by the noradrenergic nervous system, and a sustained decrease in airway blood flow after prolonged treatment. The following data support this notion: • A single dose of inhaled fluticasone (880–1760 lg) causes a decrease in airway mucosal blood flow within 30 minutes, with a return towards baseline at 90 minutes in asthmatics
and healthy subjects (Fig. 18.3).41 The effect can be blocked with an oral a1-adrenoceptor blocking agent. • Treatment with inhaled fluticasone (440 lg daily) for two weeks reverses the asthma-associated increase of airway mucosal blood flow independent of the acute vasoconstrictor action of the drug (Fig. 18.4).42 This observation suggests that airway mucosal blood flow is a marker of airway inflammation in asthma. • Long-term administration of inhaled beclomethasone (200–1500 lg daily) decreases the subepithelial area occupied by vessels in asthmatics (Fig. 18.5).43 The underlying mechanism is not known, but glucocortico-
Normal (**P 0.01 vs BSL) Asthma ( *P 0.01 vs BSL)
65 60
Qaw (µL/min per mL)
Sympathomimetics Inhaled methoxamine, an a-adrenergic agonist, causes a dose-dependent decrease in airway blood flow, with an enhanced responsiveness in asthmatics compared to healthy subjects (Fig. 18.2).40 Higher doses of methoxamine cause bronchoconstriction in asthmatics. However, this vasoconstrictor effect is already seen at methoxamine doses that do not cause bronchoconstriction or have systemic side-effects. These findings certainly encourage the exploration of inhaled a-adrenergic agonists as therapeutic agents in patients with asthma. In contrast to methoxamine, the vasodilator effect of inhaled albuterol, a b2-adrenergic agonist, is blunted in asthmatics; the responsiveness can be restored by long-term glucocorticosteroid therapy.18,40 In as much as vasodilation may be an undesirable side-effect of an inhaled b2-adrenergic when administered for bronchodilation in asthma, the vascular hyporesponsiveness to this drug can be considered a therapeutic advantage.
55 50 45 ** *
40
*
35 30 BSL
30 60 90 Time post inhalation (min)
Fig. 18.3. Effect of 880 lg of fluticasone on airway mucosal blood flow ˙ aw) in 10 healthy subjects and 10 asthmatic subjects over a 90-minute (Q observation period. Mean values SE. BSL baseline. Reproduced from reference 41, with permission.
Tracheobronchial Circulation
60
Qaw (µL/min per mL)
it has not been possible to quantitate airway blood flow noninvasively in humans, precluding information on the hemodynamic effects of pharmacologic agents and their clinical consequences in asthma. This is likely to change with the advent of new noninvasive methods to measure airway blood flow. Based on currently available data, agents that reverse the increased airway blood flow in asthma are most likely to be therapeutically useful. Alpha-adrenergic agonists and glucocorticosteroids are two classes of agents capable of accomplishing this. It is likely that other molecules with therapeutically beneficial vascular effects will emerge in the future.
*P < 0.05 vs Healthy and FP
70
181
*
50 40 30 20 10 0 Healthy
BSL
FP Asthmatics
˙ aw) in 12 healthy subjects and Fig. 18.4. Airway mucosal blood flow (Q 19 asthmatic subjects before (BSL) and after (FP) 2 weeks of treatment with inhaled fluticasone (440 lg/day). Mean values SE. Reproduced from reference 42, with permission.
*P < 0.05 vs healthy 600
485 * (390–597)
Vessels per mm2
500 400
421 (281–534)
329 (248–376)
300 200 100 0 Healthy
No BDP BDP Asthmatics
Fig. 18.5. Comparison of vessel numbers in bronchial biopsies from 15 beclomethasone dipropionate (BDP)-treated asthmatics, 7 BDP-naive asthmatics, and 11 healthy subjects. Values are means and interquartile ranges. Reproduced from reference 43, with permission.
steroids have been reported to reduce vascular endothelial growth factor expression in pulmonary vascular smooth muscle cells.44
PERSPECTIVES The tracheobronchial circulation unquestionably participates in the physiopathology of asthma while its role in COPD is unknown. Inflammatory vasodilation and new vessel formation lead to an increase in airway blood flow in asthma, and the magnitude of airway blood flow could be an index of the severity of airway inflammation. Until recently,
REFERENCES 1. Bernard SL, Glenny RW, Polissar NL et al. Distribution of pulmonary and bronchial blood supply to airways measured by fluorescent microspheres. J. Appl. Physiol. 1996; 80:430–6. 2. Charan NB, Carvalho PG. Anatomy of the normal bronchial circulatory system in humans and animals. In: Butler J (ed.), The Bronchial Circulation, pp. 45–77. NewYork: Marcel Dekker, 1992. 3. Wagner EM, Mitzner W, Brown RH. Site of functional bronchopulmonary anastomoses in sheep. Anat. Rec. 1999; 254:360–6. 4. Baile EM, Paré PD, Ernest D et al. Distribution of blood flow and neutrophil kinetics in bronchial vasculature of sheep. J. Appl. Physiol. 1997; 82:1466–71. 5. Mariassy AT, Gazeroglu H, Wanner A. Morphometry of the subepithelial circulation in sheep airways. Am. Rev. Respir. Dis. 1991; 143:162–6. 6. Wanner A, Chediak AD, Csete ME. Airway mucosal blood flow: response to autonomic and inflammatory stimuli. Eur. Respir. J. 1990; 12:618s–23s. 7. Baile EM, Paré PD. Methods of measuring bronchial blood flow. In: Butler J (ed.), The Bronchial Circulation. pp. 101–96. New York: Marcel Dekker, 1992. 8. Widdicombe JG,Webber SE. Neuroregulation and pharmacology of the tracheobronchial circulation. In: Butler J (ed.), The Bronchial Circulation, pp. 249–89. New York: Marcel Dekker, 1992. 9. Canning BJ, Fischer A. Localization of cholinergic nerves in lower airways of guinea pigs using antisera to choline acetyltransferase. Am. J. Physiol. 1997; 272:L731–8. 10. Franco-Cereceda A, Matran R, Alving K et al. Sympathetic vascular control of the laryngeotracheal, bronchial and pulmonary circulation in the pig: evidence for non-adrenergic mechanisms involving neuropeptide Y. Acta. Physiol. Scand. 1995; 155:193–204. 11. Laitinen LA, Laitinen MA,Widdicombe JG. Dose-related effects of pharmacological mediators on tracheal vascular resistance in dogs. Br. J. Pharmacol. 1987; 92:703–9. 12. Barker JA, Chediak AD, Baier HJ et al. Tracheal mucosal blood flow responses to autonomic agonists. J. Appl. Physiol. 1988; 65:829–34. 13. Onorato DJ, Demirozu MC, Breitenbücher A et al. Airway mucosal blood flow in humans: response to adrenergic agonists. Am. J. Respir. Crit. Care Med. 1994; 149:1132–7. 14. Charan NB, Carvalho P, Johnson SR et al. Effect of aerosolized acetylcholine on bronchial blood flow. J. Appl. Physiol. 1998; 85:432–6. 15. Carvalho P, Johnson SR, Charan NB. Non-cAMP-mediated bronchial arterial vasodilation in response to inhaled b-agonists. J. Appl. Physiol. 1998; 84:215–21. 16. Carvalho P, Thompson WH, Charan NB. Comparative effects of areceptor stimulation and nitrergic inhibition on bronchovascular tone. J. Appl. Physiol. 2000; 88:1685–9.
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17. Wanner A. Circulation of the airway mucosa. J. Appl. Physiol. 1989; 67:917–25. 18. Kumar SD, Emery MJ, Atkins ND et al. Airway mucosal blood flow in bronchial asthma. Am. J. Respir. Crit. Care Med. 1998; 158:153–6. 19. Pisarri TE, Zimmerman MP, Adrian TE et al. Bronchial vasodilator pathways in the vagus nerve of dogs. J. Appl. Physiol. 1999; 86:105–13. 20. Mattoli S, Soloperto M, Marini M, Fasoli A. Levels of endothelin in the bronchoalveolar lavage fluid of patients with symptomatic asthma and reversible airflow obstruction. J. Allergy Clin. Immunol. 1991; 88(3 Pt 1):376–84. 21. Wagner EM. TNF-a induced bronchial vasoconstriction. Am. J. Physiol. Heart Circ. Physiol. 2000; 279:H946–51. 22. Erjefalt I, Persson CGA. Effects of adrenaline and terbutaline on mediator-increased vascular permeability in the cat trachea. Br. J. Pharmacol. 1982; 77:399. 23. Kuwano K, Bosken CH, Paré PD. Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1993; 148:1220–5. 24. Li X, Wilson JW. Increased vascularity of the bronchial mucosa in mild asthma. Am. J. Respir. Crit. Care Med. 1997; 156:229–33. 25. Bousquet J, Jeffery PK, Busse WW et al. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am. J. Respir. Crit. Care Med. 2000; 161:1720–45. 26. Wanner A, Long WM. Airways: asthma, bronchitis, emphysema. In: Butler J (ed.), The Bronchial Circulation, pp. 493–549. New York: Marcel Dekker, 1992. 27. Cabanes LR, Weber SN, Matran R et al. Bronchial hyperresponsiveness to methacholine in patients with impaired left ventricular function. N. Engl. J. Med. 1989; 320:1317–48. 28. Csete ME, Abraham WM,Wanner A.Vasomotion influences airflow in peripheral airways. Am. Rev. Respir. Dis. 1990; 141:1409–13. 29. Gilbert IA, Winslow CJ, Lenner KA et al. Vascular volume expansion and thermally induced asthma. Eur. Respir. J. 1993; 6:189–97. 30. Blosser S, Mitzner W, Wagner EM. Effects of increased bronchial blood flow on airway morphometry, resistance, and reactivity. J. Appl. Physiol. 1994; 76:1624–9.
31. Tang GJ, Freed AN. The role of submucosal oedema in increased peripherial airway resistance by intravenous volume loading in dogs. Eur. Respir. J. 1994; 7:311–17. 32. James AL, Paré PD, Hogg JC. The mechanics of airway narrowing in asthma. Am. Rev. Respir. Dis. 1989; 139:242–6. 33. Olanoff LS, Titus CR, Shea MS et al. Effect of intranasal histamine on nasal mucosal blood flow and the antidiuretic activity of desmopressin. J. Clin. Invest. 1987; 80:890–5. 34. Kelly L, Kolbe J, Mitzner W et al. Bronchial blood flow affects recovery from constriction in dog lung periphery. J. Appl. Physiol. 1986; 60:1954–9. 35. Csete ME, Chediak AD, Abraham WM et al. Airway blood flow modifies allergic airway smooth muscle contraction. Am. Rev. Respir. Dis. 1991; 144:59–63. 36. McFadden ER. Hypothesis: exercise-induced asthma as a vascular phenomenom. Lancet 1990; 335:880–3. 37. Kim HH, LeMerre C, Demirozu CM et al. Effect of hyperventilation on airway mucosal blood flow in normal subjects. Am. Respir. Crit. Care Med. 1996; 154:1563–6. 38. Paul A, Marelli D, Shennib H et al. Mucociliary function in autotransplanted, allotransplanted, and sleve resected lungs. J. Thorac. Cardiovasc. Surg. 1989; 98:523–8. 39. Wagner EM, Foster WM. Importance of airway blood flow on particle clearance from the lung. J.Appl. Physiol. 1996; 81:1878–83. 40. Brieva J, Wanner A. Adrenergic airway vascular smooth muscle responsiveness in healthy and asthmatic subjects. J. Appl. Physiol. 2001; 90(2):665–9. 41. Kumar SD, Brieva JL, Danta I et al. Transient effect of inhaled fluticasone on airway mucosal blood flow in subjects with and without asthma. Am. J. Respir. Crit. Care Med. 2000; 161:918–21. 42. Brieva JL, Danta I, Wanner A. Effect of an inhaled glucocorticosteroid on airway mucosal blood flow in mild asthma. Am. Respir. Crit. Care Med. 2000; 161:293–6. 43. Orsida BE, Li X, Hickey B et al. Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax 1999; 54:289–95. 44. Nauck M, Roth M, Tamm M et al. Induction of vascular endothelial growth factor by platelet-activating factor and plateletderived growth factor is downregulated by corticosteroids. Am. J. Respir. Cell Mol. Biol. 1997; 16:398–406.
Fig. 18.1. Section of sheep bronchus (glutaraldehyde fixed at 100 mmHg aortic pressure, paraffin embedded, hematoxylin-eosin stained, x200). A, artery; C, capillaries; V, venule; SG, submucosal gland; N, nerve; L, airway lumen. Section kindly provided by A. Mariassy.
Chapter
Pulmonary Vessels
19
Norbert F. Voelkel and Rubin M. Tuder Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, CO, USA
INTRODUCTION Asthma and chronic obstructive pulmonary disease (COPD) are the most prevalent obstructive lung diseases worldwide and the incidence of both of these diseases is on the rise. Environmental factors, in particular air pollution, may contribute to the spreading of both disorders. In recent years investigators have compared the cellular composition of bronchoalveolar lavage (BAL) samples obtained from asthma and COPD patients, in order to assess the inflammatory component of these two diseases.1–3 These studies have contributed to our improved understanding of mechanisms of airway inflammation and have continued to place the focus of investigative activities on the airways. COPD, in particular the emphysema variety, has long been recognized for its vascular involvement and for its association with pulmonary hypertension.4–14 Both pulmonary hemodynamic studies and examination of lung tissue samples from patients with COPD have been conducted for decades and have provided a reasonable concept of the components of vascular pathology in COPD. In contrast, relatively few data shed light on bronchial vascular or pulmonary vascular involvement in asthma. Two long-term oxygen therapy trials have shown that treatment of COPD patients with supplemental oxygen improves survival associated with a decrease in the pulmonary artery pressure; this has led to the conclusion that reduction in pulmonary artery pressure, as a consequence of long-term oxygen treatment, is indeed responsible for the improved survival of these patients. Whereas this conclusion may or may not be correct, the results of the long-term oxygen trials have been generally used to make the case for the importance of pulmonary hypertension in COPD and for the treatment of pulmonary hypertension in COPD. Clearly, pulmonary hypertension is not an issue in asthma, with the exception of the patient with status asthmaticus.15–17
E V I D E N C E F O R P U L M O N A RY VA S C U L A R I N V O LV E M E N T I N C O P D Clinicians and pathologists have been seeking evidence for vascular involvement in COPD for quite some time. In-situ thrombosis or some other mechanism had been considered.18,19 Villemin in 186620 and Isaaksohn in 187121 observed that the vascularity of the alveoli was reduced in pulmonary emphysema, and many years later Liebow wrote: “Whether the loss of capillaries in emphysema is initiated by air trapping or [is] the result of atrophy otherwise induced, the effect is that the rich vascular beds vanish with the tissues that they once supplied.”22 The decreased diffusion capacity in these patients reflects this loss of alveolar capillaries. Early angiographers also noted a reduction in the number of precapillaries in patients with emphysema and a dramatic loss of their lung capillary bed23,24 (Fig. 19.1). In addition to the capillary loss, there was recognition of pulmonary arterial thickening and of a component of intimal fibrosis22,25–30 (Fig. 19.2). Whether this muscularization of the small precapillary arteries in emphysema is explained by either smooth muscle cell hypertrophy or hyperplasia or both is still unclear.31 In addition to the vessel wall thickening in the lungs of patients with COPD and pulmonary hypertension, there is occasionally in-situ small vessel thrombosis.19 Functional studies of small pulmonary arteries from surgically removed specimens of patients with COPD have been performed, and impairment of endothelium-dependent vascular relaxation found.32,33 The functional impairment of small arteries in COPD is likely to be multifactorial. The vascular smooth muscle cells may eventually undergo a phenotypic switch, triggered by oxidative stress34,35 or by mediators of inflammation or cytokines, which in turn may alter gene expression.35 Incidentally, oxidative stress can also cause a reorganization of the vascular endothelial cell microfilament network.35 Nitric oxide and peroxynitrite may be involved, and in this context it is intriguing that Clini and coworkers recently found a decrease in the expired air NO (lower airway NO) in COPD patients with cor pulmonale when compared with patients without cor pulmonale.36
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Table 19.1. Factors that influence pulmonary artery pressure and right ventricular performance in COPD
Hypoxic vasoconstriction Pulmonary vascular remodeling media hypertrophy intima fibrosis in-situ thrombosis loss of alveolar capillaries Polycythemia Auto PEEP
Fig. 19.1. Pulmonary angiography of a 60-year-old patient with endstage COPD/emphysema. There is virtually no vascularity in the right upper lung lobe, and the lower lobe shows extreme rarification and pruning of the vascular tree.
Pulmonary hypertension in COPD in most patients is mild to moderate at rest, but it can become quite severe with moderate exercise,6,11,37,38 partially because the natural properties of the lung which allow the circulation to accommodate a large increase in cardiac output without a significant increment in pulmonary arterial pressure are no longer present in COPD. Table 19.1 lists the various factors which influence pulmonary artery pressure and right ventricular performance in COPD patients.
HYPOXIC VERSUS NONHYPOXIC VA S O C O N S T R I C T I O N Hypoxic precapillary pulmonary vasoconstriction is perhaps a vestigial response, a “leftover” from the time of fetal development when the lung is not ventilated and not perfused.39 It occurs acutely and regionally “with the intention”
of protecting arterial PO2. If significant pulmonary hypertension can be documented in patients with COPD at rest, the increase in pulmonary arterial pressure may be reasoned to occur largely because of hypoxic vasoconstriction. Other etiological factors, particularly changes in intrathoracic pressure or small-vessel in-situ thrombosis, should be considered. Some patients with emphysema who breathe 100% oxygen may not experience a decrease in pulmonary arterial pressure.13 This indicates the likelihood of significant pulmonary vascular remodeling and/or the presence of nonhypoxic vasoconstriction. Lipid mediators of inflammation, for example leukotrienes,40 and thromboxane could act as vasoconstrictors. Naeje et al.41 demonstrated, in support of the existence of nonhypoxic vasoconstriction in COPD patients, that intravenous prostaglandin E1 infusion in patients with chronic obstructive lung disease caused a further reduction in pulmonary artery pressure following the first drop in the pulmonary arterial pressure due to high oxygen supplementation. Whether the presence and action of mediators of inflammation (like leukotrienes) or agonists like endothelin caused the nonhypoxic vasoconstriction in the patients of this study remains unclear.
T H E P R O B L E M O F V·/ Q· M I S M AT C H I N COPD Studies using the multiple inert gas elimination technique showed clearly that ventilation/perfusion inequality is a problem in patients with chronic obstructive pulmonary disease,42 and that the inequality tends to worsen with age.43 In patients with mild COPD there appears to be a relationship between the thickness of the pulmonary arterial intimal layer and the degree of ventilation/perfusion inequality.30 ·) The practical importance of ventilation/perfusion (V· /Q mismatch is that drugs with bronchodilator properties often perform double duty as vasodilators. These agents – · intended to improve airflow – may significantly worsen V· /Q mismatch, increase the perfusion of poorly ventilated areas of the lung, and cause or worsen hypoxemia. A patient not requiring supplemental oxygen before drug treatment may become oxygen-dependent after implementation of such drugs.
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(a)
(b)
(c)
(d)
Fig. 19.2. Lung tissue histological sections from a patient with COPD/emphysema. (a) Tortuous muscularized pulmonary artery (v) showing wall thickening, muscularization. b, bronchus with mucosa damage; a, emphysematous airspaces. HE stain. (b) Muscularized small precapillary arteries (arrows). a, emphysematous airspace. HE stain. (c) Small, muscularized pulmonary arteriole (v), thickening of alveolar septal structures with inflammatory cells (arrow), and hemosiderin precipitates. HE stain. (d) Emphysematous area with small precapillary arteries (v, arrows). Staining for musclespecific actin. Reproduced in colour between pages 56 and 57.
E M P H Y S E M A : A FA I L U R E O F T H E L U N G CELL MAINTENANCE PROGRAM Kasahara and coworkers44 have revisited Isaakssohn’s nineteenth-century vascular hypothesis of emphysema.21 They proposed that the present explanation which is based on a protease–antiprotease imbalance and destruction of the elastic framework of the lung by smoking represents a terminal event, which occurs subsequent to a failure of an endothelial cell maintenance program. Decreased tissue levels of vascular endothelial growth factor (VEGF) in the emphysema lung may cause this maintenance failure and result in the death (apoptosis) of endothelial cells.45 This concept is based on the critical function of VEGF in lung development46 and the critical function of VEGF in endothelial cell survival.47
It is thought that formation of the lung from the foregut requires a continuous interaction between the mesenchymal stroma and epithelial elements, and that disruption of this interaction due to separation of the epithelium from the mesenchymal components results in arrest of the development of the large airways and alveoli.48 Simultaneous with the growth of the epithelial component, the lung progressively acquires a rich blood supply through the sprouting of endothelial cells and recruitment of vascular support cells in the pulmonary mesenchyme. This growth may be driven by lung cell expression of VEGF and its receptors Flt (VEGF R1) and KDR (VEGF R2).49 Since the adult lung is one of the richest organs in VEGF expression,50 VEGF may have a structure maintenance role in the mature lung. Another growth factor of interest isTGF-b,51,52 and there is recent evidence that, in COPD, bronchiolar and alveolar epithelium
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express higher levels of TGF-b1 than in control lungs.53 This suggests that this endothelial cell growth inhibitor and proapoptotic factor, which also suppresses angiogenesis in vivo, may alter the cellular organization of the alveolar septum in centrilobular emphysema. Retinoic acid may be another component of the lung maintenance program after birth.54 It has a profound effect on the development of the trachea and the lung bronchopulmonary tree. Indeed, Massaro et al.,55 showed that all-trans retinoic acid increases the number of alveoli and reverses the emphysematous changes induced by elastase instillation in rats. In addition, retinoic acid upregulates the expression of HOX genes, which code for transcription factors which participate in the development of the lung.56 In this context, it is of interest that the expression of the abundant HOXA5 mRNA is decreased in lung samples from emphysema patients.56 How exactly the aforementioned components – retinoic acid and HOX genes, VEGF, TGF-b, and their receptors – are coordinated in their actions which account for the maintenance of the adult lung structure remains to be worked out. But it is perhaps not too surprising that the adult lung requires constant trophic signals for cell survival, cell replacement, cell differentiation, and structural maintenance. Interruption of these trophic signals may result in apoptosis of lung structural cells. For example, it has recently been documented that lungs from patients with smoking-induced emphysema have increased numbers of alveolar septal cell death by terminal transferase alpha UTP nick end labeling (TUNEL), DNA ligase assay, DNA oligonucleosomal fragmentation, and single-stranded DNA immunohistochemistry.45 By double labeling, both septal epithelial and capillary endothelial cells showed increased apoptosis when compared with normal lungs of nonsmokers and smokers, and this process was associated with decreased expression of VEGF mRNA, VEGF, and the VEGF receptor KDR (VEGF-RII). Moreover, the number of TUNELpositive cells in emphysema lungs correlated with reduction in FEV1 and the age of the patients.45 These data now show conclusively (as had been previously attempted by SeguraValdez et al.57) that significant apoptosis occurs in human emphysema lungs. Because studies of human tissue cannot establish causality (owing to the single timepoint observation), complementary animal model data are needed. Such data have recently been published: inhibition of the VEGF receptor II (KDR) – which is responsible for endothelial cell growth, migration, and differentiation, nitric oxide and prostacyclin production – by the VEGF receptor blocker (and angiogenesis inhibitor) SU5416, resulted in emphysema in rats.44 This emphysema was characterized by alveolar septal cell death, as assessed by TUNEL, activated caspase 3 immunostaining, and DNA oligonucleosomal laddering. The critical importance of apoptotic cell death in the development of this emphysema rodent model is highlighted by the fact that a broadspectrum caspase inhibitor (Z-Asp-CH2) blocked the development of the emphysema induced by VEGF R2
blockade.44 Interestingly, it was observed that SU5416induced emphysema was associated with evidence of lung oxidative stress. SU5416-treated lungs have higher expression of nitrated proteins, higher levels of carbonyl proteins, and higher levels of isoprostanes than control lungs. Whether scavenging oxidant radicals in this model can revert or block the development of emphysema is the subject of ongoing studies. This process of alveolar septal cell apoptosis may have broad consequences for the overall rate at which the lung ages, cells “disappear,” and the lung function impairment progresses in emphysema. As endothelial cells die, capillary blood flow progressively declines and epithelial cell death ensues. In addition, apoptosis has been linked to a prototypic cytokine response, “designed” to decrease the inflammatory cell response to the dying cells.58 Central to this response is the production of TGF-b by macrophages as they engulf apoptotic cells. TGF-b is a tumor suppressor which induces cell cycle arrest and endothelial cell apoptosis; and importantly, TGF-b downregulates VEGF receptor KDR expression, which may further enhance endothelial cell apoptosis. Finally, TGF-b is a potent suppressor of fetal lung branching.51,52 Is it possible to unify the concepts of breakdown of the lung cell maintenance program due to cigarette smoking and the protease/antiprotease imbalance in the genesis of emphysema? One possibility is that alveolar septal cell death may deplete the lung of secretory leukoprotease inhibitor.59 But perhaps more intriguing is the close, seemingly fundamental, relationship between cell growth, apoptosis, and matrix proteinases.60–62 An example of a broad cellular link between matrix remodeling and cell fate is the involution of the pregnant breast acini which requires matrix metalloproteinases (MMP) activity, since inhibition of this activity blocks mammary acinar cell apoptosis.62 Likewise, endothelial cell growth and apoptosis are also regulated by a balanced MMP activity, and degradation of matrix proteins by metalloproteinases may further enhance the susceptibility of endothelial cells to apoptosis in circumstances where the VEGF expression is decreased (as caused by cigarette smoking), where VEGF receptor signaling is blocked, or where fibroblast growth factor is withdrawn.60 Whether MMPs can activate caspases directly or caspases can activate MMPs (perhaps by decreasing tissue inhibitors of metalloproteinases – TIMPs) remains to be seen. Summary Emphysema is a chronic disease of susceptible individuals where alveolar structures are progressively being destroyed. The destruction appears to be caused by an interplay between apoptosis of alveolar endothelial and epithelial cells and proteolysis. The challenge for the future will be to provide a unifying hypothesis of emphysema, which integrates on cellular and molecular levels the concepts of proteolytic damage, activation of lung macrophages, loss of control over lung structure maintenance (endothelial cell apoptosis), and premature aging (oxidant stress, mitochondrial damage).
Pulmonary Vessels
VA S C U L A R A LT E R AT I O N S I N A S T H M A A N D S TAT U S A S T H M AT I C U S Very little information is available regarding an involvement of the lung circulation in asthma, perhaps understandably so because of the intense attention which the biologist, clinician, and pathologist pay to the airway function and morphology. Fig. 19.3 shows dilated and congested precapillary pulmonary arterioles and margination of neutrophils in pulmonary arterioles and alveolar septal capillaries in a patient who died in status asthmaticus. Whether such a component of “intravascular inflammation” occurs frequently in asthma or during asthma attacks is unknown.Perhaps future systematic investigations may define a participating role for the “intravascular inflammation” in asthma. In contrast, there is a somewhat better understanding – at least on a morphological level – of airway microvascular alterations in asthma (see Chapter 18). Increased permeability of dilated bronchial mucosa capillaries was noted early on.63 Both enlargement of existing vessels64,65 and angiogenic growth of new vessels66 can occur in the setting
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of chronic inflammation of the airway mucosa, accounting for increased vascularity in asthma.64–67 Mycoplasma infection in mouse and rat models68,69 leads to increase in tracheal mucosa vessel diameter, increased number of endothelial cells, increased sensitivity of endothelial cells to substance P,69 increased expression of neurokinin-1 receptors,69 and increased expression of p-selectin.68
T R E AT M E N T O F P U L M O N A RY H Y P E R T E N S I O N I N C O P D PAT I E N T S One position regarding the treatment of pulmonary hypertension in COPD patients can be characterized by the statement attributed to David Flenly: “The patients with chronic obstructive lung disease die with cor pulmonale, but not of cor pulmonale.” Yet, other investigators continue to explore old and new therapeutic options.70,71 Drugs Drugs used in the treatment of pulmonary hypertension associated with COPD include:
(d)
(c)
(a)
(b)
(c)
Fig. 19.3. Representative lung morphology of a 38-year-old female steroid-dependent patient, who died in status asthmaticus. (a) Dilated and congested precapillary pulmonary arteries, which are seen in close-up in (b). (b) Note the margination and accumulation of neutrophils in both the pulmonary vessel (arrow) and capillaries (arrowheads). (c) Low-power view of a mucus-filled bronchiole. Close-up of boxed area is shown in (d). (d) Note the presence of eosinophils and Charcot–Leyden crystal (arrow) admixed with mucus. (e) Dilated small bronchiolar vessel, with marginating neutrophils and eosinophils, which are seen infiltrating the bronchiolar wall. Reproduced in colour between pages 56 and 57.
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oxygen;6,7,13,14,72–74 theophylline;75 Ca++-entry blockers;76–79 ACE-inhibitors;80 b-agonists.81
Table 19.2 lists a number of clinical studies, the drugs used, and their effect on the lung circulation. Several new drugs are in development for the treatment of · mismatch pulmonary hypertension in COPD. Because V· /Q is a serious problem in many patients with COPD,30,82–85 the · mismatch through drug principle of not worsening the V· /Q treatment is very important. Most currently used vasodilator drugs will affect the PaO2, and many bronchodilators, when given in higher doses, will become effective vasodila· mismatch. Clearly, if patients are tors and worsen the V· /Q already receiving supplemental oxygen, a vasodilator agent may be of additional benefit. Certainly, drugs developed for the treatment of COPD should not induce bronchospasm or have sedative actions and worsen hypercapnia. Specific agents which could be considered are: • • • • • •
atrial natriuretic peptide clearance receptor inhibitors;31 almitrine;86–89 leukotriene receptor antagonists;90 endothelin receptor antagonists;91,92 NO, and NO donors;93 specific PDE inhibitors.
Atrial natriuretic peptide Granules in the cardiac atria harbor a biologically active substance which can induce diuresis and natriuresis, and reduce systemic and pulmonary artery pressures. This substance contained in the atrial tissue is atrial natriuretic factor (ANF).94 In addition, there are two other related factors, brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), which have similar biological activities. Small
amounts of ANF can also be demonstrated in lung tissue and in pulmonary veins. ANF activates the particulate guanylyl cyclase and causes elevation of intracellular cGMP. In addition to the guanylyl cyclase-linked ANF receptors there are additional transmembrane clearance receptors devoid of guanylyl cyclase activity. The proposed function of these receptors is to eliminate ANF from the blood stream by internalizing the peptide for intracellular degradation. It appears that the lung is an important organ for the clearance of ANF. It has been shown that acute hypoxia induced by exercise, but not moderately acute hypoxia at rest, leads to increased ANF plasma levels in healthy subjects. Elevated plasma ANF levels are also found in patients with pulmonary hypertension and hypoxia.90,93 Intravenously administered ANF in patients with COPD causes a dose-dependent decrease in pulmonary artery pressure. Andrivet et al.85 were able to show that intravenous administration of ANF in COPD patients caused pulmonary vasodilation; the decrease in arterial oxygenation was prevented apparently by an increase in minute ventilation. Because endogenously produced ANF can probably exert autocrine and paracrine effects31 on endothelial cells and vascular smooth cell growth, the chronically elevated ANF in hypoxemic pulmonary hypertensive patients could be “used” to reduce pulmonary hypertension and perhaps also pulmonary vascular remodeling. Inhibition of ANF clearance receptors by agents specifically designed to reduce the pulmonary clearance of ANF could be useful in the therapy of patients with COPD and pulmonary hypertension. Almitrine Almitrine alters the ventilation/perfusion mismatch acutely and chronically improves arterial oxygenation. Bell et al.86 assessed the effectiveness of oral almitrine in patients with COPD in a placebo controled, double-blind 8-week study; the arterial PO2 rose by at least 10 mmHg in patients receiving
Table 19.2. Clinical drug trials: effect on lung circulation
Drug
Duration
Nifedipine Nifedipine Nitrendipine Felodipine Nifedipine Nifedipine Nitroglycerin Isosorbide dinitrate Pirbuterol Pirbuterol Terbutaline Prazosin
6–9 wk 6 wk 6 wk 3–5 mo 9 wk 18 mo 6 wk 6 wk 6 wk 6 mo Acute 2 mo
Ppa
Q
PVR
Reference 108 106 104 76 79 103 109 109 107 81 105 102
↓
—
↓
—
—
—
↓
↑
↓
— — — —
— — — —
— — ––
↓
— ↑ –– ↑ ↑
— ↑ — ↓ ↓
—
— —
↓
—
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Pulmonary Vessels
100 mg of almitrine b.i.d. Arnaud et al.87 reported on 200 stable hypoxic and hypercapnic patients who participated in a 6-month double-blind placebo controlled multicenter study; a remarkable improvement in arterial PO2 was maintained for the treatment period. Melot88 investigated the effect of 100 mg almitrine orally in stable COPD patients; he likewise found a significant increase in arterial PO2, which was associated with a small increase in pulmonary artery pressure. A one-year intermittent oral almitrine therapy study (100 mg q.d.) showed a lasting improvement in arterial oxygenation. In this last study a small decrease in pulmonary artery pressure was found after 1 year.89 Unfortunately, because of side-effects, such as the development of peripheral neuropathy in some patients with longterm almitrine treatment, this drug has not been used extensively for the treatment of patients with COPD and cor pulmonale. It would be desirable to attempt to “breed” a comparable compound devoid of neurological side-effects with the effects of almitrine; i.e. one that shows improvement of ventilation/perfusion matching and improvement of oxygenation. 5-lipoxygenase inhibitors Increased expression of 5-lipoxygenase and 5-lipoxygenase activating protein (FLAP) has been shown in the lung vessels of patients with severe (primary) pulmonary hypertension.96 Comparable information is not yet available regarding expression of 5-lipoxygenase in the lungs from patients with emphysema. However, Piperno et al.90 reported increased levels of plasma leukotriene C4 (LTC4) in patients with COPD, and recently Kasahara et al.97 reported increased expression of 15-lipoxygenase in the lungs from patients with emphysema when compared with controls.
(a)
Air
Thus, a rationale may exist to treat patients with COPD and pulmonary hypertension with lipoxygenase inhibitors,98 given that lipoxygenase products have pulmonary vasoactivity and may be involved in vascular remodeling96 and may control gene expression. Endothelin antagonists Since several studies have shown elevated plasma endothelin levels in patients with pulmonary hypertension, and in patients with COPD,91 it appears that endothelin receptor antagonists could be used in the treatment of pulmonary hypertension associated with COPD. Again, it is important to emphasize that endothelin receptor antagonists could be hemodynamically useful in the absence of a large effect on ventilation/perfusion matching. Nitric oxide Nitric oxide and nitric oxide donors could be considered in the treatment of patients with COPD and pulmonary hypertension. Nitroglycerin and nitroprusside have been studied;83 and indeed the effect of acetylcholine infusion had been examined as early as 1960 by Chidsey et al.12 – certainly without the authors’ appreciation that they were studying the action of NO. Both nitroglycerin and nitroprusside were shown to decrease mean right atrial pressure, mean pulmonary artery pressure, and arterial oxygen tension. Nitric oxide inhalation during exercise in patients with COPD blunted the rise in the pulmonary artery pressure. At rest, nitric oxide decreased PaO2 from 72 ± 3 mmHg to 65 ± 2 mmHg owing to an increase in the ventilation perfusion inequality. However, during exercise PaO2 decreased during breathing of room air, whereas it remained essentially unchanged during inhalation of NO (Fig. 19.4).93
(b)
NO
10
Change in PaO2 from rest to exercise (mmHg)
Pulmonary vascular pressure gradient (mmHg)
20
15
10
5
0 0
3
6
9
Cardiac output (L/min)
12
15
*
5
0
⫺5
⫺10 Air
NO
Fig. 19.4. Changes in (a) the cardiac output and pulmonary arterial pressure gradient at rest and during exercise, and (b) in the PaO2, in COPD patients breathing either room air or 40 ppm of nitric oxide (NO). Reproduced from reference 93, with permission.
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Phosphodiesterase inhibitors Agents with phosphodiesterase (PDE) inhibitory activity are dipyridamole and theophylline. However, these inhibitors are relatively nonspecific. Theophylline treatment has been evaluated in patients with COPD and cor pulmonale.75 Theophylline infusion did not lower the pulmonary artery pressure in COPD patients, who were also unresponsive to acute treatment with 100% oxygen. It seems likely that in the near future highly specific PDE isozyme inhibitors will be developed with selectivity towards the airway smooth muscle, as well as agents which treat both pulmonary vasoconstriction and inflammation. Lung reduction surgery A recent report by Oswald-Mammosser et al.38 examined the effects of lung volume reduction surgery (LVRS) on changes of lung volume, flow rates, hemodynamics, and gas exchange at rest and during exercise.This study showed that PaO2, PaCO2, PA-aO2, and pulmonary artery pressures were unchanged after LVRS, both at rest and during exercise. However, the mean results reflecting the group patient data may not tell the entire story since some patients had a clear-cut reduction in mean pulmonary artery pressure during exercise; the drop in some patients was as much as 17 mmHg. There was also a significant overall decrease of the diastolic pulmonary arterial pressure change that occurs with respiration. Resection of the most distended areas of the lung reduces hyperinflation, and this in turn may improve the functioning of the diaphragm and other respiratory muscles. The authors concluded: “The possible effect of an anatomically reduced vascular bed after LVRS may be counterbalanced by a decrease of pulmonary vascular resistance.The latter may result from a lower degree of inflation, increased elastic recoil and, hence, from capillary recruitment and from better mechanical properties of the lung with less functional compression of the pulmonary vessels.”
PROSPECTS According to MacNee: “It seems unlikely, therefore, that therapeutic interventions that directly affect cardiac function or produce pulmonary vasodilation will have a significant effect on the long term survival in patients with pulmonary hypertension secondary to COPD.”71 However, the future seems to be elsewhere (Fig. 19.5). Regrowth of functional lung units – perhaps following treatment with pluripotent stem cells,99 or following activation of the original lung growth and development program – may be possible in the future. Therapy with stem cells and their progeny may address unmet medical needs. Their capacity for self-renewal and regeneration of tissue may lead to the development of mini-transplants based on bone marrow-derived hematopoietic and mesenchymal cells.100,101
Improve oxygenation without supplemental O2
PaO2
Decrease vascular remodeling
Repair⫽ grow new lung units
Make use of endogenous peptides like ANP
Fig. 19.5. Future strategic developments may include the design of drugs which improve ventilation/perfusion mismatch and increase tissue oxygenation, and the design of specific agents which decrease vascular wall thickening. Eventually stem cell technology may allow the building of new lung units.
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54. Chytil F. Retinoids in lung development. FASEB J. 1996; 10:986–92. 55. Massaro GD, Massaro D. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nature Med. 1997; 3:675–7. 56. Golpon HA, Geraci MW, Moore MD et al. HOX genes in human lung: altered expression in primary pulmonary hypertension and emphysema. Am. J. Pathol. 2001; 158:955–66. 57. Segura-Valdez L, Pardo A, Gaxiola M et al. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 2000; 117:684–94. 58. McDonald PP, Fadok VA, Bratton D, Henson PM. Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-beta in macrophages that have ingested apoptotic cells. J. Immunol. 1999; 163:6164–72. 59. Jaumann F, Elssner A, Mazur G, Dobmann S, Vogelmeier C. Transforming growth factor-beta1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line. Munich Lung Transplant Group. Eur. Respir. J. 2000; 15:1052–7. 60. Kuzuya M, Satake S, Ramos MA et al. Induction of apoptotic cell death in vascular endothelial cells cultured in three-dimensional collagen lattice. Exp. Cell. Res. 1999; 248:498–508. 61. Shu WH, Guo X,Villaschi S, Francesco NR. Regulation of vascular growth and regression by matrix metalloproteinases in the rat aorta model of angiogenesis. Lab. Invest. 2000; 80:545–55. 62. Basbaum CB, Werb Z. Focalized proteolysis: spatial and temporal regulation of extracellular matrix degradation at the cell surface. Curr. Opin. Cell Biol. 1996; 8:731–8. 63. Dunnill MS. The pathology of asthma, with special reference to changes in the bronchial mucosa. J. Clin. Path. 1960; 13:27–33. 64. Carroll NG, Cooke C, James AL. Bronchial blood vessel dimensions in asthma. Am. J. Respir. Crit. Care Med. 1997; 155:689–95. 65. Orsida BE, Li X, Hickey B et al. Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax 1999; 54:289–95. 66. Charan NB, Baile EM, Paré PD. Bronchial vascular congestion and angiogenesis. Eur. Respir. J. 1997; 10:1173–80. 67. Li X, Wilson JW. Increased vascularity of the bronchial mucosa in mild asthma. Am. J. Respir. Crit. Care Med. 1997; 156:229–33. 68. Thurston G, Maas K, LaBarbara A, Mclean JW, McDonald DM. Microvascular remodelling in chronic airway inflammation in mice. Clin. Exp. Pharm. Physiol. 2000; 27:836–41. 69. Baluk P, Bowden JJ, LeFevre PM, McDonald DM. Upregulation of substance P receptors in angiogenesis associated with chronic airway inflammation in rats. Am. J. Physiol. 1997; 273:L565–71. 70. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease: 1. Am. J. Respir. Crit. Care Med. 1994; 150:833–52. 71. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease: 2. Am. J. Respir. Crit. Care Med. 1994; 150:1158–68. 72. MacNee W, Wathen CG, Flenley DC, Muir AD. The effects of controlled oxygen therapy on ventricular function in patients with stable and decompensated cor pulmonale. Am. Rev. Respir. Dis. 1988; 137:1289–95. 73. Tarpy SP, Celli BT. Long-term oxygen therapy. N. Engl. J. Med. 1995; 333:710–14. 74. Weitzemblum E, Sautegeau A, Ehrhart M, Mammosser M, Pelletier A. Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1985; 131:493–8. 75. Matthay RA, Berger HJ, Loke J, Gottschalk A, Zaret BL. Effects of aminophylline upon right and left ventricular performance in chronic obstructive pulmonary disease: noninvasive assessment by radionuclide angiocardiography. Am. J. Med. 1978; 65:903–10.
76. Bratel T, Hedenstierna G, Nyguist O, Ripe E. Long-term treatment with a new calcium antagonist, felodipine, in chronic obstructive lung disease. Eur. J. Respir. Dis. 1986; 68:351–61. 77. Simonneau G, Excourrou P, Duroux P, Lockhart A. Inhibition of hypoxic pulmonary vasoconstriction by nifedipine. N. Engl. J. Med. 1981; 304:1582–5. 78. Kennedy TP, Michael JR, Huang CK et al. Nifedipine inhibits hypoxic pulmonary vasoconstriction during rest and exercise in patients with chronic obstructive pulmonary disease: a controlled double-blind study. Am. Rev. Respir. Dis. 1984; 129:544–51. 79. Agostoni P, Doria E, Galli C,Tamborini G, Guazzi MD. Nifedipine reduces pulmonary pressure and vascular tone during short- but not long-term treatment of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1989; 139:120–5. 80. Burke CM, Harte M, Duncan J et al. Captopril and domiciliary oxygen in chronic airflow obstruction. Br. Med. J. 1985; 290:1251. 81. Biernacki W, Prince K,Whyte K, Macnee W, Flenley DC.The effect of six months of daily treatment with the beta-2 agonist oral pirbuterol on pulmonary hemodynamics in patients with chronic hypoxic cor pulmonale receiving long-term oxygen therapy. Am. Rev. Respir. Dis. 1989; 139:492–7. 82. Bentivoglio LG, Beerel F, Stewart PB et al. Studies of regional ventilation and perfusion in pulmonary emphysema using xenon. Am. Rev. Resp. Dis. 1963; 88:315. 83. Brent BN, Berger HJ, Matthay RA et al. Contrasting acute effects of vasodilators (nitroglycerin, nitroprusside, and hydralazine) on right ventricular performance in patients with chronic obstructive pulmonary disease and pulmonary hypertension: a combined radionuclide-hemodynamic study. Am. J. Cardiol. 1983; 51:1682–9. 84. Diaz O, Iglesia R, Ferrer J et al. Effects of noninvasive ventilation on pulmonary gas exchange and hemodynamics during acute hypercapnic exacerbations of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 156:1840–5. 85. Andrivet P, Chabrier PE, Defouilloy C, Brun-Buisson C, Adnot S. Intravenously administered atrial natriuretic factors in patients with COPD: effects on ventilation/perfusion relationships and pulmonary hemodynamics. Chest 1994; 106:118–24. 86. Bell RC, Mullins RC, West LG, Bachand RT, Johanson WG. The effect of almitrine bismesylate on hypoxemia in chronic obstructive pulmonary disease. Ann. Int. Med. 1986; 105:342–6. 87. Arnaud F, Bertrand A, Charpin J et al. Presented by N Pauly. Long-term almitrine bismesylate treatment in patients with chronic bronchitis and emphysema: a multicentre double-blind placebo-controlled study. Eur. J. Respir. Dis. Suppl. 1983; 126:323–36. 88. Melot C. Relationships between Gas Exchange and the Pulmonary Circulation. PhD thesis, Free University of Brussels, 1989. 89. Wurtemberger G, Zielinsky J, Sliwinsky P, Anw-Haerich C, Matthys H. Survival in chronic obstructive pulmonary disease after diagnosis of pulmonary hypertension related to long-term oxygen therapy. Lung 1990; 168(Suppl.):762–9. 90. Piperno D, Pacheco Y, Hosni R et al. Increased plasma levels of atrial natriuretic factor, renin activity, and leukotriene C4 in chronic obstructive pulmonary disease. Chest 1993; 104:454–9. 91. Faller M, Kessler R, Sapin R et al. Regulation of endothelin-1 at rest and during a short steady-state exercise in 21 COPD patients. Pulm. Pharmacol.Ther. 1998; 11(2/3):151–7. 92. Bonvallet ST, Oka M, Yano M et al. BQ123, and ET1 receptor antagonist, attenuates endothelin-1-induced vasoconstriction in rat pulmonary circulation. J. Cardiovasc. Pharmacol. 1993; 22:39–43. 93. Roger N, Barbera JA, Roca J et al. Nitric oxide inhalation during exercise in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 156:800–6.
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94. Perreault T, Gutkowska J. Role of atrial natriuretic factor in lung physiology and pathology. Am. J. Respir. Crit. Care Med. 1995; 151:226–42. 95. Lordick F, Hauck RW, Senekowitsch R, Emslander HP. Atrial natriuretic peptide in acute hypoxia-exposed healthy subjects and in hypoxaemic patients. Eur. Respir. J. 1995; 8:216–21. 96. Wright L, Tuder RM, Wang J et al. 5-lipoxygenase and 5-lipoxygenase activating protein (FLAP) immunoreactivity in lungs from patients with primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 1998; 157:219–29. 97. Kasahara Y, Tuder RM, Cool CD, Voelkel NF. Expression of 15lipoxygenase and evidence for apoptosis in the lungs from patients with COPD. Chest 2000; 117:260S. 98. Amsellem C, Czarlewski W, Lagardes M, Pacheco Y. Inhibitory effect of laratadine on leukotriene B4 production by neutrophils either alone or during interaction with human airway epithelial cells. Pulm. Pharmacol. Ther. 1998; 11(4):245–52. 99. Mason RJ, Williams MC, Moses HL, Mohla S, Berberich MA. Stem cells in lung development, disease, and therapy. Am. J. Respir. Cell Mol. Biol. 1997; 16:355–63. 100. Pereira RF, Halford KW, O’Hara MD et al. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage and lung in irradiated mice. Proc. Natl Acad. Sci. USA 1995; 92:4857–61. 101. Lagasse E, Connors H, AlDhalimy M et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature Med. 2000; 6:1229–34.
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102. Vik-Mo H, Walde N, Jentoft H, Halvorsen FL. Improved haemodynamics but reduced arterial blood oxygenase, at rest and during exercise after long-term oral prasozin therapy in chronic cor pulmonale. Eur. Heart J. 1985; 6:1047–53. 103. Saadjian AY, Philip-Joet FF, Vestri R, Arnaud AG. Long-term treatment of chronic obstructive lung disease by nifedipine: an 18-month haemodynamic study. Eur. Respir. J. 1988; 1:716–20. 104. Rubin WJ, Moser K. Long-term effects of nitrendipine on hemodynamics and oxygen transport in patients with cor pulmonale. Chest 1986; 89:141–5. 105. Stockley RA, Finnegan P, Bishop JM. Effects of intravenous terbutaline on arterial blood gas tensions, ventilation and pulmonary circulation in patients with chronic bronchitis and cor pulmonale. Thorax 1977; 32:601–5. 106. Mookherjee S, Ashutosh K, Dunsky M et al. Nifedipine in chronic cor pulmonale: acute and relatively long-term effects. Clin. Pharmacol.Ther. 1988; 44:289–96. 107. MacNee W, Wathen CG, Hannan WJ, Flenley DC, Muir AJ. Effects of pirbuterol and sodium nitroprusside on pulmonary haemodynamics in hypoxic cor pulmonale. Br. Med. J. 1983; 287:1169–72. 108. Sturani C, Bassein L, Schiavina M, Gunella G. Oral nifedipine in chronic cor pulmonary secondary to severe chronic obstructive pulmonary disease (COPD): short and long term hemodynamic effects. Chest 1983; 84:135–42. 109. Delaunois L, Jonard P, Kremer N, Dubois P, Lulling J. Nitroglycerin and isosorbide dinitrate in pulmonary disease. Bull. Eur. Physiopathol. Respir. 1984; 20(1):11–18.
(a)
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Fig. 19.2. Lung tissue histological sections from a patient with COPD/emphysema. (a) Tortuous muscularized pulmonary artery (v) showing wall thickening, muscularization. b, bronchus with mucosa damage; a, emphysematous airspaces. HE stain. (b) Muscularized small precapillary arteries (arrows). a, emphysematous airspace. HE stain. (c) Small, muscularized pulmonary arteriole (v), thickening of alveolar septal structures with inflammatory cells (arrow), and hemosiderin precipitates. HE stain. (d) Emphysematous area with small precapillary arteries (v, arrows). Staining for muscle-specific actin.
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Fig. 19.3. Representative lung morphology of a 38-year-old female steroid-dependent patient, who died in status asthmaticus. (a) Dilated and congested precapillary pulmonary arteries, which are seen in close-up in (b). (b) Note the margination and accumulation of neutrophils in both the pulmonary vessel (arrow) and capillaries (arrowheads). (c) Low-power view of a mucus-filled bronchiole. Close-up of boxed area is shown in (d). (d) Note the presence of eosinophils and Charcot–Leyden crystal (arrow) admixed with mucus. (e) Dilated small bronchiolar vessel, with marginating neutrophils and eosinophils, which are seen infiltrating the bronchiolar wall.
Chapter
Plasma Exudation
20
Carl G.A. Persson,1 Jonas S. Erjefalt,2 Lena Uller,2 Morgan Andersson,3 and Lemark Grieff 3 1
Department of Clinical Pharmacology, University Hospital of Lund, Sweden Department of Physiological Sciences, University Hospital of Lund, Sweden 3 Department of Otorhinolaryngology, University Hospital of Lund, Sweden 2
INTRODUCTION Much of our knowledge of airway disease mechanisms is based on analysis of the readily available materials that emerge into the airway lumen. The appearance of plasma macromolecules on the airway surface indicates that the milieu of mucosal interstices is flooded by bioactive proteins emanating from the microcirculation. Further, the luminal entry of plasma resolves or prevents the formation of highpermeability (proteinaceous) mucosal edema in the conducting airways. Similarly, recent data suggest that the luminal entry of granulocytes may be a major mode of resolving eosinophilic airway tissue inflammation. Once in the lumen the cells are clearly in a different milieu and may not retain the phenotype that was contributing to inflammation in the diseased airway tissue (Fig. 20.1). Indeed, translation of cell biology data from “lumen” to “tissue” may be as difficult or impossible as translation from in vitro to in vivo. The latter is probably best reserved for events occurring in blood-perfused tissues in situ. Being primarily a first-line innate immunity mechanism,1 airway plasma exudation is a relatively specific sign of inflammatory mucosal processes in the respiratory tract.1–3 Indeed, it has been claimed that inflammation may not occur without protein-exuding microvessels. Inflammatory stimulus-induced release, tissue distribution, and luminal entry of the plasma proteins are barely characterized by sizeselectivity.1 During inflammatory plasma exudation events, and in mild and noninjurious conditions, all the circulating, multipotent proteins will thus appear, continuously or intermittently, in the important disease biophases. Plasma exudation is one of the cardinal features of asthma,1–7 and it occurs in chronic obstructive pulmonary disease (COPD), especially during exacerbations.4,8,9 Plasma exudation indices may correlate positively with bronchial responsiveness in asthma,4 and negatively with FEV1 in patients with COPD.9 By definition, exudation involves both plasma and cells. Notably, in the absence of eosinophil apoptosis – which may
Airway lumen Plasma Eosinophil
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Fig. 20.1. The airway lumen is a major destination for proteins and cells that are being cleared from the airway mucosal tissue. Clearance of plasma proteins (colored arrows) occurs promptly after extravasation of plasma. Luminal entry of eosinophils may be particularly pronounced during the resolution of airway inflammation. The cell phenotypes that are found in the airway lumen may differ significantly from those in airway tissues.
be exclusively an in-vitro and airway lumen phenomenon – exudation (luminal entry) of eosinophils emerges as a major mechanism in resolution of airway tissue eosinophilia in vivo. Discharged epithelial cells and the ensuing epithelial repairgels, when no longer needed, are additional components of the exudate. With their content of fibrin–fibronectin, neutrophils, and macrophages, the epithelial repair-gels are likely to contribute to exudation of plasma proteins and leucocytes in bronchial desquamative diseases.The focus of this chapter is on the plasma exudate and its content of bioactive molecules, airway exudation of leucocytes, and in-vivo mechanisms of epithelial damage and repair.
THE CONTRIBUTION OF NASAL TEST METHODOLOGIES The controlled experimental conditions attainable by current nasal methodologies in humans10 are far beyond what is
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possible to accomplish in studies of the pathophysiology of human bronchi in vivo. Moreover, the nasal mucosa represents airways receiving systemic blood (pulmonary microvascular exudative events are beyond the scope of this chapter) and may thus mimic the bronchial mucosa as regards many inflammatory, epithelial, and microvascular mechanisms.11 Nasal inflammatory disease often coexists with asthma,11,12 and steroid treatment of one part of the airway mucosa has important effects also on the airway that was not directly exposed to the drug.13,14 Further supporting a close relationship between upper and lower airways, emerging epidemiological observations suggest that significant nasal symptoms are common in both asthma and COPD.15 However, triggers of nasal symptoms differ between asthma and COPD.15 To better understand what may occur in the diseased human bronchi, this chapter discusses in-vivo data obtained from both the human nose and bronchi. Data obtained from guinea-pigs and rats further complement the present discussion on exudation of plasma, cells, and repair-gels.1,16–19 Owing to difficulties involved in translating to in vivo,20 and the current lack of balance between molecular biologydriven paradigms and patient-oriented, function-based medical research approaches,21,22 this chapter will not deal with molecular data obtained in vitro.
PLASMA RELEASE, TISSUE D I S T R I B U T I O N , A N D L U M I N A L E N T RY Mechanisms of “plasma leak”, through the formation of venular endothelial gaps, have been described.1,23,24 By receptor-mediated mechanisms, endothelial gaps are transiently and repeatedly induced in vivo in the postcapillary venules of the profuse subepithelial microcirculation. The distribution of, and particularly epithelial passage of, the extravasated plasma in the airways is of interest. It is unsieved plasma that leaves the circulation and distributes into the lamina propria.This “bulk” plasma further traverses the epithelial basement membrane and moves widely between epithelial cells in the area of interest25 (Fig. 20.2). Experimental work employing intact airway walls has demonstrated that paracellular, unidirectional epithelial pathways into the lumen are easily produced by hydraulic mechanisms.1 Thus, moderately increasing the hydrostatic pressure load on the basolateral aspects of the epithelial lining cells (this load is potentially mounted by the extravasated plasma itself) will move macromolecules across the mucosa into the airway lumen. This epithelial transmission is noninjurious, reversible, and repeatable. Similarly, the exudative response to histamine challenges of the human airway mucosa is noninjurious, reversible, and repeatable. Compatible with the “hydraulic hypothesis”, there is loss of size-selectivity for epithelial transmission of molecules at challenge-induced luminal entry of plasma in vivo. In further agreement with human airway data in vivo, experimental, hydrostatic pressure-evoked luminal entry of
Fig. 20.2. The extravasated bulk plasma (white) distributes in the lamina propria, moves through the epithelial basement membrane, continues up between and all around epithelial cells, and ends up in the airway lumen. Despite the passage across many barriers, including an epithelial lining that is relatively tight as an absorption barrier, this exudation process proceeds largely without sieving of the macromolecular content of the plasma.
“plasma” occurs without increasing the absorption capacity of the mucosa. Hence, rather than reflecting any generally increased permeability of the airway mucosa, the appearance of plasma proteins in the airway lumen reflects the activation of a valve-like, para-epithelial mechanism.1 As indicated by human in-vivo studies, where factors such as mucosal surface concentration of absorption tracer, exposed mucosal surface area, and exposure time were well controlled, the mucosal barrier may even exhibit an increased functional tightness (reduced paracellular absorption capacity) in exudative airway diseases.1,26 The observation that most of the extravasated plasma is destined to appear quickly on the mucosal surface in airways with maintained epithelial integrity is fundamental to the role of plasma exudation in airway defense.1 An additional consequence is that the occurrence of plasma contents in the readily sampled luminal material may reflect onset, intensity, and duration of those subepithelial inflammatory processes that are sufficiently intense to engage the local microcirculation.
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centrations, histamine produced increasing plasma exudation responses.1 Some tachyphylaxis of the exudative response is evident but can be overcome by increasing the dose of a single mediator or, more effectively, by alteration of the exudative stimulus.23 The exceedingly profuse mucosal microcirculation (Fig. 20.4) can be expected to deliver plasma proteins effectively and inexhaustibly to the lamina propria and epithelial lining of human airways. Supporting the possibility that the plasma exudation response reflects inflammation, IgE-mediated reactions, exposure to occupational chemicals, and viral infections evoke significant exudation of plasma proteins in nasal and bronchial airways.1,3 Thus plasma exudation determines much of the bioactive proteinaceous milieu in vivo in inflammatory airway diseases, especially at excerbations. Inhibition of plasma exudation will reduce, correspondingly, the content of bioreactive molecules of the in-vivo mucosa.
The extravasation of plasma across venular endothelium is a size-independent process, and also the passage of differentsized plasma proteins across a normal epithelial lining occurs without appreciable sieving.1 Hence, the best index of plasma exudation in sputum and bronchoalveolar lavage (BAL) samples may be a large plasma protein, such as a2-macroglobulin (700 kDa). The appearance of a2macroglobulin on the mucosal surface indicates that practically all the potent protein systems contained in circulating plasma are present in the extravasated plasma. An abundance of growth factor-active, adhesive, leucocyte-activating (etc.) molecules, emanating from plasma, thus “flood” the interstices of an exuding airway mucosa (Fig. 20.3). The highly bioactive, pluripotent proteins from a “noncellular” source are thus intermittently or continuously being added to in the extracellular matrix of a diseased, inflamed and/or repairing airway mucosa.1 Histamine, leukotrienes, bradykinins and other “histamine-type” mediators may be considered inflammatory because they induce exudative responses in human nasal and bronchial airways.1 It is noteworthy that the histamineinduced mucinous secretion – as measured by its content of fucose – in human nasal mucosa appeared to be almost depleted soon after the first effective dose had been given (unpublished observations by L. Greiff and coworkers). By contrast, over a wide range of nasal mucosal surface con-
N E U R O G E N I C E X U D AT I O N : D R I E D OUT? Methacholine is a selective secretagogue in human airways. Even supramaximal secretory doses of such a muscarinic agent may produce no exudative actions.1 Similarly many irritants of human airways, including nicotine and capsaicine (the archetypal sensory nerve stimulant), evoke marked secretory effects and coughing without inducing plasma exudation.1,27 These data speak against the direct
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is pharmacologically regulated at the level of the venular endothelial cells28 that also are target cells for mediators and drugs (Fig. 20.5). Vasopermeability effects of histamine, leukotrienes, bradykinins, and other exudative autacoids can be selectively inhibited by appropriate pharmacological antagonists. Through functional antagonism, b2-agonists attenuate mediator-induced acute exudation of plasma in animal and human bronchi,1,28,29 but a therapeutic role has not been demonstrated. Drugs that inhibit the release of vascular permeability mediators will inhibit plasma exudation in diseased airways. This result can also be brought about, as with steroids, by reducing the appearance of inflammatory cells. Such an indirect effect is probably the most important anti-exudative mechanism of airway steroids. Steroids reduce plasma exudation in asthma and, at exacerbations, in COPD.1,3,4,8 Steroids may not prevent the plasma exudation response to acute challenges with mediators and occupational chemicals.1 Similarly, steroids do not prevent the sustained plasma exudation that occurs with viral infections and during epithelial shedding-restitution processes in vivo.1 Thus, moderate doses of airway steroids do not seem to inhibit plasma exudation when this response has potentially important roles in innate immunity and repair.
Epithelium Subepithelial plexus of the blood vessels Fig. 20.4. All along human nasal/tracheobronchial airways, just beneath the epithelial lining, there is a profuse microcirculation. In airway inflammation in vivo this may be the most important reactive organ, inexhaustibly releasing pluripotent proteins into the mucosal tissue and surface.
translatability, to human airways, of the special kind of neurogenic, exudative inflammation that is so readily evoked in guinea-pigs. Hence, the plasma exudation response in man seems particularly specific to inflammation since several secretory agents as well as neural irritants may not readily evoke this response. Inhibition of airways exudation should thus be possible without impeding the component of innate immunity that involves sensory nerve stimulation and a promptly ensuing secretory response. Conversely, antisecretory drugs such as atropine cannot be expected to influence plasma exudation responses.
SEQUENTIAL INDUCTION OF E X U D AT I O N A N D S P U T U M Exuded proteins such as a2-macroglobulin bind and transport released cellular molecules, including eosinophil granule proteins and most cytokines.1,30 The binding and transporting capacity of the plasma exudation process may explain why cytokines have been detected in the airway lumen after allergen challenge (causing acute plasma exudation responses) whereas the underlying airway tissue has been depleted of the same molecules.31 This property of the plasma exudation process can also be utilized experimentally to improve the yield of tissue molecules in sputum samples. For example, it was only when histamine challenge-induced plasma exudation preceded sputum induction that increased airway levels of eosinophil cationic protein could be detected in the bronchi of patients with active allergic rhinitis.32 Histamine-induced exudation followed by sputum-producing saline inhalations, as a “dual induction method”,32 may have a role in studies of the pathophysiology and pharmacology of airway diseases.
E P I T H E L I A L R E PA I R I N V I V O A N T I - E X U D AT I V E E F F E C T S O F D R U G S Drug-induced inhibition of plasma exudation is a sign of anti-inflammatory efficacy. It is also a desirable action in its own right since it reduces significantly the occurrence of proinflammatory proteins and peptides in the airway mucosa. The microvascular–epithelial exudation of plasma
In exploratory in-vivo experiments involving shedding-like denudation (meaning that no damage is inflicted upon the basement membrane), the basement membrane is seen to be naked only very transiently. As demonstrated in guineapig trachea, exuded plasma promptly covers the basement membrane with a highly dynamic fibrin–fibronectin gel.17 It
Plasma Exudation
Inflammatory processes Anti-inflammatory drugs Increased levels of vasoactive agents Pharmacological antagonists
Functional antagonists Fig. 20.5. Venular endothelial cells are delineated and sites of interendothelial gap formation are marked as small black holes. The gaps through which bulk plasma is extravasated are produced by the action of mediators directly on the endothelial cells. Leucocytes, too, are extravasated between venular endothelial cells, but the cells move independent of gap formation.9 Steroids inhibit inflammatory processes, and so the release of vasoactive mediators is also inhibited. Thus plasma exudation is indirectly prevented by airway anti-inflammatory drugs. In addition, steroids may exert a degree of functional antagonism directly on the endothelium. Other anti-exudative drugs (e.g. antihistamines, leukotriene inhibitors) would be less active since they may antagonize the action of only a single type of vasoactive agent.
is in this plasma-derived gel (where neutrophils and other leucocytes also accumulate) that restitution of epithelial lining cells proceeds rapidly. As soon as a new cell cover has been established the local plasma exudation stops and the plasma-derived gel with numerous granulocytes is discharged into the lumen.17,19 The repair gel, which is exceedingly rich in neutrophils and fibrin(ogen) (Fig. 20.6), can be expected to contribute components of the exudate particularly in severe and infectious asthma.1 In-vivo studies of shedding-like denudation have demonstrated that epithelial restitution starts immediately and proceeds at several microns per minute in a plasmaderived molecular milieu.17,19 The migrating repair cells are recruited from all types of surrounding epithelial cells. However, with selective loss of columnar epithelial cells, a cellular barrier is restored by immediate tightening of the remaining basal cells.33 During allergic reactions or with the inhalation of dry air, epithelial damage may be exceedingly patchy. Such patches may not exhibit frank denudation unless artifacts are created, for example by employment of cryosections.34 It further seems clear that biopsy procedures may inflict artificial denudation of human bronchi.17,35 Observation of epithelial damage and repair patches in vivo suggests that damage may proceed in the apical portion of the epithelium whilst repair is already advanced at the basal level.33,34 Considerable epithelial cell loss may thus take place from many tiny patches, potentially without significant loss of the barrier function. In exploratory work in vivo in guinea-pigs, shedding-like removal of epithelial cells was followed by events in addition to plasma exudation and prompt epithelial repair. The sequelae to a nonsanguinous removal of a small, defined zone of epithelial lining cells also included the following:
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thickening of the reticular epithelial basement membrane; proliferation of fibroblasts and smooth muscle cells; enlargement of regional lymph nodes; massive accumulation and activation of granulocytes; increased secretion.33
These important changes were not confined to the zone of superficial epithelial repair events but involved subepithelial tissues and engaged the entire circumference of the airway. Major components of the disease characteristics of asthma could thus emanate from simple, patchy loss of epithelial cells as may occur with exposure to allergens, occupational chemicals, and dry air.34,36 Epithelial cell loss during infectious exacerbations may also account for a significant part of the neutrophilic inflammation that occurs in COPD as well as in asthma. Inferentially, cytoprotective agents may prove to be of significant therapeutic value provided they can prevent the occurrence of epithelial damage and shedding in inflammatory airway diseases.
T H E FAT E O F A I R WAY T I S S U E E O S I N O P H I L S : L U M I N A L E N T RY VERSUS APOPTOSIS Eosinophils are potentially involved in epithelial damage and in immunoregulation of diseased airways.16,37 Eosinophil death through apoptosis occurs in cell culture test systems.38 Apoptosis is a “silent” mode of death by which the cell shrinks and the nucleus becomes condensed.39 The apoptotic cell is instantaneously engulfed, it is thought (based exclusively on in-vitro data), by phagocytosing cells without prior release of inflammatory mediators.39 The view that steroids induce eosinophil apoptosis, and thus efficiently and gently kill a culprit cell in airway disease, has been argued effectively; but less fortunate for this attractive hypothesis, not one single apoptotic eosinophil has been demonstrated convincingly in human airway tissues in vivo, steroid-treated or not.12 Other apoptotic cells, including neutrophils and lymphocytes, have clearly been observed, suggesting that eosinophil apoptosis is a particularly rare event in human airway tissues. The author’s group has suggested that the luminal entry mechanism may fully compensate for a lack of eosinophil apoptosis in vivo16,18 (Fig. 20.7). The increased airway luminal eosinophilia that follows exacerbations of airway disease, especially asthma, has been recognized since the late 1800s.40 (At about that time the particularly profuse mucosal microcirculation of asthmatic bronchi was also well described.) Recent data further demonstrate a reciprocal relationship between tissue and luminal eosinophil numbers after allergen challenge.16,41 Whereas plasma exudation reflects ongoing inflammation, it appears that eosinophils are delivered into the airway lumen particularly at the resolution of a disease process (Figs 20.1 and 20.7). Movement into the airway lumen, followed by mucociliary transport and coughing, thus emerges as a high-capacity mode of clearing
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(d)
(a)
(e)
Blood vessel
Blood vessel
(b)
(f)
(c1)
(c2)
Fig. 20.6. (a) Schematic of epithelial restitution in vivo. De-differentiated epithelial cells, recruited from the surrounding intact epithelium, migrate to seal sites of epithelial shedding. This repair is aided by plasma extravasation that endows the site with repair-promoting factors and creates a protecting plasma-derived gel cover. (b) This scanning electron micrograph (SEM) shows that the gel attracts numerous neutrophils and other leucocytes. (c) The top portion of the upper half of this SEM shows a stretch of plasma-derived gel created over a zone where epithelium has been removed without damaging the basement membrane and without causing any bleeding. The lower half of the SEM illustrates that the subepithelial microvessels lying beneath the gel (and above the smooth muscle) supplies it continuously with extravasated plasma proteins. (d) Transmission electron microscopy (TEM) reveals the formation of fibrin fibers in the gel. (e) Fibronectin (white) that is extravasated from microvessels beneath the repair site abound in the gel that covers the denuded area as well as part of the intact epithelium (to the right; arrow). sm, smooth muscle. (f) Once an epithelial cell cover has been restored (re) the gel is rapidly dissolved and expelled into the airway lumen.
Plasma Exudation
Luminal entry
Mucociliary clearance Apoptosis
No effect
Recruitment
Inhibition
Steroid action
Fig. 20.7. In the absence of apoptosis of tissue eosinophils, emergence into the airway lumen would be a major mode of clearance of airway eosinophils. Luminal entry of eosinophils can proceed without causing further inflammation. Treatment with airway steroids may permit transepithelial clearance of granulocytes to go on unimpeded. This permissive drug action, together with well-known inhibitory effects of steroids on recruitment of eosinophils to the airways, may give the slowly induced resolution of established airway eosinophilia that is seen experimentally. There is a contrasting picture in the tissue, where many of the luminal eosinophils seem to undergo apoptosis. This may increase the efficiency of luminal entry as a path of clearance of the tissue granulocytes.
protein and cellular effectors from the diseased mucosal tissue. The normal physiological removal mechanisms operating on the mucosal surface, together with barrier functions (both the luminal material itself and the mucosal lining acting as barriers) give little opportunity for the bulk of luminal material to move back into the tissues.
CONCLUSION Exudative processes of the airways may effectively eliminate proteins and cells from diseased mucosal tissue. The solutes and cells appearing in airway discharge material can disclose what goes on beneath the surface. Appearance of large plasma proteins on the airway surface indicates that the circulating proteins are flooding the lamina propria, the basement membrane, and the epithelial lining. Inferentially, a very wide range of adhesive, growth factor-active, leucocyte-activating, and otherwise biologically active, plasma-derived molecules are dynamically being added to in the interstices of inflamed airway mucosal tissues. Plasma exudation may occur without causing significant mucosal edema. It is an event regulated by, and resulting in the deposition of, bioactive molecules. Airway steroids inhibit plasma exudation in inflammatory airway disease; by this action alone these drugs could significantly alter the reactive molecules present in the airways.
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Inflammatory stimuli and epithelial cell loss evoke acute and sustained plasma exudation in the airways. Epithelial repair in vivo is prompt. It occurs in a plasma-derived fibrin–fibronectin gel which becomes heavily infiltrated with granulocytes, particularly neutrophils. Such neutrophilic plasma gels should be frequently discharged into the airway lumen in desquamative disease. Eosinophil granule products may evoke plasma exudation responses directly, or indirectly through epithelial damage. The eosinophil itself may move into the airway lumen, particularly when local disease processes are being resolved. Luminal entry is a high-capacity mode of clearing granulocytes from diseased airway tissues. It may be unaffected by steroid treatment. Thus, by permitting noninflammatory elimination of mucosal eosinophils across the epithelial lining, and inhibiting recruitment of new eosinophils to the airways, steroids slowly attenuate established airway tissue eosinophilia.
REFERENCES 1. Persson CGA, Erjefält JS, Greiff L et al. Plasma-derived proteins in airway defence, disease and repair of epithelial injury. Eur. Respir. J. 1998; 11:958–70. 2. Dunnill MS. The pathology of asthma with special reference to changes in the bronchial mucosa. J. Clin. Pathol. 1960; 13:27–33. 3. Persson CGA. Role of plasma exudation in asthma. Lancet 1986; 2:1126–9. 4. Schoonbrood DF, Lutter R, Habets FJ et al. Analysis of plasma–protein leakage and local secretion in sputum from patients with asthma and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1994; 150:1519–27. 5. Van Vyve T, Chanez P, Bernard A et al. Protein content in bronchoalveolar lavage fluid of patients with asthma and control subjects. J. Allergy Clin. Immunol. 1995; 95:60–8. 6. Pizzichini MM, Pizzichini E, Efthimiadis A et al. Asthma and natural colds: inflammatory indices in induced sputum; a feasibility studies. Am. J. Respir. Crit. Care Med. 1998; 158:1178–84. 7. Svensson C, Grönneberg R, Andersson M et al. Allergen challengeinduced entry of alpha2-macroglobulin and tryptase into human nasal and bronchial airways. J. Allergy Clin. Immunol. 1995; 47:993–1000. 8. Persson CGA. Permeability changes in obstructive airway disease. In: Sluiter HJ, Van Der Lende R, Gerritsen J, Postma DS (eds.), Bronchitis IV, pp. 236–49. Assen: 1989. 9. Hill AT, Bayley D, Stockley RA. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am. J. Respir. Crit. Care Med. 1999; 160:893–8. 10. Greiff L, Andersson M, Persson CGA. Nasal secretions/exudations: collection and approaches to analysis. In: Rogers D, Donnelly L (eds), Methods in Molecular Medicine. London: Humana Press, 2001. 11. Persson CGA, Svensson C, Greiff L et al. Use of the nose to study the inflammatory response of the respiratory tract. Thorax 1992; 47:993–1000. 12. Simons FE. Allergic rhinobronchitis: the asthma-allergic link. J. Allergy Clin. Immunol. 1999; 104:534–40. 13. Henriksen JM,Wenzel A. Effect of an intranasally administered corticosteroid (budesonide) on nasal obstruction, mouth breathing, and asthma. Am. Rev. Respir. Dis. 1984; 130:1014–18. 14. Greiff L, Andersson M, Svensson C et al. Effects of orally inhaled budesonide in seasonal allergic rhinitis. Eur. Respir. J. 1998; 11:1014–18.
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15. Montnémery P, Svensson C, Ädelroth E et al. Prevalence of nasal symptoms and their relation to self-reported asthma and chronic bronchitis/emphysema. Eur. Respir. J. 2001; 17:596–603. 16. Erjefält JS, Persson CGA. New aspects of degranulation and fates of airway mucosal eosinophils: pulmonary perspective. Am. J. Respir. Crit. Care Med. 2000; 161:2074–85. 17. Erjefält JS, Erjefält I, Sundler F, Persson CGA. Microcirculationderived factors in airway epithelial repair in vivo. Microvasc. Res. 1994; 48:161–78. 18. Uller L, Persson CGA, Källström L, Erjefält JS. Lung tissue eosinophils may be cleared through luminal entry rather than apoptosis: effects of steroid treatment. Am. J. Respir. Crit. Care Med. 2001; 64:1948–56. 19. Erjefalt JS, Sundler F, Persson CGA. Eosinophils, neutrophils, and venular gaps in the airway mucosa at epithelial removal-restitution. Am. J. Respir. Crit. Care Med. 1996; 153:1666–74. 20. Persson CGA. In vivo veritas. Thorax 1996:51:441–3. 21. Persson CGA, Erjefält JS. Eosinophil lysis and free granules: an invivo paradigm for cell activation and drug development. Trends Pharmacol. Sci. 1997; 18:117–23. 22. Persson CGA et al. Unbalanced research. Trends Pharmacol. Sci. 2001; 22:538–41. 23. Grega G, Persson CGA, Svensjö E. Endothelial cell reactions to inflammatory mediators assessed in vivo by fluid and solute flux analysis. In: Ryan U (ed.), Endothelial Cells, pp. 103–22. Boca Raton: CRC, 1988. 24. McDonald DM. Endothelial gaps and permeability of venules in rat tracheas exposed to inflammatory stimuli. Am. J. Physiol. 1994; 266:L61–83. 25. Erjefält JS, Erjefält I, Sundler F, Persson CGA. Epithelial pathways for luminal entry of bulk plasma. Clin. Exp. Allergy 1995; 25:187–95. 26. Greiff L, Andersson M, Svensson C et al. Reduced airway absorption in seasonal allergic rhinitis. Am. J. Respir. Crit. Care Med. 1997; 156:783–6. 27. Haldorsdottir H, Greiff L, Wollmer P et al. Effects of inhaled histamine, methacholine, and capsaicin on sputum levels of a2macroglobulin. Thorax 1997; 52:964–8. 28. Persson CGA, Svensjö E.Vascular responses and their suppression: drugs interfering with venular permeability. In: Bonta IL, Bray
29.
30. 31.
32.
33. 34.
36.
37. 38.
39.
40.
41.
MA, Parnham MJ (eds.), Handbook of Inflammation. Vol. 5: The Pharmacology of Inflammation, pp. 61–81. Amsterdam: Elsevier, 1985. Greiff L, Wollmer P, Andersson M et al. Effects of formoterol on histamine challenge-induced plasma exudation in human bronchial airways. Thorax 1998; 53:1010–13. James K. Interactions between cytokines and a2-macroglobulin. Immunol.Today 1990; 11:163–6. Woolley KL, Ädelroth E, Woolley MJ, Jordana M, O´Byrne P. Effects of allergen challenge on eosinophils, eosinophil cationic protein and granulocyte–macrophage colony-stimulating factor in mild asthmatics. Am. J. Respir. Crit. Care Med. 1996; 154:237–43. Greiff L, Andersson M, Svensson C et al. Demonstration of bronchial eosinophil activity in seasonal allergic rhinitis by induced plasma exudation combined with induced sputum. Thorax 1999; 54:33–6. Erjefält JS, Persson CGA. Epithelial repair, breathtakingly quick, multipotentially pathogenic. Thorax 1997; 52:1010–12. Persson CGA, Erjefält JS, Erjefält I, Korsgren M, Nilsson M. Epithelial shedding-restitution as a causative process in airway inflammation. Clin. Exp. Allergy 1996; 26:746–55. Freed AN, Omori C, Schofield BH, Mitzner W. Dry air-induced mucosal cell injury and bronchovascular leakage in canine peripheral airways. Am. J. Respir. Cell Mol. Biol. 1994; 11:724–32. Rothenbergh ME. Eosinophilia. N. Engl. J. Med. 1998; 338:1592–600. Matsumoto K, Schleimer RP, Saito H, Iikura Y, Bochner BS. Induction of apoptosis in human eosinophils by anti-Fas antibody treatment in vitro. Blood 1995; 86:1437–43. Chilvers ER, Rossi AG, Murray J, Haslett C. Regulation of granulocyte apoptosis and implications for anti-inflammatory therapy. Thorax 1998; 53:533–4. Persson CGA. Centennial notions of asthma as an eosinophilic, desquamative, exudative, and steroid-sensitive disease. Lancet 1997; 350:1021–4. Aalbers R, de Monchy JG, Kauffman HF et al. Dynamics of eosinophil infiltration in the bronchial mucosa before and after the late asthmatic reaction. Eur. Respir. J. 1993; 6:840–7.
Chapter
Cell Adhesion Molecules
21
Aili L. Lazaar and Steven M. Albelda Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
of noncovalently associated heterodimers consisting of aand b-subunits. Currently at least 17 alpha and 8 beta chains have been described and it is clear that certain asubunits can associate with more than one b-subunit. Different a- and b-subunits are broadly expressed on all tissues in the lung (Table 21.1). Maintenance of tissue integrity requires the adhesion of cells to a variety of matrix proteins. For simplicity it is useful to consider the integrins involved in cell–matrix adhesion by their ligand specificities. One group, primarily composed of b1 integrins, binds to components of the basement membrane (collagen, laminin, tenascin), while the second group binds primarily to proteins found during inflammation, wound repair, and development (fibronectin, fibrinogen, vitronectin, and thrombospondin) (Table 21.2). Integrins are also critical for cell–cell adhesion. Their counter receptors under these conditions are primarily members of the immunoglobulin supergene family. The b2 integrins, expressed on all leucocytes, are inactive under basal conditions. Following exposure to a stimulus (such as a chemoattractant), these integrins undergo a conformational change that allows for an increase in avidity. In some instances, integrin aM is stored in intracellular granules and surface expression is rapidly increased following cell stimulation. In contrast, the b1 integrin VLA-4 (a4b1), expressed on all leucocytes, is constitutively active, although another a4 integrin, a4b7, requires activation.
Adhesion of cells to one another and to the extracellular matrix is crucial to embryonic development, maintenance of tissue architecture, the inflammatory response, tumor metastasis, and wound healing. Over the last decade much progress has been made towards determining the specific cell surface receptors that mediate these adhesive interactions. More recently, investigators have begun to address the role of adhesion molecules in airway inflammation. The purpose of this chapter is to summarize current understanding of the cell adhesion molecule (CAM) families, and then to discuss their role in lung structure and the inflammatory response observed in asthma and chronic obstructive pulmonary disease (COPD).
FA M I L I E S O F C E L L A D H E S I O N MOLECULES The known CAMs can be grouped into distinct families based on their molecular structure: integrins, the immunoglobulin supergene family, selectins, cadherins, and other proteoglycans. Integrins The integrins are a family of transmembrane glycoproteins that function in both cell–cell and cell–matrix adhesion as well as signal transduction.1 Structurally they are composed
Table 21.1. Distribution of integrin subunits in lung tissue
Tissue
Collagen/laminin receptors a1 a2 a3 a6 b4
Bronchial epithelium Endothelium Airway smooth muscle Vascular smooth muscle
● ● ●
tr
● ● ●
tr
● ● ● ●
● ●
● ●
a4
● = Readily detectable staining; tr = trace staining; = no staining; ? = unknown.
Fibronectin/vitronectin/tenascin receptors a5 a8 a9 av b3 b5 b6 ●
● ●
● ●
● ● ● ●
●
tr tr
b8
●
●
●
? ? ?
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Table 21.2. Adhesion molecules involved in inflammation
Family molecule
Distribution
Counter receptor(s)
Integrins aLb2(LFA-1) aMb2(Mac-1) aXb2(gp150/95) aDb2 a4b1 (VLA-4) aEb7 aIIbb3 a4b7 avb3
All leucocytes PMN, Mo, some Lyc PMN, Mo Eo Eo, Lyc, Mo Lyc plts Lyc PMN, EC, SMC
ICAM-1, ICAM-2 ICAM-1, fibr, C3bi fibr, C3bi(?) VCAM-1, ICAM-3 VCAM-1, FN E-cadherin fibr, FN, vWF, VN, TSP VCAM-1, FN, MAdCAM-1 FN, VN, vWF, TSP, OPN
Immunoglobulin supergenes ICAM-1 ICAM-2 VCAM-1 PECAM-1
EC, EpC, eo, SMC EC EC, SMC EC, plts
LFA-1, Mac-1 LFA-1 VLA-4 PECAM-1, CD38, GAGs
Selectins E-selectin P-selectin L-selectin
EC EC, plts Lyc, PMN, eo
sLewisx, sLewisa PSGL-1, sLewisx MAdCAM-1, GlyCAM-1, versican
Cadherins E-cadherin VE-cadherin
EpC EC
E-cadherin, aEb7 VE-cadherin
Other CD44
Widespread
Hyaluronan, FN, COL
PMN, neutrophil; Mo, monocyte; Lyc, lymphocyte; Eo, eosinophil; plts, platelets; EC, endothelial cell; EpC, epithelial cell; SMC, smooth muscle cell; fibr, fibrinogen; FN, fibronectin; VN, vitronectin; vWF, von Willebrand factor; TSP, thrombospondin; OPN, osteopontin; COL, collagen.
Immunoglobulin supergene family This family of adhesion molecules is characterized structurally by repeated immunoglobulin-like domains in the extracellular portion of the molecule.1 Members of this family, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), function as cell–cell adhesion molecules. The counter receptors for ICAM-1 and VCAM-1 include aLb2 (LFA-1) and a4b1 (VLA-4), respectively. Expression of ICAM-1 and VCAM-1 is normally low, but is upregulated following tissue injury or in areas of inflammation. ICAM-2 is constitutively expressed on endothelial cells, while ICAM-3 is present at high levels on leucocytes but not endothelial cells. Platelet endothelial cell adhesion molecule (PECAM-1), another member of this family, is constitutively expressed on endothelial cells and is important for leucocyte transendothelial migration.2,3 PECAM-1 can bind homotypically
to itself and heterotypically to CD38 and glycosaminoglycan ligands.4 The physiological importance of PECAM-1 in pathological states is not known. Selectins The selectins are a group of transmembrane glycoproteins characterized by an N-terminal lectin domain that is responsible for ligand binding.1 These adhesion molecules function in cell–cell interactions and appear crucial for the initial binding of leucocytes to endothelial cells in inflammatory responses. Many glycoproteins recognize the selectins, but the epitope recognized by all selectins is contained in the tetrasaccharide sialyl-Lewisx (sLex). The best-characterized selectin ligand is P-selectin glycoprotein ligand-1 (PSGL-1), which is also recognized by E- and L-selectin.5 MAdCAM-1, GlyCAM-1, and versican have been identified as L-selectin ligands,6,7 while MAdCAM-1 is also a ligand for a4b7.8
Cell Adhesion Molecules
Cadherins The cadherin family is characterized by calcium-dependent cell–cell adhesion.1 Structurally they are single polypeptide chains with a short cytoplasmic domain that interacts indirectly with the cytoskeleton. Unlike integrins, cadherins bind to one another on adjacent cells (homotypic adhesion) and appear to function primarily in cell–cell adhesion. The physiological importance of the cadherins in the lung is likely for maintenance of tight junctions between epithelial cells. Proteoglycans The role of non-integrin cell–matrix adhesion molecules in the lung remains to be defined.The hyaluronic acid receptor CD44 is widely distributed in the lung and has been shown to be involved in the rolling adhesion of leucocytes on endothelium in areas of inflammation.9 It may also be important in leucocyte–smooth muscle interactions10 and in matrix assembly. It is likely that other proteoglycans, such as syndecan,11 are also important in the adhesion of epithelial and endothelial cells to their basement membranes.
A D H E S I O N M O L E C U L E S I N A I R WAY I N F L A M M AT I O N A major goal of adhesion molecule research has been to elucidate the mechanisms regulating the inflammatory response, and the specific role of adhesion molecules in airway inflammation is an area of increasing investigation. For normal host defense against inhaled pathogens, leucocytes must migrate from the circulating pool to the airway lumen. However, the accumulation of eosinophils and lymphocytes in asthma or of neutrophils in COPD appears excessive and detrimental to normal airway function. Although the initial stimulus for leucocyte accumulation remains largely unknown, recent data suggest multiple roles for CAMs, not only in directing leucocyte homing, but also in immune activation, and the regulation of interstitial cell–cell interactions. The adhesive mechanisms involved in airway inflammation can be considered as sequential steps (Fig. 21.1). In the initial step, an inflammatory stimulus such as cigarette smoke, antigen–mast cell binding, or viral infection results in the production of cytokines and/or chemoattractants. Following the initial stimulus, the cytokines and chemoattractants activate bronchial microvascular endothelial cells and/or circulating leucocytes, thereby initiating a leucocyte– endothelial adhesion cascade. For a comprehensive review of the multistep interactions involved in leucocyte emigration from the circulation, the reader is referred to excellent reviews by Butcher12 and Springer.13 Once arrested in the microcirculation, leucocytes then diapedese between endothelial cells. At this stage, there may be interactions with airway smooth muscle cells or other interstitial cells, or with matrix proteins as the cells migrate along a chemoattractant gradient. In a final step, some leucocytes traverse the basement membrane and pseudostratified columnar epithelium to gain access to the airway lumen.
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The role of endothelial cell adhesion molecules in leucocyte homing The study of CAM expression in patients with asthma or chronic bronchitis provides in vivo evidence in support of this hypothesis. In patients with perennial allergic rhinitis, nasal biopsies demonstrated increased expression of VCAM-1 and ICAM-1 on endothelial cells, although expression did not correlate with tissue eosinophilia or with the severity of disease.14 Subsequent studies using bronchoscopy with or without segmental antigen challenge revealed increased soluble E-selectin, ICAM-1, and VCAM1 in bronchoalveolar lavage (BAL) fluid in patients with allergic asthma,15,16 and increased serum levels of soluble Eselectin and ICAM-1 in patients with acute asthma compared with stable asthmatics and normal subjects.17,18 Similar studies have shown increased serum and BAL levels of soluble ICAM-1 and increased circulating E-selectin and VCAM-1 in patients with COPD.19,20 Early studies analyzing bronchial biopsies, obtained after segmental allergen challenge, demonstrated an increased inflammatory cell infiltrate that was associated with increased expression of E-selectin and ICAM-1 on bronchial microvessels.21 Of note, however, was a lack of endothelial VCAM-1 expression. More recent studies present evidence that the endothelial expression of VCAM-1 and E-selectin, as well as epithelial and endothelial expression of ICAM-1, is increased in allergic asthmatics.22,23 Bronchial biopsies from patients with chronic bronchitis revealed an increased number of vessels expressing E-selectin, which appeared to correlate with the expression of ICAM-1 on the bronchial epithelium and with the presence of airway obstruction.24 In addition to E-selectin, ICAM-1, and VCAM-1, a recent study suggests that P-selectin may be important for eosinophil homing to sites of allergic inflammation. Immunohistochemistry of nasal polyps revealed increased expression of ICAM-1 and both E- and P-selectin on endothelium, with weak or absent expression of VCAM-1.25 More importantly, eosinophil adhesion to frozen sections was almost completely inhibited by antibodies to P-selectin or to the P-selectin ligand on leucocytes. In addition, Toppila et al.26 have demonstrated that endothelium and peribronchial vessels in bronchial biopsies from patients with asthma strongly expressed sialyl-LewisX glycans. Interestingly, no increase in expression was seen in biopsies obtained from patients with chronic bronchitis.26 These data suggest that P-selectin may be involved in eosinophil recruitment into the lung. In order to provide more mechanistic conclusions, numerous studies have employed blocking antibodies to CAMs or genetically engineered deficiencies of CAMs in animal models of airway hyperreactivity or eosinophil recruitment (summarized in Table 21.3). These studies must be interpreted with caution, however, as it is often difficult to extrapolate from animal studies to pathological states in humans. Nevertheless, in the majority of models, antibodies directed towards CAMs such as ICAM-1 or
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Virus Antigen Cigarettes
D
Cytokines Chemokines LFA-1
B
VCAM-1
HA
Leucocyte– epithelial interaction
ICAM-1
Leucocyte–smooth muscle cell interaction
CD44
SMC
A
Leucocyte homing, adhesion, diapedesis
C
Leucocyte–matrix interaction
EC
Fig. 21.1. Proposed steps in the development of airway inflammation. Following an inflammatory stimulus, resident airway cells release cytokines and chemoattractants. This results in activation of the leucocyte–endothelial adhesion cascade (A). In the presence of a chemoattractant gradient, leucocytes migrate between endothelial cells and through the extracellular matrix, where they may interact with interstitial cells such as airway smooth muscle cells (B) or with matrix proteins (C). Leucocytes then traverse the basement membrane and epithelium to reach the airway (D).
VLA-4 are successful in blocking antigen-induced tissue and BAL eosinophilia, as well as airway hyperreactivity (AHR). These findings have been confirmed using available knockout mice. One exception is the ICAM-2 knockout mouse that demonstrated increased tissue eosinophilia and prolonged AHR, which the authors speculate may be due to defects in eosinophil migration.27 Inhibition of E- and L-selectin binding, either by antibodies or selective peptide inhibitors, has no effect on antigeninduced eosinophilia, but does inhibit early neutrophil accumulation.P-selectin knockout mice display a delayed,but not eliminated, increase in eosinophils. Inhibition of selectins does appear to decrease antigen-induced AHR, suggesting that neutrophils are also important for this response. The role of CAMs merely as gatekeepers regulating leucocyte accumulation may be too simplistic, however. In both a sheep and a rat model of allergic airway hyperresponsiveness, administration of an anti-VLA-4 antibody blocked allergen-induced late-phase hyperresponsiveness without significantly reducing the numbers or percentages of neutrophil and eosinophils in BAL fluid.28–30 Another study in Norway rats demonstrated a reduction in
hyperresponsiveness without a reduction in airway inflammation after administration of an anti-ICAM-1 antibody.31 These data indicate that, although anti-CAM therapy appears to be effective in blunting airway hyperresponsiveness, the mechanism may not be totally dependent on inhibition of inflammatory cell influx. Indeed, Crimi et al.32 found no correlation between airway responsiveness and inflammatory cell infiltrates (either tissue or BAL) in patients with asthma. Other functions of adhesion molecules in the airway Leucocyte activation One well-established function of CAMs is as accessory molecules in leucocyte activation; for a review see Springer.33 Inhibition of leucocyte b1 or b2 integrin function can inhibit T-helper and B-lymphocyte responses to antigen and antigen-independent induced activation stimuli. Nakao et al.34 made the observation that pretreatment of mice with antibodies specific for ICAM-1 and LFA-1 induced tolerance to subsequent antigen challenge. CAMs are also critical for the function of endothelial cells and fibroblasts as nonprofessional antigen presenting cells.35,36
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Cell Adhesion Molecules
Table 21.3. Animal models of antigen-induced airway inflammation
Target
Mode
Species
Model
Eo
Lyc
Neut
AHR
References
ICAM-1
Ab Ab Ab KO KO KO KO Ab Ab Ab Ab Peptide Ab Ab Ab Peptide KO KO
Primate Rat Rat Mouse Mouse Mouse Mouse Mouse Guinea-pig Mouse Sheep Sheep Rat Rat Primate Sheep Mouse Mouse
Ascaris OVA OVA OVA OVA OVA OVA OVA OVA OVA Ascaris Ascaris OVA OVA Ascaris Ascaris OVA OVA
↓ → ↓ ↓ ↓ ↑ ↓ ↓ ↓ ↓ ↓ ↓ → ↓ → → → ↓/→
nd nd ↓ nd ↓ nd ↓ ↓ ↓ nd nd nd nd ↓ nd nd → →
nd nd nd nd ← nd nd nd nd nd nd nd nd nd ↓ ↓ nd nd
↓ ↓ ↓ ↓ nd ↑ nd nd ↓ ↓/→ ↓ ↓ ↓ ↓ ↓ ↓ nd ↓
44 31 45, 47, 49 27 49 50 51 52 28 53, 29, 38, 56 57 49 48,
ICAM-2 VCAM-1 VLA-4
E-selectin L-selectin P-selectin
46 48
54 30 55
49, 58
Ab, antibody; KO, knockout; OVA, ovalbumin; nd, not done.
Blockade of CAMs may have effects on the activation of other airway leucocytes. For example, blocking ICAM-3 blocked eosinophil secretion of leukotriene C4 induced by adhesion to CD4 T cells,37 while blocking VLA-4 on mast cells inhibited antigen-induced release of histamine and tryptase.38 Thus, blockade of adhesion molecules might blunt the responses of airway leucocytes, or preclude effective antigen presentation, independent of the recruitment of circulating cells.
airway. Lazaar et al.10 demonstrated that adhesion of stimulated T lymphocytes via integrins and CD44 induced DNA synthesis in airway smooth muscle (ASM) cells.10 Engagement of CAMs activates multiple signaling pathways in ASM cells that may affect the synthetic and growth properties of the cell.42 Others have shown that blocking ICAM-1 on ASM cells may alter the contractility and relaxation response of ASM cells, at least in vitro.43
Tissue repair Epithelial cell injury is a common feature of asthma and COPD. Repair of the epithelium requires that the cells migrate and spread over provisional matrix proteins, via matrix–integrin interactions, to restore epithelial integrity.39 Epithelial cell integrins are likely to have other roles in modifying the acute inflammatory response in the airways, although their exact physiological significance is not fully known.40 In addition, binding of T cells to VCAM-1expressing endothelial cells contributed to the induction of matrix metalloproteinases,41 which may be a necessary prerequisite to T cell migration through matrix.These data suggest that T cell–parenchymal cell interactions may contribute to alterations in cell growth and matrix deposition, thereby contributing to airway remodeling.
S U M M A RY The accumulated data suggest that CAMs potentially mediate cell migration, leucocyte activation, and interstitial cell–cell interactions in inflammatory airway diseases such as asthma and COPD. Identification of these complex, and perhaps interrelated, functions leads to an increasingly sophisticated paradigm and underscores the need for additional studies to further define the in-vivo function of the known CAMs in the airway. Development of new therapeutic modalities will, however, require knowledge of the complex regulatory interplay between leucocytes, lung parenchymal cells, cytokines, and chemoattractants in vivo.
REFERENCES Smooth muscle cell activation Recent evidence suggests that CAMs mediate a number of inflammatory cell–interstitial cell interactions and may thereby contribute to the inflammatory response in the
1. Aplin AE, Howe A, Alahari SK et al. Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, immunoglobulin-cell adhesion molecules and selectins. Pharm. Rev. 1998; 50:197–263.
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2. Albelda SM, Oliver PD, Romer LH et al. EndoCAM: a novel endothelial cell–cell adhesion molecule. J. Cell. Biol. 1990; 110:1227–37. 3. Newman PJ.The biology of PECAM-1. J. Clin. Invest. 1997; 99:3–8. 4. Deaglio S, Morra M, Mallone R et al. Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J. Immunol. 1998; 160:395–402. 5. Sako D, Chang X, Barone KM et al. Expression cloning of a functional glycoprotein ligand for P-selectin. Cell 1993; 75:1179–86. 6. Kansas GS. Selectins and their ligands: current concepts and controversies. Blood 1996; 88:3259–87. 7. Kawashima H, Hirose M, Hirose J et al. Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin, and CD44. J. Biol. Chem. 2000; 275:35448–56. 8. Berg EL, McEvoy LM, Berlin C et al. L-selectin-mediated lymphocyte rolling on MAdCAM-1. Nature 1993; 366:695–8. 9. DeGrendele HC, Estess P, Siegelman MH. Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science 1997; 278:672–5. 10. Lazaar AL, Albelda SM, Pilewski JM et al.T lymphocytes adhere to airway smooth muscle cells via integrins and CD44 and induce smooth muscle cell DNA synthesis. J. Exp. Med. 1994; 180:807–16. 11. Ruoslahti E. Proteoglycans in cell regulation. J. Biol. Chem. 1989; 264:13369–72. 12. Butcher EC. Leucocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 1991; 67:1033–6. 13. Springer TA. Traffic signals on endothelium for lymphocyte recirculation and leucocyte emigration. Annu. Rev. Physiol. 1995; 57:827–72. 14. Montefort S, Feather IH, Wilson SJ et al. The expression of leucocyte–endothelial adhesion molecules is increased in perennial allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 1992; 7:393–8. 15. Georas SN, Liu MC, Newman W et al. Altered adhesion molecule expression and endothelial activation accompany the recruitment of human granulocytes to the lung after segmental antigen challenge. Am. J. Respir. Cell Mol. Biol. 1992; 7:261–9. 16. Zangrilli JG, Shaver JR, Cirelli RA et al. sVCAM-1 levels after segmental antigen challenge correlate with eosinophil influx, IL-4 and IL-5 production, and the late phase response. Am. J. Respir. Crit. Care Med. 1995; 151:1346–53. 17. Montefort S, Lai CKW, Kapahi P et al. Circulating adhesion molecules in asthma. Am. J. Respir. Crit. Care Med. 1994; 149:1149–52. 18. Takahashi N, Liu MC, Proud D et al. Soluble intercellular adhesion molecule 1 in bronchoalveolar lavage fluid of asthmatic subjects following segmental antigen challenge. Am. J. Respir. Crit. Care Med. 1994; 150:704–9. 19. Riise GC, Larsson S, Lofdahl CG et al. Circulating cell adhesion molecules in bronchial lavage and serum in COPD patients with chronic bronchitis. Eur. Respir. J. 1994; 7:1673–7. 20. Riise GC, Larsson S, Lowhagen O et al. Circulating leucocyte adhesion molecules in stable asthma and nonobstructive chronic bronchitis. Allergy 1995; 50:693–8. 21. Montefort S, Gratziou C, Goulding D et al. Bronchial biopsy evidence for leukocyte infiltration and upregulation of leukocyte– endothelial cell adhesion molecules 6 hours after local allergen challenge of sensitized asthmatic airways. J. Clin. Invest. 1994; 93:1411–21. 22. Gosset P, Tillie-Leblond I, Janin A et al. Expression of E-selectin, ICAM-1 and VCAM-1 on bronchial biopsies from allergic and non-allergic asthmatic patients. Int. Arch. All. Immunol. 1995; 106:69–77. 23. Ohkawara Y, Yamauchi K, Maruyama N et al. In-situ expression of the cell adhesion molecules in bronchial tissues from asthmatics with air flow obstruction: in-vivo evidence of VCAM-1/VLA-4 interaction in selective eosinophil infiltration. Am. J. Respir. Cell Mol. Biol. 1995; 12:4–12. 24. Di Stefano A, Maestrelli P, Roggeri A et al. Upregulation of adhe-
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sion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am. J. Respir. Crit. Care Med. 1994; 149:803-10. Symon FA, Walsh GM, Watson SR et al. Eosinophil adhesion to nasal polyp endothelium is P-selectin-dependent. J. Exp. Med. 1994; 180:371–6. Toppila S, Paavonen T, Laitinen A et al. Endothelial sulfated sialyl Lewisx glycans, putative L-selectin ligands, are preferentially expressed in bronchial asthma but not in other chronic inflammatory lung diseases. Am. J. Respir. Cell Mol. Biol. 2000; 23:492–8. Gerwin N, Gonzalo J-A, Lloyd C et al. Prolonged eosinophil accumulation in allergic lung interstitium of ICAM-2-deficient mice results in extended hyperresponsiveness. Immunity 1999; 10:9–19. Abraham WM, Sielczak MW, Ahmed A et al. a4-integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep. J. Clin. Invest. 1994; 93:776–87. Rabb HA, Olivenstein R, Issekutz TB et al. The role of leukocyte adhesion molecules VLA-4, LFA-1, and Mac-1 in allergic airway responses in the rat. Am. J. Respir. Crit. Care Med. 1994; 149:1186–91. Laberge S, Rabb H, Issekutz TI et al. Role of VLA-4 and LFA-1 in allergen-induced airway hyperresponsiveness and lung inflammation in the rat. Am. J. Respir. Crit. Care Med. 1995; 151:822–9. Sun J, Elwood W, Haczku A et al. Contribution of intercellular adhesion molecule-1 in allergen-induced airway hyperresponsiveness and inflammation in sensitized brown Norway rats. Int. Arch. All. Immunol. 1994; 104:592–601. Crimi E, Spanevello A, Neri M et al. Dissociation between airway inflammation and airway hyperresponsiveness in allergic asthma. Am. J. Respir. Crit. Care Med. 1998; 157:4–9. Springer TA. Adhesion receptors of the immune system. Nature 1990; 46:425–34. Nakao A, Nakajima H, Tomioka H et al. Induction of T cell tolerance by pretreatment with anti-ICAM-1 and anti-lymphocyte function-associated antigen-1 antibodies prevents antigeninduced eosinophil recruitment into mouse airways. J. Immunol. 1994; 153:5819–25. Sprent J. Antigen-presenting cells: professionals and amateurs. Curr. Biol. 1995; 5:1095–7. Ma W, Pober JS. Human endothelial cells effectively costimulate cytokine production by, but not differentiation of, naive CD4T cells. J. Immunol. 1998; 161:2158–67. Douglas IS, Leff AR, Sperling AI. CD4T cell and eosinophil adhesion is mediated by specific ICAM-3 ligation and results in eosinophil activation. J. Immunol. 2000; 164:3385–91. Hojo M, Maghni K, Issekutz TB et al. Involvement of a4 integrins in allergic airway responses and mast cell degranulation in vivo. Am. J. Respir. Crit. Care Med. 1998; 158:1127–33. Rennard SI. Inflammation and repair processes in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:S12–16. Sheppard D. Airway epithelial integrins: why so many? Am. J. Respir. Cell Mol. Biol. 1998; 19:349–51. Romanic AM, Madri JA. The induction of 72-kd gelatinase in T cells upon adhesion to endothelial cells is VCAM-1 dependent. J. Cell. Biol. 1994; 125:1165–78. Lazaar AL, Krymskaya VP, Das SKP. VCAM-1 activates phosphatidylinositol 3-kinase and induces p120Cbl phosphorylation in human airway smooth muscle cells. J. Immunol. 2001; 166:155–61. Grunstein MM, Hakonarson H, Maskeri N et al. Intrinsic ICAM1/LFA-1 activation mediates altered responsiveness of atopic asthmatic airway smooth muscle. Am. J. Physiol. 2000; 278:L1154–63. Wegner CD, Gundel RH, Reilly P et al. Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma. Science 1990; 247:456–9.
Cell Adhesion Molecules
45. Nagase T, Fukuchi Y, Matsuse T et al. Antagonism of ICAM-1 attenuates airway and tissue responses to antigen in sensitized rats. Am. J. Respir. Crit. Care Med. 1995; 151:1244–9. 46. Chin JE, Winterrowd GE, Hatfield CA et al. Involvement of intercellular adhesion molecule-1 in the antigen-induced infiltration of eosinophils and lymphocytes into the airways in a murine model of pulmonary inflammation. Am. J. Respir. Cell Mol. Biol. 1998; 18:158–67. 47. Wolyniec WW, De Sanctis GT, Nabozny G et al. Reduction of antigen-induced airway hyperreactivity and eosinophilia in ICAM-1-deficient mice. Am. J. Respir. Cell Mol. Biol. 1998; 18:777–85. 48. Broide DH, Sullivan S, Gifford T et al. Inhibition of pulmonary eosinophilia in P-selectin- and ICAM-1-deficient mice. Am. J. Respir. Cell Mol. Biol. 1998; 18:218–25. 49. Gonzalo J-A, Lloyd CM, Kremer L et al. Eosinophil recruitment to the lung in a murine model of allergic inflammation: the role of T cells, chemokines, and adhesion receptors. J. Clin. Invest. 1996; 98:2332–45. 50. Nakajima H, Sano H, Nishimura T et al. Role of vascular cell adhesion molecule-1/very late activation antigen-4 and intercellular adhesion molecule-1/lymphocyte function-associated antigen-1 interactions in antigen-induced eosinophil and T cell recruitment into the tissue. J. Exp. Med. 1994; 179:1145–54. 51. Pretolani M, Ruffie C, Silva J-RLe et al. Antibody to very late activation antigen-4 prevents antigen-induced bronchial hyperreactivity and cellular infiltration in the guinea pig airways. J. Exp. Med. 1994; 180:795–805.
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52. Henderson WR, Chi EY, Albert RK et al. Blockade of CD49d (a4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. J. Clin. Invest. 1997; 100:3083–92. 53. Abraham WM, Ahmed A, Sielczak MW et al. Blockade of latephase airway responses and airway hyperresponsiveness in allergic sheep with a small-molecule peptide inhibitor of VLA-4. Am. J. Respir. Crit. Care Med. 1997; 156:696–703. 54. Abraham WM, Gill A, Ahmed A et al. A small-molecule, tightbinding inhibitor of the integrin a4b1 blocks antigen-induced airway responses and inflammation in experimental asthma in sheep. Am. J. Respir. Crit. Care Med. 2000; 162:603–11. 55. Richards IM, Kolbasa KP, Hatfield CA et al. Role of very late activation antigen-4 in the antigen-induced accumulation of eosinophils and lymphocytes in the lungs and airway lumen of sensitized brown Norway rats. Am. J. Respir. Cell Mol. Biol. 1996; 15:172–83. 56. Gundel RH, Wegner CD, Torcellini CA et al. Endothelial leukocyte adhesion molecule-1 mediates antigen-induced acute airway inflammation and late-phase airway obstruction in monkeys. J. Clin. Invest. 1991; 88:1407–11. 57. Abraham WM, Ahmed A, Sabater JR et al. Selectin blockade prevents antigen-induced late bronchial responses and airway hyperresponsiveness in allergic sheep. Am. J. Respir. Crit. Care Med. 1999; 159:1205–14. 58. De Sanctis GT, Wolyniec WW, Green FH et al. Reduction of allergic airway responses in P-selectin-deficient mice. J. Appl. Physiol. 1997; 83:681–7.
Chapter
Extracellular Matrix
22
Maurice Godfrey Center for Human Molecular Genetics, University of Nebraska Medical Center, Omaha, NE, USA
The extracellular matrix comprises a large and varied group of structural macromolecules and their regulatory factors.1 The extracellular matrix:
Table 22.1. Summary of the major extracellular matrix constituents of the lung and their localization
Constituent
• • • •
provides structural support; provides a physical barrier; elicits cellular responses; compartmentalizes tissue.
Its interactions are involved in development and organ formation. The temporal and spatial expression of many of these components has been studied in several organ systems and species. The role these matrix or regulatory molecules play in disease has also been examined at both the biochemical and molecular levels. Thus, pathogenesis of a number of human disorders has been studied extensively. In some cases, the pathophysiology of pulmonary abnormalities has emerged. This chapter reviews the extracellular matrix constituents of the respiratory system. It is important to remember that these extracellular matrix molecules are a part of a finely regulated system of development, maintenance, and repair. In addition to the structural macromolecules that are discussed in this chapter, the fact that regulatory molecules are essential components of the extracellular matrix cannot be overlooked. Discussion of these components is found elsewhere in this volume.
COMPONENTS OF THE EXTRACELLULAR M AT R I X Connective tissue in the lung imparts the appropriate mechanical sturdiness and elastic resilience that permits the lung to expand and relax repeatedly. In addition to this mechanical function, the extracellular matrix is organized to allow for efficient gas exchange (Table 22.1). Collagens The collagens are the largest (in numbers) and most abundant (in content) of the extracellular matrix elements. In
Collagens Type I Type II Type III Type IV Type V Elastin Microfibrils Proteoglycans Laminin Integrin
Fibronectin
Localization Alveolar, bronchial, vascular walls Bronchial and tracheal cartilage Colocalizes with type I collagen Basement membrane Basement membrane, interstitium Alveolar septa, blood vessels, bronchial walls, pleura Found with elastin, scaffold for elastin deposition Alveolar walls, basement membrane Basement membrane Mesenchymal and epithelial cells (receptors for extracellular matrix molecules) Basement membrane, interstitium
fact, type I collagen is the single most abundant glycoprotein in the human body. There are some 19 different collagen types and even more genes that encode these collagens.1 Collagens are characterized by a triple helical structure whereby three polypeptide chains wind around each other. To form this helical configuration, every third amino acid must be a glycine. Glycine, with its very small side-chain, is the only amino acid that is able to fit in the center of the helix without causing any distortion. The primary structure of the triple helical region of collagens is described by the general pattern of [Gly-X-Y]n as a repeating triplet. About 20% of the X and Y positions in this triplet are the imino acids, proline and hydroxyproline. The hydroxyl group of hydroxyproline is essential for hydrogen bonding that imparts stability to the triple helix. Similarly, lysine and
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hydroxylysine residues in the helical region are important for covalent cross-links within and between collagen molecules. Hydroxylysines are also subject to glycosylation. The number of glycosylated residues varies with the different collagen types.2,3 Collagen a-chains are synthesized as pro-a-chains with nonhelical amino and carboxy terminal ends. Cleavage of the propeptides is essential for the proper stacking of triple helical collagen molecules to form an extracellular matrix. Amino acid substitutions, especially the invariant glycine residues, cause a delay in formation of the triple helix. This delay leads to an increase in hydroxylated and glycosylated residues. These so-called “overmodified” collagens are characteristic of a number of heritable connective tissue disorders.4 About 60% of the connective tissue protein mass in the adult lung is collagen. As expected, type I is the predominant type. The lung also contains a significant amount of type III collagen, a major constituent of skin and vascular tissues. The type III fibers are thin, which allows for a more compliant tissue. Studies have shown that type III collagen is essential for fibrillogenesis of type I collagen in normal development.5–8 Type IV collagen is an important constituent of basement membranes.1,9 The basement membrane, as visualized by electron microscopy, consists of two layers, the lamina lucida and lamina densa. In the lung, the basement membrane forms continuously along the bronchial epithelia from before 12 weeks’ gestation.10 In addition to type IV collagen, basement membranes contain other extracellular matrix molecules such as proteoglycans and laminins. The type IV collagen appears to serve as a scaffold for binding of laminin and proteoglycans leading to the formation of the basement membrane.11 During lung branching, the epithelium of the elongating bronchial buds and tubules is lined with type IV collagen. Type III collagen, on the other hand, does not appear to play a significant role in lung branching.12 Type V collagen has also been localized in the lung. While it is found near the basement membrane, it is unclear whether this minor collagen is part of the basement membrane or solely in the nearby interstitial matrix.13 The basement membrane of the lung also contains type XVIII collagen, a member of the collagen subfamily called multiplexins.14 These have multiple triple helical domains and interruptions, hence their name.1 Cartilage collagens, types II, IX, and XI along with cartilage matrix protein (not a collagen), are primary components of the trachea.15 Despite the biochemical, immunochemical, ultrastructural, and now molecular characterization of collagens in normal lung, their precise function and roles in pulmonary homeostasis is still not completely elucidated. Studies continue to determine the cellular influence of collagens, their mechanical properties as they relate to lung mechanics, interactions between collagen types and other matrix molecules, kinetics of maturation and turnover, and their self-assembly.
Elastin Elastin is the main elastic protein in vertebrates and is responsible for the ability of the lung to recoil following each cycle of expansion and contraction. Thus, like collagen, elastin is an integral component of the interstitial matrix of the lung. Given its importance for this elastic resilience, elastin has been localized to the alveoli, pleura, conducting airways, and vascular tissues.16 Elastin is secreted as a monomer of so-called tropoelastin, generally by cells that are of mesenchymal origin. The exquisite ability of repeated recoil is a unique property of the elastic fiber. The ability to undergo repeated rounds of recoil is believed to be due to the high hydrophobic amino acid content of elastin.17 These hydrophobic amino acids are arranged as to allow cross-links to form which are believed to be critical for its function. It is important to note that none of these extracellular matrix elements functions in a vacuum. They comprise a characteristic architecture and thus a function in an interrelated and integrated fashion. Therefore, elastin provides its unique function in the context of the collagens, proteoglycans, and microfibrils. The elastic fiber is among the most lasting structures in the body. Studies have shown that humans retain elastin for an entire lifetime.18 This stability appears to be due to very specific cross-links between elastin monomers in the mature elastic fibers. It is in fact these unique cross-links, formed from lysine residues, that produce novel amino acids, desmosine and isodesmosine, that are markers for the presence of elastin in tissues. Given the incomparable properties of elastin, its broad distribution in the mammalian body should not be surprising. In addition to their high proportion of the extracellular matrix of the lung, elastic fibers are a major constituent of skin and blood vessels. In the lung, the wide distribution of elastic fibers in conjunction with collagen fibers provides expiratory force. Early structural studies tended to describe elastic fibers as having an amorphous appearance; more recent studies have shown a rather complex structure.Two morphologically and chemically distinct entities have been identified: elastin, the insoluble polymer composed of tropoelastin monomers, and microfibrils. The structure and function of microfibrils are discussed below.19,20 Elastin, in its polymerized form, constitutes more than 90% of the mature elastic fiber. Tropoelastin is highly conserved in evolution.21 In all species studied, tropoelastin has a modular structure of alternating hydrophobic and crosslinking domains. While sequence variation exists, it is the hydrophobicity that is exquisitely conserved, and the conservation appears greater in the cross-linking regions. Unlike the large variety and numerous gene products that encode the collagens, elastin is present as a single gene in a single copy. Interestingly, the various isoforms of elastin that are present are produced by alternative splicing of a common transcript.22–24 At present, however, the functional roles of these isoforms are not understood.25
Extracellular Matrix
Microfibrils Elastin-associated microfibrils have been classically defined as 10–12 nm diameter fibrils when seen by electron microscopy.26 They were initially identified as structures that surrounded or were within mature elastic fibers. It is now known that microfibrils can also exist without the presence of elastin.27 Analyses of developing tissues, including the lung and major blood vessels, have shown that microfibrils are deposited first, followed by the deposition of elastin.28 Thus, the hypothesis that microfibrils act as a scaffold for the deposition of elastin to produce mature elastic fibers has emerged. The complete function and constituents of the microfibrils are unknown. Ultrastructurally, microfibrils display a “beads on a string” structure with a diameter of 8–12 nm.They are composed of several proteins, the most abundant of which is fibrillin-1.29 Fibrillin-1, the product of the FBNI gene, is a cysteine-rich glycoprotein with a molecular weight of about 350 kDa.The extracellular domain structure of fibrillin-1 is divided into five distinct regions.The most abundant of these domains are calcium-binding epidermal growth factor-like (EGF) motifs, that occur some 43 times. Four additional EGF motifs that do not bind calcium are also present. Interspersed between these calcium-binding domains are seven transforming growth factor b1-binding protein domains each containing eight cysteine residues.30,31 These eight cysteine domains are globular in structure and interrupt the multiple stretches of the EGF modules that are believed to form rod-like structures. The middle eight-cysteine domains contain an RGD (arginine–glycine–aspartate) site. RGD motifs interact with cell surface receptors to mediate cell adhesion.32 These receptors are part of the integrin family, transmembrane proteins that interact with extracellular matrix proteins to anchor cells within the extracellular matrix. While the role of elastin in mediating elastic recoil is well established, microfibrils, too, appear to have some elasticity. In fact, speculation exists that microfibrils alone performed the function of elastic fibers prior to the evolution of tropoelastin. Closely related to fibrillin-1 is fibrillin-2. This shares the domain structure with fibrillin-1, and in the EGF containing regions are about 80% identical at the amino acid level. There are several important differences that may reflect differing functional roles. Fibrillin-2 contains two RGD sites, and the domain that is proline-rich in fibrillin-1 is glycinerich in fibrillin-2.30,31,33 Fibrillin-1 and -2 are differentially expressed both temporally and spatially. In most cases, developmental expression of the fibrillin genes displays a diphasic pattern. Thus, expression of fibrillin-2 occurs earlier than fibrillin-1. Studies at the message level have shown FBN2 transcript accumulation prior to tissue differentiation followed by their rapid decrease. FBN1 transcripts then begin to increase gradually. Studies have shown that fibrillin-2 is found preferentially in elastic tissues, such as elastic cartilage, tunica media of the aorta, and along the bronchial tree. The two fibrillins, therefore, may have differing functional roles. It
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has been hypothesized that fibrillin-2 may have a greater role during early morphogenesis in directing the assembly of elastic fibers, while fibrillin-1 is mainly responsible for load bearing.33–35 While the fibrillins are regarded as the major constituents of microfibrils, there are additional families of proteins that are part of the microfibrils and the elastic fiber. While less understood than the fibrillins, these additional families include: • the latent transforming growth factor beta-binding proteins (LTBP); • microfibril-associated glycoproteins (MAGP); • microfibril-associated proteins (MFAP); • fibulins; • emilin; • Big-H3; • lysyl oxidase. The structural and functional roles of most of these proteins are not clear. We do know that LTBP-2 is evolutionarily the closest of the LTBPs to the fibrillins and has been isolated from tissue rich in microfibrils. MAGP-1 has also been immunolocalized to both elastin-associated and naked microfibrils. MAGP1 interacts directly with tropoelastin monomers and may play a primary role in elastic fiber formation. See Robinson and Godfrey36 for a review. Little is known, however, about the molecular interactions involved with the numerous proteins noted above that are required to build an elastic fiber. It is also unknown which interactions are required to form the microfibrils. The temporal or tissue-specific expression of the various microfibrillar components is also largely unknown. Proteoglycans Proteoglycans comprise a large group of multidomain core proteins to which glycosaminoglycans are attached. Glycosaminoglycans are unbranched carbohydrate chains of repeating disaccharide units. Since most are negatively charged, they bind to other matrix molecules, cell adhesion molecules, and growth factors.37,38 They are integral to maintain normal pulmonary structure and function. Of the species of proteoglycans, heparan sulfate and dermatan sulfate appear to be the most abundant.39 These proteoglycans are also a reservoir for heparin. Chondroitin sulfates, proteoglycans found in cartilagenous tissues, are present in bronchioles, while heparan sulfate is the major proteoglycan of the gas exchange tissue. Heparin is also found primarily in the gas exchange tissues and pleura, but, as expected, not the cartilagenous bronchioles.39,40 Biochemical studies over the past quarter century have helped to elucidate the composition of lung proteoglycans, but their precise functions are still not completely understood. Heparan sulfate interacts with laminin and appears to be essential for human development and lung branching.41–43 Studies also demonstrate that proteoglycans are important for the function of growth factors. Much of this modulation
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by proteoglycans appears to involve binding and signaling of TGF-b and its receptor.44–47 These molecules may also stimulate production of other matrix constituents or act as receptors for the extracellular matrix.48,49 Laminin Laminins are cross-shaped molecules that comprise several different types and are a part of lung development.1,50,51 Analysis of the developing lung has shown the expression of some laminin chains at as early as 10 weeks of human gestation.52 Laminins are expressed along the basement membrane, but temporal and spatial expression of different laminin subunits has been documented.12,53 Laminin expression may play a role in cell differentiation in the lung as well as other tissues. There is some evidence to suggest that laminin may play a role in alveolar morphogenesis.54 A laminin–heparan sulfate interaction may be essential to lumen formation and branching morphogenesis.55 Integrins Integrins are cell surface glycoproteins that serve as receptors for the extracellular matrix.56–58 Integrins are composed of many subtypes all arranged as heterodimers.57 These heterodimers can selectively bind several different matrix constituents.59 In fact, the RGD sequence of extracellular matrix molecules is the binding site for integrins.60,61 Integrins are expressed early in human lung development.62 Animal model manipulation of some integrins has resulted in reduced bronchial branching, suggesting a vital role for some integrin-dependent interactions in lung development.56,60,63 Integrins also function in signaling pathways to mediate migration and differentiation of epithelial cells.64–66 Fibronectin Fibronectin is a widely distributed glycoprotein found in embryonic tissue that plays a material role in morphogenesis.67,68 Fibronectin plays an important role in cell attachment.69 While it has been localized in several regions of the developing lung, it is primarily seen in regions of airway bifurcation.61 Fibronectin is co-distributed with collagen and may be required for normal collagen deposition.70,71 Its precise role, however, has not yet been elucidated.
E X T R A C E L L U L A R M AT R I X A N D L U N G FUNCTION The matrix of the normal lung imparts the strength and resilience for the continuous cycling of inspiration and expiration. For proper gas exchange, the components of the extracellular matrix are distributed in a fashion to reduce the boundary between erythrocytes and oxygen.13 When the exquisite balance of matrix glycoproteins is disturbed, the consequences on the lung are manifest by pathology. In most cases the assault on the lung leads to fibrosis. Fibrosis leads to the thickening of the alveolar walls, reduction in lung volume, reduced lung elasticity, and fundamentally
anomalous gas exchange. There are a number of causes of pulmonary fibrosis in addition to those due to genetic abnormalities of matrix molecules or their modifiers (see below). In some cases, pulmonary fibrosis is a result of some other primary disease.72 Examples include infections (viral and fungal) or immune disorders (rheumatoid arthritis, scleroderma). As expected, environmental assaults comprise the greatest number of causes of pulmonary fibrosis. As one might predict, tobacco smoke causing emphysema is among the major causes of chronic obstructive pulmonary disease (COPD). Fibrogenic dusts such as asbestos and toxins, and chemicals such as insecticides and herbicides, are additional causes of fibrosis in the lung. Iatrogenic causes, such as pharmacotherapy and therapeutic irradiation, may also lead to pulmonary fibrosis.
H E R I TA B L E D I S O R D E R S O F CONNECTIVE TISSUE Heritable disorders of connective tissue (HDCT) are a series of disorders caused by mutations in structural or modifying components of the extracellular matrix. Since most of these gene products are expressed in multiple tissues, pleiotropic manifestations are observed in most cases of HDCT. It is important to distinguish HDCT from connective tissue disorders that are autoimmune in nature, such as rheumatoid arthritis and systemic lupus erythematosus. For comprehensive reviews of HDCTs, see Beighton,4 Royce and Steinmann.73 Despite the abundance of collagen and elastic fibers in the lung, the number of HDCTs with primary and severe pulmonary disease is rather small. While there are numerous HDCTs, for the purposes of this abbreviated review only those disorders caused by defects in genes expressed in the pulmonary system or with pulmonary complications will be discussed. Osteogenesis imperfecta (OI) comprises several disorders of varying severity that are caused by mutations in type I collagen. In its most severe form, OI type II is characterized by severe bone fragility and stillbirth or neonatal death. Owing to the small chest in these neonates, pulmonary insufficiency and failure to ventilate can cause death in the few who are not stillborn. In OI type III, characterized by moderate to severe bone fragility, the thorax is often conical in shape. Owing to the softness of the bones in the chest, an often lethal respiratory failure may occur in neonates. Despite these findings, most individuals with OI, except of course type II OI, do not have severe pulmonary deficiency even though type I collagen is abundant in the lung matrix. The Ehlers–Danlos syndromes (EDS) are another series of HDCTs.The classic type, previously called types I and II, is now known to be caused by mutations in type V collagen. The most severe form of EDS is the so-called vascular type, previously called type IV EDS. This form of EDS is caused by mutations in type III collagen.
Extracellular Matrix
Pulmonary complications are rare in EDS. However, some cases of mediastinal and subcutaneous emphysema and spontaneous pneumothorax have been reported. In addition, dilation of the trachea and bronchi has also been described in some cases of EDS. Pseudoxanthoma elasticum (PXE) is an HDCT whose molecular pathogenesis has been recently elucidated. PXE is characterized by abnormalities in the skin, eyes, and vasculature. Although the mechanism of the pathogenesis remains unclear, the generalized dystrophy of elastic fibers does occasionally manifest in the lung. Degenerative changes in the walls of alveoli and miliary mottling of the lungs have been reported. The mucopolysaccharidoses (MPS) are a large group of disorders that are defects in enzymes required in the processing of glycosaminoglycan molecules (see proteoglycans above). The large number of different enzymatic defects makes a comprehensive review here impossible. Nevertheless, pulmonary complications have been observed in several MPSs. For example, Hurler syndrome (MPS I H) is due to defects in aL-iduronidase. It is characterized by diagnosis prior to age 2, early corneal clouding, kyphoscoliosis, mental retardation, and death by age 10. All individuals with Hurler syndrome experience severe respiratory problems. Accumulation of glycosaminoglycans in the oropharyngeal trachea leads to airway obstruction. Radical pharyngoplasty provides some temporary relief, but obstruction recurs. These individuals are also prone to repeated upper respiratory infections. Deformity of the thorax and abnormalities of bronchial cartilage contributes to reduced chest expansion and decreased vital capacity. Bronchopneumonia is a frequent cause of death. Hunter syndrome (MPS II), caused by a deficiency in iduronate 2 sulfatase, is characterized by diagnosis prior to age 4, mental retardation, and death before age 15. A mild form has also been described with moderate skeletal and respiratory involvement and survival to adulthood without intellectual impairment. Respiratory complications include upper airway obstruction, nasal congestion, and thick rhinorrhea. As children grow older, pharyngeal hypertrophy, tongue enlargement, and supraglottic swelling may result in obstructive sleep apnea and death. Upper respiratory infections are common. Abnormalities of the trachea have been documented. MPS II is an X-linked disorder, so virtually all affected individuals are male. Pulmonary complications are observed in the majority of individuals with the gamut of MPS types. The chondrodysplasias are another group of HDCTs often classified based on radiographic involvement of the long bones. Severe respiratory difficulty is present in a number of these disorders owing to a greatly restricted thorax, which leads to early death. Defects in type II collagen are well documented in several of these disorders. The Marfan syndrome (MFS) is a prototypical member of the HDCTs. It is now well known that mutations in the gene encoding fibrillin-1 cause MFS. Thus, MFS is due to abnormalities of the elastic fiber system. Clinically, MFS is characterized by defects in the cardiovascular, skeletal, and
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ocular systems. Given the presence of elastic fibers in the lung it is not surprising that pulmonary complications also occur.The principal respiratory system abnormality in MFS is spontaneous pneumothorax, which occurs in approximately 5% of affected individuals. This indicates that spontaneous pneumothorax is statistically several hundred times more likely in a person with MFS than in the general population. In fact, the diagnosis of MFS has often been made after an initial event of a spontaneous pneumothorax. Spontaneous pneumothorax may be familial even in the absence of MFS. Apical bullae are also known to occur in MFS and may be a predisposing factor for spontaneous pneumothorax. Emphysema and congenital cystic lung have also been documented in MFS. Pulmonary function, too, has been studied in MFS but has been interpreted as essentially normal. In some cases of MFS, severe kyphoscoliosis may be a major contributor to pulmonary failure; however, that cannot be attributed to abnormal fibrillin in the lung, but to the generalized skeletal dysplasia. Therefore, one can conclude that primary defects in extracellular matrix proteins or their modifying enzymes can cause an array of pulmonary diseases. However, even when the pulmonary abnormality leads to premature death, the manifestations in other organ systems are often more prominent.
E X T R A C E L L U L A R M AT R I X I N A S T H M A AND COPD COPD Alterations in connective tissue are likely to play key roles in the pathogenesis of both asthma and COPD. Destruction of elastin is thought to be a major feature in the development of emphysema. Exposure of the lung to enzymes with elastolytic activity results in emphysema in animals.74 Histologic examination of the emphysematous lung shows disrupted elastic fibers.75 Urinary excretion of desmosine, a specific marker for degradation of elastin, has been observed to be increased in smokers and former smokers with COPD. Smokers without COPD did not excrete increased amounts of desmosine.76,77 Because individuals with severe deficiency of a1 protease inhibitor, an inhibitor of several serine proteases, are at markedly increased risk to develop emphysema,78 these proteases have been thought to have a major role in the destruction of elastin. Recent studies, however, suggest that the matrix metalloproteases contribute to the development of emphysema.79,80 In addition to tissue destruction, there is evidence of excess deposition of extracellular matrix (i.e. fibrosis) in COPD. In addition to the destruction of elastin in emphysema, there is an increase in deposition of collagen.81–83 Fibrosis of the small airways is also a regular feature of chronic bronchitis,84 and is related to the development of airflow limitation.85,86 The airways in COPD are of smaller than expected diameter; this may be a direct consequence of this fibrotic process.86
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Asthma Fewer studies have been performed of the connective tissue in asthma. Alterations in the connective tissue in the large airways, however, have been well described and include thickening of the lamina reticularis with increased deposition of collagen type I, III, and fibronectin,87 tenascin,88 and fragmentation of the airway elastic fiber network.89,90 The thickened lamina reticularis is particularly striking as the epithelium can be seen to rest on a dense nearly acellular layer of apparently homogeneous connective tissue.Whether these changes are altered with therapy of asthma is controvesial,91–94 but the connective tissue changes may occur somewhat independently of measures of clinical severity.93,95 The functional significance of the altered connective tissue in asthma is unknown, but it is likely that the altered matrix milieu can modulate the inflammatory response in asthma. In addition, similar changes in the small airways may account for increased peripheral airway resistance, reduced airway compliance,96 and progressive airflow limitation in asthma.97,98 Recognizing the complexity of the extracellular matrix, it seems likely that many alterations in these structural molecules will contribute to the pathophysiology of asthma and COPD. It seems likely, too, that the many genetic variations in connective tissue metabolism, which are beginning to be characterized, will contribute to the heterogeneity observed in asthma and COPD.
S U M M A RY Albeit briefly, this chapter has attempted to highlight most of the major extracellular matrix constituents that are critical for structure and function of the lung. As described, some enzymopathies that affect processing of several extracellular matrix macromolecules may lead directly to obstructive pulmonary disease as one of their pleiotropic manifestations. The recent sequencing of the human genome will undoubtedly lead to the identification of additional factors involved in extracellular matrix structure and homeostasis. In is not difficult to imagine that a primary defect or allelic variation (genetic polymorphism) in any number of matrix constituents of the lung may lead to pulmonary disease. Moreover, one must always be cognizant of the fact that our genome and its gene products are a part of our environmental milieu. These gene–environmental interactions are going to become increasingly more important to our overall understanding of the severity of numerous conditions. There is little doubt that chronic obstructive pulmonary disease and asthma will be a part of the revolution in genomic medicine.
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2. Burgeson RE, Morris NP. The collagen family of proteins. In: Uitto J, Perejda AJ (eds), Connective Tissue Disease: Molecular Pathology of the Extracellular Matrix, pp. 3–28. New York: Marcel Dekker, 1987. 3. Bornstein P, Sage H. Structually distinct collagen types. Annu. Rev. Biochem. 1980; 49:957–1003. 4. Beighton P. (ed.). McKusick’s Heritable Disorders of Connective Tissue. St Louis: Mosby, 1993. 5. Hay ED. Cell Biology of the Extracellular Matrix. New York: Plenum, 1991. 6. Bienskowski RS. Interstitial collagens. In: Crystal RG, West JB (eds), The Lung, pp. 381–8. New York: Raven Press, 1991. 7. Bradley K, McConnell Breul S, Crystal RG. Lung collagen heterogeneity. Proc. Natl Acad. Sci. USA 1974; 71:2828–32. 8. Bradley KH, McConnell SD, Crystal RG. Lung collagen composition and synthesis: characterization and changes with age. J. Biol. Chem. 1974; 249:2674–83. 9. Yurchenco PD, Furthmayr H. Self-assembly of basement membrane collagen. Biochemistry 1984; 23:1839–50. 10. Lallemand AV, Ruocco SM, Gaillard DA. Expression and immunohistochemical localization of laminin and type IV collagen in developing human fetal tracheal glands. Int. J. Dev. Biol. 1993; 37:491–5. 11. Leblond CP, Inoue S. Structure, composition, and assembly of basement membrane. Am. J. Anat. 1989; 185:367–90. 12. Virtanen I, Laitinen A, Tani T et al. Differential expression of laminins and their integrin receptors in developing and adult human lung. Am. J. Respir. Cell Mol. Biol. 1996; 15:184–96. 13. Clark JG, Kuhn C, McDonald JA, Mecham RP. Lung connective tissue. Int. Rev. Connect.Tissue Res. 1983; 10:249–331. 14. Saarela J, Rehn M, Oikarinen A, Autio Harmainen H, Pihlajaniemi T. The short and long forms of type XVIII collagen show clear tissue specificities in their expression and location in basement membrane zones in humans. Am. J. Pathol. 1998; 153:611–26. 15. Kelley J. Collagen. In: Massaro D (ed.), Lung Cell Biology, pp. 821–66. New York: Marcel Dekker, 1989. 16. Foster JA, Rich CB, Curtiss SW, Regan J. Elastin. In: Massaro D (ed.), Lung Cell Biology, pp. 867–905. New York: Marcel Dekker, 1989. 17. Sandberg LB, Soskel NT, Leslie JG. Elastin structure, biosynthesis, and relation to disease states. N. Engl. J. Med. 1981; 304:566–79. 18. Shapiro SD, Endicott SK, Province MA, Pierce JA, Campbell EJ. Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weaponsrelated radiocarbon. J. Clin. Invest. 1991; 87:1828–34. 19. Mecham RP, Heuser J. Three-dimensional organization of extracellular matrix in elastic cartilage as viewed by quick freeze, deep etch electron microscopy. Connect.Tissue Res. 1990; 24:83–93. 20. Brown PL, Mecham L, Tisdale C, Mecham RP. The cysteine residues in the carboxy terminal domain of tropoelastin form an intrachain disulfide bond that stabilizes a loop structure and positively charged pocket. Biochem. Biophys. Res. Commun. 1992; 186:549–55. 21. Boyd CD, Christiano AM, Pierce RA, Stolle CA, Deak SB. Mammalian tropoelastin: multiple domains of the protein define an evolutionarily divergent amino acid sequence. Matrix 1991; 11:235–41. 22. Parks WC, Secrist H, Wu LC, Mecham RP. Developmental regulation of tropoelastin isoforms. J. Biol. Chem. 1988; 263:4416–23. 23. Heim RA, Pierce RA, Deak SB et al. Alternative splicing of rat tropoelastin mRNA is tissue-specific and developmentally regulated. Matrix 1991; 11:359–66. 24. Indik Z,Yeh H, Ornstein-Goldstein N, Rosenbloom J. Structure of the elastin gene and alternative splicing elastin mRNA. In: Sandell L, Boyd CD (eds), Extracellular Matrix Genes, pp. 221–50. New York: Academic Press, 1990. 25. Parks WC, Deak SB. Tropoelastin heterogeneity: implications for protein function and disease. Am. J. Respir. Cell Mol. Biol. 1990; 2:399–406.
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26. Low FM. Microfibrils: fine filamentous components of the tissue space. Anat. Rec. 1962; 142:131–7. 27. Streeten BW, Licari PA, Marucci AA, Dougherty RM. Immunohistochemical comparison of ocular zonules and the microfibrils of elastic tissue. Invest. Ophthalmol.Vis. Sci. 1981; 21:130–5. 28. Cleary EG. The microfibrillar component of the elastic fibers: morphology and biochemistry. In: Uitto J, Perejda AJ (eds), Connective Tissue Disease: Molecular Pathology of the Extracellular Matrix, pp. 55–81. New York: Marcel Dekker, 1987. 29. Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J. Cell Biol. 1986; 103:2499–509. 30. Pereira L, D’Alessio M, Ramirez F et al. Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan syndrome. Hum. Mol. Genet. 1993; 2:961–8. 31. Lee B, Godfrey M, Vitale E et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 1991; 352:330–4. 32. Sakamoto H, Broekelmann T, Cheresh DA et al. Cell-type specific recognition of RGD- and non-RGD-containing cell binding domains in fibrillin-1. J. Biol. Chem. 1996; 271:4916–22. 33. Zhang H, Apfelroth SD, Hu W et al. Structure and expression of fibrillin-2 a novel microfibrillar component preferentially located in elastic matrices. J. Cell Biol. 1994; 124:855–63. 34. Zhang H, Hu W, Ramirez F. Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J. Cell Biol. 1995; 129:1165–76. 35. Mariencheck MC, Davis EC, Zhang H et al. Fibrillin-1 and fibrillin-2 show temporal and tissue-specific expression in developing elastic tissues. Connect.Tiss. Res. 1995; 31:87–97. 36. Robinson PN, Godfrey M. The molecular genetics of Marfan syndrome and related microfibrillopathies. J. Med. Genet. 2000; 37:9–25. 37. Ruoslahti E. Structure and biology of proteoglycans. Annu. Rev. Cell Biol. 1988; 4:229–55. 38. Ruoslahti E. Proteoglycans in cell regulation. J. Biol. Chem. 1989; 264:13369–72. 39. Radhakrishnamurthy B, Berenson SG. Proteoglycans of the lung. In: Massaro D (ed.), Lung Cell Biology, pp. 981–1010. New York: Marcel Dekker, 1989. 40. Hance AJ, Crystal RG. The connective tissue of lung. Am. Rev. Respir. Dis. 1975; 112:657–711. 41. Schuger L, O’Shea KS, Nelson BB, Varani J. Organotypic arrangement of mouse embryonic lung cells on a basement membrane extract: involvement of laminin. Development 1990; 110:1091–9. 42. Schuger L, Skubitz AP, O’Shea KS, Chang JF, Varani J. Identification of laminin domains involved in branching morphogenesis: effects of anti-laminin monoclonal antibodies on mouse embryonic lung development. Dev. Biol. 1991; 146:531–41. 43. Schuger L, Skubitz AP, Gilbride K, Mandel R, He L. Laminin and heparan sulfate proteoglycan mediate epithelial cell polarization in organotypic cultures of embryonic lung cells: evidence implicating involvement of the inner globular region of laminin beta 1 chain and the heparan sulfate groups of heparan sulfate proteoglycan. Dev. Biol. 1996; 179:264–73. 44. Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 1990; 346:281–4. 45. Hildebrand A, Romaris M, Rasmussen LM et al. Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. Biochem. J. 1994; 302:527–34. 46. Border WA, Ruoslahti E. Transforming growth factor-beta in disease: the dark side of tissue repair. J. Clin. Invest. 1992; 90:1–7. 47. Lopez Casillas F,Wrana JL, Massague J. Betaglycan presents ligand to the TGF beta signaling receptor. Cell 1993; 73:1435–44. 48. Bernfield M, Kokenyesi R, Kato M et al. Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans. Annu. Rev. Cell Biol. 1992; 8:365–93.
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49. Mast BA, Diegelmann, RF, Krummel TM, Cohen IK. Hyaluronic acid modulates proliferation, collagen and protein synthesis of cultured fetal fibroblasts. Matrix 1993; 13:441–6. 50. Timpl R, Rohde H, Robey PG et al. Laminin: a glycoprotein from basement membranes. J. Biol. Chem. 1979; 254:9933–7. 51. Burgeson RE, Chiquet M, Deutzmann R et al. A new nomenclature for the laminins. Matrix Biol. 1994; 14:209–11. 52. Lallemand AV, Ruocco SM, Gaillard DA. Synthesis and expression of laminin during human foetal lung development. Anat. Rec. 1995; 242:233–41. 53. Uehara Y, Minowa O, Mori C et al. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 1995; 373:702–5. 54. Kouretas D, Karinch AM, Rishi A, Melchers K, Floros J. Conservation analysis of rat and human SP-A gene identifies 5 flanking sequences of rat SP-A that bind rat lung nuclear proteins. Exp. Lung Res. 1993; 19:485–503. 55. Schuger L, O’Shea S, Rheinheimer J, Varani J. Laminin in lung development: effects of anti-laminin antibody in murine lung morphogenesis. Dev. Biol. 1990; 137:26–32. 56. Wu JE, Santoro SA. Differential expression of integrin alpha subunits supports distinct roles during lung branching morphogenesis. Dev. Dyn. 1996; 206:169–81. 57. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69:11–25. 58. Albelda SM, Buck CA. Integrins and other cell adhesion molecules. FASEB J. 1990; 4:2868–80. 59. Glukhova MA, Koteliansky VE. Integrins, cytoskeletal and extracellular matrix proteins in developing smooth muscle cells of human aorta. In: Schwartz SM, Mecham RP (eds), TheVascular Smooth Muscle Cell, pp. 37–79. San Diego: Academic Press, 1995. 60. Roman J, Little CW, McDonald JA. Potential role of RGD-binding integrins in mammalian lung branching morphogenesis. Development 1991; 112: 551–8. 61. Roman J, McDonald JA. Expression of fibronectin, the integrin alpha 5, and alpha-smooth muscle actin in heart and lung development. Am. J. Respir. Cell Mol. Biol. 1992; 6:472–80. 62. Coraux C, Delplanque A, Hinnrasky J et al. Distribution of integrins during human fetal lung development. J. Histochem. Cytochem. 1998; 46:803–10. 63. Kreidberg JA, Donovan MJ, Goldstein SL et al. Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development 1996; 122:3537–47. 64. Sheppard D. Epithelial integrins. Bioessays 1996; 18:655–60. 65. Clark EA, Brugge JS. Integrins and signal transduction pathways: the road taken. Science 1995; 268:233–9. 66. Caniggia I, Liu J, Han R et al. Identification of receptors binding fibronectin and laminin on fetal rat lung cells. Am. J. Physiol. 1996; 270:L459–68. 67. Hynes RO, Yamada KM. Fibronectins: multifunctional modular glycoproteins. J. Cell Biol. 1982; 95:369–77. 68. Murphy-Ullrich JE, Mosher DF. Fibronectin and disease processes. In: Uitto J, Perejda AJ (eds), Connective Tissue Disease: Molecular Pathology of the Extracellular Matrix, pp. 455–73. New York: Marcel Dekker, 1987. 69. Ruoslahti E. Fibronectin and its receptors. Annu. Rev. Biochem. 1988; 57:375–413. 70. Furie MB, Frey AB, Rifkin DB. Location of a gelatin-binding region of human plasma fibronectin. J. Biol. Chem. 1980; 255:4391–4. 71. Hahn LH, Yamada KM. Identification and isolation of a collagenbinding fragment of the adhesive glycoprotein fibronectin. Proc. Natl Acad. Sci USA 1979; 76:1160–3. 72. Clark JG. The molecular pathology of pulmonary fibrosis. In: Uitto J, Perejda AJ (eds), Connective Tissue Disease: Molecular Pathology of the Extracellular Matrix, pp. 321–43. New York: Marcel Dekker, 1987. 73. Royce PM, Steinmann B (eds). Connective Tissue and its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York: Wiley–Leiss, 1993.
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74. Snider GL, Lucey EC, Stone PJ. Animal models of emphysema. Am. Rev. Respir. Dis. 1986; 133:149–69. 75. Fukuda Y, Masuda Y, Ishizaki M, Masugi Y, Ferrans VJ. Morphogenesis of abnormal elastic fibers in lungs of patients with panacinar and centriacinar emphysema. Hum. Pathol. 1989; 20:652–9. 76. Stone PJ, Gottlieb DJ, O’Connor GT et al. Elastin and collagen degradation products in urine of smokers with and without chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1995; 151:952–9. 77. Gottlieb DJ, Stone PJ, Sparrow D et al. Urinary desmosine excretion in smokers with and without rapid decline of lung function: the Normative Aging Study. Am. J. Respir. Crit. Care Med. 1996; 154:1290–5. 78. Laurell CB, Eriksson S. The electrophoretic alpha 1-globulin pattern of serum in alpha 1-antitrypsin deficiency. Scand. J. Clin. Lab. Invest. 1963; 15:132–40. 79. D’Armiento J, Dalal SS, Okada Y, Berg RA, Chada K. Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell 1992; 71:955–61. 80. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 1997; 277:2002–4. 81. Lang MR, Fiaux GW, Gillooly M et al. Collagen content of alveolar wall tissue in emphysematous and non-emphysematous lungs. Thorax 1994; 49:319–26. 82. Finlay GA, O’Donnell MD, O’Connor CM, Hayes JP, FitzGerald MX. Elastin and collagen remodeling in emphysema: a scanning electron microscopy study. Am. J. Pathol. 1996; 149:1405–15. 83. Pierce JA, Hocott JB, Ebert RV. The collagen and elastin content of the lung in emphysema. Ann. Intern. Med. 1961; 55:210–21. 84. Cosio M, Ghezzo H, Hogg JC et al. The relations between structural changes in small airways and pulmonary-function tests. N. Engl. J. Med. 1978; 298:1277–81. 85. Finkelstein R,Ma HD,Ghezzo H et al.Morphometry of small airways in smokers and its relationship to emphysema type and hyperresponsiveness. Am. J. Respir. Crit. Care Med. 1995; 152:267–76. 86. Kuwano K, Bosken CH, Paré PD et al. Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1993; 148:1220–5.
87. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989; i:520–4. 88. Laitinen A, Altraja A, Kampe M et al. Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid. Am. J. Respir. Crit. Care Med. 1997; 156:951–8. 89. Mauad T, Xavier AC, Saldiva PH, Dolhnikoff M. Elastosis and fragmentation of fibers of the elastic system in fatal asthma. Am. J. Respir. Crit. Care Med. 1999; 160:968–75. 90. Bousquet J, Lacoste JY, Chanez P et al. Bronchial elastic fibers in normal subjects and asthmatic patients. Am. J. Respir. Crit. Care Med. 1996; 153:1648–54. 91. Olivieri D, Chetta A, Del Donno M et al. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebocontrolled study. Am. J. Respir. Crit. Care Med. 1997; 155:1864–71. 92. Trigg CJ, Manolitsas ND, Wang J et al. Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma. Am. J. Respir. Crit. Care Med. 1994; 150:17–22. 93. Laitinen LA, Laitinen A, Altraja A et al. Bronchial biopsy findings in intermittent or “early” asthma. J. Allergy Clin. Immunol. 1996; 98:S3–6. 94. Hoshino M, Nakamura Y, Sim JJ et al. Inhaled corticosteroids reduced lamina reticularis of the basement membrane by modulation of insulin-like growth factor (IGF)-I expresson in bronchial asthma. Clin. Exp. Allergy 1998; 28:568–77. 95. Laitinen LA, Altraja A, Karjalainen E, Laitinen A. Early interventions in asthma with inhaled corticosteroids. J. Allergy Clin. Immunol. 2000; 105:S582–5. 96. Wagner EM, Liu MC, Weinmann GG, Permutt S, Bleecker ER. Peripheral lung resistance in normal and asthmatic subjects. Am. Rev. Respir. Dis. 1990; 141:584–8. 97. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year followup study of ventilatory function in adults with asthma. N. Engl. J. Med. 1998; 339:1194–200. 98. Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur. J. Respair. Dis. 1987; 70:171–9.
Prostanoids Paul M. O'Byrne St. Joseph's Hospital and the Department of Medicine, McMaster Hamilton, Ontario, Canada
A R A C H I D O N I C ACID METABOLISM The release of arachidonic acid from cell membrane phospholipids, through the action of a family of phospholipases, can result in the production of a wide variety of mediators which may be relevant in the pathogenesis of asthma. These lipid mediators have traditionally been considered in two classes: •
mediators which result from the nases on arachidonic acid, which or thromboxane (Tx); • mediators which result from the lipoxygenase on arachidonic leukotrienes (LT).
CELL MEMBRANE - * —
1
,
ARACHIDONIC ACID
More recently, however, other products have been identified which result from the activity of different enzymes, such as 12- and 15-lipoxygenase. Lastly, platelet activating factor (PAF) has been recognized to be a mediator formed during arachidonic acid metabolism. T h e oxidative metabolism of arachidonic acid by cycloxygenase produces the cyclic endoperoxides P G G j and P G H j . The subsequent action of prostaglandin isomerases produces either P G D j or PGEj, reductive cleavage produces PGFjc, while one of two terminal synthetases on the endoperoxide produces PGIj and TxAj (Fig. 23.1). Cycloxygenase appears to be present in most cells; however, the cycloxygenase metabolite (s) released from a particular cell are quite specific (for example TxAj from platelets, and PGI2 from endothelial cells). This suggests that terminal synthetases are cell-specific. Two isoforms of cycloxygenase have been identified: cycloxygenase-1 (COX-1), which is constitutively present mainly in the gastric mucosa, kidney and platelets; cycloxygenase-2 (COX-2), which is mainly an inducible form, although also to some extent present constitutively in the C N S , in the juxtaglomerular apparatus of the kidney, in the lung, and in the placenta during late gestation.
1
cycloxy'genase
PAF
5-lipoxygenase
1
\
PGG2
5-HPETE
1
1
PGH, PGD2
phosphc lipase
i
\ LYSC)-PAF
action of the cycloxygeare prostaglandins (PG) action of the enzyme 5acid, which are the
University,
/ PGD2
LTA4
\ w
TXA2 PGI2
1
T LTC4
TXB2
LTD4
PGF2„
6-keto PGFi„
LTB4
1 15-lipoxygenase
1
15-HPETE
\ Lipoxins
1 1
LTE4
Fig. 2 3 . 1 . The spectrum of eicosanoids produced as a consequence of arachidonic acid metabolism.
Both isoforms contribute to the inflammatory process, but COX-2 is induced during inflammation, resulting in an enhanced formation of prostaglandins, during acute and chronic inflammation.' Prostaglandins and thromboxane mediate their effects through activation of specific receptors,^ and there is crossactivation of these receptors by the different agonists. The receptor designation has been accepted as the most potent agonist followed by the term "prostanoid". Thus, the thromboxane receptor is designated the T P receptor and the P G E receptor is the EP receptor. There are DP, EP, F P , T P receptors; the EP receptors are subdivided into E P l - 4 .
ROLE I N A S T H M A All of the cycloxygenase products of arachidonic acid metabolism have been synthesized and, with the exception of thromboxane, are readily available for study. Thromboxane
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has an exceedingly short half-life (about 30 seconds) and studies with thromboxane have been limited to a few, very circumscribed, experimental preparations, none of them in the airways. Fortunately, several stable thromboxane mimetics have been synthesized. These are endoperoxides which activate the thromboxane receptor and mimic the biological actions of thromboxane, but have substantially longer half-lives. Prostaglandins are believed to have a variety of effects on airway function in asthma. The prostaglandins are most easily considered in two classes. These are stimulatory prostaglandins, such as PGD2, PGF2a, and TxA2, which are potent bronchoconstrictors, and inhibitory prostaglandins, such as PGE2, which can reduce bronchoconstrictor responses and attenuate the release of bronchoconstrictor mediators, such as acetylcholine, from airway nerves. Evidence has been obtained in both animal models of airway hyperresponsiveness and in human subjects with asthma that cycloxygenase metabolites are involved in causing bronchoconstriction and also airway hyperresponsiveness after inhalation of stimuli, such as allergens. There is, however, little convincing evidence that cycloxygenase metabolites are important in causing the ongoing, persisting airway hyperresponsiveness that is characteristic of asthma. This is because several studies have failed to demonstrate any effect of cycloxygenase inhibitors on stable airway hyperresponsiveness in asthmatic subjects. The initial studies examining the role of cycloxygenase metabolites in the pathogenesis of transient airway hyperresponsiveness after an inflammatory stimulus were carried out using a cycloxygenase inhibitor, indomethacin, in dogs with airway hyperresponsiveness after inhaled ozone. Indometacin did not alter baseline airway responsiveness to inhaled acetylcholine, but did prevent the development of airway hyperresponsiveness after inhaled ozone.3 Despite the absence of airway hyperresponsiveness, the magnitude of the inflammatory response, as measured by the numbers of neutrophils in the airway epithelium, was not altered by indomethacin. This suggested that a cycloxygenase product was not responsible for the chemotaxis of acute inflammatory cells into the airways after inhaled ozone; however, a cycloxygenase product was released during the inflammatory response which caused airway hyperresponsiveness. Subsequently, a reputed combined cycloxygenase and lipoxygenase inhibitor, BW755C, was also demonstrated to prevent the development of airway hyperresponsiveness after inhaled ozone in dogs.4 Inhibition of cycloxygenase by indomethacin also prevents the development of airway hyperresponsiveness in other species that occurs after C5a des Arg exposure in rabbits,5 and following inhaled allergen in sheep.6 The importance of cycloxygenase products in these responses may be species-dependent. For example BW755C, but not indomethacin, prevents airway hyperresponsiveness after inhaled ozone in guinea-pigs,7 suggesting that a lipoxygenase rather than a cycloxygenase product was causing airway hyperresponsiveness in this species.
Cycloxygenase products have been implicated in the pathogenesis of allergen-induced early asthmatic8 as well as late asthmatic responses9 in human subjects. This has been done by pretreating subjects with several different cycloxygenase inhibitors. One study reported that pretreatment with indomethacin inhibited the late response in 10 out of 11 subjects studied, without having a major effect on the early response.10 Another study, however, where subjects were pretreated with indomethacin (100 mg/day), could not confirm these observations on either allergen-induced early or late responses.11 However, in this latter study indomethacin resulted in a significant inhibition of the development of allergen-induced airway hyperresponsiveness, which suggests that a cycloxygenase product is involved in the pathogenesis of this response. The most likely candidates are the stimulatory prostaglandins PGD2, PGF2a or TxA2.
S T I M U L AT O RY P R O S TA G L A N D I N S Prostaglandin D2 PGD2 is known to be released from stimulated dispersed human lung cells in vitro12 and from the airways of allergic human subjects which have been stimulated by allergen.13 PGD2 is a bronchoconstrictor of human airways,14 and is more potent when inhaled by human subjects than PGF2a. PGD2 causes bronchoconstriction, in part through stimulation of TP receptors,15 and in part indirectly through a presynaptic action on airway cholinergic nerves to release acetylcholine.16 Subthreshold contractile concentrations of PGD2 have been demonstrated to increase airway responsiveness to inhaled histamine and methacholine in asthmatic subjects.17 Thus, PGD2 released in human airways after allergen inhalation has the potential to both cause acute bronchoconstriction and increase airway hyperresponsiveness to other constrictor mediators. However, specific receptor antagonists for PGD2 or inhibitors of its production are not available to allow a precise evaluation of the importance of this cycloxygenase metabolite in the asthmatic response. Prostaglandin PGF2a PGF2a may also play a role as a mediator of bronchoconstriction and airway hyperresponsiveness following inhaled allergen in human subjects. PGF2a is a potent bronchoconstrictor in asthmatic airways,18 and when inhaled at subthreshold constrictor concentrations increases airway responsiveness in dogs19 and human subjects.20,21 PGF2a also causes bronchoconstriction in human subjects partially through cholinergic-mediated bronchoconstriction.22 Similar to the case with PGD2, there are no selective PGF2a receptor antagonists available, which would allow identification of the specific importance of these metabolites in mediating these airway responses. It has been suggested that all contractile prostaglandins act via the TP1 receptor.23 Therefore, differentiation of the relative importance of the contractile prostaglandins in causing asthmatic responses may prove to be difficult.
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• the pathogenesis of airway hyperresponsiveness in dogs26,27 and primates;28 • in the late cutaneous response to intradermal allergen in humans;29 • in the late asthmatic response after inhaled allergen in humans;30 • in airway hyperresponsiveness in asthmatic subjects.31 Other studies, however, have demonstrated slight, but statistically significant, inhibition of the magnitude of the allergen-induced early, but not the late responses after pretreatment with a thromboxane synthetase inhibitor32 or receptor antagonist.33 These studies suggest that thromboxane may be released following allergen challenge, and may account for a portion of the airway narrowing observed during the early asthmatic response; in contrast to the situation in dogs, thromboxane is not likely to be important in the airway hyperresponsiveness that occurs following allergen inhalation. The possible mechanisms by which TxA2 causes bronchoconstriction include presynaptic modulation of acetylcholine release, or a direct effect on airway smooth muscle. TxA2 was demonstrated to modulate acetylcholine release in airways initially by Munoz et al.,34 who showed that the TxA2 mimetic U46619 increased the response to field stimulation in canine trachealis muscle. No increase in the response to exogenous acetylcholine by U46619 was demonstrated, suggesting that the contractile augmentation was occurring presynaptically, through increased acetylcholine release in response to field stimulation. Further support for this hypothesis was provided by Tamaoki et al.,16 who demonstrated that aggregated platelets in an organ bath released TxA2. The TxA2 transiently increased the responses to field stimulation and this effect was prevented by a TxA2 receptor antagonist. Once again, the responses to an exogenous cholinergic agonist were not altered by the released TxA2. Recent studies suggest that this effect also occurs in asthmatic subjects. The bronchoconstrictor effects of the thromboxane mimetic, U46619, given by inhalation, are markedly attenuated by the nonselective cholinergic antagonist, atropine,35 while this effect does not occur when bronchoconstriction is induced by inhaled histamine.
I N H I B I T O RY P R O S TA G L A N D I N S The differentiation of the prostaglandins into stimulatory and inhibitory classes is somewhat inappropriate. For example, both PGE2 and PGF2a can have different effects on the airways depending on the time after inhalation at which the response is measured.36,37 However, the main action of PGE2 and PGI2 on airway function is to relax airway smooth muscle and to antagonize the contractile responses of other bronchoconstrictor agonists. In addition PGE2 is extremely potent at inhibiting the release of acetylcholine from airway cholinergic nerves.38 This effect is thought to occur through stimulation of presynaptic receptors. The evidence that inhibitory prostaglandins play a role in modulating the contractile responses of agonists in asthmatic subjects comes from studies which have demonstrated that tachyphylaxis (a decreased response to repeated stimulation) occurs following repeated challenges with inhaled histamine, when challenges are separated by up to 6 hours.39 Also, repeated exercise challenges in asthmatic subjects, at intervals up to 4 hours, also result in less bronchoconstriction occurring after the second when compared to the initial exercise challenge.40 This has been termed “exercise refractoriness”. All of these inhibitory effects are abolished by pretreatment with indomethacin39–41 (Fig. 23.2). This suggests that inhibitory prostaglandins, released as a consequence of exercise, could modify bronchoconstrictor responses in asthmatics. This hypothesis is supported by studies which have demonstrated that pretreatment of asthmatic subjects with oral PGE1, in doses which do not cause bronchodilation, reduce airway responsiveness to both histamine and methacholine,42 and that inhaled PGE2 largely abolishes exercise-induced bronchoconstriction43 (Fig. 23.3).
Placebo 1
Placebo 2
Indomethacin
0.0 0.1 Change in FEV1 (L)
Thromboxane A2 TxA2 is a potent constrictor of smooth muscle. It was originally described as being released from platelets,24 but it is now known to be released from other cells, including macrophages and neutrophils.25 As noted above, the biological half-life of TxA2 is very short, so it has been implicated in disease processes through identification of its more stable metabolite thromboxane B2 (TxB2) in biological fluids; through the use of the stable TxA2 analogs U44069 or U46619, which mimic most of the biological effects of TxA2; and through the use of inhibitors of TxA2 synthesis and antagonists of the TxA2 receptor. Using these techniques, TxA2 has been implicated in:
0.2 0.3 0.4 0.5 0.6 0.7 0.8 3
5
7
9 3 5 7 9 3 Time after exercise (min) 1st exercise
5
7
9
2nd exercise
Fig. 23.2. Effect of pretreatment with indomethacin or placebo (on two occasions) on exercise-induced bronchoconstriction and refractoriness. Reproduced from reference 40, with permission.
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Change in FEV1 (%)
14 During cycling
0
PGE2
10
Placebo
20
30 0
5 10 15 20 Time after exercise (min)
25
30
Fig. 23.3. Effect of pretreatment with inhaled PGE2 and placebo on exercise-induced bronchoconstriction. Reproduced from reference 43, with permission.
These results are consistent with studies of airway smooth muscle in vitro, where histamine tachyphylaxis occurs through inhibitory prostaglandin release,44 and with studies of dogs in vivo where histamine tachyphylaxis is inhibited by indomethacin.45 In addition, histamine tachyphylaxis in asthmatic subjects is blocked by pretreatment with a H2receptor antagonist, cimetidine, in asthmatics,46 suggesting that H2 receptor stimulation is involved with the development of histamine tachyphylaxis. Stimulation of H2 receptors in the lung in vitro has previously been shown to be associated with PGE2 release in guinea-pigs,12 and PGE2 release from canine trachealis by histamine is antagonized by cimetidine.47 Contraction of asthmatic airways by histamine also reduces airway responsiveness to acetylcholine48 and exercise.49 This lack of specificity suggests that either receptor downregulation or an alteration of the contractile properties of airway smooth muscle is occurring. However, there is no current evidence from either in vivo or in vitro preparations to support this speculation. An initial hypothesis to explain exercise refractoriness in asthmatics was that histamine is released following exercise, causing bronchoconstriction, but this also provides partial protection against subsequent exercise bronchoconstriction, through PGE2 released by stimulation of histamine H2 receptors. However, several studies have suggested that this hypothesis is incorrect. First, the marked attenuation of exercise-induced bronchoconstriction by pretreatment with leukotriene (LT)D4-receptor antagonists50,51 indicates that LTD4, rather than histamine, is the main mediator responsible for exercise-induced bronchoconstriction. Second, exercise refractoriness is not prevented by pretreatment with the H2-receptor antagonists, cimetidine or ranitidine, which effectively prevent histamine tachyphylaxis.52 Therefore, histamine-stimulated inhibitory prostaglandin release does not appear to be the cause of exercise refractoriness.
These studies raise the possibility that exercise refractoriness is caused by leukotriene-stimulated inhibitory prostaglandin release (Fig. 23.4). This possibility has been tested in a study in asthmatic subjects who develop exerciseinduced bronchoconstriction and refractoriness.53 The study demonstrated that there is an interdependence between the cycloxygenase and lipoxygenase pathways of arachidonate metabolism in causing exercise bronchoconstriction and refractoriness in asthmatic subjects. This hypothesis is supported by the facts that: • exercise refractoriness and LTD4 tachyphylaxis exist in the same subjects and the magnitude of the protection afforded by exercise correlates with that afforded by LTD4; • cross refractoriness exists between exercise and LTD4; • all of these effects are attenuated by cycloxygenase inhibition, suggesting that the release of inhibitory prostaglandins is the common mechanism affording protection after each of these stimuli. The release of cysteinyl leukotrienes in the airways is also important in the pathophysiology of aspirin-intolerant asthma54 (see Chapter 24). This is associated with overexpression of the enzyme LTC4 synthetase in the airways of patients with aspirin-intolerant asthma.55 In addition, pretreatment with inhaled PGE2 prevents not only the bronchoconstriction caused by aspirin, but also the increases in urinary LTE4 associated with it.56 These results suggest that, in patients with aspirin-intolerant asthma, PGE2 may play a critical role in inhibiting the overproduction of cysteinyl leukotrienes, as this inhibiting effect is lost when the patients ingest aspirin or other cycloxygenase inhibitors. Inhaled PGE2 has also been demonstrated to abolish allergen-induced bronchoconstrictor responses and airway hyperresponsiveness,57 and to attenuate allergen-induced airway eosinophlic inflammation58 (Fig. 23.5). Thus, these findings suggest that endogenous PGE2, produced in response to inhaled allergen, may play a role in regulating the associated airway inflammation.
First exercise challenge Cys LTs
PGE2 Second exercise challenge
Fig. 23.4. Hypothesis to explain the mechanism of exercise-induced refractoriness.
Sputum metachromatic cells (%)
Sputum EG2-positive cells (%)
Sputum eosinophils (%)
Prostanoids
40
*
* 20 0 40 20
*
*
0 1.0 *
0.5
*
0.0 Baseline
7 hours 24 hours Time after allergen exposure Placebo
PGE2
Fig. 23.5. Percentage sputum eosinophils, EG2-positive cells, and metachromatic cells, for placebo and PGE2 treatments, shown at baseline and at 7 and 24 hours following allergen challenge. PGE2 treatment significantly reduced the allergen-induced increase in eosinophils, EG2positive cells, and metachromatic cells (P < 0.05). indicates P < 0.05 allergen-induced change from baseline; * indicates P < 0.05 difference from baseline, placebo versus PGE2. Reproduced from reference 58, with permission.
S U M M A RY Despite almost 30 years of research on the release, metabolism, and clinical relevance of prostaglandins and thromboxane in lung disease, no definitive role in the pathogenesis of asthma or chronic obstructive pulmonary disease has been proven for any one of these mediators. However, in asthmatic patients, it is likely that PGD2 and TxA2 are involved in causing acute bronchoconstriction after stimuli such as inhaled allergen in asthmatic patients. Also, there is evidence which indicates that inhibitory prostaglandins can be released by asthmatic airways, which reduces bronchoconstrictor responses to stimuli such as exercise, and that this effect is mediated by leukotriene-induced PGE2 release. PGE2 also appears to play a role in inhibiting leukotriene overproduction in patients with aspirin-intolerant asthma. Finally, PGE2 can also attenuate allergen-induced airway responses and eosinophilic inflammation. These studies suggest that endogenous production of PGE2 does have an important influence on the magnitude of asthmatic responses to stimuli such as exercise or inhaled allergens.
REFERENCES 1. Everts B, Wahrborg P, Hedner T. COX-2-specific inhibitors: the emergence of a new class of analgesic and anti-inflammatory drugs. Clin. Rheumatol. 2000; 19:331–43.
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2. Coleman RA, Eglen RM, Jones RL et al. Prostanoid and leukotriene receptors: a progress report from the IUPHAR working parties on classification and nomenclature. Prostagland. Rel. Comp. 1996; 23:280–5. 3. O’Byrne PM, Walters EH, Aizawa H et al. Indomethacin inhibits the airway hyperresponsiveness but not the neutrophil influx induced by ozone in dogs. Am. Rev. Respir. Dis. 1984; 130:220–4. 4. Fabbri LM, Aizawa H, O’Byrne PM et al. An anti-inflammatory drug (BW755C) inhibits airway hyperresponsiveness induced by ozone in dogs. J. Allergy Clin. Immunol. 1985; 76:162–6. 5. Berend N, Armour CL, Black JL. Indomethacin inhibits the increased airway responsiveness to histamine following inhalation of C5a des Arg in rabbits. Agents Actions 1986; 18:468–72. 6. Lanes S, Stevenson JS, Codias E et al. Indomethacin and FPL57231 inhibit antigen-induced airway hyperresponsiveness in sheep. J. Appl. Physiol. 1986; 61:864–72. 7. Lee HK, Murlas C. Ozone-induced bronchial hyperreactivity in guinea pigs is abolished by BW755C or FPL55712 but not by indomethacin. Am. Rev. Respir. Dis. 1985; 132:1005–9. 8. Fish JE, Ankin MG, Adkinson NF, Peterman VI. Indomethacin modification of immediate-type immunologic airway responses in allergic asthmatic and nonasthmatic subjects: evidence for altered arachidonic acid metabolism in asthma. Am. Rev. Respir. Dis. 1981; 123:609–14. 9. Fairfax AJ. Inhibition of the late asthmatic response to house dust mite by nonsteroidal anti-inflammatory drugs. Prostagland. Leuk. Med. 1982; 8:239–48. 10. Joubert JR, Shephard E, Mouton W, Van Zyl L, Viljoen I. Nonsteroid anti-inflammatory drugs in asthma: dangerous or useful therapy? Allergy 1985; 40:202–7. 11. Kirby JG, Hargreave FE, Cockcroft DW, O’Byrne PM. Effect of indomethacin on allergen-induced asthmatic responses. J. Appl. Physiol. 1989; 66:578–83. 12. Yen SS, Mathe AA, Dugan JJ. Release of prostaglandins from healthy and sensitized guinea-pig lung and trachea by histamine. Prostaglandins 1976; 11:227–39. 13. Murray JJ, Tonnel AB, Brash AR et al. Release of prostaglandin D2 into human airways during acute antigen challenge. N. Engl. J. Med. 1986; 315:800–4. 14. Hardy CC, Robinson C, Tattersfield AE, Holgate ST. The bronchoconstrictor effect of inhaled prostaglandin D2 in normal and asthmatic men. N. Engl. J. Med. 1984; 311:209–13. 15 Johnston SL, Freezer NJ, Ritter W, O’Toole S, Howarth PH. Prostaglandin D2-induced bronchoconstriction is mediated only in part by the thromboxane-prostanoid receptor. Eur. Respir. J. 1995; 8:411–15. 16. Tamaoki J, Sekizawa K, Graf PD, Nadel JA. Cholinergic neuromodulation by prostaglandin D2 in canine airway smooth muscle. J. Appl. Physiol. 1987; 63:1396–400. 17. Fuller RW, Dixon CM, Dollery CT, Barnes PJ. Prostaglandin D2 potentiates airway responsiveness to histamine and methacholine. Am. Rev. Respir. Dis. 1986; 133:252–4. 18. Thomson NC, Roberts R, Bandouvakis J, Newball H, Hargreave FE. Comparison of bronchial responses to prostaglandin F2 alpha and methacholine. J. Allergy Clin. Immunol. 1981; 68:392–8. 19. O’Byrne PM, Aizawa H, Bethel RA, Chung KF, Nadel JA, Holtzman MJ. Prostaglandin F2 alpha increases responsiveness of pulmonary airways in dogs. Prostaglandins 1984; 28:537–43. 20. Walters EH, Parrish RW, Bevan C, Smith AP. Induction of bronchial hypersensitivity: evidence for a role for prostaglandins. Thorax 1981; 36:571–4. 21. Fish JE, Jameson A, Albright A, Norman PS. Modulation of the bronchometer effects of chemical mediators by PGF2a in asthmatic subjects. Am. Rev. Respir. Dis. 1984; 130:571–4. 22. Beasley R,Varley J, Robinson C, Holgate ST. Cholinergic-mediated bronchoconstriction induced by prostaglandin D2, its initial metabolite 9 alpha,11 beta-PGF2, and PGF2 alpha in asthma. Am. Rev. Respir. Dis. 1987; 136:1140–4.
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23. Gardiner PJ. Eicosanoids and airway smooth muscle. Pharmacol. Therapeut. 1989; 44:1–62. 24. Hamberg M, Svensson J, Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc. Natl Acad. Sci. USA 1975; 72:2994–8. 25. Higgs GA, Moncada S, Salmon JA, Seager K. The source of thromboxane and prostaglandins in experimental inflammation. Br. J. Pharmacol. 1983; 79:863–8. 26. Aizawa H, Chung KF, Leikauf GD et al. Significance of thromboxane generation in ozone-induced airway hyperresponsiveness in dogs. J. Appl. Physiol. 1985; 59:1918–23. 27. Chung KF, Aizawa H, Becker AB et al. Inhibition of antigeninduced airway hyperresponsiveness by a thromboxane synthetase inhibitor (OKY-046) in allergic dogs. Am. Rev. Respir. Dis. 1986; 134:258–61. 28. Letts GL, McFarlane CS. Thromboxane A2 and airway responsiveness to acetylcholine aerosol in the conscious primate. Prog. Clin. Biol. Res. 1988; 263:91–8. 29. Dorsch WD, Ring J, Melzer H. A selective inhibitor of thromboxane biosynthesis enhances immediate and inhibits late cutaneous allergic reactions in man. J. Allergy Clin. Immunol. 1983; 72:168–74. 30. Shephard EG, Malan L, Macfarlane CM, Mouton W, Joubert JR. Lung function and plasma levels of thromboxane B2, 6-ketoprostaglandin F1 alpha and beta-thromboglobulin in antigeninduced asthma before and after indomethacin pretreatment. Br. J. Clin. Pharmacol. 1985; 19:459–70. 31. Fujimura M, Sasaki F, Nakatsumi Y et al. Effects of a thromboxane synthetase inhibitor (OKY-046) and a lipoxygenase inhibitor (AA-861) on bronchial responsiveness to acetylcholine in asthmatic subjects. Thorax 1986; 41:955–9. 32. Manning PJ, Stevens WH, Cockcroft DW, O’Byrne PM.The role of thromboxane in allergen-induced asthmatic responses. Eur. Respir. J. 1991; 4:667–72. 33. Beasley RC, Featherstone RL, Church MK et al. Effect of a thromboxane receptor antagonist on PGD2- and allergen-induced bronchoconstriction. J. Appl. Physiol. 1989; 66:1685–93. 34. Munoz NM, Shioya T, Murphy TM et al. Potentiation of vagal contractile response by thromboxane mimetic U-46619. J. Appl. Physiol. 1986; 61:1173–9. 35. Saroea HG, Inman MD, O’Byrne PM. U46619-induced bronchoconstriction in asthmatic subjects is mediated by acetylcholine release. Am. J. Respir. Crit. Care Med. 1995; 151:321–4. 36. Walters EH, Bevan C, Parrish RW, Davies BH, Smith AP. Timedependent effect of prostaglandin E2 inhalation on airway responses to bronchoconstrictor agents in normal subjects. Thorax 1982; 37:438–42. 37. Fish JE, Newball HH, Norman PS, Peterman VI. Novel effects of PGF2 alpha on airway function in asthmatic subjects. J. Appl. Physiol. 1983; 54:105–12. 38. Walters EH, O’Byrne PM, Fabbri LM et al. Control of neurotransmission by prostaglandins in canine trachealis smooth muscle. J. Appl. Physiol. 1984; 57:129–34. 39. Manning PJ, Jones GL, O’Byrne PM. Tachyphylaxis to inhaled histamine in asthmatic subjects. J. Appl. Physiol. 1987; 63:1572–7. 40. O’Byrne PM, Jones GL. The effect of indomethacin on exerciseinduced bronchoconstriction and refractoriness after exercise. Am. Rev. Respir. Dis. 1986; 134:69–72. 41. Margolskee DJ, Bigby BG, Boushey HA. Indomethacin blocks airway tolerance to repetitive exercise but not to eucapnic
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hyperpnea in asthmatic subjects. Am. Rev. Respir. Dis. 1988; 137:842–6. Manning PJ, Lane CG, O’Byrne PM. The effect of oral prostaglandin E1 on airway responsiveness in asthmatic subjects. Pulm. Pharmacol. 1989; 2:121–4. Melillo E, Woolley KL, Manning PJ, Watson RM, O’Byrne PM. Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects. Am. J. Respir. Crit. Care Med. 1994; 149:1138–41. Anderson WH, Krzanowski JJ, Polson JB, Szentivanyi A. Prostaglandins as mediators of tachyphylaxis to histamine in canine tracheal smooth muscle. Adv. Prostagland.Thrombox. Res. 1980; 7:995–1001. Shore S, Irvine CG, Shenkier T, Martin JG. Mechanism of histamine-induced contraction of canine airway smooth muscle. Physiologist 1981; 24:56–60. Jackson PJ, Manning PJ, O’Byrne PM. A new role for histamine H2-receptors in asthmatic airways. Am. Rev. Respir. Dis. 1988; 138:784–8. Manning PM, Jones GL, Lane CG, O’Byrne PM. Histamineinduced prostaglandin E2 release from canine tracheal smooth muscle is inhibited by H2-receptor blockade. Am. Rev. Respir. Dis. 1988; 137:373. Manning PJ, O’Byrne PM. Histamine bronchoconstriction reduces airway responsiveness in asthmatic subjects. Am. Rev. Respir. Dis. 1988; 137:1323–5. Hamielec CM, Manning PJ, O’Byrne PM. Exercise refractoriness after histamine inhalation in asthmatic subjects. Am. Rev. Respir. Dis. 1988; 138:794–8. Manning PJ, Watson RM, Margolskee DJ et al. Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N. Engl. J. Med. 1990; 323:1736–9. Coreno A, Skowronski M, Kotaru C, McFadden ER. Comparative effects of long-acting beta2-agonists, leukotriene receptor antagonists, and a 5-lipoxygenase inhibitor on exercise-induced asthma. J. Allergy Clin. Immunol. 2000; 106:500–6. Manning PJ, Watson R, O’Byrne PM. The effects of H2-receptor antagonists on exercise refractoriness in asthma. J. Allergy Clin. Immunol. 1992; 90:125–6. Manning PJ, Watson RM, O’Byrne PM. Exercise-induced refractoriness in asthmatic subjects involves leukotriene and prostaglandin interdependent mechanisms. Am. Rev. Respir. Dis. 1993; 148:950–4. Israel E, Fischer AR, Rosenburg MA et al. The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am. Rev. Respir. Dis. 1993; 148:1447–51. Cowburn AS, Sladek K, Soja J et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirinintolerant asthma. J. Clin. Invest. 1998; 101:834–46. Sestini P, Armetti L, Gambaro G et al. Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTE4 excretion in aspirin-sensitive asthma. Am. J. Respir. Crit. Care Med. 1996; 153:572–5. Pavord ID, Wong CS, Williams J, Tattersfield AE. Effect of inhaled prostaglandin E2 on allergen-induced asthma. Am. Rev. Respir. Dis. 1993; 148:87–90. Gauvreau GM, Watson RM, O’Byrne PM. Effect of inhaled prostaglandin E2 on inflammatory responses after inhaled allergen. Am. J. Respir. Crit. Care Med. 1999; 159:31–6.
Leukotrienes
Chapter
24
Jeffrey M. Drazen Brigham and Women’s Hospital, Boston, MA, USA
The leukotrienes (LTB4, LTC4, LTD4, and LTE4) and lipoxins (LxA4 and LxB4) are molecules derived by lipoxygenation of arachidonic acid. Although each of these molecules is potentially important in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD), the currently available evidence suggests that, among these molecules, the cysteinyl leukotrienes, namely LTC4, LTD4 and LTE4, play a significant role in initiating and maintaining an asthmatic response. This chapter focuses primarily on those molecules.
F O R M AT I O N A N D M E TA B O L I S M O F T H E LEUKOTRIENES Arachidonic acid, a normal component of many cell membrane phospholipids, is commonly found esterified to these phospholipids in the middle or sn2 position. In the presence of appropriately activated phospholipase A2, arachidonic acid is cleaved from the membrane of the mast cell (Fig. 24.1). There are at least two distinct forms of phospholipase A2 (PLA2) with this catalytic capacity.1–3 Cytosolic PLA2 (cPLA2) is the enzyme activated when arachidonic acid is cleaved in the intracellular microenvironment. This form of the enzyme is catalytically active at calcium and pH levels consistent with the intracellular microenvironment and cleaves arachidonic acid from phospholipids in the perinuclear membrane. In contrast, the family of enzymes known as secretory PLA2 (sPLA2) operates in the extracellular microenvironment to cleave arachidonic acid4–7 from the cell’s exterior plasma membrane; precisely how the arachidonic acid so cleaved enters the cell to serve as a substrate for various enzymes is not clear. Arachidonic acid, released as a result of PLA2 action, enters into a series of reactions at the perinuclear membrane. The first of these requires a specific 5-lipoxygenase activating protein (FLAP),8–10 which allows arachidonate to serve as a substrate for the enzyme 5-lipoxygenase.11–16 5lipoxygenase sequentially catalyzes the addition of oxygen to arachidonic acid to form 5-hydroperoxy eicosatetraenoic
acid (5-HPETE) and leukotriene A4 (LTA4), respectively; LTA4 is a major branch point in the formation of the leukotrienes.17,18 A variety of cells, most notably neutrophilic polymorphonuclear leucocytes (PMN), express a specific epoxide hydrolase that catalyzes the formation of LTB4 from LTA4.19–23 It is also possible for multiple lipoxygenases to act sequentially on arachidonic acid to form the lipoxins.18,24 In distinction to the neutrophil, other cells, including eosinophils, mast cells, and alveolar macrophages, not only have the capacity to form LTA4 from arachidonic acid, but they also possess a unique and specific glutathionyl-S-transferase, LTC4 synthase, which catalyzes the conjugation of glutathione to LTA4, at carbon 6, to form leukotriene C4 (LTC4). LTC4 synthase has a high degree of homology with the FLAP and is also an integral perinuclear membrane protein.25–28 Once formed, LTC4 exits the cell via a specific transmembrane transporter.29,30 In the extracellular microenvironment LTC4 serves as a substrate for c-glutamyl transpeptidase which cleaves the glutamic acid moiety from its peptide chain to form leukotriene D4 (LTD4); LTD4 is further processed by the removal of the glycine moiety from its peptide chain to form leukotriene E4 (LTE4).31,32 LTC4, LTD4, and LTE4 make up the material formerly known as slow-reacting substance of anaphylaxis or SRS-A and are collectively known as the cysteinyl leukotrienes. Once formed, and in the presence of appropriately activated PMNs, the cysteinyl leukotrienes are degraded to their respected sulfoxides and 6-trans diastereoisomers of LTB4.33 In the absence of such cells the major degradation and excretion products of the cysteinyl leukotrienes are native LTE4, N-acetyl LTE4, or the products resulting from x-oxidation and b-elimination of LTE4.34–36
LEUKOTRIENES IN ASTHMA Since the structural identification of the leukotrienes, a number of lines of evidence have accrued indicating that the cysteinyl leukotrienes may be involved in the asthmatic response. These are reviewed below.
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Cytosol
Extracellular space
Cytosolic phospholipase A2
Chemotaxis BLT receptor
Arachidonic acid
Nucleus
5-Lipoxygenase– activating protein
Leukotriene B4 Transmembrane transporter Leukotriene D4
Epoxide hydrolase Zileuton
Leukotriene C4
Leukotriene E4
5-Lipoxygenase Leukotriene C4 Leukotriene A4
Montelukast Pranlukast Zafirlukast
CysLT1 receptor Nuclear membrane
Leukotriene C4 synthase
Cell membrane
Airway Smooth-muscle constriction Eosinophil migration Edema
Fig. 24.1. Schematic showing the synthesis of leukotrienes from arachidonic acid and the site of action of various drugs in the pathway. Reproduced from reference 143 with permission.
Cysteinyl leukotrienes in the pathology of chronic mild asthma The cysteinyl leukotrienes are synthesized and exported into the microenvironment by constitutive and infiltrating cells including mast cells and eosinophils;37 these two cell types are known to be critical cells in the asthmatic lesion.38–41 Cysteinyl leukotrienes produced by these cells act at leukotriene receptors on airway smooth muscle and the bronchial vasculature mediating airway obstruction and microvascular leak.42 In addition to the synthesis of leukotrienes by eosinophils and mast cells, it is also likely that the bronchial vascular endothelium will be exposed to cells such as PMNs, capable of donating LTA4. When LTA4 is provided for effector cells, such as vascular endothelial cells or platelets which contain LTC4 synthase,43–45 the cysteinyl leukotrienes can be produced by transcellular metabolism. Thus both resident cells as well as infiltrating cells found in the asthmatic lesion have the capacity to produce cysteinyl leukotrienes. Biological effects of cysteinyl leukotrienes relevant to the asthmatic response The leukotrienes are known to have profound biochemical and physiological effects, even in picomolar concentrations,
including induction of airway obstruction, tissue edema, and expression of bronchial mucus from submucosal glands;37,46,47 these pathobiological effects make them part of the panel of mediators which characterize asthmatic responses. Prominent among the effects of the cysteinyl leukotrienes is their ability to mediate airway narrowing in normal individuals and persons with asthma. Indeed, when aerosols of leukotrienes are inhaled by normal subjects, airway obstruction occurs, as manifested by a decrease in flow rates during a forced exhalation.48–60 When flow rates at 30% of vital capacity measured from partial flow–volume curves (V˙30P) are used as the index of airway obstruction, it has been established that LTC4 and LTD4 have bronchoconstrictor effects that are prolonged compared with those induced by histamine or methacholine. When a 30% decrease in the V˙30P is induced, the duration of bronchoconstrictor effect of histamine or methacholine is on the order of 3–5 minutes. In contrast, the duration of bronchoconstriction resulting from the cysteinyl leukotrienes, when an equivalent peak magnitude of effect is achieved, is on the order of 25–30 minutes. More important than differences in the duration of effect is the relative potency of the cysteinyl leukotrienes compared with agonists such as histamine or methacholine.
Leukotrienes
The range of nebulizer concentrations required to achieve a 30–40% decrease in the V˙30P due to inhalation of LTD4 in normal subjects varies about 100-fold from approximately 3 lmol/L to 300 lmol/L. These concentrations are about 3000-fold less than the nebulizer concentrations of histamine required to achieve an equivalent degree of airway narrowing. In addition, among normal subjects there is a relationship between responsiveness to the leukotrienes and responsiveness to reference agonists such as histamine or methacholine.53,54 Subjects that are more responsive to histamine are those that are more responsive to the leukotrienes.When the FEV1 is used as the outcome indicator, rather than the V˙30P, approximately five times greater leukotriene nebulizer concentrations are required to achieve a 15–20% decrease in this airway response index. Although these data are consistent with the hypothesis that the airways which narrow in order to reduce the FEV1 are less sensitive to the cysteinyl leukotrienes than the airways that narrow to decrease the V˙30P, this hypothesis has never been established by direct experiment. In subjects with asthma, LTC4 and LTD4 are potent bronchoconstrictor agonists when administered by aerosol, as indicated by induced decrements in the FEV1, in the V˙30P, or in specific conductance.53,54,56,58,60–62 When the V˙30P or the V˙40P is used as the outcome indicator, nebulizer concentrations of LTD4 of the order of 0.3–30 lmol/L are required to decrease airflow rates by approximately 30%. These nebulizer concentrations are approximately one-tenth of those required by normal subjects in order to achieve the same decrement in airflow rates. Since normal subjects are approximately 100-fold less sensitive to histamines or methacholine than asthmatic subjects, while they are only 10-fold less responsive to the cysteinyl leukotrienes, this indicates that the relative degree of hyperresponsiveness to the cysteinyl leukotrienes is less than that observed when histamine or methacholine is used as the contractile agonist. LTE4 is also a potent bronchoactive agonist. The potency of LTE4 relative to histamine differs between normal and asthmatic subjects. In normal subjects, LTE4 is about 30fold more potent than histamine,58 while in subjects with asthma LTE4 is about 300-fold more potent than histamine,63 regardless of whether flow rates low in the vital capacity from partial flow–volume curves or specific conductance55 are used as the outcome indicators. There is evidence that patients with aspirin-induced asthma are more hyperresponsive to LTE4 than are other asthmatic subjects,64,65 indicating a potentially unique role for this cysteinyl leukotriene in the pathogenesis of this uncommon form of asthma. Leukotriene recovery in asthma Cysteinyl leukotrienes have been recovered after experimental challenges which elicit clinical symptoms similar to those that occur in spontaneously occurring asthmatic conditions. Leukotrienes have also been recovered in the nasal lavage fluid after intranasal challenge with either antigen or cold
229
air.66,67 Leukotrienes are recovered in significantly greater amounts in the bronchoalveolar lavage (BAL) fluid from subjects with symptomatic asthma than from subjects with asymptomatic asthma or normal subjects,68–73 suggesting that the leukotrienes are produced locally in the lungs of patients with asthma. Although leukotrienes can be recovered from BAL fluid of patients with active asthma or after airway challenge, because of the invasive nature of the procedure required to obtain the fluid, it is unlikely that the extensive clinical use of BAL fluid leukotriene levels as an index of leukotriene production will occur. In this regard, indices of leukotriene production that rely on measurements made on blood or urine samples offer potential utility in the assessment of which asthmatic responses represent states in which the leukotrienes are among the effector molecules mediating bronchoconstriction. A number of investigators have detected cysteinyl leukotrienes in the plasma during asthma attacks,74–76 but the methods used to assure the authenticity of the materials identified have been suboptimal and the findings have not been widely reproduced, probably for technical reasons.77 In contrast, it has been shown that accurate and quantitative measurements of LTE4 can be made in urine samples.78–82 In normal human subjects, after intravenous administration of radiolabeled LTC4, 12–48% of the counts are recovered in the urine with 4–13% as intact LTE4.83,84 Not only can exogenously administered leukotrienes be recovered in the urine, but it is now common to measure leukotriene recovery from the urine as an index of endogenous production of leukotrienes.78,79,85 For example, it has been shown that there is an increase in the recovery of authentic LTE4 in the urine of asthmatic subjects in the early phase after antigen challenge.86 After antigen challenge the magnitude of the induced fall in the FEV1 and the amount of LTE4 in the urine are closely correlated.85,87,88 Taylor et al.79 used solid-phase extraction followed by RPHPLC and RIA to measure LTE4 in the urine. To allow quantitative determination of the amounts of LTE4 in the urine, they used recovery of radiolabeled LTE4 added as an internal standard. In normal subjects they recovered 23.8 ng of LTE4 per mmol of creatinine; while in 20 asthmatic subjects during acute spontaneous attacks they recovered slightly over three times as much LTE4, 78.3 ng/mmol creatinine. There was no relationship observed between the severity of the attack as measured by the FEV1 and the amount of LTE4 recovered in the urine. In six of the eight subjects in whom urinary LTE4 measurements were available both before and after treatment for an acute asthmatic exacerbation (all received prednisolone), there was a decrease in the LTE4 excretion rate. Drazen et al.89 demonstrated that over two-thirds of subjects presenting for emergency treatment of asthma had elevated urinary LTE4 compared to a reference group of normal subjects. Interestingly, among the individuals presenting for emergency asthma treatment those whose lung function responded initially to inhaled b-agonist treatment were those most likely to have elevated urinary LTE4 levels.
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Asano et al.90 examined urinary LTE4 excretion rates in eight patients with mild chronic stable asthma (FEV1 ~70% predicted, inhaled b-agonists as the only asthma treatment) followed on a metabolic ward for 4 days. They were able to show that there was not a diurnal variation in urinary LTE4 excretion. Furthermore they demonstrated that, on average, patients with asthma have significantly higher urinary LTE4 levels than normal subjects. However, among the asthmatics studied there were individuals who were persistent hyperexcretors of urinary LTE4 and others with urinary LTE4 levels that were persistently within the normal range. Among the explanations for this finding is the possibility that, among patients with asthma, whose clinical phenotype is similar, there are individuals whose asthma is associated with leukotriene production and others for whom this is not the case. Of course the difference among individuals could also reflect differences in renal excretion or production rather than differences in pulmonary production. These data clearly indicate that, during spontaneous, induced, or chronic stable asthma, at least in some individuals, there is enhanced urinary LTE4 excretion, and by inference an increased cysteinyl leukotriene production. Leukotriene receptor blockade and synthesis inhibition Two classes of pharmacological agents have been available for probing the role of cysteinyl leukotrienes in asthma: leukotriene receptor antagonists and leukotriene synthesis inhibitors. These agents have been used in clinical trials in human asthma. It is well established that there are at least two distinct receptors, termed the cysteinyl leukotriene receptors type 1 and type 2 (CysLT1 and CysLT2), for the cysteinyl leukotrienes in contractile tissue.42 Although over a dozen chemically distinct antagonists at the CysLT1 receptor have been recognized, only three have been introduced into the clinical marketplace; namely, pranlukast, zafirlukast, and montelukast. With regard to leukotriene synthesis inhibitors, agents have been developed which are direct inhibitors of 5-LO, such as zileuton,91 as well as agents that inhibit the interaction between arachidonic acid and 5-lipoxygenase activating protein (MK-0591 and Bay x1005).92,93 Inhibition of induced asthma A number of LTD4 receptor antagonists or synthesis inhibitors have been tested for their effects on the bronchospasm that accompanies asthma induced by an antigen, cold air, exercise, or aspirin in humans.88,94–116 Although there is variation among agents and protocols, all of the agents tested inhibit the asthmatic bronchospasm induced by exercise or cold air by 30–70%.These agents are also effective inhibitors of allergen-induced asthma; a 30–70% inhibition of the airway obstruction associated with the early allergen response is achieved. For reasons which are not clear, leukotriene receptor antagonists have been more effective than 5-lipoxygenase inhibitors in reducing the severity of laboratory-studied
allergen-induced asthma. Also in allergen-induced asthma with regard to 5-lipoxygenase inhibitors, FLAP antagonists have been somewhat more effective than direct inhibitors of 5-lipoxygenase in inhibiting allergen-induced asthma.103 Both leukotriene receptor antagonists and synthesis inhibitors have been very effective in preventing the physiological changes which accompany aspirin-induced asthma.96,101,102,117–120 Current data indicate that virtually all the physiological effects of aspirin-induced asthma derive from the action of the cysteinyl leukotreines. It is important to note that, although all the physiological effects of aspirininduced asthma derive from the effects of the leukotreines, this does not mean that anti-leukoriene treatment can prevent all the clinical manifestations of aspirin ingestion in patients with aspirin-sensitive asthma. Indeed, there have been reports of aspirin-induced asthma in patients receiving treatment with CysLT1 receptor antagonists.121,122 These findings are consistent with the known competitive nature of CysLT1 antagonists and the massive release of cysteinyl leukotrienes after aspirin-ingestion in patients with aspirininduced aspirin. Taken together, the above data indicate that inhibition of the synthesis or action of the leukotrienes is associated with an amelioration of the physiological changes that occur in laboratory-induced asthma. Leukotriene inhibition in chronic stable asthma The data reviewed above indicate that the leukotrienes mediate a portion of the physiological effects observed in induced asthma. If chronic stable asthma represents repeated occurrence of naturally occurring induced asthma episodes, then one could postulate that chronic stable asthma might be improved by treatment with such agents. Such improvement has been noted in multiple clinical trials in patients with mild-to-moderate chronic stable asthma reported in the archival literature.123–132 The general design of these trials has been similar. They have recruited and enrolled patients whose asthma was marginally controlled solely by use of inhaled b-agonists, who had FEV1 values most often between 40% and 80% of predicted, who had moderate asthma symptoms as judged from daily symptom diaries. Each trial incorporated a 1–3 week “run-in” period when all patients had their asthma control monitored while on single-blind oral placebo. During this period baseline lung function, b-agonist use, and symptom data were gathered. Patients then entered a period in which they received randomized treatment with an active agent or placebo. Patients returned on a regular basis to their clinical centers where their lung function and asthma symptom data were recorded; the results from these trials are summarized in Table 24.1. In each of these trials anti-leukotriene treatment was shown to be more effective than placebo in controlling asthma symptoms and asthma rescue medication use in improving lung function and in preventing asthma exacerbations. An example of the effect of anti-leukotriene on FEV1 in patients with chronic mild-to-moderate asthma is
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Leukotrienes
Table 24.1. Studies of leukotriene modifiers in patients with chronic persistent asthmaa
No. of patientsb Length of study Dose (oral) Baseline FEV1 (% of predicted) Trough improvement in FEV1 litresc Trough improvement in FEV1 per centc,d Peak improvement in FEV1d,e b-adrenergic agonist use reductiond Improvement in AM PEFRd Treatment failure or glucocorticoid rescue therapy (treatment vs placebo)f Decrease in symptoms: day/night (%)
Zafirlukast
Montelukast
Pranlukast
Zileuton
70 6 wk 20 mg b.i.d. 66% 0.23 Lg 11% (13–14%)g – 31% 6%
408 12 wk 10 mg q.d. 66% – – 13% 27%j 6.1%
45 6 wk 337.5 mg b.i.d. 66% ~0.31 Lg ~11.5%g,h – NC ~5%g
122 6 mo 600 mg q.d. 62% 0.34 L 15(18)% 20%i (23%)g (30%) 7.1% (8.5%)
2% vs 10% 28/46
– 20/NC
– NC/28
8.3% vs 21.5%g 36/33
a
Compared with pretreatment values. Only data from double-blind, randomized, and placebo-controlled studies are included. Although additional studies with each drug have been reported, the study chosen for display is representative. All values were statistically significant from placebo unless otherwise indicated. b Number of patients receiving active treatment at the dose indicated. Zafirlukast was administered at twice the currently recommended dose. c Trough values: values immediately before next dose or those values not reported as obtained at times of expected peak plasm concentrations or effects. d Figures not in parentheses represent means over the study period or end-point analyses. Figures in parentheses represent maximum effect among the study observation intervals reported. e Values recorded at or near time of drug’s expected peak plasma concentration or effects. f Treatment failure for zafirlukast; glucocorticoid rescue therapy for zileuton. g Derived from figures or statistics. h 225 mg dose. i End-point value: NS vs placebo at week 26. j Percentage difference compared with placebo. NC, no significant change; PEFR, peak expiratory flow rate. Reproduced from reference 143. © 1999 Massachusetts Medical Society. All rights reserved with permission.
shown in Fig. 24.2. Thus these trials established that leukotreines are important, but not the sole, mediators of the physiological and clinical events that characterize the asthmatic response.
LEUKOTRIENES IN COPD There are far fewer data concerning the role of leukotrienes in the pathogenesis of COPD than are available about this class of mediators in asthma. Introduction of leukotrienes into the microenvironment of the airway is associated with expression of mucus from glands.133,134 Thus if leukotrienes were to become available in the microenvironment of the airway they have the potential to contribute to aspects of the bronchotic phenotype. Leukotrienes have been recovered in greater quantities from the bronchoalveolar lavage fluid of patients with chronic bronchitis than from normal subjects.135,136 In addition to the release of mucus into the airways, there are data suggesting that LTB4 is involved in the neutrophil influx into the airway microenvironment that characterizes chronic bronchitis. Sputum obtained from
patients in the midst of an infective exacerbation of chronic bronchitis contained high levels of LTB4, which fell with treatment.137 In these samples LTB4 constituted about onethird of the total chemotactic activity at the time of disease presentation, and the importance of LTB4 as a chemotactic factor fell with antibiotic treatment. There are no data in the archival literature from studies in which agents active on various components of the 5lipoxygenase pathway have been studied on lung function in patients with COPD. Because of the potential importance of this pathway in this disorder it seems likely that such data may be acquired in the future.
CONCLUSIONS The available data support the following conclusions as to the role of leukotrienes in bronchial asthma and COPD: • They are produced by constitutive cells (mast cells/macrophages) and infiltrating cells (eosinophils, neutrophils) implicated in asthma and COPD.
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Zileuton, 600 mg Zileuton, 400 mg Placebo
15
20 † *
10 5 0
FEV1, % Change
FEV1, % Change
20
15
*
10 5 0 0
2
4
6
8
10
12
14
Treatment week Fig. 24.2. Mean percentage change in forced expiratory volume rate in the first second (FEV1) (SE) from prerandomization baseline during 13 weeks of treatment with 600 mg of zileuton, 400 mg of zileuton, or placebo, each given four times daily. Asterisk indicates P 0.05 vs placebo; and the dagger, P 0.01 vs placebo. Left panel, average FEV1 2–4 hours after drug ingestion (expected time of peak drug levels). Right panel, FEV1 before ingestion of morning dose of drug (expected time of low drug levels). Reproduced from reference 126, with permission.
• They are potent bronchoconstrictor agonists. • Their administration results in the expression of mucus from mucous glands. • Laboratory-induced asthma and spontaneous asthma or COPD is associated with an enhanced recovery of leukotrienes in the urine of subjects with asthma and sputum leukotrienes in COPD. • Asthma control is enhanced (compared with placebo) by agents capable of interfering with leukotriene action or synthesis. Similar data are not available for COPD. The data indicate that the leukotrienes play an important role in the asthmatic response.We are not sure of the importance of the pathogenetic role of the leukotrienes in COPD.
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71. Sladek K, Dworski R, Soja J et al. Eicosanoids in bronchoalveolar lavage fluid of aspirin-intolerant patients with asthma after aspirin challenge. Am. J. Respir. Crit. Care Med. 1994; 149:940–6. 72. Wenzel SE, Trudeau JB, Kaminsky DA et al. Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma. Am. J. Respir. Crit. Care Med. 1995; 152:897–905. 73. Kane GC, Pollice M, Kim CJ et al. A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings. J. Allergy Clin. Immunol. 1996; 97:646–54. 74. Okubo T, Takahashi H, Sumitomo M, Shindoh K, Suzuki S. Plasma levels of leukotrienes C4 and D4 during wheezing attack in asthmatic patients. Int. Arch. Allergy Appl. Immunol. 1987; 84:149–55. 75. Shindo K, Fukumura I, Miyakawa K. Plasma levels of leukotriene E4 during clinical course of bronchial asthma and the effect of oral prednisolone. Chest 1994; 105:1038–41. 76. Sampson AP, Castling DP, Green CP, Price JF. Persistent increase in plasma and urinary leukotrienes after acute asthma. Arch. Dis. Child 1995; 73:221–5. 77. Heavey DJ, Soberman RJ, Lewis RA, Spur B, Austen KF. Critical considerations in the development of an assay for sulfidopeptide leukotrienes in plasma. Prostaglandins 1987; 33:693–708. 78. Tagari P, Ethier D, Carry M et al. Measurement of urinary leukotrienes by reversed-phase liquid chromatography and radioimmunoassay. Clin. Chem. 1989; 35:388–91. 79. Taylor GW, Taylor I, Black P et al. Urinary leukotrienes E4 after antigen challenge and in acute asthma and allergic rhinitis. Lancet 1989; i:584–8. 80. Westcott JY, Johnston K, Batt RA, Wenzel SE, Voelkel NF. Measurement of peptidoleukotrienes in biological fluids. J. Appl. Physiol. 1990; 68:2640–8. 81. Wu YH, Li LYT, Henion JD, Krol GJ. Determination of LTE(4) in human urine by liquid chromatography coupled with ionspray tandem mass spectrometry. J. Mass. Spectrom. 1996; 31:987–93. 82. Mizugaki M, Hishinuma T, Suzuki N. Determination of leukotriene E-4 in human urine using liquid chromatography-tandem mass spectrometry. J. Chromatogr. B. 1999; 729:279–85. 83. Orning L, Kaijser L, Hammarstrom S. In-vivo metabolism of leukotriene C4 in man: urinary excretion of leukotriene E4. Biochem. Biophys. Res. Commun. 1985; 130:214–20. 84. Maltby NH, Taylor GW, Ritter JM et al. Leukotriene C4 elimination and metabolism in man. J. Allergy Clin. Immunol. 1990; 85:3–9. 85. Sladek K, Dworski R, Fitzgerald GA et al. Allergen-stimulated release of thromboxane A2 and leukotriene E4 in humans: effect of indomethacin. Am. Rev. Respir. Dis. 1990; 141:1441–5. 86. Tagari P, Rasmussen JB, Delorme D et al. Comparison of urinary leukotriene E4 and 16-carboxytetranordihydro leukotriene E4 excretion in allergic asthmatics after inhaled antigen. Eicosanoids 1990; 3:75–80. 87. Manning PJ, Rokach J, Malo JL et al. Urinary leukotriene E4 levels during early and late asthmatic responses. J. Allergy Clin. Immunol. 1990; 86:211–20. 88. Manning PJ, Watson RM, Margolskee DJ et al. Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N. Engl. J. Med. 1990; 323:1736–9. 89. Drazen JM, Obrien J, Sparrow D et al. Recovery of leukotriene-E4 from the urine of patients with airway obstruction. Am. Rev. Respir. Dis. 1992; 146:104–8. 90. Asano K, Lilly CM, Odonnell WJ et al. Diurnal variation of urinary leukotriene E4 and histamine excretion rates in normal subjects and patients with mild-to-moderate asthma. J. Allergy Clin. Immunol. 1995; 96:643–51. 91. Carter GW, Young PR, Albert DH et al. 5-lipoxygenase inhibitory activity of zileuton. J. Pharmacol. Exp.Ther. 1991; 256:929–37.
92. Depre M, Friedman B, Vanhecken A et al. Pharmacokinetics and pharmacodynamics of multiple oral doses of MK-0591, a 5lipoxygenase-activating protein inhibitor. Clin. Pharmacol. Ther. 1994; 56:22–30. 93. Gardiner PJ, Cuthbert NJ, Francis HP et al. Inhibition of antigeninduced contraction of guinea-pig airways by a leukotriene synthesis inhibitor,BAY x1005.Eur.J.Pharmacol. 1994;258:95–102. 94. Fuller RW, Black PN, Dollery CT. Effect of the oral leukotriene D4 antagonist LY171883 on inhaled and intradermal challenge with antigen and leukotriene D4 atopic subjects. J. Allergy Clin. Immunol. 1989; 83:939–44. 95. Israel E, Juniper EF, Callaghan JT et al. Effect of a leukotriene antagonist, LY171883, on cold air-induced bronchoconstriction in asthmatics. Am. Rev. Respir. Dis. 1989; 140:1348–53. 96. Christie L, Lee TH. The effects of SKF04353 on aspirin induced asthma. Am. Rev. Respir. Dis. 1991; 144:957–8. 97. Dahlen S, Dahlen B, Eliasson E et al. Inhibition of allergic bronchoconstriction in asthmatics by the leukotriene-antagonist ICI204,219. Adv. Prost.Thromb. Leuk. Res. 1991; 21A:461–4. 98. Taylor IK, O’Shaughnessy KM, Fuller RW, Dollery CT. Effect of cysteinyl-leukotriene receptor antagonist ICI 204,219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet 1991; 337:690–4. 99. Findlay SR, Barden JM, Easley CB, Glass M. Effect of the oral leukotriene antagonist, ICI-204,219, on antigen-induced bronchoconstriction in subjects with asthma. J.Allergy Clin. Immunol. 1992; 89:1040–5. 100. Finnerty JP, Wood-Baker R, Thomson H, Holgate ST. Role of leukotrienes in exercise-induced asthma: inhibitor effect of ICI 204,219, a potent LTD4 receptor antagonist. Am. Rev. Respir. Dis. 1992; 145:746–9. 101. Dahlen B, Kumlin M, Margolskee DJ et al. The leukotrienereceptor antagonist MK-0679 blocks airway obstruction induced by inhaled lysine-aspirin in aspirin-sensitive asthmatics. Eur. Respir. J. 1993; 6:1018–26. 102. Dahlen B, Margolskee DJ, Zetterstrom O, Dahlen SE. Effect of the leukotriene receptor antagonist MK-0679 on baseline pulmonary function in aspirin-sensitive asthmatic subjects. Thorax 1993; 48:1205–10. 103. Friedman BS, Bel EH, Buntinx A et al. Oral leukotriene inhibitor (MK-886) blocks allergen-induced airway responses. Am. Rev. Respir. Dis. 1993; 147:839–44. 104. Makker HK, Lau LC, Thomson HW, Binks SM, Holgate ST. The protective effect of inhaled leukotriene-D4 receptor antagonist ICI-204,219 against exercise-induced asthma. Am. Rev. Respir. Dis. 1993; 147:1413–18. 105. O’Shaughnessy KM, Taylor IK, O’Connor B et al. Potent leukotriene-D(4) receptor antagonist ICI-204,219 given by the inhaled route inhibits the early but not the late phase of allergen-induced bronchoconstriction. Am. Rev. Respir. Dis. 1993; 147:1431–5. 106. Dahlen B, Zetterstrom O, Bjorck T, Dahlen SE. The leukotrieneantagonist ICI-204,219 inhibits the early airway reaction to cumulative bronchial challenge with allergen in atopic asthmatics. Eur. Respir. J. 1994; 7:324–31. 107. Diamant Z, Timmers MC, Vanderveen H et al. The effect of MK0591, a novel 5-lipoxygenase activating protein inhibitor, on leukotriene biosynthesis and allergen-induced airway responses in asthmatic subjects in vivo. J. Allergy Clin. Immunol. 1995; 95:42–51. 108. Bronsky EA, Kemp JP, Zhang J, Guerreiro D, Reiss TF. Doserelated protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval. Clin. Pharmacol. Ther. 1997; 62:556–61. 109. Dahlen B, Nizankowska E, Szczeklik A et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am. J. Respir. Crit. Care Med. 1998; 157:1187–94.
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110. Edelman JM,Turpin JA, Bronsky EA et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction: a randomized, double-blind trial. Ann. Intern. Med. 2000; 132:97–104. 111. Hamilton A, Faiferman I, Stober P, Watson RM, O’Byrne PM. Pranlukast, a cysteinyl leukotriene receptor antagonist, attenuates allergen-induced early- and late-phase bronchoconstriction and airway hyperresponsiveness in asthmatic subjects. J. Allergy Clin. Immunol. 1998; 102:177–83. 112. Kemp JP, Dockhorn RJ, Shapiro GG et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-yearold children with asthma. J. Pediatr. 1998; 133:424–8. 113. Leff JA, Busse WW, Pearlman D et al. Montelukast, a leukotrienereceptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N. Engl. J. Med. 1998; 339:147–52. 114. Meltzer SS, Hasday JD, Cohn J, Bleecker ER. Inhibition of exercise-induced bronchospasm by zileuton: a 5-lipoxygenase inhibitor. Am. J. Respir. Crit. Care Med. 1996; 153:931–5. 115. Reiss TF, Hill JB, Harman E et al. Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 1997; 52:1030–5. 116. Villaran C, O’Neill SJ, Helbling A et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. J. Allerg. Clin. Immunol. 1999; 104:547–53. 117. Christie PE, Smith CM, Lee TH. The potent and selective sulfidopeptide leukotriene antagonist, SK&F 104353, inhibits aspirin-induced asthma. Am. Rev. Respir. Dis. 1991; 144:957–8. 118. Israel E, Fischer AR, Rosenberg MA et al. The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am. Rev. Respir. Dis. 1993; 148:1447–51. 119. Nasser SMS, Lee TH. Aspirin-induced early and late asthmatic responses. Clin. Exper. Allergy 25:1–3. 120. Nasser SM, Bell GS, Foster S et al. Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. Thorax 1994; 49:749–56. 121. Menendez R, Venzor J, Ortiz G. Failure of zafirlukast to prevent ibuprofen-induced anaphylaxis. Ann. Allergy Asthma Immunol. 1998; 80:225–6. 122. Enrique E, Garcia Ortega P, Gaig P, San Miguel MM. Failure of montelukast to prevent anaphylaxis to diclofenac. Allergy 1999; 54:529–30. 123. Cloud ML, Enas GC, Kemp J et al. A specific LTD4/LTE4-receptor antagonist improves pulmonary function in patients with mild, chronic asthma. Am. Rev. Respir. Dis. 1989; 140: 1336–9. 124. Israel E, Rubin P, Kemp JP et al. The effct of inhibition of 5lipoxygenase by zileuton in mild to moderate asthma. Ann. Intern. Med. 1993; 119:1059–66. 125. Spector SL, Smith LJ, Glass M et al. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Am. J. Respir. Crit. Care Med. 1994; 150:618–23. 126. Israel E, Cohn J, Dube L, Drazen JM. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma: a randomized controlled trial. JAMA 1996; 275:931–6. 127. Reiss TF, Altman LC, Chervinsky P et al. Effects of montelukast (MK-0476), a new potent cysteinyl leukotriene (LTD4) recep-
128.
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tor antagonist, in patients with chronic asthma. J. Allergy Clin. Immunol. 1996; 98:528–34. Liu MC, Dube LM, Lancaster J. Acute and chronic effects of a 5lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. J. Allergy Clin. Immunol. 1996; 98:859–71. Barnes NC, Pujet JC. Pranlukast, a novel leukotriene receptor antagonist: results of the first European, placebo controlled, multicentre clinical study in asthma. Thorax 1997; 52: 523–7. Grossman J, Faiferman I, Dubb JW et al. Results of the first US double-blind, placebo-controlled, multicenter clinical study in asthma with pranlukast, a novel leukotriene receptor antagonist. J. Asthma 1997; 34:321–8. Reiss TF, Chervinsky P, Dockhorn RJ et al. Montelukast, a oncedaily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Monelukast Clinical Research Study Group. Arch. Intern. Med. 1998; 158:1213–20. Knorr B, Matz J, Bernstein JA et al. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, doubleblind trial. JAMA 1998; 279:1181–6. Coles SJ, Neill KH, Reid LM et al. Effects of leukotrienes C4 and D4 on glycoprotein and lysozyme secretion by human bronchial mucosa. Prostaglandins 1983; 25:155–70. Piacentini GL, Kaliner MA. The potential roles of leukotrienes in bronchial asthma. Am. Rev. Respir. Dis. 1991; 143:S96–9. Wardlaw AJ, Hay H, Cromwell O, Collins JV, Kay AB. Leukotrienes, LTC4 and LTB4, in bronchoalveolar lavage in bronchial asthma and other respiratory diseases. J. Allergy Clin. Immunol. 1989; 84:19–26. Efimov W, Blazhko VI,Voeikova LS, Karanysheva SA, Bondar TN. The leukotriene B4 content of the bronchoalveolar lavage fluid and the function of the prostacyclin–thromboxane system in patients with variants of chronic bronchitis. Terapevticheskii Arkhiv 1990; 62:94–6. Crooks SW, Bayley DL, Hill SL, Stockley RA. Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur. Respir. J. 2000; 15:274–80. Barnes N, Piper PJ, Costello J. The effect of an oral leukotriene antagonist L-649,923 on histamine and leukotriene D4induced bronchoconstriction in normal man. J. Allergy Clin. Immunol. 1987; 79:816–21. Phillips GD, Rafferty P, Robinson C, Holgate ST. Dose-related antagonism of leukotriene D4-induced bronchoconstriction by p.o. administration of LY-171883 in nonasthmatic subjects. J. Pharmacol. Exp.Ther. 1988; 246:732–8. Evans JM, Barnes NC, Zakrzewski JT et al. L-648,051, a novel cysteinyl-leukotriene antagonist is active by the inhaled route in man. Br. J. Clin. Pharmacol. 1989; 28:125–35. Smith LJ, Geller S, Ebright L, Glass M, Thyrum PT. Inhibition of leukotriene D4-induced bronchoconstriction in normal subjects by the oral LTD4 receptor antagonist ICI 204,219. Am. Rev. Respir. Dis. 1990; 141:988–92. Kips JC, Joos GF, Delepeleire I et al. MK-571, a potent antagonist of leukotriene D4-induced bronchoconstriction in the human. Am. Rev. Respir. Dis. 1991; 144:617–21. Drazen JM, Israel E, O’Byrne P. Treatment of asthma with drugs modifying the leukotriene pathway. N. Engl. J. Med. 1999; 340:197–206.
Chapter
Kinins
25
David Proud Johns Hopkins University School of Medicine, Baltimore, MD, USA
Kinins are potent vasoactive peptides that are generated during inflammatory events in vivo. It is over 50 years since the nonapeptide, bradykinin, and its analog lysylbradykinin were first discovered.1,2 In the intervening years, major progress has been made in delineating the pharmacological properties of kinins and in understanding the biochemical pathways by which these peptides are formed and metabolized in humans. Moreover, evidence has accumulated to suggest that kinins may be important mediators during inflammatory diseases of the airways. Since there have been virtually no studies on the role of kinins in chronic obstructive pulmonary disease (COPD), the present chapter reviews current knowledge of the potential role of kinins in airway inflammation and in asthma.
S T R U C T U R E , F O R M AT I O N , A N D M E TA B O L I S M O F K I N I N S Kinins are generated from a2-globulin precursor proteins called kininogens. The two kininogens found in humans, high-molecular-weight (HMW) kininogen and lowmolecular-weight (LMW) kininogen, are synthesized in the liver from a single gene as a consequence of alternative RNA splicing.3 HMW kininogen represents approximately one-third of the kininogen in blood, while LMW kininogen constitutes the remaining two-thirds. The total level of kininogen in human blood is adequate to permit the generation of approximately 2 lmol/L of bradykinin. Despite the presence of such huge pools of circulating precursors, it is now generally accepted that kinins are not circulating hormones, and that generation does not occur on a systemic basis except under conditiions of profound pathology, such as septic shock. Rather, kinin generation occurs primarily at local sites, either by activation of kininogens that are known to be present in the interstitium and lymph,4 or as a result of local increased vascular permeability and influx of plasma proteins. Once vascular leakage is initiated, the availability of large levels of plasma kininogens could then support chronic kinin generation at a local inflammatory site.
Enzymes that release kinins from kininogens are referred to collectively as kininogenases. Although plasmin, trypsin, and mast cell tryptase5 are capable of generating bradykinin in vitro, these enzymes are likely to play little role in kinin generation in vivo. The historical name, “kallikrein”, is still used to refer to the most physiologically important kininogenases from blood (plasma kallikrein) and from the major exocrine organs (tissue, or glandular, kallikrein).This shared nomenclature is unfortunate, because the plasma and tissue enzymes are derived from different genes and are biochemically and immunologically distinct from each other. Plasma kallikrein is synthesized in the liver and exists in the blood as a single-chain c-globulin zymogen, prekallikrein, which circulates as a complex with HMW kininogen.6 Activation of prekallikrein to kallikrein in vivo occurs principally as a result of the factor XII-dependent process, referred to as contact activation.7 In this process, kallikrein is generated by the interaction of prekallikrein, HMW kininogen, and factor XII with certain negatively charged surfaces. Once produced, kallikrein is then in close proximity to interact with its preferred substrate, HMW kininogen, to release bradykinin.8 The kallikrein is then rapidly inactivated by interactions with the plasma protease inhibitors, C1inactivator and a2-macroglobulin. While plasma kallikrein acts only on HMW kininogen to generate bradykinin, human tissue kallikreins are unique in that they hydrolyze two dissimilar bonds (Arg-Ser and Met-Lys) within either HMW or LMW kininogen to release lysylbradykinin. Tissue kallikreins are known to be widely distributed in exocrine and endocrine tissues.7 This includes both the upper and lower airways in humans,9,10 where it is localized primarily to the serous cells of submucosal glands.11 Levels of tissue kallikrein are increased in airway secretions of asthmatic, compared with normal, subjects.10,12 There are no effective, naturally occurring inhibitors of tissue kallikreins in humans, such that the activity of this enzyme in airway secretions lasts for many hours.13 The ability of tissue kallikreins to generate kinins from both HMW and LMW kininogens provides it with more available substrate than plasma kallikrein. This, together with its resistance to inhibition, suggests that tissue
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kallikrein may be of particular importance in kinin generation in asthma. It is also of interest, therefore, that quantitative trait locus mapping studies found that airway hyperresponsiveness in an inbred mouse model of asthma was linked to an area of chromosome 7 that maps closely to the murine tissue kallikrein gene.14 Moreover, two wholegenome scans in humans found linkage, in Caucasian populations, between asthma susceptibility and an area on chromosome 19q13 that maps close to the human tissue kallikrein gene.15,16 Once kinins are formed in vivo, metabolic degradation is a major mechanism for regulating their actions. Virtually all tissues and biological fluids contain enzymes (kininases) that are capable of degrading kinins. Hydrolysis of any of the peptide bonds within the bradykinin moiety leads to a loss of biological activity. Although many enzymes can degrade kinins in vitro, those kininases that are believed to be the most important regulators of these peptides during airway inflammation in humans are shown in Fig. 25.1. These peptidases are either derived from plasma and enter the airway mucosa by transudation during inflammatory events, or are present on the surface of structural cells within the airway. Hydrolysis of kinins by plasma peptidases has been reasonably well delineated, but the full profile of cells in the airways expressing kinases remains to be determined. One peptidase that is present in the airways cleaves lysylbradykinin without any resultant loss of biological activity. Aminopeptidase M, which is present on the surface of respiratory epithelial cells,17 but which can also enter by plasma transudation during inflammatory events,18 converts lysylbradykinin to bradykinin via removal of the N-terminal lysine. The major plasma enzymes that would contribute to kinin degradation are carboxypeptidase N (kininase 1) and angiotensinconverting enzyme (ACE; kininase 2). Carboxypeptidase N-like activity has been shown to enter airway secretions from plasma during allergic inflammation,18 and degrades kinins by removal of the C-terminal
Aminopeptidase M
LYS-ARG-PRO-PRO-GLY-PHE-SER-PRO-PHE-ARG (lysylbradykinin/kallidin)
Aminopeptidase P
Angiotensin converting enzyme (kininase 2)
ARG-PRO-PRO-GLY-PHE-SER-PRO-PHE-ARG (bradykinin)
Neutral endopeptidase
Carboxypeptidase N (kininase 1)
Fig. 25.1. Structure of bradykinin and lysylbradykinin and the sites of hydrolysis of these peptides by some of the major kininases.
arginine residue to produce the putative B1 receptor agonists des-Arg9-bradykinin and des-Arg10-lysylbradykinin (see below). Lower levels of ACE also enter the airway mucosa from plasma, although the major source of this enzyme is the surface of structural cells. ACE degrades kinins by sequential removal of C-terminal dipeptides, and will also degrade des-Arg-kinins by removal of the C-terminal tripeptide. Interestingly, decreased epithelial expression of ACE has been observed in asthmatic subjects.19 In addition, a polymorphism has been described that is caused by a 287 bp insertion (I) or deletion (D) in intron 16 of the ACE gene.20 Although it has been reported that the D allele occurs with increased frequency in asthmatic subjects,21 several other studies have failed to find any association between asthma and ACE gene polymorphism.22–24 The other major peptidase in the airways is neutral endopeptidase, which is present on the surface of respiratory epithelial cells, as well as other structural cells, and which hydrolyzes and inactivates kinins to release the C-terminal depeptide.17,25
KININ RECEPTORS Bradykinin and lysylbradykinin display essentially identical pharmacological properties. Some minor differences in potency are observed in intact tissues, probably reflecting variations in rates of metabolism. Kinins exert their actions via two subtypes of receptors, originally defined in animal tissues.26 In this original definition, the B1 kinin receptor was characterized by the fact that the carboxypeptidase metabolites of kinins, des-Arg9-bradykinin and des-Arg10-lysylbradykinin, are more potent agonists than their parent peptides, and their actions are antagonized by Leu8-desArg9-bradykinin. On the B2 receptor, bradykinin and lysylbradykinin are equipotent, but the carboxypeptidase metabolites are completely inactive. The existence of these two subtypes of kinin receptors has since been confirmed. Selective antagonists have been developed,27–31 and both human kinin receptors have been cloned.32,33 The two human receptors show only 36% sequence homology, with most of this in the putative transmembrane regions. The genes for both human kinin receptors are located in close proximity to one another on chromosome 14q32.34,35 Several polymorphisms have been identified in the human B2 kinin receptor gene,36,37 and one such polymorphism has been associated with hereditary angioedema.37 To date, however, there have been no reports of associations of any kinin receptor polymorphism with airway diseases. Studies with the cloned human B1 receptor have revealed that, in contrast to the receptor from animal species, desArg9-bradykinin is an ineffective ligand, and it is clear that des-Arg10-lysylbradykinin is the natural ligand.33,38 Although both B1 and B2 kinin receptors couple to the Gq and Gai members of the G protein family,38 there are striking differences in the properties of these two receptors (Table 25.1). For example, while the B2 receptor is constitutively expressed on many cells and tissues,39 B1 receptor expression requires
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Table 25.1. Comparative properties of human B1 and B2 kinin receptors
B1 receptor
B2 receptor
De-novo synthesized Limited distribution Ligand: des-Arg10-lysylbradykinin Slow ligand dissociation No receptor sequestration No/partial desensitization Upregulation upon long-term stimulation
Constitutively expressed Ubiquitous Ligand: bradykinin/lysylbradykinin Rapid ligand dissociation Ligand-induced receptor sequestration Complete desensitization Downregulation upon long-term stimulation
induction by any of several stimuli, including bacterial lipopolysaccharide and proinflammatory cytokines.26,40 Moreover, the B2 receptor is rapidly internalized and sequestered upon stimulation with bradykinin, a property that is conferred by information provided by the cytoplasmic tail of the receptor.41 By contrast, the B1 receptor does not undergo ligand-induced internalization or desensitization.38 Thus, once the receptor is induced by proinflammatory stimuli, functional responses can continue unabated as long as ligand is present. These properties have raised considerable interest in the potential role of the B1 receptor in inflammatory events (see below).
K I N I N F O R M AT I O N A N D A C T I O N S I N T H E A I R WAY S Kinin generation has been demonstrated during several types of airway inflammation in both the upper and lower airways of humans.42 In the lower airways, endobronchial challenge of allergic asthmatic subjects with allergen leads to increased kinin generation during both early and late-phase reactions.12,43 A detailed analysis during allergic inflammation in the upper airways showed that both bradykinin and lysylbradykinin are produced, and that both plasma and tissue kallikreins are activated.9,44,45 Kinin levels are also increased in bronchoalveolar lavage fluids, obtained without any challenge procedures, from subjects with active asthma compared with those from healthy controls.10 To date, there has been no rigorous examination of kinin generation in subjects with COPD, but analysis of lavage fluid from a single subject with chronic bronchitis found evidence of elevated levels of both tissue kallikrein activity and of kinins.10 Although kinins may be expected to exert several actions in the airways, most studies have focused on its effects on airway smooth muscle tone. The effects of bradykinin on isolated airway smooth muscle vary depending upon the species being examined. In humans, however, bradykinin is, at best, a very weak constrictor of isolated large human airways.46–49 Although it has been reported that bronchial strips from patients with chronic airflow obstruction show enhanced sensitivity to bradykinin,47 this has not been
confirmed in other studies and responses were still observed only at very high concentrations of the peptides. Isolated peripheral human airways (<2 mm diameter) are contracted by bradykinin via a cycloxygenase-dependent mechanism, but the maximal contraction observed is still only about 30% of that induced by cholinergic agonists.49,50 Despite the minimal effects of bradykinin on airway smooth muscle in vitro, bradykinin can have profound effects in vivo, depending upon the subject population and the route of administration. To date, there have been no studies on the effects of bradykinin on airway function in subjects with COPD. When administered intravenously to asthmatic subjects, bradykinin causes a modest, transient fall in airway function that has been suggested to be due to alveolar duct constriction.48 Given the very short half-life of bradykinin in the systemic circulation, in most studies the peptide has been administered by inhalation. Under these conditions, bradykinin is a potent bronchoconstrictor in asthmatic, but not normal, subjects.51–53 Inhaled bradykinin also induces retrosternal discomfort and cough in both normal and asthmatic subjects.52 When administered to the peripheral airways, bradykinin increases plasma transudation in both normal and asthmatic subjects but increases peripheral airway resistance only in the asthmatic population. Interestingly, reactivity in the peripheral airways does not correlate with whole lung reactivity to bradykinin in the same subjects.54 Increased kinin generation in asthmatic airways would lead to additional effects beyond modulating airway tone. Kinins increase ciliary beat frequency via a prostaglandindependent pathway.55 They can also increase the volume of airway secretions by three different mechanisms: • increasing glandular secretion via stimulation of neuronal reflexes;56,57 • increasing vascular permeability and transudation of plasma;54 • increasing transepithelial water transport as a consequence of stimulating epithelial chloride secretion.58 Kinins may also contribute to the continued inflammatory response by release of other proinflammatory molecules from structural cells in the airways. It has been known for
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many years that kinins can stimulate the production of several lipid mediators from a variety of cell types.39 More recent data also demonstrate that bradykinin can induce the production of cytokines, such as IL-1 and IL-8, from airway epithelial cells, fibroblasts, and smooth muscle cells.59–61
MECHANISMS OF ACTION The lack of any pronounced direct effects of kinins on isolated human airway smooth muscle suggests that bradykinin-induced bronchoconstriction in vivo occurs via indirect mechanisms. Bradykinin-induced bronchoconstriction is not inhibited by administration of cycloxygenase inhibitors,52,53 or antihistamines.53 This latter finding is consistent with observations that bradykinin is not a secretagogue for human mast cells.62 Interestingly, bronchoconstriction induced by bradykinin is exacerbated by prior administration of an inhibitor of nitric oxide (NO) synthases,63 indicating that NO normally serves to inhibit bronchoconstriction induced by bradykinin. The source/ isoform of NO synthase responsible for these actions has yet to be elucidated. Although the exact mechanism by which bradykinin causes bronchoconstriction remains to be defined, growing evidence implies that neural reflexes are involved. Moreover, the ability of bradykinin to induce these neural reflexes seems to be restricted to inflammed airways. This is supported by the inability of bradykinin to induce bronchoconstriction in normal subjects, and by the observation that airway reactivity to bradykinin correlates with the degree of airway eosinophilic inflammation.64,65 Furthermore, recent studies have shown that exacerbation of airway inflammation by allergen provocation increases airway reactivity to bradykinin to a much greater degree than that to methacholine.66 Conversely, reducing inflammation by administration of inhaled corticosteroids profoundly reduces airway reactivity to bradykinin in asthmatic subjects, while only modestly affecting reactivity to the direct smooth muscle spasmogen, methacholine.67 The ability of bradykinin to evoke cough indicates that sensory nerves are stimulated in the airway, and the tachyphylactic response to repeated challenge that has been noted in some studies would be consistent with neuronal desensitization.68 The ability of ipratropium bromide to inhibit bradykinin-induced bronchoconstriction in a limited number of subjects indicates a role for cholinergic reflexes.52 This concept is further supported by studies in the human upper airways, where subjects with active allergic inflammation show hyperreactivity to bradykinin. This hyperreactivity is due to the stimulation of neuronal reflexes, including central cholinergic reflexes, that do not occur in normal, noninflamed airways.57 These data, together with the observation that bradykinin causes bronchoconstriction in dogs by vagal reflex following stimulation of bronchial C-fibers,69 suggest that the bronchoconstrictive effects of bradykinin in humans may also
involve sensory stimulation, induction of parasympathetic reflexes and, possibly, concomitant release of neuropeptides. The relationship between airway inflammation and the ability of kinins to trigger bronchoconstriction raises the issue of whether the actions of kinins could be mediated via induction of B1 kinin receptors. Interestingly, a B1 receptor antagonist has been shown to inhibit allergen-induced airway hyperresponsiveness to acetylcholine in a rat model.70 However, a double-blind comparison of airway reactivity of asthmatic subjects to bradykinin and the specific human B1 receptor agonist, des-Arg10-lysylbradykinin, demonstrated that, even in subjects with good sensitivity to bradykinin, the B1 receptor agonist caused no bronchoconstriction. Similarly, des-Arg10-lysylbradykinin did not induce glandular secretion or increased vascular permeability in inflamed human airways.71 Thus, the actions of bradykinin in the asthmatic airways are predominantly induced via effects at B2 receptors.
I N T E RV E N T I O N S T U D I E S To definitively establish the role of kinins in airway diseases, it is obviously necessary to intervene using specific pharmacological agents and demonstrate a concomitant effect on symptoms. An inhibitor of tissue kallikrein was shown to reduce airways resistance and eosinophilia in an animal model of allergic inflammation,72,73 but such compounds have not been tested in humans. The only approach used to evaluate the role of kinins in airway disease in humans has been the use of successive generations of selective B2 kinin receptor antagonists. Although the first compound examined, NPC 567, was shown to inhibit both antigen-induced hyperreactivity and the late-phase response in a sheep model of allergen challenge,74,75 it was of low potency and was readily susceptible to enzymatic degradation. Indeed, when administered to the human upper airways, NPC 567 was ineffective at blocking the response to bradykinin challenge.76 The second generation of B2 antagonists, exemplified by Hoe 140 (icatibant), were significantly more potent and resistant to degradation.29 This compound still suffered from a relatively short half-life in the airways, however, most probably due to mucociliary clearance.77 Despite this limitation, and some concerns with study design, Hoe 140 did have beneficial effects when administered for 4 weeks to moderately severe asthmatic patients. Pulmonary function (FEV1 and peak flow) was significantly improved in patients receiving Hoe 140. Although symptom scores were also improved, this failed to achieve statistical significance. Interestingly, both pulmonary function values and symptom scores were still improving when treatment was stopped after 4 weeks.78 Given these results, and the fact that third-generation (nonpeptide) bradykinin antagonists are now in development,30,31 it will be of interest to use such compounds to more clearly delineate the role of kinins in the pathogenesis of asthma and of other inflammatory diseases of the airways.
Kinins
REFERENCES 1. Werle E, Götze W, Keppler A. Über die wirkung des kallikreins auf den isolierten darm une über eine neue darmkontrahierende substanz. Biochem. Z. 1937; 281:217–33. 2. Roche e Silva M, Beraldo WT, Rosenfield G. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globin by snake venoms and by trypsin. Am. J. Physiol. 1949; 156:261–73. 3. Kitamura N, Kitagawa H, Fukushima D et al. Structural organization of the kininogen gene and a model for its evolution. J. Biol. Chem. 1985; 260:8610–17. 4. Proud D, Nakamura S, Carone FA et al. Kallikrein–kinin and renin–angiotensin systems in rat renal lymph. Kidney Int. 1984; 25:880–5. 5. Proud D, Siekierski ES, Bailey GS. Identification of human lung mast cell kininogenase as tryptase and relevance of tryptase kininogenase activity. Biochem. Pharmacol. 1988; 37:1473–80. 6. Mandle RJJ, Colman RW, Kaplan AP. Identification of prekallikrein and HMW-kininogen as a circulating complex in human plasma. Proc. Natl Acad. Sci. USA 1976; 73:4179–83. 7. Proud D, Kaplan AP. Kinin formation: mechanisms and role in inflammatory disorders. Annu. Rev. Immunol. 1988; 6:49–83. 8. Pierce JV, Guimaraes JA. Further characterization of highly purified human plasma kininogens. In: Pisano JJ, Austen KF (eds), Chemistry and Biology of the Kallikrein–Kinin System in Health and Disease, pp. 121–7. Washington, DC: DHEW publ. no. (NIH)76-791, 1976. 9. Baumgarten CR, Nichols RC, Naclerio RM, Proud D. Concentrations of glandular kallikrein in human nasal secretions increase during experimentally induced allergic rhinitis. J. Immunol. 1986; 137:1323–8. 10. Christiansen SC, Proud D, Cochrane CG. Detection of tissue kallikrein in the bronchoalveolar lavage fluid of asthmatic subjects. J. Clin. Invest. 1987; 79:188–97. 11. Proud D, Vio CP. Localization of immunoreactive tissue kallikrein in human trachea. Am. J. Respir. Cell Mol. Biol. 1993; 8:16–19. 12. Christiansen SC, Proud D, Sarnoff RB et al. Elevation of tissue kallikrein and kinin in the airways of asthmatic subjects after endobronchial allergen challenge. Am. Rev. Respir. Dis. 1992; 145:900–5. 13. Christiansen SC, Zuraw BL, Proud D, Cochrane CG. Inhibition of human bronchial kallikrein in asthma. Am. Rev. Respir. Dis. 1989; 139:1125–31. 14. De Sanctis GT, Singer JB, Jiao A et al. Quantitative trait locus mapping of airway responsiveness to chromosomes 6 and 7 in inbred mice. Am. J. Physiol. 1999; 277:L1118–23. 15. The Collaborative Study on the Genetics of Asthma. A genomewide search for asthma susceptibility loci in ethnically diverse populations. Nat. Genet. 1997; 15:389–92. 16. Ober C, Cox NJ, Abney M et al. Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma. Hum. Mol. Genet. 1998; 7:1393–8. 17. Proud D, Subauste MC, Ward PE. Glucocorticoids do not alter peptidase expression on a human bronchial epithelial cell line. Am. J. Respir. Cell Mol. Biol. 1994; 11:57–65. 18. Proud D, Baumgarten CR, Naclerio RM, Ward PE. Kinin metabolism in human nasal secretions during experimentally induced allergic rhinitis. J. Immunol. 1987; 138:428–34. 19. Roisman GL, Danel CJ, Lacronique JG, Alhenc-Gelas F, Dusser DJ. Decreased expression of angiotensin-converting enzyme in the airway epithelium of asthmatic subjects is associated with eosinophil inflammation. J. Allergy Clin. Immunol. 1999; 104:402–10. 20. Hubert C, Houot AM, Corvol P, Soubrier F. Structure of the angiotensin-1 converting enzyme gene. J. Biol. Chem. 1991; 266:15377–83.
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21. Benessiano J, Crestani B, Mestari F et al. High frequency of a deletion polymorphism of the angiotensin converting enzyme gene in asthma. J. Allergy Clin. Immunol. 1997; 99:52–7. 22. Tomita H, Sato S, Matsuda R et al. Genetic polymorphism on the angiotensin-converting enzyme (ACE) in asthmatic patients. Respir. Med. 1998; 92:1305–10. 23. Chagani T, Paré PD, Zhu S et al. Prevalence of tumor necrosis factor-alpha and angiotensin converting enzyme polymorphism in mild/moderate and fatal/near-fatal asthma. Am. J. Respir. Crit. Care Med. 1999; 160:278–82. 24. Lee YC, Cheon KT, Lee HB et al. Gene polymorphisms of endothelial nitric oxide synthase and angiotensin-converting enzyme in patients with asthma. Allergy 2000; 55:959–63. 25. Erdös EG, Skidgel RA. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. FASEB J. 1989; 3:145–51. 26. Regoli D, Barabe J. Pharmacology of bradykinin and related kinins. Pharmacol. Rev. 1980; 32:1–46. 27. Marceau F. Kinin B1 receptors: a review. Immunopharmacology 1995; 30:1–26. 28. Vavrek RJ, Stewart JM. Competitive antagonists of bradykinin. Peptides 1985; 6:161–4. 29. Wirth K, Hock FJ, Albus U et al. Hoe 140, a new potent and longacting bradykinin-antagonist: in-vivo studies. Br. J. Pharmacol. 1991; 102:774–7. 30. Asano M, Inamura N, Hatori C et al.The identification of an orally active, nonpeptide bradykinin B2 receptor antagonist, FR173657. Br. J. Pharmacol. 1997; 120:617–24. 31. Pruneau D, Luccarini J-M, Fouchet C et al. LF16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B2 receptor. Br. J. Pharmacol. 1998; 125:365–72. 32. Hess JF, Borkowski JA, Young GS, Strader CD, Ransom RW. Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor. Biochem. Biophys. Res. Commun. 1992; 184:260–8. 33. Menke JG, Borkowski JA, Bierilo KK et al. Expression cloning of a human B1 bradykinin receptor. J.Biol.Chem. 1994; 269:21583–6. 34. Ma J, Wang D, Ward DC et al. Structure and chromosomal localization of the gene (BDKRB2) encoding human bradykinin B2 receptor. Genomics 1994; 23:362–9. 35. Chai KX, Ni A, Wang D et al. Genomic DNA sequence, expression, and chromosomal localization of the human B1 bradykinin receptor gene BDKRB1. Genomics 1996; 31:51–7. 36. Braun A, Kammerer S, Böhme E, Müller B, Roscher AA. Identification of polymorphic sites of the human bradykinin B2 receptor gene. Biochem. Biophys. Res. Commun. 1995; 211:234–40. 37. Lung C-C, Chan EKL, Zuraw BL. Analysis of an exon 1 polymorphism of the B2 bradykinin receptor gene and its transcript in normal subjects and patients with C1 inhibitor deficiency. J. Allergy Clin. Immunol. 1997; 99:134–46. 38. Austin CE, Faussner A, Robinson HE et al. Stable expression of the human kinin B1 receptor in Chinese Hamster ovary cells: characterization of ligand binding and effector pathways. J. Biol. Chem. 1997; 272:11420–5. 39. Bathon JM, Proud D. Bradykinin antagonists. Annu. Rev. Pharmacol.Toxicol. 1991; 31:129–62. 40. Davis AJ, Perkins MN. The involvement of bradykinin B1 and B2 receptor mechanisms in cytokine-induced mechanical hyperalgesia in the rat. Br. J. Pharmacol. 1994; 113:63–8. 41. Faussner A, Proud D, Towns M, Bathon JN. Influence of the cytosolic carboxy termini of human B1 and B2 kinin receptors on receptor sequestration, ligand internalization and signal transduction. J. Biol. Chem. 1998; 272:2617–23. 42. Proud D. The kinin system in rhinitis and asthma. Clin. Rev. Allergy Immunol. 1998; 16:351–64. 43. Liu MC, Hubbard WC, Proud D et al. Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics: cellular, mediator, and permeability changes. Am. Rev. Respir. Dis. 1991; 144:51–8.
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44. Proud D, Togias A, Naclerio RM et al. Kinins are generated in vivo following nasal airway challenge of allergic individuals with allergen. J. Clin. Invest. 1983; 72:1678–85. 45. Baumgarten CR, Nichols RC, Naclerio RM et al. Plasma kallikrein during experimentally induced allergic rhinitis: role in kinin formation and contribution to TAME-esterase activity in nasal secretions. J. Immunol. 1986; 137:977–82. 46. Bhoola KD, Collier HOJ, Schachter M, Shorley PG. Actions of some peptides on bronchial muscle. Br. J. Pharmacol. 1962; 19:190–7. 47. Simonsson BG, Skoogh B-E, Bergh NP, Andersson R, Svedmyr N. In-vivo and in-vitro effects of bradykinin on bronchial motor tone in normal subjects and patients with airway obstruction. Respiration 1973; 30:378–88. 48. Newball HH, Keiser HR, Webster ME, Pisano JJ. Effects of bradykinin on human airways. In: Pisano JJ, Austen KF (eds), Chemistry and Biology of the Kallikrein–Kinin System in Health and Disease, pp. 505–11. Washington, DC: DHEW publ. no. (NIH)76-791, 1976. 49. Molimard M, Martin CAE, Naline E, Hirsch A, Advenier C. Contractile effects of bradykinin on the isolated human small bronchus. Am. J. Respir. Crit. Care Med. 1994; 149:123–7. 50. Hulsmann AR, Raatgep HR, Saxena PR, Kerrebijn KF, De Jongste JC. Bradykinin-induced contraction of human peripheral airways mediated by both bradykinin B2 and thromboxane prostanoid receptors. Am. J. Respir. Crit. Care Med. 1994; 150: 1012–18. 51. Herxheimer H, Streseman E. The effects of bradykinin aerosol in guinea pigs and man. J. Physiol. Lond. 1961; 158:38–9. 52. Fuller RW, Dixon CMS, Cuss FMC, Barnes PJ. Bradykinininduced bronchoconstriction in humans: mode of action. Am. Rev. Respir. Dis. 1987; 135:176–80. 53. Polosa R, Philips GD, Lai CKW, Holgate ST. Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma. Allergy 1990; 45:174–82. 54. Berman AR, Liu MC, Wagner EM, Proud D. Dissociation of bradykinin-induced plasma exudation and reactivity in the peripheral airways. Am. J. Respir. Crit. Care Med. 1996; 154:418–23. 55. Tamaoki J, Kobayashi K, Saki N et al. Effect of bradykinin on airway ciliary motility and its modulation by neutral endopeptidase. Am. Rev. Respir. Dis. 1989; 140: 430–5. 56. Davis B, Roberts AM, Coleridge HM, Coleridge JCG. Reflex tracheal gland secretion evoked by stimulation of bronchial Cfibers in dogs. J. Appl. Physiol. 1982; 53:985–91. 57. Riccio MM, Proud D. Evidence that enhanced nasal reactivity to bradykinin in patients with symptomatic allergy is mediated by neural reflexes. J. Allergy Clin. Immunol. 1996; 97:1252–63. 58. Leikauf GD, Ueki IF, Nadel JA, Widdicombe JH. Bradykinin stimulates C1 secretion and prostaglandin E2 release by canine tracheal epithelium. Am. J. Physiol. 1985; 248:F48–55. 59. Pan ZK, Zuraw BL, Lung C-C et al. Bradykinin stimulates NF-jB activation and interleukin-1b gene expression in cultured human fibroblasts. J. Clin. Invest. 1996; 98:2042–9. 60. Pan ZK, Ye RD, Christiansen SC et al. Role of the rho GTPase in bradykinin-stimulated nuclear factor-jB activation and IL-1b gene expression in cultured human epithelial cells. J. Immunol. 1998; 160:3038–45.
61. Pang L, Knox AJ. Bradykinin stimulates Il-8 production in cultured human airway smooth muscle cells: role of cyclooxygenase products. J. Immunol. 1998; 161:2509–15. 62. Lawrence ID, Warner JA, Cohan VL et al. Bradykinin analogs induce histamine release from human skin mast cells. Adv. Exp. Med. Biol. 1989; 247A:225–9. 63. Ricciardolo FLM, Geppetti P, Mistretta A et al. Randomised doubleblind placebo-controlled study of the effects of inhibition of nitric oxide synthesis in bradykinin-induced asthma. Lancet 1996; 348:374–7. 64. Roisman GL, Lacronique JG, Desmazes-Dufeu N et al. Airway responsiveness to bradykinin is related to eosinophilic inflammation in asthma. Am. J. Respir. Crit. Care Med. 1996; 153:381–90. 65. Polosa R, Renaud L, Cacciola G et al. Sputum eosinophilia is more closely associated with airway responsiveness to bradykinin than methacholine in asthma. Eur. Respir. J. 1998; 12:551–6. 66. Berman AR, Togias AG, Skloot G, Proud D. Allergen-induced hyperresponsiveness to bradykinin is more pronounced than that to methacholine. J. Appl. Physiol. 1995; 78:1844–52. 67. Reynolds CJ, Togias A, Proud D. Airways hyperreactivity to bradykinin and methacholine: differential effects of inhaled fluticasone. J. Allergy Clin. Immunol. 2000; 105:S20. 68. Rajakulasingam K, Church MK, Howarth PH, Holgate ST. Factors determining bradykinin bronchial responsiveness and refractoriness in asthma. J. Allergy Clin. Immunol. 1993; 92:140–2. 69. Kaufman MP, Coleridge HM, Coleridge JCG, Baker DG. Bradykinin stimulates afferent vagal C-fibers in intrapulmonary airways in dogs. J. Appl. Physiol. 1980; 48:511–17. 70. Huang T-J, Hadda E-B, Fox AJ et al. Contribution of bradykinin B1 and B2 receptors in allergen-induced bronchial hyperresponsiveness. Am. J. Respir. Crit. Care Med. 1999; 160:1717–23. 71. Reynolds RJ, Togias A, Proud D. Airway neural responses to kinins: tachyphylaxis and role of receptor subtypes. Am. J. Respir. Crit. Care Med. 1999; 159:431–8. 72. Szelke M, Evans DM, Jones DM et al. Synthetic inhibitors of tissue kallikrein: effects in vivo in a model of allergic inflammation. Brazilian J. Med. Biol. Res. 1994; 27:1943–7. 73. Evans DM, Jones DM, Pitt GR et al. Synthetic inhibitors of tissue kallikrein. Immunopharmacology 1996; 32:117–18. 74. Soler M, Sielczak M, Abraham WM. A bradykinin-antagonist blocks antigen-induced airway hyperresponsiveness and inflammation in sheep. Pulm. Pharmacol. 1990; 3:9–15. 75. AbrahamWM, Burch RM, Farmer SG et al. A bradykinin antagonist modifies allergen-induced mediator release and late bronchial responses in sheep. Am. Rev. Respir. Dis. 1991; 143:787–96. 76. Pongracic JA, Naclerio RM, Reynolds CJ, Proud D. A competitive kinin receptor antagonist, [DArg0, Hyp3, DPhe7]-bradykinin, does not affect the response to nasal provocation with bradykinin. Br. J. Clin. Pharmacol. 1991; 31:287–94. 77. Proud D, Bathon JM, Togias AG, Naclerio RM. Inhibition of the response to nasal provocation with bradykinin by Hoe 140: efficacy and duration of action. Can. J. Physiol. Pharmacol. 1995; 73:820–6. 78. Akbary AM, Wirth KJ, Schölkens BA. Efficacy and tolerability of icatibant (Hoe 140) in patients with moderately severe chronic bronchial asthma. Immunopharmacology 1996; 33:238–42.
Reactive Oxygen Species
Chapter
26
Irfan Rahman and William MacNee Respiratory Medicine Unit, University of Edinburgh, Edinburgh, UK
INTRODUCTION Reactive oxygen species (ROS) such as superoxide anion (O2•) and the hydroxyl radical (•OH) are unstable molecules with unpaired electrons, capable of initiating oxidation. Biological systems are continuously exposed to oxidants that are generated either endogenously by metabolic reactions (e.g. from mitochondrial electron transport during respiration or during activation of phagocytes) or exogenously (such as by air pollutants or cigarette smoke). The lung exists in a high-oxygen environment and, together with its large surface area and blood supply, is susceptible to injury mediated by ROS. Production of ROS has been directly linked to oxidation of proteins, DNA, and lipids which may cause direct lung injury or induce a variety of cellular responses, through the generation of secondary metabolic reactive species. ROS may result in remodeling of extracellular matrix, cause apoptosis and mitochondrial respiration, and regulate cell proliferation.1,2 Alveolar repair responses and immune
modulation in the lung may also be influenced by ROS.1,2 Furthermore, high levels of ROS have been implicated in initiating inflammatory responses in the lungs through the activation of transcription factors such as nuclear factor-jB (NF-jB) and activator protein-1 (AP-1), and thus signal transduction and gene expression of proinflammatory mediators.3,4 It is proposed that ROS produced by phagocytes that have been recruited to sites of inflammation are a major cause of the cell and tissue damage associated with many chronic inflammatory lung diseases, including asthma and chronic obstructive pulmonary disease (COPD).5–9 The composition of inflammatory cell types varies widely in asthma and COPD, which may result in the differences in the characteristics of the ROS produced in these diseases10–12 (Fig. 26.1). This chapter reviews the evidence for the role of ROS in the pathogenesis of asthma and COPD, and discusses the molecular mechanisms (cell signaling and gene expression) and pathophysiological consequences of increased ROS release in these conditions.
Inhaled oxidants Cigarette smoke, NO2, SO2 particulates
EPO
Eos
MPO
PMNs
AMs
Epithelium
O2•/•OH/ H2O2/HOCl/ HOBr ROS
Lipid peroxidation (4-hydroxy-2-nonenal, F2a-isoprostanes)
Transcription of chemokine and cytokine genes
Inflammation in asthma and COPD
Mitochondria
Fig. 26.1. Mechanisms of ROS-mediated lung inflammation in asthma and COPD. The inflammation response is triggered by oxidants either inhaled and/or released by the activated neutrophils, alveolar macrophages, eosinophils, and epithelial cells leading to production of ROS and membrane lipid peroxidation. Activation of transcription of proinflammatory cytokine and chemokine genes, upregulation of adhesion molecules, and increased release of proinflammatory mediators occur, all of which are the inflammatory responses in patients with asthma and COPD.
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CELL-DERIVED ROS A common feature of all inflammatory lung diseases is the development of an inflammatory–immune response, characterized by activation of epithelial cells, and resident macrophages, and the recruitment and activation of neutrophils, eosinophils, monocytes, and lymphocytes. The degree to which this occurs and the cell types involved vary widely in asthma and COPD. Inflammatory cells once recruited in the airspace become activated and generate ROS in response to a sufficient level of a secretagogue stimulus (threshold concentration). The activation of macrophages, neutrophils, and eosinophils generates O2•, which is rapidly converted to H2O2 under the influence of superoxide dismutase (SOD), and •OH is formed nonenzymatically in the presence of Fe2 as a secondary reaction. ROS and reactive nitrogen species (RNS) can also be generated intracellularly from several sources such as mitochondrial respiration, the NADPH oxidase system, xanthine/ xanthine oxidase (Fig. 26.2). However, the primary ROSgenerating enzyme is NADPH oxidase, a complex enzyme system that is present in phagocytes and epithelial cells. Activation of this enzyme involves a complex mechanism with the assembly of various cytosolic and membraneassociated subunits, resulting in the one-electron reduction of oxygen to O2• using NADPH as the electon donor. In addition to NADPH oxidase, phagocytes employ other enzymes to produce ROS, which involves the activity of heme peroxidases (myeloperoxidase, MPO) or eosinophil peroxidase (EPO). Activation of EPO results in the formation of the potent oxidant hypochlorous acid (HOCl) and hypobromous acid (HOBr) from H2O2 in the presence of chloride (Cl) and bromide (Br) ions, respectively. It is believed that the oxidant burden produced by eosinophils is substantial because these cells possess several times greater
NADPH (mitochondrial respiration) Xanthine (xanthine oxidase)
O2
OH•
H2O2
NADPH (NADPH oxidase)
O2
NO•
Excess NO• NADPH and arginine (nitric oxide synthase)
ONOO
OH•
NO2•
Fig. 26.2. Sources of intracellular reactive oxygen species. O2•, superoxide anion; NO, nitric oxide; H2O2, hydrogen peroxide; •OH, hydroxyl radical; NO2, nitrogen dioxide; ONOO, peroxynitrite.
capacity to generate O2• and H2O2 than do neutrophils, and the content of EPO in eosinophils is 3–10 times higher than the amount of MPO present in neutrophils13–15 (Fig. 26.3). The physiological consequences of EPO-dependent formation of brominating oxidants such as HOBr in vivo are unknown. HOBr reacts rapidly with a variety of nucleophilic targets such as thiols, thiol ethers, amines, unsaturated groups, and aromatic compounds.16 Several transition metal salts react with H2O2 to form • OH. Most attention in vivo for the generation of •OH has focused on the role of iron.17 Iron is a critical element in many oxidative reactions (Fig. 26.4). Free iron in the ferrous form catalyzes the Fenton reaction and the superoxide driven Haber–Weiss reaction, which generate the •OH, a ROS which damages tissues, particularly cell membranes by lipid peroxidation. MPO- and EPO-derived ROS can also interact with nitrite (NO2) and H2O2 to promote formation of RNS. ROS may also be released by lung epithelial cells18 and stimulate inflammatory cells directly, thereby amplifying lung inflammatory and oxidant events. ROS interact with a variety of molecules and donate electrons in biological systems. Reactive oxygen and nitrogen species also act on certain amino acids such as methionine, tyrosine, and cysteine in proteins (e.g. enzymes, kinases), profoundly altering the function of these proteins in inflammatory lung diseases.19
INHALED OXIDANTS AND CIGARETTE SMOKE Cigarette smoking, or inhalation of airborne pollutants that may be either oxidant gases (such as ozone, nitrogen dioxide (NO2), sulfur dioxide (SO2)) or particulate air pollution, results in direct lung damage as well as the activation of inflammatory responses in the lungs. Cigarette smoke is a complex mixture of over 4700 chemical compounds, including high concentrations of oxidants (1014 molecules per puff ).20 Short-lived oxidants such as O2• and nitric oxide (NO) are predominantly found in the gas phase. NO and O2• immediately react to form the highly reactive peroxynitrite (ONOO) molecule. The radicals in the tar phase of cigarette smoke are organic in nature, such as long-lived semiquinone radicals, which can react with O2• to form • OH and H2O2.21 The aqueous phase of cigarette smoke condensate may undergo redox recycling for a considerable period of time in the epithelial lining fluid (ELF) of smokers.22,23 The tar phase is also an effective metal chelator and can bind iron to produce tar-semiquinone tar-Fe2+, which can generate H2O2 continuously.22,23 Quinone (Q), hydroquinone (QH2), and semiquinone (QH•) in the tar phase are present in equilibrium: Q + QH2 → 2H+ + Q•. Aqueous extracts of cigarette tar contain the quinone radical (Q•), which can reduce oxygen to form O2•, which may dismutate to form H2O2:
245
Reactive Oxygen Species
O2
H2O2
O2•
Br
Eosinophil
[NOx]
NO2
Eosinophil peroxidase H2O2 HOBr
Bromination Nitration
O2•
CO2 ONOO
NO Epithelium
Fig. 26.3. Model of potential pathways used by eosinophils for the generation of NO-derived reactive oxygen species and reactive halogen species.
Macrophage Ferritin
Transferrin
Fe
Mobilization of reducing agents Vit C, NADPH, superoxide anion
Release of iron Cleavage/decreased synthesis of transferrin
FREE IRON Fe2
H2O2 Fenton’s reaction
H2O2 O2• Haber–Weiss reaction
OH• OH
O2 OH OH Fe3 Lipid peroxidation
Fig. 26.4. Free iron catalyzes peroxidation membrane lipid peroxidation via Fenton and Harber–Weiss reactions.
Q• O2 → Q O2• 2 O2• 2H+ → O2 H2O2. Furthermore, since both cigarette tar and lung epithelial lining fluid contain metal ions, such as iron, Fenton chemistry will result in the production of the •OH which is a highly reactive and potent ROS.
ROS AND MEMBRANE LIPID P E R O X I D AT I O N Oxygen species such as O2• and •OH are highly reactive, and when generated close to cell membranes they oxidize membrane phospholipids (lipid peroxidation), a process which may continue as a chain reaction (Fig. 26.5). Thus, a single •OH can result in the formation of many molecules of lipid hydroperoxides in the cell membrane.19 The peroxidative breakdown of polyunsaturated fatty acids impairs
membrane function, inactivates membrane-bound receptors and enzymes, and increases tissue permeability. Each of these processes has been implicated in the pathogenesis of many forms of lung injury. There is increasing evidence that aldehydes, generated endogenously during the process of lipid peroxidation, are involved in many of the pathophysiological effects associated with oxidative stress in cells and tissues.19 Compared with free radicals, lipid peroxidation aldehydes are generally stable, can diffuse within, or even escape from the cell, and attack targets far from the site of the original free radical event. In addition to their cytotoxic properties, lipid peroxides are increasingly recognized as being important in signal transduction for a number of important events in the inflammatory response.24 Many of the effects of ROS in airways may be mediated by the secondary release of inflammatory lipid mediators such as 4-hydroxy-2-nonenal (4-HNE). 4-HNE, a highly reactive diffusible end-product of lipid peroxidation, is known to induce/regulate various cellular events, such as proliferation,
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Reactive radical extracts atom of hydrogen from polyunsaturated fatty-acid side-chain in lipoprotein
Carbon radical reacts with oxygen O2•
H C
X•
XH
C•
Resulting radical attacks adjacent fatty-acid side-chain to generate a new carbon radical O2• C
C
C
The chain reaction continues
H
O2
C•
O2•
O2H C•
C
C•
O2
C
Lipid peroxide
Fig. 26.5. ROS-mediated mechanism of membrane lipid peroxidation in a chain reaction.
apoptosis, and activation of signaling pathways.24,25 4-HNE has a high affinity towards cysteine, histidine, and lysine residues. It forms adducts with proteins, altering their function.
ROLE OF ROS IN SIGNAL TRANSDUCTION ROS have been implicated in the activation of transcription factors such as NF-jB and AP-1, and in the signal transduction and gene expression involved in cellular proinflammatory actions.26 Both environmental and inflammatory cell-derived ROS can lead to the activation and phosphorylation of the mitogen-activated protein kinase (MAPK) family, including extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 kinase, and Pl-3K, via sensitive cysteine-rich domains; activation of the sphingomyelinase–ceramide pathway also occurs leading to increased gene transcription.3,4,26 Activation of members of the MAPK family leads to the transactivation of transcription factors such as c-Jun, activating factor-2 (ATF2), cyclic AMP response element binding proteins (CREB)-binding protein (CBP), and Elk-1.26–28 This eventually results in chromatin remodeling and expression of genes regulating a battery of distinct proinflammatory and antioxidant genes involved in several cellular events, including apoptosis, proliferation, transformation, and differentiation. The intracellular molecular mechanisms responsible for these actions of ROS have not been completely characterized. Redox-sensitive molecular targets usually contain highly conserved cysteine residues; their oxidation, nitration, and the formation of disulfide links are crucial events in oxidant/redox signaling. It is hypothesized that oxidation of sulfide groups in signaling proteins causes structural modifications, resulting in the exposure of
active sites and consequent protein activation. Such molecular targets include transcription factors (NF-jB, AP-1), signaling molecules such as ras/rac or JNK, protein tyrosine phosphatases, and p21ras.29 Thiol molecules such as intracellular glutathione (GSH) and thioredoxin are of central importance in regulating such redox signaling pathways, by reducing disulfide bridges or oxidized cysteine residues.26,30 In response to tumor necrosis factor (TNF-a) and lipopolysaccharide (LPS), which are relevant stimuli for the inflammatory response in COPD, airway epithelial cells can concurrently produce increased amounts of intracellular ROS and RNS.18 This intracellular production of oxidants and the subsequent changes in intracellular redox status is important in the molecular events controlling the expression of genes for inflammatory mediators.3 The signaling pathways and activation of transcription factors in response to ROS are the subject of rigorous investigation.
ROS IN ASTHMA Recent evidence indicates that increased oxidative stress occurs in the airways of patients with asthma.8 Inflammatory and immune cells in the airways, such as macrophages, neutrophils, and eosinophils, release increased amounts of ROS.31–34 ROS can result in lung injury as a result of direct oxidative damage to epithelial cells and cell shedding.35,36 ROS have been shown to be associated with the pathogenesis of asthma by evoking bronchial hyperreactivity.37,38 Viral infections, ozone, and cigarette smoke, potential triggers for asthma, may serve as sources of ROS which enhances inflammation and asthmatic symptoms. Animal studies suggest that ROS may contribute to airway hyperresponsiveness by increasing vagal tone due to inhibition
Reactive Oxygen Species
of b-adrenergic receptors and by decreasing mucociliary clearance.39,40 The actions of ROS can produce many of the pathophysiological features of asthma, including: • • • • • •
enhanced arachidonic acid release; airway smooth muscle contraction; increased airway reactivity and secretions; increased vascular permeability; increased synthesis of chemoattractants; impaired b-adrenergic responsiveness.37,40
ROS-mediated injury to the airway epithelium produces hyperresponsiveness of human peripheral airways, suggesting that ROS may play a role in the pathogenesis of asthma.36 Much of the evidence for this is indirect, since there are no specific and reliable methods to assess oxidative stress in vivo. Neutrophils isolated from peripheral blood of asthmatic patients generate greater amounts of O2• and H2O2 than do cells from normal subjects, and their ability to produce O2• is related directly to the degree of airway hyperresponsiveness to inhaled methacholine.41,42 Inflammatory cells obtained from asthmatic patients, particularly eosinophils derived from peripheral blood, produce increased amounts of ROS and RNS such as NO spontaneously and after stimulation ex vivo.31–35,43 This observation suggests that the inflammatory milieu in asthma contains factors which may prime ROS generation. Eosinophils are thought to play a critical role in the inflammation of asthma. They are present in large numbers in bronchoalveolar lavage (BAL) fluid and blood, and the number of cells correlates with bronchial hyperresponsiveness.44,45 BAL fluid eosinophils, alveolar macrophages, and neutrophils from asthmatic patients produce more ROS (O2•, H2O2, hypothalites) than do those from normal subjects.46,47 ROS cause direct contraction of airway smooth muscle preparations, and this effect is enhanced when the epithelium is injured or removed. This observation might provide a mechanistic link between epithelial injury arising from a variety of causes and airway hyperresponsiveness.36 ROS also stimulate histamine release from mast cells and mucus secretion from airway epithelial cells.48 ROS generation is thought to be a nonspecific process initiated by the concurrent action of numerous inflammatory mediators which have been shown to be present in increased amounts in asthmatics. Several mediators, including lipid mediators, chemokines, adhesion molecules, and eosinophil granule proteins (EPO), are potential stimuli or promoters of ROS production in the airways of asthmatic patients.49,50 Numerous surrogate markers of oxidative stress have been measured in exhaled air or breath condensate. The concentration of H2O2 in exhaled air condensate is increased in asthmatics,51 and it has been suggested that airway inflammation increases exhaled peroxides. The increased levels of exhaled H2O2 may be due to decreased dismutation of O2• since superoxide dismutase activity is reduced in lung cells of patients with asthma.52 The significance of elevated levels of various ROS markers to the disease pathogenesis has not been studied.
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The role of EPO-derived ROS Recently a specific role for eosinophil granule proteins in the generation of oxidants by the phagocytes and in protein oxidation has been described.53 Eosinophil activation (peroxidase–H2O2 system + halides) in vivo results in oxidative damage to proteins through bromination of tyrosine residues, as shown by the formation of 3-bromotyrosine in BAL fluid of patients with asthma.16 The formation of 3bromotyrosine is a specific response to the release of oxidants from eosinophils. Neutrophil- and monocyte-derived myeloperoxidase, which are increased in smokers and patients with COPD, produce 3-chlorotyrosine.16 Thus, distinction between these “footprints” might be useful in assessing the ROS burden in patients with asthma and COPD. A specific marker of protein modification by reactive brominating species 3-bromotyrosine has been shown to be markedly increased in BAL proteins obtained from asthmatics.16 EPO-generated oxidants can interact with RNS present in asthmatics and promote protein nitration.15 Thus oxidative modification of critical biological targets in asthmatic airways may contribute to the pathophysiological features of asthma, such as epithelial cell damage, airway hyperreactivity, bronchoconstriction, b-adrenergic receptor dysfunction, mucus hypersecretion, microvascular leak, and airway edema.54,55 Interaction between ROS and RNS The levels of nitric oxide are elevated in the exhaled air of patients with asthma.56–59 Increased levels of exhaled NO, together with increased exhaled H2O2 in asthmatic patients, are associated with a pro-oxidant activity in airway walls resulting in lipid peroxidation and nitration of proteins.15,16,56,60,61 The recent finding that NO reduces the potency of b-adrenergic signaling pathways may be an important deleterious effect of elevated RNS in asthma.39 The presence of allergic inflammation, involving the recruitment and activation of eosinophils, may be a contributing factor in these pro-oxidant effects. Eosinophil granule proteins may participate in the formation of nitrating oxidants as well as unique molecules such as brominated products, which have been shown to be elevated in patients with asthma.15,16 However, the significance of these inflammatory ROS in the etiology of asthma is not established. A reaction between NO and O2• results in the formation of peroxynitrite anions (ONOO), a highly reactive oxidant species. ONOO adds a nitro group to the 3-position adjacent to the hydroxyl group of tyrosine to produce the stable product nitrotyrosine. ONOO induces hyperresponsiveness in airways of guinea-pigs, inhibits pulmonary surfactant function, induces membrane lipid peroxidation, results in tyrosine/MAP kinase activation, and damages pulmonary epithelial cells.59,61–64 The levels of 3-nitrotyrosine are elevated in the exhaled breath of asthmatic patients.65 Furthermore, there is strong immunoreactivity for nitrotyrosine in the airway epithelium, lung parenchyma, and inflammatory cells in the airways of patients with asthma.65,66
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Generation of ROS-mediated lipid peroxidation products The measurement of aldehydes in exhaled breath has been proposed as a means to assess lipid peroxidation in vivo.The levels of lipid peroxides such as 8-isoprostane (a prostaglandin analog, which is a member of the F2-isoprostane class and a product of the peroxidation of arachidonic acid), hydrocarbons such as ethane and pentane, and nonspecific products of lipid peroxidation such as thiobarbituric acid reactive substances (TBARS) are increased in exhaled breath condensate of patients with asthma.67–70 The levels of 8-isoprostane are also increased in BAL fluid of patients with asthma.71 Urinary excretion of 15-F2t-IsoProstane (8isoprostaglandin2a, family of F2-isoprostanes) was increased in mild atopic asthmatics following inhaled allergen provocation, whereas no increase in the urinary excretion of 15-F2tIsoProstane was observed after inhalation of methacholine.72 The presence of various markers of oxidative stress provide evidence that oxidative stress is present in the airspaces in asthma, but do not provide definitive evidence for a role for oxidative stress in the pathogenesis of asthma. Measurement of systemic or exhaled isoprostane 8isoPGF2a levels may provide a useful tool in monitoring clinical status in asthma.73 The level of plasma F2-isoprostanes (an 8-isoPGF2a isomer) is significantly increased in asthmatics and is related to disease severity.73 Similarly, arachidonic acid is increased in airway inflammatory cells of patients with bronchial asthma.74 Arachidonic acid may undergo oxidation to produce an end-product of lipid peroxidation such as 4-HNE.24,25 The levels of plasma lipid peroxides (TBARS) have been shown to be elevated in asthma, and are negatively correlated with the FEV1, suggesting a role for increased oxidative stress in the pathogenesis of asthma.75,76 Further studies are needed to define the source, significance, and specificity of these peroxidation products.
O X I D AT I V E S T R E S S I N S M O K E R S A N D PAT I E N T S W I T H C O P D More than 90% of patients with COPD are smokers, but not all smokers develop COPD.77–79 However, 15–20% of cigarette smokers show a rapid decline in FEV1 over time, and develop COPD. An increased oxidant burden in smokers derives from the fact that cigarette smoke contains an estimated 1014 oxidants per puff, and many of these are relatively long-lived – such as tar-semiquinone which can generate •OH and hydrogen peroxide (H2O2) by the Fenton reaction.20–23 Other factors that may exacerbate COPD, such as air pollutants, infections, and occupational dusts, also have the potential to produce oxidative stress.5,80 ROS in the alveolar space The oxidant burden in the lungs is enhanced in smokers by the release of ROS from macrophages and neutrophils.5 Oxidants present in cigarette smoke can stimulate alveolar
macrophages to produce ROS and to release a host of mediators, some of which attract neutrophils and other inflammatory cells into the lungs. Both neutrophils and macrophages, which are known to migrate in increased numbers into the lungs of cigarette smokers compared with nonsmokers,5 can generate ROS via the NADPH oxidase system. Moreover, the lungs of smokers with airway obstruction have more neutrophils than smokers without airway obstruction.81 Circulating neutrophils from cigarette smokers and patients with exacerbations of COPD release more O2•.76 Cigarette smoking is associated with increased content of myeloperoxidase (MPO) in neutrophils, which correlates with the degree of pulmonary dysfunction.82,83 MPO activity also has a negative correlation with FEV1 in patients with COPD, suggesting that neutrophil MPOmediated oxidative stress may play a role in the pathogenesis of COPD.84 Alveolar macrophages obtained by BAL fluid from the lungs of smokers display higher levels of activation than those from nonsmokers.5 One manifestation of this is the release of increased amounts of ROS such as O2• and H2O2 in response to stimulation.5,85,86 Exposure to cigarette smoke in vitro has also been shown to increase the oxidative metabolism of alveolar macrophages.87 Subpopulations of alveolar macrophages with a higher granular density appear to be more prevalent in the lungs of smokers and are responsible for the increased O2• production of smoker’s macrophages.87,88 Hydrogen peroxide, measured in exhaled breath, is thought to be a direct measurement of oxidant burden in the airspaces. Smokers and patients with COPD have higher levels of exhaled H2O2 than nonsmokers,89–91 and levels are even higher during exacerbations of COPD.91 The source of the increased H2O2 is unknown but may in part derive from increased release of O2• from alveolar macrophages in smokers.91 However, in one study smoking did not appear to influence the levels of exhaled H2O2;89 the levels of exhaled H2O2 in this study correlated with the degree of airflow obstruction as measured by the FEV1. However, the variability of the measurement of exhaled H2O2, along with the presence of other confounding factors, has led to concerns over its reproducibility as a marker for oxidative stress in smokers and in patients with COPD.The generation of ROS in epithelial lining fluid may be further enhanced by the presence of increased amounts of free iron in the airspaces in smokers.92,93 This is relevant to COPD since the intracellular iron content of alveolar macrophages is increased in cigarette smokers and is increased further in those who develop chronic bronchitis, compared with nonsmokers.94 In addition, macrophages obtained from smokers release more free iron in vitro than those from nonsmokers.95 In some studies, both in stable bronchitis12 and mild exacerbations,10 eosinophils have been shown to be prominent in the airways. BAL fluid from patients with COPD has also been shown to contain increased eosinophilic cationic protein.83 Furthermore, peripheral blood eosinophilia is also considered to be a risk factor for the development of airway obstruction in patients with chronic bronchitis and is an
249
Reactive Oxygen Species
adverse prognostic sign.96,97 However, despite the presence of an increased number of eosinophils, EPO-mediated generation of 3-bromotyrosine has not been detected in COPD patients.16 This does not provide support for a role of brominating oxident in eosinophil-mediated ROS damage in COPD. Superoxide anion and H2O2 can be generated by the xanthine/xanthine oxidase (XO) reaction. XO activity has been shown to be increased in cell free BAL fluid and plasma from COPD patients, compared with normal subjects; and this has been associated with increased O2• and lipid peroxide levels.98–100 ROS in blood The neutrophil appears to be a critical cell in the pathogenesis of COPD.101 Previous epidemiological studies have shown a relationship between circulating neutrophil numbers and FEV1.102,103 A relationship has also been shown between the change in peripheral blood neutrophil count and the change in airflow limitation over time.103 Similarly, a correlation between O2• release by peripheral blood neutrophils and bronchial hyperreactivity in patients with COPD has been shown, suggesting a role for systemic ROS in the pathogenesis of the airway abnormalities in COPD.104 Another study has shown a relationship between peripheral blood neutrophil luminol enhanced chemiluminescence, as a measure of the release of ROS, and measurements of airflow limitation in young cigarette smokers.105
Various studies have demonstrated increased production of O2• from peripheral blood neutrophils obtained from patients during acute exacerbations of COPD; these levels returned to normal when the patients were clinically stable.76,106,107 Other studies have shown that circulating neutrophils from patients with COPD show upregulation of their surface adhesion molecules, which may also be an oxidant-mediated effect.76,108 Activation may be even more pronounced in neutrophils that are sequestered in the pulmonary microcirculation in smokers and in patients with COPD, since neutrophils sequestered in the pulmonary microcirculation in animal models of lung inflammation release more ROS than circulating neutrophils.109 Thus neutrophils sequestered in the pulmonary microcirculation may be a source of ROS, and may have a role in inducing endothelial adhesion molecule expression in COPD. Interaction between ROS and RNS Nitric oxide has been used as a marker of airway inflammation and indirectly as a measure of oxidative stress. There have been reports of increased levels of NO in exhaled breath in patients with COPD, but not as high as the levels reported in asthmatics.110–112 One study failed to confirm this result.113 Smoking cessation increases NO levels in exhaled air,114 and the reaction of NO with O2• limits the usefulness of this marker in COPD, except perhaps to differentiate from asthma (Table 26.1).
Table 26.1. ROS markers in asthma and COPD
References Biochemical marker
Asthma
COPD
51,61
89–91
31–35,43,46
76,102,104,107
45,47
85
Increased MPO and EPO levels
15
82–84
Increased BAL fluid xanthine/xanthine oxidase activity
--
98–100
67–69,71,73
123–125
70,75,76
76,93,126,127
Increased formation of 4-hydroxy-2-nonenal-protein adducts in lungs
--
129
Elevated plasma protein carbonyls
--
117
Increased exhaled CO
67,132
123
Increased exhaled NO
56,57
110–113
60,65,66
115,116,118
15,16
16
Elevated hydrogen peroxide level in exhaled breath Release of ROS from peripheral blood neutrophils, eosinophils, and macrophages Increased release of ROS from alveolar macrophages, eosinophils, and neutrophils
Elevated plasma and exhaled F2-isoprostane, ethane and pentane levels Elevated plasma and exhaled lipid peroxide (TBARS) levels
Increased 3-nitrotyrosine in plasma, BAL fluid, and exhaled breath Increased 3-chlorotyrosine and 3-bromotyrosine
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Cigarette smoking increases the formation of RNS and results in nitration and oxidation of plasma proteins. The levels of nitrated proteins (fibrinogen, transferrin, plasminogen, and ceruloplasmin) were higher in smokers than in nonsmokers.115 Evidence of NO/ONOO activity in plasma has been shown in cigarette smokers.116 In vitro, exposure to gas-phase cigarette smoke results in increased lipid peroxidation and protein carbonyl formation in plasma.117 It is likely that alpha, beta-unsaturated aldehydes (acrolein, acetaldehyde, and crotonaldehyde) that are abundantly present in cigarette smoke may react with protein-SH and -NH2 groups leading to the formation of a protein-bound aldehyde functional group, and are capable of converting tyrosine to 3-nitrotyrosine and dityrosine.117 Nitric oxide and ONOO mediated formation of 3-nitrotyrosine in plasma and free catalytic iron (Fe2+) levels in epithelial lining fluid are elevated in chronic smokers.118 Nitration of tyrosine residues or proteins in plasma leads to the production of 3nitrotyrosine.119 The levels of nitrotyrosine and inducible NO synthetase (iNOS) were higher in airway inflammatory cells obtained by induced sputum from patients with COPD, compared to those with asthma.118 The levels of nitrotyrosine were negatively correlated with the percentage predicted FEV1. These direct and indirect studies indicate that increased RNS- and ROS-mediated protein nitration and lipid peroxidation respectively may play a role in the pathogenesis of COPD. Generation of ROS-mediated lipid peroxidation products Isoprostanes are products of nonenzymatic lipid peroxidation and have therefore been used as markers of oxidative stress.120 The isoprostanes are ROS catalyzed isomers of arachidonic acid and are stable lipid peroxidation products, which circulate in plasma and are excreted in the urine.121,122 The levels of lipid peroxides, such as 8-isoprostane, and hydrocarbons, such as ethane and pentane, are increased in exhaled air condensate in smokers and in patients with COPD.123–125 Furthermore, the levels of these lipid peroxidation products have been correlated with airway obstruction.125 Urinary levels of isoprostane F2a-III have been shown to be elevated in patients with COPD compared with control subjects, and are even more elevated during exacerbations of COPD.122 These studies indicate that there is increased lipid peroxidation in patients with COPD. However, it is not known whether the increased level of lipid peroxidation products found in these diseases is the result of primary lung-associated processes such as alveolar macrophage activation, neutrophil activity, or the ongoing lipid peroxidative chain reaction in the alveoli, parenchyma, or airways, which are induced by inhaled oxidants/cigarette smoke. Indirect and nonspecific measurements of lipid peroxidation products, such as thiobarbituric acid reactive substances (TBARS), have also been shown to be elevated in breath condensate and in lungs of patients with stable
COPD.93,126,127 The levels of plasma lipid peroxides have been shown to be elevated in COPD, and negatively correlated with the FEV1.75 Oxidative stress, measured as lipid peroxidation products in plasma, has also been shown to correlate inversely with the percentage predicted FEV1 in a population study,128 suggesting that in patients with COPD lipid peroxidation may play a role in the progression of the disease. 4-HNE is a highly reactive and specific diffusible endproduct of lipid peroxidation. Increased 4-HNE-modified protein levels are present in airway and alveolar epithelial cells and endothelial cells, and in neutrophils in smokers with airway obstruction compared to subjects without airway obstruction.129 This demonstrates not only the presence of 4-HNE but that 4-HNE modifies proteins in lung cells to a greater extent in patients with COPD. The increased level of 4-HNE adducts in alveolar epithelium, airway endothelium, and neutrophils was inversely correlated with FEV1, suggesting a role for 4-HNE in the pathogenesis of COPD.
P R O I N F L A M M AT O RY G E N E E X P R E S S I O N Inflammatory mediators play a crucial role in chronic inflammatory processes and appear to determine the nature of the inflammatory response by directing the selective recruitment and activation of inflammatory cells and their survival within the lungs. In-vitro studies using macrophage, alveolar, and bronchial epithelial cells, have shown that ROS increased gene expression of inflammatory mediators such as IL-1 and TNF-a. Direct or indirect oxidant stress to the airway epithelium and alveolar macrophages may also generate cytokines such asTNF-a, which in turn can activate airway epithelial cells to induce proinflammatory genes such as TNF-a, IL-8, IL-1, iNOS, COX-2, ICAM-1, IL-6, MIP-1, GM-CSF, stress response genes (HSP-27, 70, 90, HO-1), and antioxidant enzymes (c-glutamylcysteine synthetase (c-GCS), MnSOD, thioredoxin).7 The genes for these inflammatory mediators are regulated by redoxsensitive transcription factors such as NF-jB and AP-1.
ANTIOXIDANT PROTECTIVE GENE EXPRESSION An important effect of oxidative stress and inflammation is the upregulation of protective antioxidant genes. Amongst antioxidants, GSH and its redox enzymes appear to have an important protective role in the lung. Oxidative stress causes upregulation of c-glutamylcysteine synthetase (c-GCS), an important enzyme involved in the synthesis of GSH, as an adaptive mechanism against subsequent oxidative stress. A recent study has shown that the expression of c-GCS mRNA is elevated in smokers’ lungs and is even more pronounced in smokers with COPD.130 This implies that GSH synthesis is upregulated in lungs of smokers with and without COPD. Similarly, bronchial epithelial cells of rats
Reactive Oxygen Species
exposed to cigarette smoke have shown increased expression of genes for manganese superoxide dismutase (MnSOD), metallothionein, and glutathione peroxidase (GPx), suggesting the importance of the antioxidant gene adaptive response against the injurious effects of cigarette smoke.131 Important protective antioxidant genes such as genes for MnSOD, c-GCS, heme oxygenase-1 (HO-1), GPx, thioredoxin reductase, and metallothionein are induced by various oxidative stresses, including hyperoxia and inflammatory mediators such as TNF-a and lipopolysaccharide in lung cells.26–29 Thus oxidative/nitrosative stresses cause increased expression of proinflammatory genes by oxidant-mediated activation of transcription factors such as AP-1 and NF-jB, as well as activation of stress-response protective genes such as c-GCS-HS, HO-1, and MnSOD in lungs. A balance may therefore exist between pro- and anti-inflammatory gene expression and the levels of GSH in response to ROS and during inflammation, which may be critical to whether this leads to cell injury or protection against the injurious effects of inflammation.
S U M M A RY There is now considerable evidence for the increased generation of ROS in asthma and COPD, which may be important in the pathogenesis of these conditions. ROS may be critical to the inflammatory response to cigarette smoke/ environmental oxidants, through the upregulation of redoxsensitive transcription factors and hence proinflammatory gene expression; but they are also involved in the protective mechanisms against the effects of cigarette smoke by the induction of antioxidant genes. Further understanding of the effects of ROS in basic cellular functions such as amplification of proinflammatory and immunological responses, signaling pathways, activation of transcription factors and gene expression, chromatin modeling, and apoptotic mechanisms will provide important information regarding basic pathological processes contributing to asthma and COPD. Further studies that investigate the mechanisms of the differential response of immune-inflammatory and epithelial cells to inhaled oxidants or endogenous ROS are required in patients with asthma and COPD. More work in elucidating the mechanisms of ROS-mediated modulations of these processes needs to be done before we can embark on the path of pharmacological therapy to manipulate these processes in asthma and COPD.
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50. McBride DE, Koenig JQ, Luchtel DL, Williams PV, Henderson WR. Inflammatory effects of ozone in the upper airways of subjects with asthma. Am. J. Respir. Crit. Care Med. 1994; 149:1192–7. 51. Emelyanov A, Fedoseev G, Abulimity A et al. Elevated concentrations of exhaled hydrogen peroxide in asthmatic patients. Chest 2001; 120:1136–9. 52. Smith LJ, Shamsuddin M, Sporn PH, Denenberg M, Anderson J. Reduced superoxide dismutase in lung cells of patients with asthma. Free Rad. Biol. Med. 1997; 22:1301–7. 53. Mitra SN, Slungaard A, Hazen SL. Role of eosinophil peroxidase in the origins of protein oxidation in asthma. Redox Rep. 2000; 5:215–24. 54. Motojima S, Fukuda T, Makino S. Effect of eosinophil peroxidase on beta-adrenergic receptor density on guinea pig lung. Biochem. Biophys. Res. Commun. 1992; 189:1613–19. 55. Yoshikawa S, Kayes SG, Parker JC. Eosinophils increase lung microvascular permeability via the peroxidase–hydrogen peroxide–halide system: bronchoconstriction and vasoconstriction unaffected by eosinophil peroxidase inhibition. Am. Rev. Respir. Dis. 1993; 147:914–20. 56. Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur. Respir. J. 1993; 6:1368–70. 57. Silkoff PE, Sylvester JT, Zamel N, Permutt S. Airway nitric oxide diffusion in asthma: role in pulmonary function and bronchial responsiveness. Am. J. Respir. Crit. Care Med. 2000; 161:1218–28. 58. Ashutosh K. Nitric oxide and asthma: a review. Curr. Opin. Pulm. Med. 2000; 6:21–5. 59. Beckman DL, Mehta P, Hanks V, Rowan WH, Liu L. Effects of peroxynitrite on pulmonary edema and the oxidative state. Exp. Lung Res. 2000; 26:349–59. 60. Saleh D, Ernst P, Lim S, Barnes PJ, Giaid A. Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid. FASEB J. 1998; 12:929–37. 61. Dohlman AW, Black HR, Royall JA. Expired breath hydrogen peroxide is a marker of acute airway inflammation in paediatric patients with asthma. Am. Rev. Respir. Dis. 1993; 148:955–60. 62. Zhang P, Wang YZ, Kagan E, Bonner JC. Peroxynitrite targets the epidermal growth factor receptor, Raf-1, and MEK independently to activate MAPK. J. Biol. Chem. 2000; 275:22479–86. 63. Groves JT. Peroxynitrite: reactive, invasive and enigmatic. Curr. Opin. Chem. Biol. 1999; 3:226–35. 64. Hogg N, Kalyanaraman B. Nitric oxide and lipid peroxidation. Biochim. Biophys. Acta 1999; 1411:378–84. 65. Hanazawa T, Kharitonov SA, Barnes PJ. Increased nitrotyrosine in exhaled breath condensate of patients with asthma. Am. J. Respir. Crit. Care Med. 2000; 162(4 Pt 1):1273–6. 66. Kaminsky DA, Mitchell J, Carroll N et al. Nitrotyrosine formation in the airways and lung parenchyma of patients with asthma. J. Allergy Clin. Immunol. 1999; 104:747–54. 67. Montuschi P, Corradi M, Ciabattoni G et al. Increased 8isoprostane, a marker of oxidative stress, in exhaled condensate of asthma patients. Am. J. Respir. Crit. Care Med. 1999; 160:216–20. 68. Paredi P, Kharitonov SA, Barnes PJ. Elevation of exhaled ethane concentration in asthma. Am. J. Respir. Crit. Care Med. 2000; 162:1450–4. 69. Olepade CO, Zakkar M, Swedler WI. Exhaled pentane levels in acute asthma. Chest 1997; 111:862–5. 70. Antczak A, Nowak D, Shariati B et al. Increased hydrogen peroxide and thiobarbituric acid-reactive products in expired breath condensate of asthma patients. Eur. Respir. J. 1997; 10:1235–41. 71. Dworski R, Murry JJ, Roberts LJ et al. Allergen-induced synthesis of F2-isoprostanes in atopic asthmatics: evidence for oxidant stress. Am. J. Respir. Crit. Care Med. 1999; 160:1947–51.
Reactive Oxygen Species
72. Dworski R, Roberts LJ, Murry JJ et al. Assessment of oxidant stress in allergic asthma by measurement of the major urinary metabolite of F2-isoprostane, 15-F2t-IsoP (8-iso-PGF2alpha). Clin. Exp. Allergy 2001; 31:387–90. 73. Wood LG, Fitzgerald DA, Gibson PG, Cooper DM, Garg ML. Lipid peroxidation as determined by plasma isoprostanes is related to disease severity in mild asthma. Lipids 2000; 35:967–74. 74. Calabrese C, Triggiani M, Marone G, Mazzarella G. Arachidonic acid metabolism in inflammatory cells of patients with bronchial asthma. Allergy 2000; 55(Suppl.):27–30. 75. Tsukagoshi H, Shimizu Y, Iwamae S et al. Evidence of oxidative stress in asthma and COPD: potential inhibitory effect of theophylline. Respir. Med. 2000; 94:584–8. 76. Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in asthma, COPD, and smokers. Am. J. Respir. Crit. Care Med. 1996; 154:1055–60. 77. British Thoracic Society guidelines for the management of chronic obstructive pulmonary disease. Thorax 1997; 52:S1–28. 78. American Thoracic Society standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1995; 152:S77–120. 79. Snider G. Chronic obstructive pulmonary disease: risk factors, pathophysiology and pathogenesis. Ann. Rev. Med. 1989; 40:411–29. 80. Repine JE, Bast A, Lankhorst I, and the Oxidative Stress Study Group. Oxidative stress in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 156:341–57. 81. Bosken CH, Hards J, Gatter K, Hogg JC. Characterization of the inflammatory reaction in the peripheral airways of cigarette smokers using immunocytochemistry. Am. Rev. Respir. Dis. 1992; 145:911–17. 82. Aaron SD, Angel JB, Lunau M et al. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 163:349–55. 83. Fiorini G, Crespi S, Rinaldi M et al. Serum ECP and MPO are increased during exacerbations of chronic bronchitis with airway obstruction. Biomed. Pharmacother. 2000; 54:274–8. 84. Gompertz S, Bayley DL, Hill SL, Stockley RA. Relationship between airway inflammation and the frequency of exacerbations in patients with smoking related COPD. Thorax 2001; 56:36–41. 85. Morrison D, Rahman I, Lannan S, MacNee W. Epithelial permeability, inflammation and oxidant stress in the airspaces of smokers. Am. J. Respir. Crit. Care Med. 1999; 159:473–9. 86. Nakashima H, Ando M, Sugimoto M et al. Receptor-mediated O2 release by alveolar macrophages and peripheral blood monocytes from smokers and nonsmokers. Am. Rev. Respir. Dis. 1987; 136:310–15. 87. Drath DB, Larnovsky ML, Huber GL. The effects of experimental exposure to tobacco smoke on the oxidative metabolism of alveolar macrophages. J. Reticul. Soc. 1970; 25:597–604. 88. Schaberg T, Klein U, Rau M, Eller J, Lode H. Subpopulation of alveolar macrophages in smoker and nonsmokers: relation to the expression of CD11/CD18 molecules and superoxide anion production. Am J. Respir. Crit. Care Med. 1995; 151:1551–8. 89. Nowak D, Kasielski M, Pietras T, Bialasiewicz P, Antczak A. Cigarette smoking does not increase hydrogen peroxide levels in expired breath condensate of patients with stable COPD. Monaldi Arch. Chest Dis. 1998; 53:268–73. 90. Nowak D, Antczak A, Krol M et al. Increased content of hydrogen peroxide in expired breath of cigarette smokers. Eur. Respir. J. 1996; 9:652–7. 91. Dekhuijzen PNR, Aben KKH, Dekke I et al. Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1996; 154:813–16. 92. Mateos F, Brock JF, Perez-Arellano JL. Iron metabolism in the lower respiratory tract. Thorax 1998; 53:594–600.
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93. Lapenna D, Gioia SD, Mezzetti A et al. Cigarette smoke, ferritin, and lipid peroxidation. Am. J. Respir. Crit. Care Med. 1995; 151:431–5. 94. Thompson AB, Bohling T, Heires A, Linder J, Rennard SI. Lower respiratory tract iron burden is increased in association with cigarette smoking. J. Lab. Clin. Med. 1991; 117:494–9. 95. Wesselius LJ, Nelson ME, Skikne BS. Increased release of ferritin and iron by iron loaded alveolar macrophages in cigarette smokers. Am. J. Respir. Crit. Care Med. 1994; 150:690–5. 96. Lacoste JY, Bousquet J, Chanez P et al. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 1993; 149:803–10. 97. Lebowitz MD, Postma DS. Adverse effects of eosinophilic and smoking on the natural history of newly diagnosed chronic bronchitis. Chest 1995; 108:55–61. 98. Pinamonti S, Muzzuli M, Chicca C et al. Xanthine oxidase activity in bronchoalveolar lavage fluid from patients with chronic obstructive lung disease. Free Rad. Biol. Med. 1996; 21:147–55. 99. Heunks LM,Vina J, van Herwaarden CL et al. Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease. Am. J. Physiol. 1999; 277:R1697–704. 100. Pinamonti S, Leis M, Barbieri A et al. Detection of xanthine oxidase activity products by EPR and HPLC in bronchoalveolar lavage fluid from patients with chronic obstructive pulmonary disease. Free Rad. Biol. Med. 1998; 25:771–9. 101. Chan-Yeung M, Dybuncio A. Leucocyte count, smoking and lung function. Am. J. Med. 1984; 76:31–7. 102. Van Antwerpen VL, Theron AJ, Richards GA et al. Vitamin E, pulmonary functions, and phagocyte-mediated oxidative stress in smokers and nonsmokers. Free Rad. Biol. Med. 1995; 18:935–43. 103. Chan-Yeung M, Abboud R, Dybuncio A, Vedal S. Peripheral leucocyte count and longitudinal decline in lung function. Thorax 1988; 43:426–68. 104. Postma DS, Renkema TEJ, Noordhoek JA et al. Association between nonspecific bronchial hyperreactivity and superoxide anion production by polymorphonuclear leukocytes in chronic airflow obstruction. Am. Rev. Respir. Dis. 1988; 137:57–61. 105. Richards GA, Theron AJ, van der Merwe CA, Anderson R. Spirometric abnormalities in young smokers correlate with increased chemiluminescence responses of activated blood phagocytes. Am. Rev. Respir. Dis. 1989; 139:181–7. 106. Rahman I, Skwarska E, MacNee W. Attenuation of oxidant/antioxidant imbalance during treatment of exacerbations of chronic obstructive pulmonary disease. Thorax 1997; 52:565–8. 107. Muns G, Rubinstein I, Bergmann KC. Phagocytosis and oxidative bursts of blood phagocytes in chronic obstructive airway disease. Scand. J. Infect. Dis. 1995; 27:369–73. 108. Noguera A, Busquets X, Sauleda J et al. Expression of adhesion molecules and G-proteins in circulating neutrophils in COPD. Am. J. Respir. Crit. Care Med. 1998; 158:1664–8. 109. Brown DM, Drost E, Donaldson K, MacNee W. Deformability and CD11/CD18 expression of sequestered neutrophils in normal and inflamed lungs. Am. J. Respir. Cell Mol. Biol. 1995; 13:531–9. 110. Maziak W, Loukides S, Culpitt S et al. Exhaled nitric oxide in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 147:998–1002. 111. Corradi M, Majori M, Cacciani GC et al. Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease. Thorax 1999; 54:572–5. 112. Delen FM, Sippel JM, Osborne ML et al. Increased exhaled nitric oxide in chronic bronchitis: comparison with asthma and COPD. Chest 2000; 117:695–701. 113. Rutgers SR, van der Mark TW, Coers W et al. Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease. Thorax 1999; 54:576–680.
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114. Robbins RA, Millatmal T, Lassi K, Rennard S, Daughton D. Smoking cessation is associated with an increase in exhaled nitric oxide. Chest 1997; 112:313–18. 115. Pignatelli B, Li CG, Boffetta P et al. Nitrated and oxidized plasma proteins in smokers and lung cancer patients. Cancer Res. 2001; 61:778–84. 116. Petruzzelli S, Puntoni R, Mimotti P et al. Plasma 3-nitrotyrosine in cigarette smokers. Am. J. Respir. Crit. Care Med. 1997; 156:1902–7. 117. Eiserich JP, van der Vliet A, Handelman GJ, Halliwell B, Cross CE. Dietary antioxidants and cigarette smoke-induced biomolecular damage: a complex interaction. Am. J. Clin. Nutr. 1995; 62:1490S–500S. 118. Ichinose M, Sugiura H,Yamagata S, Koarai A, Shirato K. Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways. Am. J. Respir. Crit. Care Med. 2000; 162:701–6. 119. Van der Vliet A, Smith D, O’Neill CA et al. Interactions of peroxynitrite and human plasma and its constituents: oxidative damage and antioxidant depletion. Biochem. J. 1994; 303:295–301. 120. Morrow JD, Roberts LJ. The isoprostanes: unique bioactive products of lipid peroxidation. Prog. Lipid Res. 1997; 36:1–21. 121. Reilly M, Delanty N, Lawson JA, FitzGerald GA. Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation 1996; 94:19–25. 122. Pratico D, Basili S, Vieri M et al. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2a-III, an index of oxidant stress. Am. J. Respir. Crit. Care Med. 1998; 158:1709–14. 123. Paredi P, Kharitonov SA, Leak D, Ward S, Cramer D, Barnes PJ. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 162:369–73.
124. Euler DE, Dave SJ, Guo H. Effect of cigarette smoking on pentane excretion in alveolar breath. Clin. Chem. 1996; 42:303–8. 125. Montuschi P, Collins JV, Ciabattoni G et al. Exhaled 8-isoprostane as an in-vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am. J. Respir. Crit. Care Med. 2000; 162:1175–7. 126. Nowak D, Kasielski M, Antczak A, Pietras T, Bialasiewicz P. Increased content of thiobarbiturate reactive acid substances in hydrogen peroxide in the expired breath condensate of patients with stable chronic obstructive pulmonary disease: no significant effect of cigarette smoking. Resp. Med. 1999; 93:389–96. 127. Fahn H, Wang L, Kao S et al. Smoking-associated mitochondrial DNA mutation and lipid peroxidation in human lung tissue. Am. J. Respir. Cell Mol. Biol. 1998; 19:901–9. 128. Britton JR, Pavord ID, Richards KA et al. Dietary antioxidant vitamin intake and lung function in the general population. Am. J. Respir. Crit. Care Med. 1995: 151:1383–7. 129. Rahman I, Crowther A, de Boer WI et al. 4-hydroxy-2-nonenal, a specific lipid peroxidation product is elevated in lungs of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 163:A31. 130. Rahman I, van Schadewijk AM, Hiemstra PS et al. Localisation of c-glutamylcysteine synthetase messenger RNA expression in lungs of smokers and patients with chronic obstructive pulmonary disease. Free Rad. Biol. Med. 2000; 28:920–5. 131. Gilks CB, Price K, Wright JL, Churg A. Antioxidant gene expression in rat lung after exposure to cigarette smoke. Am. J. Pathol. 1998; 152:269–78. 132. Zayasu K, Sekizawa K, Okinaga S et al. Increased carbon monoxide in exhaled air of asthmatic patients. Am. J. Respir. Crit. Care Med. 1997; 156:1140–3.
Chapter
Chemokines
27
James E. Pease and Timothy J. Williams Biomedical Sciences Division, Imperial College of Science, Technology and Medicine, London, UK
The defenses of the body are dependent on the localization of different types of white blood cells in different tissue compartments and the rapid recruitment of these cells to sites of injury or infection. This is dependent on the ability of white blood cells to detect and move towards chemical signals (chemoattractants) produced constitutively in specialized locations, or upregulated at sites of damage or invasion by pathogens, or in conditions characterized by sterile inflammation such as asthma or chronic obstructive pulmonary diease (COPD). Until recently, little was known about how the immune system organizes its geography under basal conditions or how specific cell types can be recruited to sites of inflammation. Chemoattractants had been discovered in Boyden chamber chemotaxis assays (e.g. complement-derived C5a, leukotriene B4, and platelet activity factor), but none of these had the specificity necessary for many of the migratory responses seen in the body. This situation changed dramatically with the discovery of the first chemokines in the late 1980s and the growing number of family members that have been discovered over the last decade.
THE CHEMOKINES The chemokines are a large family of small chemotactic proteins of 6–14 kDa; see Rossi and Zlotnik1 for a review. They have many roles in the organization of the immune system under basal conditions and during infection, and are also involved in angiogenesis. An important role of chemokines is the recruitment of different types of leucocytes from the blood to sites of inflammation. Selected types of cells are recruited by means of locally produced chemokines; the particular chemokine secreted depends on the type of stimulus and the tissue involved. Specificity is provided by the expression of different types of receptor on different leucocyte types. Most of the known chemokines (Table 27.1) belong to two major families defined by the position of four conserved cysteine residues (Fig. 27.1). CXC chemokines (of
which 15 distinct forms have been identified to date) have two cysteine residues near the N-terminus with an interposed amino acid; some CXC chemokines have three disulfide bonds. CC chemokines, the biggest subfamily (28 in number), have adjacent cysteines near the N-terminus. In both cases the first cysteine forms a disulfide bond with the third, and the second with the fourth cysteine. CXC chemokines are characteristically chemotactic for neutrophils and lymphocytes. CC chemokines act on leucocytes apart from neutrophils. CXC chemokines are further subdivided into those having an ELR motif immediately before the first cysteine, and those lacking the ELR.The former are associated with angiogenic properties, while most of the latter are angiostatic. There are some nonconforming chemokines: lymphotactin that has only a single disulfide bond, and fractalkine that has a CXXXC motif. Fractalkine is also unusual in that it is produced attached to a cellbound mucin stalk. Chemokines are thought to bind to presenting molecules on the luminal surface of the venular endothelium where they engage chemokine receptors on the leucocyte surface. Leucocytes typically roll on the endothelium through intermolecular interactions mediated by selectins. Stimulation of chemokine receptors induces an upregulation of adhesion molecules on the leucocyte surface and cytoskeletal changes, both of which facilitate attachment of the leucocyte followed by migration through the endothelium into the tissues. Chemokines bind to and transduce their actions via 7transmembrane region receptors coupled to heterotrimeric G proteins. To date six CXC and 11 CC chemokine receptors have been characterized; single receptors have been identified for fractalkine and for lymphotactin. The chemokines and their receptors have now been given a nomenclature to alleviate some of the problems associated with multiple names for the same ligands. Chemokine receptors are designated as CXCRn, CCRn, CX3CR1, and XCR1. The chemokine ligands that stimulate these receptors are now designated CXCLn, CCLn, CX3CLn and XCLn, respectively (Table 27.1).
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CHEMOKINES IN COPD
Table 27.1. Chemokines and their receptors
Chemokine Original name
Chemokine receptor(s)
CXCL1
GRO-a/MGSA-a
CXCL2 CXCL3 CXCL4 CXCL5 CXCL6 CXCL7 CXCL8 CXCL9 CXCL10 CXCL11 CXCL12 CXCL13 CXCL14 (CXCL15) CXCL16
GRO-b/MGSA-b GRO-c/MGSA-c PF4 ENA-78 GCP-2 NAP-2 IL-8 Mig IP-10 I-TAC SDF-1a/b BLC/BCA-1 BRAK/bolekine Unknown SexCkine
CXCR2 > CXCR1 CXCR2 CXCR2 Unknown CXCR2 CXCR1, CXCR2 CXCR2 CXCR1, CXCR2 CXCR3 CXCR3 CXCR3 CXCR4 CXCR5 Unknown Unknown CXCR6
CCL1 CCL2 CCL3 CCL4 CCL5
I-309 MCP-1/MCAF MIP-1a/LD78a MIP-1b RANTES
(CCL6) CCL7
Unknown MCP-3
CCL8 (CCL9/10) CCL11 (CCL12) CCL13 CCL14 CCL15 CCL16 CCL17 CCL18 CCL19 CCL20 CCL21 CCL22 CCL23 CCL24 CCL25 CCL26 CCL27 CCL28
MCP-2 Unknown Eotaxin Unknown MCP-4 HCC-1 HCC-2/Lkn-1/MIP-1d HCC-4/LEC TARC DC-CK1/PARC AMAC-1 MIP-3b/ELC/exodus-3 MIP-3a/LARC/exodus-1 6Ckine/SLC/exodus-2 MDC/STCP-1 MPIF-1 MPIF-2/eotaxin-2 TECK Eotaxin-3 CTACK/ILC CCL28, MEC
CCR8 CCR2 CCR1, CCR5 CCR5 CCR1, CCR3, CCR5 Unknown CCR1, CCR2, CCR3 CCR3 Unknown CCR3 CCR2 CCR2,CCR3 CCR1 CCR1,CCR3 CCR1 CCR4 Unknown CCR7,CCR11 CCR6 CCR7, CCR11 CCR4 CCR1 CCR3 CCR9,CCR11 CCR3 CCR10 CCR10, CCR3
XCL1 XCL2
Lymphotactin/SCM-1a/ATAC SCM-1b
XCR1 XCR1
CX3CL1
Fractalkine/neurotactin
CX3CR1
Neutrophils are strongly implicated in the pathogenesis of COPD. There is considerable interest in the mechanisms involved in the recruitment of these cells to the lung to provide the opportunity for potential therapeutic intervention. Neutrophils are found in high numbers in lung tissue and sputum in COPD, and it is believed that activation of these cells to release activated oxygen species and proteases, such as elastase, is important in lung damage and chronic dysfunction. Interleukin-8 is a CXC chemokine that is a potent chemoattractant for neutrophils. This chemokine was the first to be discovered and characterized.2–4 Early studies showed that this chemokine was present in the inflammatory exudate induced by microbial infection in vivo,5,6 and its production was often preceded by a phase of appearance of the complement fragment, C5a, which is also a potent neutrophil attractant but is generated in tissue fluid rather than as a secretory product of a cell.7 Neutrophils themselves have been shown to produce IL-8 during phagocytosis;8–10 these effects can be blocked by antibodies to integrins and platelet-activating factor antagonists.9 A similar pattern of chemoattractant production, C5a followed by IL-8, has also been observed in response to myocardial ischemia, and interestingly the IL-8 production is dependent on the presence of neutrophils in the heart – implying that neutrophils are the source of the chemokine.11 In a lung model of ischemia, neutralization of IL-8 by an antibody suppresses tissue damage; thus providing a link between neutrophils and injury to lung tissues.12 IL-8 was first discovered as a secretory product of stimulated macrophages and other cells. It stimulates neutrophils via two different receptors on the plasma membrane of the leucocyte, CXCR1 and CXCR2. One other related chemokine, GCP-2, can stimulate both receptors.13 There are several other chemokines that can stimulate CXCR2 only (i.e. GRO-a, GRO-b, GRO-c, and NAP-2). IL-8 appears to be an important mediator of neutrophil accumulation in COPD. IL-8 has been detected by ELISA in the bronchoalveolar lavage (BAL) fluid and in the circulation of patients with the disease.14–16 The levels of IL-8 have been found to correlate with neutrophil accumulation. Recently, it has been shown that IL-8 is elevated in sputum from COPD patients during disease exacerbation and declines about one month afterwards.17 In this study it was concluded that there was no correlation between IL-8 levels, acute inflammation, and viral or bacterial airway infections. However, another study showed a correlation between sputum IL-8 levels and Haemophilus influenzae exacerbations.18 A more complete understanding of the role of chemokines in COPD could open the door for effective therapeutic intervention.
CHEMOKINES IN ASTHMA There is a very extensive literature on the mechanisms underlying asthma and allergy. Considerable evidence
257
Chemokines
(a) CC
C
C
CC or α class
NH2
COOH
C C
C
C
CXC or β class
NH2
COOH
C
C C or γ class
NH2 C NH2
COOH
C
C
C
CX3C or δ class
COOH (c)
NH2
(b) HOOC
NH2
COOH
Fig. 27.1. (a) Linear representations of the major chemokine classes. (b) Primary structure of the human homolog of eotaxin20, showing disulfide bridges. (c) Secondary structure of human eotaxin represented as a ribbon model, modeled from the coordinates given in Crump et al.51 Reproduced from reference 51 with permission.
underpins the link between the infiltration of inflammatory cells in the lung and the progressive changes in lung pathophysiology. The late asthmatic response to allergen exposure is associated with activation of Th2-lymphocytes that are believed to regulate the massive eosinophil influx that occurs. Eosinophils are thought to make an important contribution to lung damage and dysfunction by releasing their toxic granular contents. For this reason, there has been a long-term interest in the endogenous chemoattractants involved in the recruitment of eosinophils to the lung. Eosinophils are believed to have evolved in host defense to parasitic worms. Thus, unlike neutrophils that are essential for survival against microbial infection, eosinophils present an attractive therapeutic target. Eosinophil chemoattraction The selective recruitment of eosinophils during the late response to allergen in sensitized individuals implies the existence of endogenous selective eosinophil chemoattractants. A protein was purified from BAL fluid of allergenchallenged, sensitized guinea-pigs that had this property.
On sequencing, the protein was found to be a novel CC chemokine that was termed “eotaxin”.19 Eotaxin homologs have been discovered in several species, including humans.20,21 The eotaxin gene is located on chromosome 17q11.2 in the CC-chemokine cluster. Two human functional homologs, with low sequence similarity but closely related biological properties, have been described and designated eotaxin-2 and eotaxin-3. The genes for these chemokines are located on chromosome 7q11.2. The eotaxins are highly potent chemoattractants for eosinophils acting via a single receptor, CCR3, that is highly expressed on eosinophils. CCR3 has also been detected on mast cells,22 basophils,23 and a subpopulation of Th2 lymphocytes.24 Studies in guinea-pigs and mice have shown expression of eotaxin mRNA and protein in the lung during the early response to allergen exposure.19,25–27 Human eotaxin has been detected in airway biopsies,28,29 BAL fluid,30 and sputum31 from asthmatic patients. In both animal and human studies of allergic airways disease, the expression of the chemokine has been observed in many cell types, including airway epithelium, microvascular
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endothelium, tissue macrophages, and infiltrating inflammatory cells.26,28 An increasing number of CC chemokines, in addition to eotaxin, have been found to stimulate CCR3. RANTES and certain of the monocyte chemotactic peptides (MCP-2, -3, and -4) stimulate CCR3, but also act on other chemokine receptors so that they are nonselective chemoattractants. Eotaxin generated in the lung induces migration of eosinophils from the blood into the tissue. After eotaxin is cleared from the lung in allergen challenge in guinea-pigs, it appears in the circulation and can induce migration of eosinophil precursors and mature eosinophils across the bone marrow sinus endothelium, leading to an elevation of circulating eosinophils.32 In this respect, eotaxin exhibits a marked synergism with IL-5.32,33 The number of eosinophils in the blood appears to be an important determinant of the number that can be recruited to a site of allergic inflammation.34 Different approaches have been made to determine the role of particular chemokines in eosinophil recruitment in vivo. Guinea-pig CCR3 has been cloned and an antibody raised against it has been shown to inhibit the migration of eosinophils in vivo.35 Neutralizing antibodies to eotaxin have also been shown to block allergen-induced eosinophil infiltration and airway hyperresponsiveness in mouse lung.36 Mixed results have been produced with eotaxin genedeleted mice: one study showing a marked suppression of the first phase of eosinophil infiltration,37 but another study could show no effect.38 This may be because of other ligands acting through CCR3 in vivo (e.g. eotaxin-2) or because of the involvement of other chemokine receptors (e.g. CCR1 in mice). Chemoattraction of Th2 lymphocytes T cell depletion has been shown to prevent allergeninduced eotaxin generation and eosinophil accumulation in the lungs of sensitized mice.39 Cytokines produced by Th2 lymphocytes, IL-4 and IL-13, have been shown to stimulate eotaxin production by other cells in vitro,40,41 thus providing a link between Th2 lymphocytes and eosinophil recruitment. However, IL-5 does not appear to induce eotaxin production.26 Th2 lymphocytes have chemokine receptors (CCR3, CCR4, and CCR8). In a mouse model of asthma it has been shown that neutralizing eotaxin, using an antibody, suppresses the accumulation of the Th2 cells measured 4 days after allergen challenge. However, neutralizing MDC, a ligand for CCR4, suppresses an even later phase of Th2 cell accumulation.42 More recently it has been shown that CCR8 gene-deleted mice have impaired Th2-driven responses, whereas Th1-driven responses are unaffected.43 Other chemokines may also be involved in Th2 cell polarization (e.g. MCP-144). Polarization may also be amplified by chemokines acting as antagonists; e.g. eotaxin is an antagonist acting on CXCR3 expressed in Th1 cells,45 whereas ligands stimulating CXCR3 (IP10, MIG, and ITAC) act as antagonists to CCR3 expressed on Th2 cells.46
CHEMOKINES AND THEIR RECEPTORS A S T H E R A P E U T I C TA R G E T S The observations outlined above provide the basis for the development of low-molecular-weight compounds aimed at selectively preventing the recruitment of a particular leucocyte type to a site of inflammation and thus suppressing the pathogenesis associated with that cell type. A vast library of compounds has been produced that modifies interaction between 7-transmembrane G protein-coupled receptors and their ligands; such compounds, either agonists or antagonists, provide a large proportion of the drugs currently in use. The first low-molecular-weight compound to be developed against a chemokine receptor was a CXCR2 antagonist. This compound, SB225002, is a potent and selective antagonist that blocks IL-8 binding and inhibits neutrophil chemotaxis in vitro and neutrophil accumulation in vivo.47 CXCR2 antagonists could be developed to prevent neutrophil accumulation in the lung in COPD. However, such effects would have to be monitored carefully as neutrophils are essential for host defense against microbial pathogens. Because of its prominence on cells associated with Th2 lymphocyte-driven allergic reactions, CCR3 has become a prime target for the development of antagonists. The first publication of such an antagonist described the effects of a low-molecular-weight compound (UCB 35625, a structure based on a compound produced by Banyu, Japan) that blocks CCR3.48 This compound also blocks CCR1, the receptor for MIP-1a. This may be an advantage as around 1 in 10 individuals have eosinophils that respond to MIP-1a (via CCR1) in addition to eotaxin (via CCR3).49 The compound is unusual in that it blocks the stimulation of receptors by chemokines at low concentrations, but displaces ligand only at high concentrations.48 Potent competitive antagonists of CCR3 have also been described in the scientific press (SB-297006 and SB328437)50 and several others have appeared in the patent literature.
CONCLUSION A combination of clinical observations, in vitro cell biology and in-vivo animal modeling has delineated potentially important mechanisms underlying lung inflammation in COPD and asthma. These extensive studies have generated novel targets for the development of future therapeutic compounds. It is now clear that chemokines have a fundamental role in regulating leucocyte trafficking in inflammatory diseases. Early studies show that it is possible to block the receptors for these chemokines selectively with low-molecular-weight antagonists. Clinical trials will provide the crucial information that will define the chemokine receptors that can be blocked to provide future therapy in COPD and asthma.
Chemokines
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19. Jose PJ, Griffiths-Johnson DA, Collins PD et al. Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea-pig model of allergic airways inflammation. J. Exp. Med. 1994; 179:881–7. 20. Ponath PD, Qin S, Ringler DJ et al. Cloning of the human eosinophil chemoattractant, eotaxin: expression, receptor binding and functional properties suggest a mechanism for the selective recruitment of eosinophils. J. Clin. Invest. 1996; 97:604–12. 21. Garcia-Zepeda EA, Rothenberg ME, Ownbey RT et al. Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nature Med. 1996; 2:449–56. 22. Romagnani P, De Paulis A, Beltrame C et al. Tryptase–chymase double-positive human mast cells express the eotaxin receptor CCR3 and are attracted by CCR3-binding chemokines. Am. J. Pathol. 1999; 155:1195–204. 23. Uguccioni M, Mackay CR, Ochensberger B et al. High expression of the chemokine receptor CCR3 in human blood basophils: role in activation by eotaxin, MCP-4, and other chemokines. J. Clin. Invest. 1997; 100:1137–43. 24. Sallusto F, Mackay CR, Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science 1997; 277:2005–7. 25. Rothenberg ME, Luster AD, Lilly CM, Drazen JM, Leder P. Constitutive and allergen-induced expression of eotaxin mRNA in the guinea-pig lung. J. Exp. Med. 1995; 181:1211–16. 26. Humbles AA, Conroy DM, Marleau S et al. Kinetics of eotaxin generation and its relationship to eosinophil accumulation in allergic airways disease: analysis in a guinea pig model in vivo. J. Exp. Med. 1997; 186:601–12. 27. Gonzalo J-A, Jia G-Q, Aguirre V et al. Mouse eotaxin expression parallels eosinophil accumulation during lung allergic inflammation but it is not restricted to a Th2-type response. Immunity 1996; 4:1–14. 28. Ying S, Robinson DS, Meng Q et al. Enhanced expression of eotaxin and CCR3 mRNA and protein in atopic asthma: association with airway hyperresponsiveness and predominant co-localization of eotaxin mRNA to bronchial epithelial and endothelial cells. Eur. J. Immunol. 1997; 27:3507–16. 29. Lamkhioued B, Renzi PM, Younes A et al. Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation. J. Immunol. 1997; 159:4593–601. 30. Mattoli S, Stacey MA, Sun G, Bellini A, Marini M. Eotaxin expression and eosinophilic inflammation in asthma. Biochem. Biophys. Res. Commun. 1997; 236:299–301. 31. Zeibecoglou K, Ying S, Meng Q et al. Expression of eotaxin in induced sputum of atopic and nonatopic asthmatics. Allergy 2000; 55:1042–8. 32. Palframan RT, Collins PD, Williams TJ, Rankin SM. Eotaxin induces a rapid release of eosinophils and their progenitors from the bone marrow. Blood 1998; 91:2240–8. 33. Palframan RT, Collins PD, Severs NJ et al. Mechanisms of acute eosinophil mobilization from the bone marrow stimulated by interleukin 5: the role of specific adhesion molecules and phosphatidylinositol 3-kinase. J. Exp. Med. 1998; 188:1621–32. 34. Collins PD, Marleau S, Griffiths-Johnson DA, Jose PJ, Williams TJ. Co-operation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J. Exp. Med. 1995; 182:1169–74. 35. Sabroe I, Conroy DM, Gerard NP et al. Cloning and characterisation of the guinea pig eosinophil eotaxin receptor, CCR3: blockade using a monoclonal antibody in vivo. J. Immunol. 1998; 161:6139–47. 36. Campbell EM, Kunkel SL, Strieter RM, Lukacs NW.Temporal role of chemokines in a murine model of cockroach allergen-induced
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airway hyperreactivity and eosinophilia. J. Immunol. 1998; 161:7047–53. Rothenberg ME, MacLean JA, Pearlman E, Luster AD, Leder P. Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia. J. Exp. Med. 1997; 185:785–90. Yang Y, Loy J, Ryseck RP, Carrasco D, Bravo R. Antigen-induced eosinophilic lung inflammation develops in mice deficient in chemokine eotaxin. Blood 1998; 92:3912–23. MacLean JA, Ownbey R, Luster AD. T cell-dependent regulation of eotaxin in antigen-induced pulmonary eosinophilia. J. Exp. Med. 1996; 184:1461–9. Li L, Xia Y, Nguyen A et al. Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells. J. Immunol. 1999; 162:2477–87. Teran LM, Mochizuki M, Bartels J et al. Th1- and Th2-type cytokines regulate the expression and production of eotaxin and RANTES by human lung fibroblasts. Am. J. Respir. Cell Mol. Biol. 1999; 20:777–86. Lloyd CM, Delany T, Nguyen T et al. CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo. J. Exp. Med. 2000; 191:265–73. Chensue SW, Lukacs NW,Yang TY et al. Aberrant in-vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor-8 knockout mice. J. Exp. Med. 2001; 193:573–84.
44. Gu L, Tseng S, Horner RM et al. Control of Th2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 2000; 404:407–11. 45. Weng Y, Siciliano SJ, Waldburger KE et al. Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors. J. Biol. Chem. 1998; 273:18288–91. 46. Loetscher P, Pellegrino A, Gong JH et al. The ligands of CXC chemokine receptor 3, I-TAC, Mig and IP10, are natural antagonists for CCR3. J. Biol. Chem. 2001; 276:2986–91. 47. White JR, Lee JM,Young PR et al. Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8induced neutrophil migration. J. Biol. Chem. 1998; 273:10095–8. 48. Sabroe I, Peck MJ, Jan Van Keulen B et al. A small molecule antagonist of the chemokine receptors CCR1 and CCR3: potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J. Biol. Chem. 2000; 275:25985–92. 49. Sabroe I, Hartnell A, Jopling LA et al. Differential regulation of eosinophil chemokine signalling via CCR3 and non-CCR3 pathways. J. Immunol. 1999; 162:2946–55. 50. White JR, Lee JM, Dede K et al. Identification of potent, selective non-peptide CCR3 antagonist that inhibits eotaxin-1, eotaxin-2 and MCP-4 induced eosinophil migration. J. Biol. Chem. 2000; 275:36626–31. 51. Crump MP, Rajarathnam K, Kim KS, Clark-Lewis I, Sykes BD. Solution structure of eotaxin, a chemokine that selectively recruits eosinophils in allergic inflammation. J. Biol. Chem. 1998; 273:22471–9.
Chapter
Cytokines
28
Kian Fan Chung National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
INTRODUCTION
• chemoattractant cytokines (chemokines) for eosinophils, neutrophils and T cells; • anti-inflammatory cytokines; • growth factors.
Cytokines are extracellular signaling proteins, usually less than 80 kDa in size. They are produced by different cell types involved in cell-to-cell interactions, have an effect on closely adjacent cells, and therefore function in a predominantly paracrine fashion. They may also act at a distance (endocrine) and may have effects on the cell of origin (autocrine). Originally, lymphokines were described.These are soluble factors generated by activated lymphocytes, particularly CD4 T cells, in response to specific or polyclonal antigen. They formed the most important class of cytokines involved in immunological mechanisms. Particular subsets of CD4 T cells may be induced preferentially, secreting defined patterns of cytokines, resulting in initiation and propagation of distinct immune effector mechanisms. Studies in mouse CD4 T cell clones, and later in human CD4 T cells, have revealed two basic functional polarized subsets, termed T-helpers (Th1 and Th2). Th1 cells are characterized by predominant secretion of interleukin (IL-2), interferon (IFN-c), and tumor necrosis factor (TNF), triggering both cell-mediated immunity and production of opsonizing antibodies. Th2 cells secrete predominantly IL-4, IL-5, IL-10, and IL-13, responsible for IgE and IgG4 antibody production, and activation of mast cells and eosinophils.1 A third subset of T-helper cells, Th0, shows a composite profile producing both Th1- and Th2associated cytokines. These soluble factors can also be expressed by macrophages, epithelial cells, and mast cells, and may take part in more general inflammatory processes. Other classes of cytokines include chemokines, which have important chemoattractant properties; and growth factors, which mediate proliferation, differentiation, and survival of cells. Classification of cytokines in the context of airways disease is best considered functionally, (Table 28.1) such as:
I N F L A M M AT I O N A N D C Y T O K I N E S I N ASTHMA
• pro-inflammatory cytokines; • Th2-derived cytokines involved in the pathogenesis of atopy and of eosinophilic inflammation;
Cytokine expression The chronic airway inflammation of asthma is characterized by an infiltration of T cells, eosinophils, macrophages/
Cytokines are rarely produced individually; rather, they are produced with other cytokines in patterns characteristic of particular diseases. There is a wide pleiotropy and element of redundancy in the cytokine family, in that each cytokine has many overlapping functions, with each function potentially mediated by more than one cytokine. However, the effects of an individual cytokine may be influenced by other cytokines released simultaneously from the same cell or from target cells following activation by the cytokine, to induce either synergistic or antagonistic effects. The effects of cytokines are mediated by binding to cell-surface highaffinity receptors usually present in low numbers, which can be upregulated with cell activation. The receptors for many cytokines have been grouped into superfamilies based on the presence of common homology regions (Table 28.2). Cytokines themselves may induce the expression of receptors which may change the responsiveness of both source and target cells. Some cytokines may stimulate their own production in an autocrine manner; others stimulate the synthesis of different cytokines that have a stimulatory feedback effect on the first cytokine. The potential contribution of cytokines to disease has been explored in studies using cytokines as agonists, by blocking the effects of specific cytokines, by overexpression and deletion of cytokines in transgenic mice, and by genetic studies.The sources and effects of cytokines are summarized in Table 28.2, and have been recently reviewed in Chung and Barnes.2
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Table 28.1. Classification of cytokines and cytokine receptors
Cytokines Proinflammatory cytokines Cytokines of eosinophil recruitment and activation Cytokines from T-helper (Th) cells Cytokines of T cell recruitment Cytokines of neutrophil recruitment and activation Anti-inflammatory cytokines Growth factors
IL-1a/b, TNF-a/b, IL-6, IL-11, IFN-c IL-2, IL-3, IL-4, IL-5, GM-CSF, RANTES, eotaxin, MCP-3, MCP-4 Th1: IFN-c, IL-2, IL-12, GM-CSF, TNF-b Th2: IL-4, IL-5, IL-6, IL-10, IL-13 IL-16, RANTES, MIP-1a/b IL-8, IL-1a/b, TNF-a/b IL-10, IL-4, IL-13, IL-12, IL-1ra PDGF, TGF-b, FGF, EGF, TNF-a, SCF
Cytokine receptor superfamilies Cytokine receptor superfamily
IL-2R b and c chains, IL-4R, IL-3R a and b chains, IL-5 a and b chains, IL-6R, gp130, IL-12R, GM-CSFR Soluble forms by alternative splicing (e.g. IL-4R) Immunoglobulin superfamily IL-1R, IL-6R, PDGFR, M-CSFR Protein kinase receptor superfamily PDGFR, EGFR, FGFR Interferon receptor superfamily IFN-a/b receptor, IFN-c receptor, IL-10 receptor Nerve growth factor superfamily NGFR, TNFR-I (p55), TNFR-II (p75) Seven-transmembrane G-protein-coupled receptor superfamily Chemokine receptors EGF, epidermal growth factor; FGF, fibroblast growth factor; GM-CSF, granulocyte–macrophage colony stimulating factor; IFN, interferon; IL, interleukin; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; NGFR, nerve growth factor receptor; PDGF, platelet-derived growth factor; R, receptor; RANTES, regulated on activation, normal T cell expressed, and secreted; SCF, stem cell factor; TGF, transforming growth factor.
monocytes, and mast cells, and sometimes neutrophils. Acute-on-chronic inflammation may be observed with acute exacerbations of the disease, with an increase in eosinophils and neutrophils in the airway submucosa and release of mediators such as histamine and cysteinyl leukotrienes from eosinophils and mast cells to induce bronchoconstriction, airway edema, and mucus secretion. Changes in the resident cells are also observed, such as: • an increase in the thickness of the airway smooth muscle with hypertrophy and hyperplasia; • more myofibroblasts with an increase in collagen deposition in the lamina reticularis; • more vessels and an increase in the goblet cell numbers in the airway epithelium.3 Cytokines play an integral role in the coordination and persistence of the chronic allergic inflammatory process in asthma (Fig. 28.1). Of the more important classes of cytokines identified in the airway mucosa of patients with asthma are the Th2-associated cytokines. By in-situ hybridization, increased proportions of cells in bronchial biopsies and in bronchoalveolar lavage (BAL) fluid from patients with atopic asthma express mRNA for IL-3, IL-4, IL-5, IL-13, and granulocyte–macrophage colony-stimulating factor (GM-CSF), the Th2 gene cluster, when compared with those of nonatopic control subjects.4–6 In a model
of inhalational allergen challenge, an increase in mRNA for these Th2 cytokines, but not for IFN-c, has been demonstrated in bronchial biopsies and BAL cells of atopic asthmatics.7 Thus, lung T cells are activated and express and release high levels of Th2-type cytokines. Although CD4 T cells appear to be the main cell expressing these Th2 cytokine transcripts, mast cells and eosinophils also express IL-4 and IL-5 mRNA.8–10 Mast cells in mucosal biopsies from atopic asthmatics were positive for IL-3, IL-4, IL-5, IL-6, and TNF-a by immunohistochemistry, while immunoreactive IL-5 and GM-CSF in eosinophils have been detected after endobronchial allergen challenge in asthmatics.9 Alveolar macrophages from patients with asthma release more proinflammatory cytokines, IL-1b,TNF-a, GM-CSF, and MIP-1a, compared with normal subjects.11,12 Antigen presentation and release of cytokines The primary signals that activate Th2 cells are related to the presentation of a restricted panel of antigens in the presence of appropriate cytokines. Allergens are taken up and processed by specialized cells within the mucosa, such as dendritic cells (antigen-presenting cells), followed by presentation of peptide fragments to naive T cells.The activation of naive T cells occurs firstly via the CD4 T cell receptor through the antigen-presenting cell (APC)-bound antigen to MHC-II complex and, secondly, via the costimulatory
Cytokines
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Table 28.2. Sources and effects of cytokines
Cytokine
Sources
Important cellular and mediator effects
IL-3
Th2 cell Mast cells Eosinophils
• Eosinophilia in vivo • Pluripotential hematopoietic factor
IL-4
Th2 cell Mast cells Basophils Eosinophils
• • • •
↑ Eosinophil growth ↑ Th2; ↓ Th1 ↑ IgE ↑ Mucin expression and goblet cells
IL-5
Th2 cell Mast cells Eosinophils
• • • •
Eosinophil maturation ↓ Apoptosis ↑ Th2 cells BHR
IL-9
Th2 cells Eosinophils
• • • •
↑ Activated T cells and IgE from B cells ↑ Mast cell growth and differentiation ↑ Mucin expression and goblet cells Causes eosinophilic inflammation and BHR
IL-13
Th2 cells Basophils Eosinophils Natural killer cells
• Activates eosinophils • ↓ Apoptosis • ↑ IgE • ↑ Mucin expression and goblet cells
IL-15
T cells Lung fibroblasts Monocytes
• As for IL-2 • Growth and differentiation of T cells
IFN-c
Th1 cells Natural killer cells
• ↓ Eosinophil influx after allergen • ↓ Th2 cells • Activates endothelial cells, epithelial cells, alveolar macrophages/monocytes • ↓ IgE • ↓ BHR
IL-2
Th0 & Th1 cells Eosinophils Airway epithelial cells
• Eosinophilia in vivo • Growth and differentiation of T cells
IL-12
B cells Monocytes/macrophages Dendritic cells Eosinophils
• • • •
IL-18
Th1 cells Airway epithelium
• Induces IFN-c release from mitogen-stimulated blood mononuclear cells • Induces Th1 cell development together with IL-12 • Causes release of IL-8, MIP1a and MCP-1 from mononuclear cells
Th2 cytokines
Th1 cytokines
Regulates Th1 cell differentiation ↓ Expansion of Th2 cells ↓ IL-4-induced IgE synthesis Stimulates NK cells and T cells to produce IFN-c
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Table 28.2. Sources and effects of cytokines (Continued)
Cytokine
Sources
Important cellular and mediator effects
Proinflammatory IL-1
Monocytes/macrophages Fibroblasts B cells Th1 and Th2 cells Neutrophils Endothelial cells Airway epithelial cells Airway smooth muscle cells
• ↑ Adhesion to vascular endothelium; eosinophil accumulation in vivo • Growth factor for Th2 cells • B cell growth factor; neutrophil chemoattractant; T cell and epithelial activation • BHR
TNF-a
Macrophages T cells Mast cells Airway epithelial cells
• Activates epithelium, endothelium, antigen-presenting cells, monocytes/macrophages • BHR • ↑ IL-8 from epithelial cells • ↑ Matrix metalloproteinases from macrophages
IL-6
Monocytes/macrophages T cells B cells Fibroblasts Airway epithelial cells
• T cell growth factor • B cell growth factor • ↑ IgE
IL-8
Monocytes/macrophages Airway epithelial cells Airway smooth muscle cells Eosinophils
• Neutrophil chemoattractant and activator • Chemotactic for CD8 T cells • Activates 5-lipoxygenase in neutrophils • Induces release of histamine and cys-leukotrienes from basophils
IL-11
Airway epithelial cells Airway smooth muscle cells Fibroblasts Eosinophils
• B cell growth factor • Activates fibroblast • BHR
IL-16
CD8 T cells Epithelial cells Eosinophils Mast cells
• Eosinophil migration • Growth factor and chemotaxis of CD4 T cells
IL-17
CD4 T cells
• T cell proliferation • Activates epithelia, endothelial cells, fibroblasts • Induces release of IL-6, IL-8, and GM-CSF • Neutrophil chemoattractant and activator
GM-CSF
T cells Macrophages Eosinophils Fibroblasts Endothelial cells Airway smooth muscle cells Airway epithelial cells
• • • •
SCF
Bone marrow stromal cells Fibroblasts Epithelial cells
• ↑ VCAM-1 on eosinophils • Growth factor for mast cells
Eosinophil apoptosis and activation; induces release of leukotrienes Proliferation and maturation of hematopoietic cells Endothelial cell migration BHR
Cytokines
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Table 28.2. Sources and effects of cytokines (Continued)
Cytokine
Sources
Important cellular and mediator effects
Inhibitory cytokines ↓ ↓ ↓ ↓
IL-10
Th2 cells CD8+ T cells Monocytes/macrophages
• • • •
Eosinophil survival Th1 and Th2 Monocyte/macrophage activation; ↑ B cell; ↑ Mast cell growth BHR
IL-1ra
Monocytes/macrophages
• ↓ Th2 proliferation • ↓ BHR
IL-18
Dendritic cells Monocytes NK cells
• Enhances Th1 cells via IFN-c release • Releases IFN-c from Th1 cells • Activates NK cells, monocytes • ↓ IgE
Growth factors PDGF
Macrophages Airway epithelium Fibroblasts
• Fibroblast and airway smooth muscle proliferation • Release of collagen
TGF-b
Macrophages Eosinophils Airway epithelium
• • • • •
↓ T cell proliferation Blocks IL-2 effects Fibroblast proliferation Chemoattractant for monocytes, fibroblasts, mast cells ↓ ASM proliferation
ASM, airway smooth muscle; BHR, bronchial hyperresponsiveness; GM-CSF, granulocyte–macrophage colony stimulating factor; IgE, immunoglobulin E; IFN, interferon; IL, interleukin; IL-1ra, interleukin-1 receptor antagonist; MIP, macrophage inflammatory factor; NK, natural killer; TNF, tumor necrosis factor; VCAM, vascular adhesion molecule.
pathway linked by the B7 family and T-cell-bound CD28.13 CD28 itself has two major ligands: B7.1 which inhibits Th2 cell activation and development, and B7.2 which induces T cell activation and Th2 cell proliferation. Cytokines may play an important role in antigen presentation. Airway macrophages are usually poor at antigen presentation and suppress T cell proliferative responses (possibly via release of cytokines such as IL-1 receptor antagonist), but in asthma there is reduced suppression after exposure to allergen.14 Both GM-CSF and IFN-c increase the ability of macrophages to present allergen and express HLA-DR.15 IL-1 is important in activating T lymphocytes and is an important costimulator of the expansion of Th2 cells after antigen presentation.16 Airway macrophages may be an important source of “first wave” cytokines, such as IL-1, TNF-a, and IL-6, which may be released on exposure to inhaled allergens via FceRI receptors.These cytokines may then act on epithelial cells to cause release of a “second wave” of cytokines, including GM-CSF, eotaxin and RANTES, which then leads to influx of secondary cells, such as eosinophils, which themselves may release multiple cytokines.
The immunoglobulin-E response and mast cells IL-4 is the most important cytokine mediating IgE synthesis through isotype switching by B cells, but IL-13 is also capable of a similar action on B cells.17 IL-4 also activates B cells through increasing the expression of class II MHC molecules, as well as enhancing the expression of CD23, the low-affinity IgE (FceRII) receptor. CD40 antigen is expressed on B cells after antigen recognition. IL-4 together with the engagement of CD40 antigen with its ligand, CD40-L on activated T cells, promotes IgE class switching and B cell growth. Because IL-4 can also be produced by basophils, mast cells, and eosinophils, and also have surface CD40-L, these cells may contribute to the amplification of IgE responses. IL-4 and IL-13 share the a-chain of the IL4 receptor (IL-4Ra). On engagement of the ligand with IL4Ra, signal transducer and activator of transcription 6 (Stat 6) translocates to the nucleus, and germline e mRNA transcription is initiated together with e-class switching of immunoglobulin genes. Individuals with gain of function mutations in both the extracytoplasmic and intracellular domains of IL-4Ra show an enhanced IgE response and predisposition to atopic disease.18
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Allergen GM-CSF, eotaxin RANTES
Epithelial cells
Dendritic cells
IL-1β TNF-α
PDGF TGF-β MHC II Peptide TCR
B7.2 CD28
IL-12 Th0
Fibroblast IF IL N-γ -1 2
Macrophage
Monocyte
ASM
IL-4 IL-13 Th1
0
-1
IL
MCP-1
GMC
SF
GMCSF RANTES Eotaxin
Th2
TGF-β
IL-5
I L-
TNF-α IL-4 1L-5
3
IL-4 IL-13
Eosinophil
Mast cell IgE
IL-5 GMCSF
B cell
Fig. 28.1. Interactions of cells and cytokines in airway inflammation of asthma. Antigen presentation by dendritic cells to T cells with the subsequent polarization to Th2 cells appear to be important initial process. The roles of other cells are also crucial, such as airway epithelium, eosinophils, neutrophils, macrophages, and airway smooth muscle cells. Broken arrows show potential interactions of allergens through high-affinity IgE receptors with macrophages and mast cells. GM-CSF, granulocyte–macrophage colony stimulating factors; IFN, interferon; IgE, immunoglobulin E; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; PDGF, platelet-derived growth factor; RANTES, regulated on activation, normal T cell expressed, and secreted; TCR, T cell receptor; Th2, T cell helper type 2; TGF, transforming growth factor; TNF, tumor necrosis factor.
IgE produced in asthmatic airways binds to FceRI receptors (“high affinity” IgE receptors) on mast cells and basophils, priming them for activation by antigen. Crosslinking of FceRI receptors upregulates its own expression and leads to mast cell degranulation, with the release of mediators such as histamine and cysteinyl leukotrienes. The low-affinity IgE receptor, FceRII or CD23, is present on B cells, macrophages and eosinophils; it may serve principally as a negative regulator of IgE synthesis. The maturation and expansion of mast cells from bone marrow cells involves growth factors and cytokines such as stem cell factor (SCF) and IL-3 derived from structural cells. Bronchoalveolar mast cells from asthmatics show enhanced release of mediators such as histamine. Mast cells also elaborate IL-4 and IL-5.8 IL-4 also increases the
expression of an inducible form of the low-affinity receptor for IgE (FceRII or CD23) on B lymphocytes and macrophages.19 IL-4 drives the differentiation of CD4 T-helper precursors into Th2-like cells. Eosinophil-associated cytokines The differentiation, migration, and pathobiological effects of eosinophils may occur through the actions of GM-CSF, IL-3, IL-5, and certain chemokines such as eotaxin.20–22 IL5 influences the production, maturation, and activation of eosinophils, acting predominantly at the later stages of eosinophil maturation and activation, and can also prolong the survival of eosinophils. IL-5 causes eosinophils to be released from the bone marrow, while the local release of an eosinophil chemoattractant such as eotaxin may be
267
Cytokines
Cigarette smoke Pollutants Oxidative stress
Macrophage
Neutrophil elastase
Neutrophil
Bacteria TNF-α, IL-1β
?
TNF-α
Viruses? Epithelium
Macrophage Fibrogenic cytokines eg.TGF-β, EGF Neutrophil
CD8 T cell
Fibroblast proliferation Mucin genes
IL-6, IL-8, MCP-1 LTB4 Proteases Oxidants Defensins IL-8, LTB4
?
Eosinophil (Acute)
MMP, TIMP
Tissue damage Remodeling Mucus hypersecretion
Fig. 28.2. Interaction of cells and cytokines in airway inflammation of COPD. The initiating factors include cigarette smoke with macrophages and airway epithelium, inducing the release of chemotactic factors for neutrophils, which in turn are important effector cells for inflammation, tissue damage and repair. EGF, epidermal growth factor; IL, interleukin; LTB4, leukotriene B4; MCP, monocyte chemotactic protein; MMP, matrix metalloproteinase; TGF, transforming growth factor; TIMP, tissue inhibitor of matrix metalloproteinase; TNF, tumor necrosis factor.
necessary for the tissue localization of eosinophils.23 Mature eosinophils may show increased survival in bronchial tissue, secondary to the effects of GM-CSF, IL-3, and IL-5.24 Eosinophils themselves may also generate other cytokines such as IL-3, IL-5, and GM-CSF.25 Cytokines such as IL-4 may also exert an important regulatory effect on the expression of adhesion molecules such as VCAM-1, both on endothelial cells of bronchial blood vessels and on airway epithelial cells. IL-1 and TNF-a increase the expression of ICAM-1 in both vascular endothelium and airway epithelium.26 An anti-IL5 monoclonal antibody administered to mild allergic asthmatics has been shown to suppress allergen-induced blood and sputum eosinophilia, without affecting the degree of the late-phase response, indicating that IL-5 may not be the only cytokine involved in allergen-induced late-phase responses. Eotaxin is a chemoattractant cytokine (chemokine) selective for eosinophils and acts through the chemokine receptor CCR3 present on eosinophils, basophils, and T cells. Cooperation between IL-5 and eotaxin appears necessary for the mobilization of eosinophils from the bone marrow during allergic reactions and for the local release of chemokines to induce homing and migration into tissues. Airway wall remodeling cytokines Experimental approaches made possible by genetically modified mice have highlighted the potential role of various
T-cell-derived cytokines in aspects of airway wall remodeling. Overexpression of these cytokines in the airway epithelium causes various features of airway wall remodeling. A CC10-driven overexpression of IL-13 in the lungs caused eosinophilic and mononuclear inflammation with goblet cell hyperplasia, subepithelial fibrosis, airway obstruction, and airway hyperresponsiveness.27 IL-4, IL-5, and IL-9 overexpression lead to substantial mucus metaplasia, while IL-9 and IL-5 overexpression also caused subepithelial fibrosis and airways hyperresponsiveness.28–30 Airway smooth muscle hyperplasia occurs following IL-11 overexpression.31 Proliferation of myofibroblasts and the hyperplasia of airway smooth muscle may also occur through the action of several growth factors, such as platelet-derived growth factor (PDGF) and transforming growth factor-b (TGF-b). They may be released from inflammatory cells in the airways, such as macrophages and eosinophils, but also by structural cells such as airway epithelium, endothelial cells, and fibroblasts. These growth factors may stimulate fibrogenesis by recruiting and activating fibroblasts or transforming myofibroblasts. Epithelial cells may release growth factors, since collagen deposition occurs underneath the basement membrane of the airway epithelium.32 Growth factors may also stimulate the proliferation and growth of airway smooth muscle cells. PDGF and epidermal growth factor (EGF) are potent stimulants of human airway
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smooth muscle proliferation,33 and these effects are mediated via activation of tyrosine kinase and protein kinase C. Airway smooth muscle cells have the capacity to elaborate a range of cytokines, including IL-4, IL-5, GM-CSF, IL-8, eotaxin, and MCP-1, and therefore may play a role in the induction of local inflammatory responses.34 Cytokines, such as TNF-a and fibroblast growth factors (FGF), may also play an important role in angiogenesis of chronic asthma. A greater expression of airway mucosal eosinophils expressing TGF-b mRNA and protein has been reported, correlating with the severity of asthma and the degree of subepithelial fibrosis,35 but this has not been confirmed in other studies.36 EGF expression is reported to be increased in the submucosa of asthmatic patients.37
I N F L A M M AT I O N A N D C Y T O K I N E S I N COPD Inflammation in COPD Chronic obstructive pulmonary disease (COPD) is characterized by chronic obstruction of expiratory flow affecting peripheral airways, often associated with chronic bronchitis (mucus hypersecretion with goblet cell and submucosal gland hyperplasia), and emphysema (destruction of airway parenchyma). Tissue damage with airway wall remodeling and thickening, inflammation, and fibrosis in the small airways appear to play an important role in patients with COPD. The accompanying emphysema leads to loss of lung elastic recoil, contributing to decreased expiratory flow. Increased numbers of neutrophils and macrophages are usually recovered in BAL fluid and in induced sputum from such patients. In the small airways there is a mucosal increase in inflammatory mononuclear cells and CD8 T cells, but without prominence of neutrophils.38 In acute exacerbations of COPD, eosinophils are prominent among the cells recovered in sputum or in bronchial biopsies, but there is no increase in expression of IL-5 in tissues.39 Some patients with COPD have a preponderance of eosinophils in sputum, an observation that has been associated with significant improvement of FEV1 with corticosteroid therapy.40 Neutrophils are more prominent in COPD than in asthma. Neutrophils have been implicated in causing tissue damage in COPD through the release of a number of mediators, including proteases such as neutrophil elastases and matrix metalloproteinases, oxidants, and toxic peptides such as defensins. A primary role for macrophages is also proposed because of their capacity to produce several metalloproteinases, including matrix metalloproteinases (MMP) such as MMP-1, MMP-9, and MMP-12.41 Expression and production of MMP-1 and MMP-9 mRNA is enhanced in macrophages from patients with COPD.42 Inhaled cigarette smoke may induce alveolar macrophages to produce macrophage metalloelastase (MMP-12) which in turn induces chemotactic fragments that attracts blood monocytes to the lung parenchyma.
The role of the CD8 T cell remains unclear, but they produce granzymes and perforin that can contribute to cell damage. One possibility is that these cells may be induced by certain virus infections, and virus-specific CD8 T cells may produce IL-5. The cytokine profile in COPD Increased levels of IL-6, IL-1b, TNF-a, and IL-8 have been observed in induced sputum of patients with stable COPD.43 During exacerbations, further increases in the levels of these cytokines were also observed in sputum.44 Increased release of proinflammatory cytokines IL-8, IL-1, and, TNF-a, and of the anti-inflammatory cytokine, IL-10, from alveolar macrophages of cigarette smokers and of COPD patients has been observed.45 The initiation of cytokine release in COPD is likely to be due to the direct effect of cigarette smoking. Thus, cigarette smoking increases IL-8 release by bronchial epithelial cells and by alveolar macrophages, and oxidants that are present in cigarette smoke cause the release of proinflammatory cytokines such as IL-1 and IL-8 from macrophages and epithelial cells. A higher expression of MCP-1,TGF-b1, and IL-8 mRNA and protein has been observed in bronchiolar epithelium, and of CCR2 expression in macrophages of smokers with COPD compared with those smokers without COPD.46 Since MCP-1 binds to CCR2 and MCP-1 can induce T cell and monocytic migration, this chemokine of the CXC class47 may contribute to the recruitment of these cells in COPD. With the absence of IL-5 expression in COPD airways with eosinophilia, other eosinophil chemoattractants such as eotaxin or RANTES may be implicated. Alternatively, IL-5 may be produced by CD8 T cells, particularly the T cytotoxic (Tc2) subset, that are in abundance in tissues of COPD. Properties of specific cytokines in COPD TNF-a is produced by many cells, including macrophages, T cells, mast cells, and epithelial cells; but the principal source is the macrophage.The secretion of TNF-a by monocytes/macrophages is greatly enhanced by other cytokines such as IL-1, GM-CSF, and IFN-c. A polymorphism in the 5 promoter region of the TNF-a gene (position 308; TNF2 variant) leading to increased TNF-a production has been linked to COPD in a Taiwanese population, but this association has not been reproduced in other studies. TNF-a activates the transcription factor, NF-jB, that switches on the transcription of the IL-8 gene and increases IL-8 release from the airway epithelium and neutrophils. Bacteria and bacterial products such as lipopolysaccharide can induce IL-8 expression, probably as a result of initial TNF-a production.48,49 TNF-a increases the expression of the adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), which is increased in serum of COPD patients.50 TNF-a may activate macrophages to produce matrix metalloproteinases. This effect is inhibited by IL-10, which also enhances the release of tissue inhibitor of metalloproteinases (TIMP) in macrophages from normal volunteers, but in
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Cytokines
smokers IL-10 increases TIMP-1 release without modifying MMP-9 release from alveolar macrophages.45 TNF-a also stimulates bronchial epithelial cells to produce tenascin, an extracellular matrix glycoprotein. Increased serum concentrations of TNF-a have been measured in patients with COPD with weight loss,51,52 and this may be related to the effects of TNF-a on bodyweight and energy balance homeostasis, and in mediating acute-phase responses. IL-1b induces leucocytosis by the release of neutrophils from the bone marrow, and induces the release of many other cytokines such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, RANTES, GM-CSF, IFN-c, TNF, and PDGF from a variety of cells. It induces fibroblasts to proliferate, increases prostaglandin secretion and collagenase secretion, and increases the synthesis of fibronectin and collagen. Together with TNF-a, IL-1b induces ICAM-1 expression on endothelial cells. IL-8, a CXC chemokine, is a mainly neutrophil chemoattractant and activator which induces a transient shape change, rise in intracellular calcium, exocytosis with release of enzymes and proteins from intracellular storage organelles, and respiratory burst. It also upregulates the expression of two integrins (CD11b/CD18 and CD11c/CD18) during exocytosis of specific granules. IL-8 activates neutrophil 5-lipoxygenase with the formation of LTB4 and 5-HETE, and LTB4 may contribute to the chemotactic activity of sputum from COPD patients. IL-8 also has chemoattractant properties for T cells. Bacteria can induce IL-8 expression in epithelial cells, and the increased levels of IL-8 found in sputum samples of COPD patients correlate with airway bacterial load and with myeloperoxidase released from activated neutrophils. Up to 43% of the chemotactic activity of sputum can be attributed to IL-8.53 Elastase released from neutrophils may also stimulate epithelial cells to produce more IL-854 and LTB4.55 An increase in the expression of TGF-b and also of EGF in the epithelium and submucosal cells of patients with chronic bronchitis has been reported.37 TGF-b1 mRNA and protein expression in bronchiolar and alveolar epithelium of COPD patients is increased and correlates with the number of intraepithelial macrophages.56 Tobacco smoke is capable of directly activating transcription of the mucin MUC5AC through an EGF-receptor (EGFR) kinase-dependent pathway. EGF is of interest since EGFR activation by TNF-a leads to the expression of mucin genes, in particular MUC5A.57 These growth factors may be implicated in repair responses following injury, particularly to the epithelium. Growth factors such as TGF-b and EGF may be involved in fibroblast activation and proliferation, leading to peribronchiolar fibrosis.
state categorically whether cytokine profiles are different or overlap between these two diseases. However, analysis of cytokines in asthma and COPD from the separate studies available so far reveals different profiles, indicating different pathophysiologies, as may be expected from the different initiating mechanisms for these two conditions. An attempt is made to summarize current findings in Table 28.3. Two recent observations may indicate that there is an overlap of some of these cytokines or that they may contribute equally in these conditions. For example, overexpression of the Th2 cytokine, IL-13, in lungs of adult mice induces emphysema, mucus goblet cell hyperplasia, and airway inflammation with macrophages, lymphocytes, and eosinophils, and increased matrix metalloproteinases, which are many of the features associated with COPD.58 IL-13 is also overexpressed in an allergen-exposed sensitized mouse model, contributing to the eosinophilia, mucus hypersecretion, and bronchial hyperresponsiveness in this asthma model.59 A preliminary study reports that both IL-4 and IL5 mRNA expression in biopsies from smokers with chronic bronchitis alone are increased in the airway wall, but not in smokers with COPD.60 More studies are needed to compare asthma and COPD directly, and to focus on patients who manifest clinical features of both COPD and asthma. Further analysis of cytokine expression in asthma and COPD may help determine whether these conditions have common mechanisms or similar predisposing factors. In addition, this may reveal some common pathways in these two conditions.
Table 28.3. Expression of cytokines in asthma and COPDa
IL-3 IL-4 IL-5 IL-10 IL-13 Eotaxin RANTES MCP-1 IL-8 IL-1b TNF-a MCP-1 TGF-b EGF a
CONCLUSION Because there has been little direct comparison of tissues between asthma and COPD patients, it is not possible to
Asthma
COPD
or ? ? ?
? ? ? ? ? ? ?
Expression is usually reported as gene or protein in airway tissues, in addition to measurement of protein release in airway fluids. The degree of expression has been arbitrarily assessed as: reduced; or increased by a small or large extent; ? not known or uncertain.
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38. Jeffery PK. Structural and inflammatory changes in COPD: a comparison with asthma. Thorax 1998; 53:129–36. 39. Saetta M, Di SA, Maestrelli P et al. Airway eosinophilia and expression of interleukin-5 protein in asthma and in exacerbations of chronic bronchitis. Clin. Exp. Allergy 1996; 26:766–74. 40. Chanez P, Vignola AM, O’Shaugnessy T et al. Corticosteroid reversibility in COPD is related to features of asthma. Am. J. Respir. Crit. Care Med. 1997; 155:1529–34. 41. Shapiro SD. The macrophage in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:S29–32. 42. Finlay GA, O’Driscoll LR, Russell KJ et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am. J. Respir. Crit. Care Med. 1997; 156:240–7. 43. Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-a in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Resp. Crit. Care Med. 1996; 153:530–4. 44. Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 2000; 55:114–20. 45. Lim S, Roche N, Oliver BG et al. Balance of matrix metalloprotease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers: regulation by interleukin-10. Am. J. Resp. Crit. Care Med. 2000; 162(4 pt 1):1355–60. 46. de BW, Sont JK, van SA et al. Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J. Pathol. 2000; 190:619–26. 47. Premack BA, Schall TJ. Chemokine receptors: gateways to inflammation and infection. Nat. Med 1996; 2:1174–8. 48. Khair OA, Devalia JL, Abdelaziz MM et al. Effect of Haemophilus influenzae endotoxin on the synthesis of IL-6, IL-8, TNF-alpha and expression of ICAM-1 in cultured human bronchial epithelial cells. Eur. Respir. J. 1994; 7:2109–16. 49. Inoue H, Massion PP, Ueki IF et al. Pseudomonas stimulates interleukin-8 mRNA expression selectively in airway epithelium, in gland ducts, and in recruited neutrophils. Am. J. Respir. Cell Mol. Biol. 1994; 11:651–63.
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50. Riise GC, Larsson S, Lofdahl CG, Andersson BA. Circulating cell adhesion molecules in bronchial lavage and serum in COPD patients with chronic bronchitis. Eur. Respir. J. 1994; 7:1673–7. 51. Di FM, Barbier D, Mege JL, Orehek J. Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1994; 150:1453–5. 52. Schols AM, Buurman WA, Staal van den Brekel AJ et al. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 1996; 51:819–24. 53. Mikami M, Llewellyn-Jones CG, Bayley D, Hill SL, Stockley RA. The chemotactic activity of sputum from patients with bronchiectasis. Am. J. Respir. Crit. Care Med. 1998; 157:723–8. 54. Nakamura H, Yoshimura K, McElvaney NG, Crystal RG. Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. J. Clin. Invest. 1992; 89:1478–84. 55. McCain RW, Holden EP, Blackwell TR, Christman JW. Leukotriene B4 stimulates human polymorphonuclear leukocytes to synthesize and release interleukin-8 in vitro. Am. J. Respir. Cell Mol. Biol. 1994; 10:651–7. 56. de BW, van SA, Sont JK et al. Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 158:1951–7. 57. Takeyama K, Dabbagh K, Lee HM et al. Epidermal growth factor system regulates mucin production in airways. Proc. Natl Acad. Sci. USA 1999; 96:3081–6. 58. Zheng T, Zhu Z, Wang Z et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsindependent emphysema. J. Clin. Invest. 2000; 106:1081–93. 59. Wills-Karp M, Luyimbazi J, Xu X et al. Interleukin-13: central mediator of allergic asthma. Science 1998; 282:2258–61. 60. Zhu J, Qiu YS, Majumder S et al. Exacerbations of bronchitis: bronchial eosinophilin and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. Am. J. Respir. Crit. Care Med. 2001; 164:109–16.
Matrix Degrading Proteinases
Chapter
29
Steven D. Shapiro Washington University School of Medicine at St Louis Children’s Hospital, St Louis, MO, USA
Edward J. Campbell Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
INTRODUCTION Proteinases cleave internal peptide bonds in proteins, and thus can also be classified as endopeptidases. There are four general types of endopeptidase, which are classified according to the biochemical characteristics of their active sites: • • • •
serine proteinases; cysteine (or thiol) proteinases; metalloproteinases (MMP); aspartic proteinases.
To be relevant to the pathogenesis of chronic obstructive pulmonary disease (COPD), proteinases must have the capacity to be active in the extracellular space. Among the classes of proteinases, aspartic proteinases are exclusively active within the acidic environment of cellular lysosomes. Thus, this class of proteinases will not be further considered in this chapter. The remaining classes of enzymes, however, are thought to have potentially important roles in obstructive airway diseases. Proteinases play important roles in the pathogenesis of a number of the clinical and pathological features of obstructive airways diseases. In particular, they contribute to abnormalities of secretion and transport of airway mucus, and they are involved in the pathogenesis of airway remodeling in asthma and alveolar septal destruction in pulmonary emphysema. Any discussion of proteinases must also include a discussion of endogenous proteinase inhibitors. With the exception of a2-macroglobulin, there are endogenous proteinase inhibitors that are each specific for a particular class of proteinases. In hypotheses concerning the pathogenesis of COPD, the historical focus has been on elastolytic proteinases, and particularly on the serine proteinase neutrophil elastase.
Recently, however, several MMPs have been associated with human COPD, and MMPs have been found to be responsible for the production of emphysema in transgenic and genetargeted mice. Elastolytic cysteine proteinases, particularly cathepsin S, are also candidates to be involved in the alveolar septal injury that results in emphysema. With respect to asthma, the hyperresponsive and mitogenic effects of mast cell tryptase are most well defined. The role of MMPs in matrix remodeling and inflammatory cell migration has begun to receive attention, but their role in asthma is uncertain at present. This chapter will not consider the intracellular cysteine proteinases, such as caspases that regulate cell death, and nonhost serine proteinases of dust mites and other allergens that may also play a role in initiating asthma.
SERINE PROTEINASES Serine proteinases (Table 29.1) have evolved from a single gene product that has undergone duplication and mutations to yield enzymes with diverse biological functions. These include digestive enzymes of exocrine glands, clotting factors, and leucocyte granule-associated proteinases. Several of the latter degrade extracellular matrix proteins and are relevant to this discussion. Host serine proteinases associated with COPD and asthma largely belong to the SA clan, S1(trypsin/chymotrypsin) family. S1 serine proteinases are characterized by conserved His, Asp, and Ser residues that form a charge relay system that functions by transfer of electrons from the carboxyl group of Asp to the oxygen of Ser, which then becomes a powerful nucleophile that is able to attack the carbonyl carbon atom of a peptide bond in the substrate.These enzymes are synthesized as pre-proenzymes in the endoplasmic reticulum and processed by cleavage of the signal peptide (pre-) and removal of a dipeptide (pro-) by cathepsin C. They are then stored in granules as active
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Table 29.1. Main inflammatory cell matrix degrading proteinases in the lung parenchyma
Cell (major source)
Proteinase
Class
Molecular mass (kDa)a
Matrix substratesb
Other cells expressing proteinase
Neutrophil
Neutrophil elastase
Serine
27–31
Proteinase 3
Serine
28–34
Cathepsin G
Serine
27–32
Proinflammatory monocyte Monocyte Mast cell Monocyte Mast cell
MMP-8 MMP-9
MMP MMP
Pro-55 Pro-92–95
Elastin bm components Elastin bm components (elastin) bm components Interstitial collagens Denatured collagens Types IV, V, and VII collagen
MMP-12 MMP-1
MMP MMP
Pro-54 Pro-55
Cathepsin L Cathepsin S
Cysteine Cysteine
29 28
Macrophage
Elastin bm components Interstitial collagens Elastin (at acidic pH) Elastin
Macrophage Endothelial cell
Fibroblasts Epithelial cells CD4 T cell
a
Denotes (pre)proenzyme forms. Pro- denotes molecular mass of the proenzyme form. b bm components include fibronectin, laminin, entactin, vitronectin, and type IV collagen (nonhelical domains).
packaged proteins. Distinct subsets of serine proteinases are expressed in a lineage-restricted manner in immune and inflammatory cells. Serine proteinases are also expressed in a developmentally specific manner. For example, neutrophil elastase, proteinase 3, and cathepsin G are major components of primary or azurophil granules that are formed during a very specific stage during the development of myeloid cells. Neutrophil elastase Neutrophil elastase, like cathepsin G and proteinase 3, is a 30 kDa glycoprotein containing about 20% neutral sugars. Its tertiary structure is similar to other chymotrypsin-like serine proteinases with two interacting antiparallel b-barrel cylindrical domains that form a crevice encompassing the catalytic triad.1 Neutrophil elastase (NE) prefers substrates with Val Ala Ser, Cys at the P1 position. It has activity against a broad range of extracellular matrix proteins, and is among a small group of enzymes (elastases) that have the capacity to solubilize mature elastin. Neutrophil elastase expression is localized to primary (azuriphil) granules of neutrophils and a subset of proinflammatory monocytes.2 In addition to its capacity to degrade ECM, neutrophil elastase mediates killing of Gram-negative bacteria,3 and may be involved in neutrophil migration. Proteinase 3 Proteinase 3 (or myeloblastin) is structurally similar to neutrophil elastase, but it cleaves at small aliphatic residues at the P1 position. PR3 is roughly 40% as potent as human neutrophil elastase against elastin. Like NE, proteinase 3 is
stored in neutrophil azurophil granules and is produced by monocytes. In addition to its matrix degrading capacity, proteinase 3 might be involved in leucocyte differentiation. This molecule has been identified as the autoantigen target of cytoplasmic-staining anti-PMN autoantibody in Wegener’s granulomatosis. Cathepsin G Cathepsin G (CG) is a chymotrypsin-like serine proteinase stored in neutrophil azurophil granules and to a lesser degree in mast cells and a subset of peripheral blood monocytes. CG has the capacity to degrade ECM components, but has only 20% the elastolytic capacity of neutrophil elastase. CG may facilitate neutrophil penetration of epithelial and endothelial barriers by increasing their permeability. CG appears to have a minor role in bacterial killing,4 perhaps through noncatalytic mechanisms. It may play an important role in platelet activation at sites of inflammation. Tryptase Tryptase is a mast cell product with trypsin-like activity.The enzyme is composed of 245 amino acids, and its molecular mass varies between 30 and 35 kDa due to variable glycosylation. A unique feature of this enzyme is that its active form is a tetramer that is stabilized by heparin. In the absence of heparin, tryptase is found as an inactive monomer.5,6 This is an interesting mechanism of enzyme regulation, since it involves no known endogenous proteinase inhibitors. Tryptase is not an effective matrix degrading enzyme, but cleaves a variety of nonmatrix proteins including H-
Matrix Degrading Proteinases
275
kininogen, C3 to C3a, fibrinogen, and vasoactive intestinal peptide (VIP). In addition, tryptase has been shown to be a cell mitogen.7
The relative contributions of each of these molecules to the inhibition of serine proteinases in vivo is unknown.
Serine proteinase inhibitors Serine proteinase inhibitors are abundant in the plasma. Alpha2-macroglobulin, a large protein usually restricted to the bloodstream because of its mass (725,000 kDa), inhibits proteinases of several classes by “entrapping” them during a rearrangement of its tetrameric structure following cleavage of susceptible regions of the inhibitor. At a concentration of 150–350 mg/dL (approximately 30 lmol/L), a1-antitrypsin (a1-AT) has the highest concentration of the plasma inhibitors. It belongs to a family of serine proteinase inhibitors called the serpins. Serpins share considerable sequence homology, particularly around their reactive sites. They are important for homeostasis, since they exert some control over such major proteolytic cascades as the complement system and coagulation. a1-AT is a 52 kDa glycoprotein synthesized primarily by the liver, consisting of a single polypeptide chain of 394 amino acids. Proteolytic inhibition by a1-AT involves cleavage of the “strained” reactive open center of a1-AT between Met358 and Ser359, resulting in an altered, “relaxed” a1-AT conformation in complex with the proteinase. Formation of the complex renders the proteinase inactive and, because the complex is quite stable, inactivation is essentially permanent. The association and inhibition of neutrophil elastase by a1-AT is much faster than with other serine proteinases, including trypsin, yet the name “a1-antitrypsin” is retained out of historical respect for those who discovered the molecule. a1-AT is the major inhibitor of serine proteinases in the lower respiratory tract. As discussed below, inherited deficiency of a1-AT represents the only genetic abnormality that is currently known to be associated with COPD. Additional low-molecular-weight serine proteinase inhibitors are abundant in airway fluid and hence are thought to represent the primary defenses against proteinase-mediated airway damage. Secretory leukoprotease inhibitor (SLPI) is a 12-kDa protein produced by mucus-secreting and epithelial cells in the airway as well as type 2 pneumocytes. SLPI inhibits NE and CG and many other serine proteinases, but not proteinase 3. Elafin, also produced by airway secretory and epithelial cells, is released as a 12-kDa precursor which is processed to a 6-kDa form that specifically inhibits NE and PR3.8 These inhibitors are able to inhibit NE bound to substrate, giving them an added dimension that a1-AT lacks. Remold-Odonnell et al.9 have described an additional serpin, monocyte/neutrophil elastase inhibitor, which has considerable activity against neutrophil elastase. Airway mucus contains several other substances that partially inhibit NE, including polyanionic molecules such as mucins, other glycosaminoglycans, and fatty acids. DNA, released from inflammatory leucocytes as they undergo necrosis at sites of inflammation, binds to SLPI and greatly enhances its rate of association with NE.
CYSTEINE (THIOL) PROTEINASES Cysteine proteinases (Table 29.1) utilize the sulfhydryl group of Cys as a nucleophile. In a mechanism having some similarity to that of serine proteinases, a proton donor from His forms a catalytic dyad (and in some cases triads) that is required for endopeptidase activity. Cysteine proteinases represent a large, diverse group of plant and animal enzymes with amino acid homology at the active site only.10 Human alveolar macrophages produce the lysosomal thiol proteinases, cathepsins B, H, L, and S that have been implicated in COPD. CD4 cells express cathepsin S, which functions in antigen processing and thus might prove to play a role in asthma.11 These enzymes share similar sizes of 24–32 kDa and high mannose side-chains (typical of proteins targeted for lysosomal accumulation). Cathepsins B and H These have little endopeptidase activity and may function to activate other proteins through a mechanism that is similar to that of interleukin converting enzyme. Cathepsin C Cathepsin C, or dipeptidyl peptidase I, has limited extracellular matrix degrading activity, but it is relevant to this discussion in that it is required for activation of nearly all matrix degrading serine proteinase proenzymes to their active forms. Cathepsins L and S These have large active pockets with relatively indiscriminate substrate specificities that include elastin and other matrix components. These enzymes have acidic pH optima, but cathepsin S is unique in this group in that it retains about 25% of its elastolytic capacity at neutral pH, making it approximately equal in elastolytic activity to NE. Cathepsin K This is a potent elastase that is predominantly expressed in osteoclasts, but it is also expressed by macrophages in the vasculature and perhaps other tissues. Cysteine proteinases clearly have the capacity to cause lung destruction if they are targeted to the cell surface retained within acidic microenvironments in the extracellular space. Cysteine proteinase inhibitors These consist of the cystatins. Some cystatins are strictly intracellular, while others, such as cystatin C, possess a signal peptide and are secreted by a variety of cells into the extracellular fluid. Cystatin C is comprised of a single nonglycosylated 120 amino acid peptide chain (13 kDa) that forms reversible 1:1 complexes with enzymes in competition with substrates. Cystatin C, the most ubiquitous cystatin, is
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found in all human tissues and body fluids that have been tested. It provides general protection against tissue destruction by intracellular cathepsin enzymes that leak from dying cells. Lack of cystatin C has been associated with destructive lesions in the vasculature.12
M AT R I X M E TA L L O P R O T E I N A S E S ( M M P ) MMPs comprise a family of over 20 matrix degrading enzymes that are believed to be essential for normal development and for physiologic tissue remodeling and repair during health (Table 29.1). Abnormal expression of metalloproteinases has been implicated in many destructive processes, including tumor cell invasion and angiogenesis, arthritis, atherosclerosis, arterial aneurysms, and pulmonary emphysema.13 MMPs are secreted as inactive proenzymes which are activated at the cell membrane surface or within the extracellular space by proteolytic cleavage of the N-terminal domain. Catalytic activity of these enzymes is dependent on coordination of a zinc ion at the active site. MMP family members share 40–50% identity at the amino acid level, and they possess common structural domains. These domains include: • a proenyzme domain that maintains the enzyme in its latent form; • an active domain that coordinates binding of the catalytic zinc molecule; • (except for MMP-7) a C-terminal domain involved in substrate and cell binding; • a TIMP binding domain. The gelatinases A and B (MMP-2 and MMP-9, respectively) have an additional fibronectin-like domain which mediates their high binding affinity to gelatins and elastin. MMP-9 has one more domain with homology to type V collagen. Membrane-type MMPs (MT1-4 -MMP or MMP-14-17) have an additional C-terminal membrane-spanning domain. Individual members of the MMP family can be loosely divided into groups based on their matrix degrading capacity. As a group, they are able to cleave all extracellular matrix components. • Collagenases (MMPs -1, -8, -13) have the unique capacity to cleave native triple helical interstitial collagens but not elastin. • Gelatinases of 72 kDa (gelatinase A, MMP-2) and 92 kDa (gelatinase B, MMP-9) differ in their cellular origin and regulation, but share the capacity to degrade gelatins (denatured collagens), type IV collagen, elastin, and other matrix proteins. • Stromelysins (MMP-3, -10) have a broad spectrum of susceptible substrates, including most basement membrane components. • Matrilysin (MMP-7), the smallest MMP (28 kDa as a proenzyme), has broad substrate specificity of
stromelysins and some elastase activity.While a potent and potentially destructive enzyme, gene targeting of MMP-7 has also demonstrated a physiologic role for this MMP in tracheal wound repair,14 and activation of defensins.15 • Macrophage elastase (MMP-12) also has a potent broad substrate specificity which includes elastin. MMP-12 is required for cigarette smoke-induced emphysema in mice, as described below. Membrane-type metalloproteinases (MT-MMPs) are localized at the cell surface; at least one, MT1-MMP, activates MMP-2. MT-MMPs also appear to directly degrade ECM proteins, but their catalytic capacities are not well defined at present. MMPs are also active against a variety of non-ECM proteins. For example, MMPs cleave and activate latent TNF-a, thereby regulating inflammation. They cleave plasminogen, generating the antiangiogenic fragment, angiostatin.16 MMPs, particularly MMP-12,17 degrade and inactivate a1-AT, thus indirectly enhancing the activity of neutrophil elastase. Thus, MMPs play both direct and indirect roles in matrix destruction associated with emphysema, and may indirectly influence cytokine release and angiogenesis that could influence the development and progression of COPD. Specific MMP inhibitors Specific MMP inhibitors are the members of another gene family, called TIMPs (tissue inhibitors of matrix metalloproteinases). Four TIMPs have been described. Optimal activity of MMPs is expressed at around pH 7.4. The TIMPs have molecular masses ranging between 21 kDa (TIMP-2, non-glycosylated) and 27.5 kDa (TIMP-1, glycosylated).18 Each TIMP inhibits MMPs via tight, noncovalent binding with 1:1 stoichiometry. • TIMP-1 binds to the C-terminal domain of MMPs, but how this leads to inhibition of catalysis is unknown. Those MMPs that lack the C-terminal domain, including MMP-7 and the fully processed form of MMP-12, are still susceptible to TIMP inhibition, although with a lower Ki. • TIMP-2 is secreted complexed to MMP-2 in fibroblasts. A significant body of work has uncovered complex mechanisms whereby TIMP-2 not only inhibits MMP-2 but is also involved in docking pro-MMP-2 to the cell surface where the enzyme is activated by membrane type 1-MMP. • TIMP-3 is expressed predominantly by epithelial cells and binds to extracellular matrix and thus may be important in preventing emphysema and in allowing excess matrix accumulation in asthmatic airways. • TIMP-4 was recently discovered, and little is known regarding its properties. TIMPs are secreted from many cell types and are abundant in tissues. Alveolar macrophages secrete not
Matrix Degrading Proteinases
only a variety of metalloproteinases, but also TIMP-1 and TIMP-2. Endotoxin induces synthesis of macrophage MMPs and TIMP-1, but inhibits TIMP-2 production,19 whereas dexamethasone inhibits LPS induction of MMPs and TIMP-1.20 Other cytokines, such as interferon-c inhibit MMP-1 and MMP-3 expression in macrophages with little effect on TIMP-1.21 Thus, depending on the inflammatory stimulus, MMPs and TIMPs may be regulated in concert perhaps to limit tissue injury during normal remodeling associated with inflammation, or regulation may be discoordinate, potentially increasing the risk of tissue injury.
C H R O N I C O B S T R U C T I V E P U L M O N A RY DISEASE COPD encompasses both chronic bronchitis and emphysema.22 Pulmonary emphysema is defined by “abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, and without obvious fibrosis”.23 Most patients have an admixture of large airway changes (accounting for symptoms of chronic bronchitis), small airway changes, and emphysema. The pathogenesis of emphysema This is closely tied to cigarette smoking. The destructive cycle begins when cigarette smoke causes inflammatory cell recruitment. These inflammatory cells have the capacity to release elastolytic proteinases that locally overwhelm or evade inhibitors, causing destruction of lung elastin and other extracellular matrix proteins. Lung destruction, coupled with failure to restore the normal lung architecture during repair, leads to the coalescence of adjoining airspaces into larger and larger units that are characteristic of emphysema. This concept of the pathogenesis of emphysema has stemmed from the elastase:antielastase hypothesis that was first introduced over 35 years ago and has withstood the test of time. The foundations of this hypothesis were built upon two seminal observations, one of which was experimental and the other clinical. The initial experimental observation occurred in 1963, when Gross instilled the proteinase papain intratracheally into the lungs of rodents, and observed subsequent pathological changes that resembled human pulmonary emphysema.24 Subsequently, investigators have instilled a variety of proteinases into animal lungs. A very consistent observation has been that only elastases have had the capacity to produce emphysematous changes in animal models. The initial clinical observation was reported one year later, in 1964. Laurel and Eriksson described five patients with deficiency of a1-antitrypsin. Three of these initial subjects had emphysema.25 Since a1-AT is the major circulating inhibitor of neutrophil elastase, these basic and clinical studies led to the elastase:antielastase hypothesis for the pathogenesis of emphysema.
277
Inflammation and proteinases in human COPD The importance of the neutrophil and elastase versus macrophages and other proteinases in emphysema in nona1-AT deficient patients (PiM) has been debated for years. It has been difficult to settle this debate based on correlative studies on human tissue taken at fixed points in time. Results from various studies have yielded conflicting results with respect to the cell types and proteinases present in emphysematous lungs. An informative study by Hogg and colleagues26 examined end-stage lung disease in tissue taken from patients undergoing volume reduction surgery, many of whom had discontinued smoking years prior to their surgery. The inflammatory process in this tissue had not ceased, as might have been expected. Instead, the lungs demonstrated large numbers of many types of inflammatory and immune cells that included neutrophils, macrophages, and T cells. Synthesis of data regarding inflammatory cell response in human lungs following cigarette smoke exposure suggests the following sequence of events. Macrophages patrol the lower airspace under normal conditions. Acutely following cigarette smoke exposure, macrophages become activated and release chemoattractants for neutrophils, such as leukotriene B4, and neutrophils quickly arrive. Subacutely, macrophages accumulate in respiratory bronchioles, probably recruited in large part by the products of extracellular matrix injury. Chronically, macrophages, neutrophils, and CD8 CD4 T cells accumulate in the airspace. Moreover, loss of cilia predisposes to airway infection with a prominent neutrophilic response. It is clear that these events are not simple, and that the inflammatory cell populations may differ during different stages of the disease. Neutrophils Studies from several laboratories have shown that neutrophil elastase (NE) is responsible for most of the degradative activity of neutrophils toward extracellular matrix (ECM) structures. Early studies of neutrophil activation typically used cytochalasin B in concert with a chemoattractant, or phorbol esters, to stimulate the cells. In response to such stimuli, neutrophils promptly release up to 40% of the NE contained within their azurophil granules into the extracellular space. More recent studies have shown that when optimally primed and stimulated by biologically relevant agonists, neutrophils release 2% of their content of NE freely into the extracellular space, but they are able to translocate as much as 12% of their total NE to the cell membrane, where it is catalytically active and resistant to inhibitors.27 The high concentration of NE (~5 mmol/L) within azurophil granules transiently overwhelms local NE inhibitors, resulting in a quantum burst of obligate catalytic activity near the cell surface when each granule is released.28 These mechanisms allow NE to proteolyze ECM in a focused and protected manner while limiting widespread tissue destruction. Neutrophil elastase might also be freely released during “frustrated phagocytosis”, or by necrotic or apoptotic neutrophils if the latter are not cleared efficiently by macrophages.
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Asthma and Chronic Obstructive Pulmonary Disease
Regardless of the mechanisms by which active neutrophil elastase reaches the extracellular matrix, it is relatively protected from inhibitors following binding to insoluble macromolecules. For example, Damiano et al.29 found immunoreactive NE intimately associated with elastic fibers in emphysematous tissue. During bacterial exacerbations of COPD, overwhelmingly large concentrations of active NE can be found as a result of brisk neutrophil influx, and active NE can often be found within the airways of patients with a1-AT deficiency. Neutrophil elastase is also a potent secretagogue and induces mucin gene expression, which might aggravate airflow obstruction in COPD. Mononuclear phagocytes A subpopulation of human blood monocytes, believed to be proinflammatory, contain serine proteinases (NE, PR3, and CG),2 as well as a single metalloproteinase, matrilysin (MMP-7).30 Upon differentiation from monocytes to macrophages, these cells lose their armamentarium of serine proteinases and acquire the capacity to produce several metalloproteinases, including the elastolytic enzymes MMP-9 and MMP-12.31 Correlative studies in human emphysematous lung tissue have demonstrated the presence of MMP-1, MMP-2 membrane type-1MMP,32 MMP-9, and MMP-12.33 RT-PCR of cultured macrophages found a correlation between MMP-1 and MMP-9 in smokers with emphysema as opposed to smokers without emphysema.34 This study suggests that expression of certain MMPs might predict those smokers susceptible to emphysema. Animal models to determine the pathogenesis of COPD Animal models have been critical experimental tools in the study of COPD. Since Gross’s seminal observation, emphysema has been produced in experimental models by the intratracheal instillation of other elastolytic proteinases, including pancreatic elastase,35 neutrophil elastase,36,37 proteinase 3,38 and cathepsin L.39 Transgenic mice Transgenic mice can define the potential of a proteinase to cause emphysema, but have had limited usefulness since subtle aberrant prenatal expression of proteinases could alter matrix scaffolding, leading to abnormal lung development with airspace enlargement.This might be independent of the capacity of the proteinase to destroy mature alveoli, which is the process that defines pulmonary emphysema. For example, overexpression of MMP-1 in transgenic mice resulted in airspace enlargement,40 but it is still not clear whether this is due to collagen turnover in mature lungs, or to abnormal lung development. Nevertheless, this study raises the important concept that collagen turnover is involved in emphysema. Clearly there is loss of collagen from destroyed alveoli, but there is also excess collagen accumulation in the small airways.41 Thus, collagen turnover in emphysema is likely to be important but complicated.
Inducible transgenic mice can now be used to overcome the potential problem of transgene expression during growth and development. Using this technique, Elias and colleagues have found that overexpression of either IL-1342 or IFN-c43 results in inflammation and airspace enlargement that is proteinase dependent. Gene targeting Application of gene-deficient mice to disease models represents a means for performing highly controlled experiments in mammals. To directly determine the contribution of individual elastases to the development of emphysema, mice deficient in specific proteinases have been generated by gene targeting. These mice have been applied to a model of cigarette smoke-induced emphysema. Long-term exposure of mice to two cigarettes per day for 6 days a week was well tolerated and resulted in inflammatory cell recruitment and airspace enlargement similar to human emphysema.44 Macrophage elastase (MMP-12) targeting in mice was very informative regarding the pathogenesis of cigarette smoke-induced emphysema in these animals. MMP-12 is characterized by macrophage-specific expression and broad potent matrix degrading capacity. MMP-12 also degrades nonmatrix substrates. In fact, MMP-12, to a much greater degree than other MMPs, degrades and inactivates a1-antitrypsin, thus indirectly augmenting neutrophil elastase activity.17 When MMP-12 was targeted, it was observed that MMP-12/ mice develop, grow, and breed normally. However, it is important to note that macrophages from MMP-12/ mice have a markedly diminished capacity to degrade extracellular matrix components, and they are essentially unable to penetrate reconstituted basement membranes both in vitro and in vivo.45 When compared with wild-type mice, MMP-12-deficient mice were remarkably protected from the development of emphysema despite heavy long-term smoke exposure.44 Surprisingly, MMP-12/ mice also failed to recruit monocytes into their lungs in response to cigarette smoke. Because MMP-12 and most other MMPs are not expressed by monocytes, it appeared unlikely that MMP12 is involved in transvascular migration of monocytes. The current working model is that cigarette smoke induces constitutive macrophages to produce MMP-12, which cleaves elastic fibers and generates fragments that are chemotactic for circulating monocytes. This positive feedback loop perpetuates and accentuates macrophage accumulation and lung destruction. The observation that proteolytically generated elastin fragments mediate monocyte chemotaxis was not original to this murine model. Independent studies in the early 1980s by Senior and colleagues46 as well as Hunninghake and colleagues47 demonstrated that elastasegenerated elastin fragments were chemotactic for monocytes and fibroblasts. Gene targeting reinforces this process as a major in-vivo mechanism of macrophage accumulation in a chronic inflammatory condition. Neutrophil-elastase-deficient mice, too, have been generated by gene targeting.3 These mice have demonstrated a
279
Matrix Degrading Proteinases
role for N E in killing Gram-negative bacteria.^ Neutrophilelastase-mediated bacterial killing is related to proteolytic degradation of Omp proteins on the outer wall of Gramnegative bacteria.''* NE—/— mice have now also been exposed to cigarette smoke, and they were significantly protected from the development of emphysema (Shapiro, unpublished observations). Interactions between serine proteinases and MMPs How can mice deficient in M M P - 1 2 and neutrophil elastase each be substantially protected from the development of emphysema following exposure to cigarette smoke? A clue to understanding this paradox has come from a mouse model of bullous pemphigoid. In this model, intradermal injection of antibodies against hemidesmosomes results in neutrophil recruitment and blister formation. Blisters do not form in either MMP-9—/— or NE—/— mice. Further studies demonstrated that M M P - 9 degrades ttj-AT, allowing N E to degrade hemidesmosomes and tight junctions, resulting in blister formation.''^ See also Fig. 29.1. E m p h y s e m a associated with ai-antitrypsin deficiency The clearest example of the association of proteinaseantiproteinase imbalance and emphysema occurs with inherited deficiency of ttj-AT. Several abnormal ttj-AT alleles are associated with very low serum concentrations of ttj-AT and enhanced risk for emphysema.^" Of these, the Pi Z variant is by far the most common, and more than 9 5 % of tti-AT-deficient individuals have only the Z variant detectable. A variety of rare deficiency variants, including nonexpressing alleles that do not result in detectable ttj-AT in plasma, comprise the remaining individuals. Pi Z individuals have about 15% of the normal serum concentration of tti-AT.The abnormality leading to the Pi Z variant is a point mutation involving a single nucleotide at codon 342 that
Neutrophil
orAT
l"?^
€7-
chemotaxis ECM
\XI^
^
.•!. •
1/
Assessing the magnitude of the increased risk for lung disease among individuals with a ^ A T deficiency has been difficult because most individuals with the deficiency worldwide have gone undetected. Thus, the existence and severity of lung disease among identified individuals has been strongly influenced by ascertainment bias. Nevertheless, most PiZ individuals who have been identified eventually become symptomatic with C O P D . Even among identified individuals, there is considerable variation in lung disease, and some individuals reach advanced age with minimal symptoms. In a group of Pi Z subjects and their families, Silverman et al.^^ confirmed the wide variability in pulmonary function among Pi Z subjects and found evidence for familial factors that segregated with deterioration in pulmonary function. Smoking has a marked effect on the age at which shortness of breath appears; on the average. Pi Z smokers have symptoms by age 40, about 15 years earlier than Pi Z nonsmokers.
PROTEINASES I N A S T H M A Bronchoconstriction Tryptase has been linked to bronchoconstriction, although the mechanism of its action is unclear (Fig. 29.2). Support
Macrophage
TIMP
E \ MM P-12 3
results in coding for lysine instead of glutamic acid. This amino acid substitution changes the charge attraction between the amino acids at positions 342 and 290 present in the normal form of ttj-AT and prevents the formation of a fold in the molecule. With this change in tertiary structure, the molecule is susceptible to loop-sheet polymerization in the endoplasmic reticulum that impedes secretion of the protein from the hepatocyte.^' In addition, its rate of association with neutrophil elastase is slightly but significantly slower than the association rate of normal ttj-AT with N E . The prevalence of the Pi Z phenotype in the United States is about one in 2800 people.^^ The Z allele is not commonly found in Asians and African populations.
^
^M
o o
Tryptase
^
MMP.
\
chemotaxis
•
•
ECM fragments Fig. 2 9 . 1 . Interactions between neutrophil and macrophage proteinases in emphysema. Neutrophil elastase (NE) originating from azurophil granules directly degrades elastin and indirectly augments elastolysis via degradation of TIMP(s). Macrophage MMP-12 also directly degrades elastin and also indirectly augments NE activity by degrading its inhibitor a-1-antitrypsin (a,-AT). Extracellular matrix (ECM) fragments released during proteolysis play a role in perpetuating inflammatory cell recruitment.
Bronchoconstriction
Proliferation Collagen production
Migration
Fig. 29.2. Potential functions of proteinases in asthma. Tryptase mediates bronchoconstriction and fibroblast proliferation, most likely via proteolytic activation of protease activated receptor-2. MMPs have been linked to both fibroblast proliferation (MMP-2) and collagenolysis (MMP-1). MMP-9 might promote eosinophil transvascular migration. MMPs and related ADAMs (a disintigrin and metalloproteinase domain) might regulate cell survival via shedding of surface molecules such as Fas, TNF/TNF receptor.
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for this effect comes from studies demonstrating that tryptase-specific inhibitors, such as AMG-126737, inhibit the development of early- and late-phase airway hyperresponsiveness in several allergen-challenge animal models.53 Airway remodeling Airway remodeling with subepithelial collagen accumulation is a characteristic histopathological feature of chronic asthma. This suggests either a net decrease in matrix turnover or an increase in collagen deposition accompanying airway inflammation. Support for reduced matrix turnover has come from several studies measuring proteinase and inhibitor levels in asthmatic sputum and bronchoalveolar lavage (BAL) fluid. It is difficult to determine proteolytic activity in cell-matrix microenvironments from gross measures of proteinases and inhibitors in crude lung samples. However, these types of study will be important in the future to identify the relevant molecules and to build hypotheses. TIMP-1 levels have been reported to be elevated relative to MMPs in BAL fluid from untreated asthmatics supporting net matrix accumulation in asthmatic airways.54 However, another study found that patients with acute asthma have increased MMP-9 in their sputum, and upon glucocorticoid treatment TIMP-1 levels increased, lowering the MMP-9/TIMP-1 ratio.55 This could be interpreted to mean that untreated asthma is a destructive disease or that steroids promote fibrosis. Neither concept has much support. In fact, administration of inhaled corticosteroids to asthmatics results in decreased subepithelial collagen accumulation.56 It is known that steroids inhibit fibroblast production of collagen, collagenase (MMP-1), and TIMP1.57 Steroids also inhibit macrophage MMP and TIMP-1 production.20 The net effect might vary depending upon the initial activity of each; but in general, steroids limit matrix accumulation.
difficult to demonstrate the presence of MMP-9 in eosinophils present in asthmatic lungs. The importance of MMPs in asthma has been supported by several animal studies. For example, antigen challenge in animal models led to increased MMP-9 by zymography in BAL fluid, predominantly of neutrophil origin. TIMP-1 was also increased. Airway administration of various MMP inhibitors, includingTIMP-1,TIMP-2, and a low-molecularweight synthetic inhibitor, all inhibited the antigen-induced infiltration of lymphocytes and eosinophils to airway wall and lumen, reduced antigen-induced airway hyperresponsiveness, and increased the numbers of eosinophils and lymphocytes in peripheral blood.61 In contrast, mice genetically deficient in MMP-9 and wild-type littermates, had equivalent inflammatory cell migration or hyperresponsiveness in a similar allergen-challenge model in mice (Birkland, Parks, and Shapiro, unpublished observations). Cell proliferation and survival Mast cell tryptase, through activation of protease-activated receptor-2,62 stimulates human lung fibroblast proliferation directly and promotes collagen production.63 Tryptase is also mitogenic for smooth muscle cells and epithelial cells with potential consequences in asthma. Autocrine production of matrix metalloproteinase-2 has also been shown to be required for human airway smooth muscle proliferation.64 The role of apoptosis in asthma has recently received much attention. Prolonged survival of eosinophils or other inflammatory cells may aggravate asthma, while epithelial cell death could also potentiate inflammation. MMPs and the closely related ADAMs (a disintegrin and metalloprotease domain) have the capacity to shed Fas and thus may influence cell survival. Caspases, which are cysteine proteinases, are beyond the scope of this discussion, but of course play central roles in apoptosis.
PERSPECTIVES Status asthmaticus Status asthmaticus might be an asthmatic condition in which true proteolytic tissue destruction occurs. Several MMPs (9, 1, 3) and TIMP-1 have been found to be markedly upregulated in staticus asthmaticus.58 Whether they participate in destructive pathology or are a marker of inflammatory cell accumulation is not defined. Inflammatory cell migration Proteinases are believed to be important in promoting extravasation of certain cell types through the basement membrane as they egress from the vasculature into tissues. MMP-9, prominent in neutrophils and macrophages, is also expressed by mast cells and eosinophils. Inhibitors of both serine proteinases and MMPs have been unable to alter neutrophil migration through endothelial basement membranes in culture.59 MMP inhibitors and antibodies to MMP-9 were able to decrease eosinophil invasion through basement membranes in vitro.60 However, it has been
The role of proteinases in causing lung destruction, leading to the development of emphysema, is clear and supported by extensive research. The precise proteinases and matrix targets remain focal points of investigation, and for other than hereditary a1-AT deficiency most findings are speculative. Additional functions of proteinases in COPD, such as secretagogue function, are another area of active study. The potential role of proteinases in asthma has only recently become appreciated. In asthma, the focus has been on matrix remodeling and the role of proteinases in inflammatory cell migration. However, tryptase in particular has also been shown to be involved in bronchoconstriction and fibroblast proliferation, and collagen deposition. As the roles of proteinases are further defined in obstructive airways diseases, common mechanisms in both COPD and asthma will almost certainly emerge. More importantly, proteinase inhibitors might prove to have important roles in the prevention and management of both problems.
Matrix Degrading Proteinases
REFERENCES 1. Bode W, Meyer EJ, Powers JC. Human leucocyte and porcine pancreatic elastase: X-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors. Biochemistry 1989; 28:1951–63. 2. Owen CA, Campbell MA, Boukedes SS, Stockley RA, Campbell EJ. A discrete subpopulation of human monocytes expresses a neutrophil-like proinflammatory (P) phenotype. Am. J. Physiol. 1994; 267(6 Pt 1):L775–85. 3. Belaaouaj A, McCarthy R, Baumann M et al. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nat. Med. 1998; 4:615–18. 4. Tkalcevi J, Novelli M, Phylactides M et al. Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity 2000; 12(2):201–10. 5. Schwartz L, Bradford T, Lee D, Chlebowski J. Immunologic and physicochemical evidence for conformational changes occurring on conversion of human mast cell tryptase from active tetramer to inactive monomer: production of monoclonal antibodies recognizing active tryptase. J. Immunol. 1990; 144:2304–11. 6. Schector N, Eng G, McCaslin D. Human skin tryptase: kinetic characterization of its spontaneous inactivation. Biochemistry 1993; 32:2617–25. 7. Hartman T, Ruoss S, Raymond W, Seuwen K, Caughey G. Human tryptase as a potent, cell-specific mitogen: role of signaling pathways in synergistic responses. Am. J. Physiol. 1992; 262:L528–34. 8. Sallenave J-M, Silva A, Marsden ME, Ryle AP. Secretion of mucus proteinase inhibitor and elafin by Clara cell and type II pneumocyte cell lines. Am. J. Respir. Cell Mol. Biol. 1993; 8:126–33. 9. Remold-O’Donnell E, Nixon J, Rose R. Elastase inhibitor: characterization of the human elastase inhibitor molecule associated with monocytes, macrophages, and neutrophils. J. Exp. Med. 1989; 169:1071–86. 10. Chapman HA, Munger JS, Shi G-P. The role of thiol proteases in tissue injury and remodeling. Am. J. Respir. Crit. Care Med. 1994; 150(6 Pt 2):S155–9. 11. Chapman H, Riese R, Shi G-P. Emerging roles for cysteine proteases in human biology. Annu. Rev. Physiol. 1997; 59:63–88. 12. Shi G-P, Sukhova G, Grubb A et al. Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J. Clin. Invest. 1999; 104:1191–7. 13. Shapiro SD. Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Curr. Opin. Cell. Biol. 1998; 10:602–8. 14. Dunsmore SE, Saarialho-Kere UK, Roby JD et al. Matrilysin expression and function in airway epithelium. J. Clin. Invest. 1998; 102:1321–31. 15. Wilson C, Ouellette A, Satchell D et al. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 1999; 286:113–17. 16. Cornelius LA, Nehring L, Klein B et al. Matrix metalloproteinases generate angiostatin: effects on neovascularization. J. Immunol. 1998; 161:6845–52. 17. Gronski TJ, Martin R, Kobayashi DK et al. Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase. J. Biol. Chem. 1997; 272:12189–94. 18. Parks WC, Mecham RP. Matrix metalloproteinases – Comprehensive and up to date reviews on many aspects of MMP biology and chemistry. Academic Press, 1998. 19. Shapiro SD, Kobayashi DK, Welgus HG. Identification of TIMP-2 in human alveolar macrophages: regulation of biosynthesis is opposite to that of metalloproteinases and TIMP-1. J. Biol. Chem. 1992; 267:13890–4. 20. Shapiro SD, Campbell EJ, Kobayashi DK, Welgus HG. Dexamethasone selectively modulates basal and lipopolysaccharideinduced metalloproteinase and tissue inhibitor of
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41. Wright JL. Emphysema: concepts under change – a pathologist’s perspective. Mod. Pathol. 1995; 8:873–80. 42. Zheng T, Zhu Z, Wang Z et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsindependent emphysema. J. Clin. Invest. 2000; 106:1081–93. 43. Wang Z, Zheng T, Zhu Z et al. Interferon gamma induction of pulmonary emphysema in the adult murine lung. J. Exp. Med. 2000; 192:1587–600. 44. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 1997; 277:2002–4. 45. Shipley JM, Wesselschmidt RL, Kobayashi DK, Ley TJ, Shapiro SD. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Natl Acad. Sci. USA 1996; 93:3942–6. 46. Senior RM, Griffin GL, Mecham RP. Chemotactic activity of elastin-derived peptides. J. Clin. Invest. 1980; 66:859–62. 47. Hunninghake GW, Davidson JM, Rennard S et al. Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema. Science 1981; 212:925–7. 48. Belaaouaj A, Kim KS, Shapiro S. Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase. Science 2000; 289:1185–8. 49. Liu Z, Zhou X, Shapiro S. The serpin alpha1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo. Cell 2000; 102:647–55. 50. Brantly M, Nukiwa T, Crystal R. Molecular basis of alpha-1antitrypsin deficiency. Am. J. Med. 1988; 84:13–31. 51. Lomas DA, Evans DL, Stone SR et al. Effect of the Z mutation on the physical and inhibitory properties of alpha 1-antitrypsin. Biochemistry 1993; 32:500–8. 52. Silverman E, Miletich J, Pierce J et al. Alpha-1-antitrypsin deficiency: high prevalence in the St Louis area determined by direct population screening. Am. Rev. Respir. Dis. 1989; 140:961–6. 53. Silverman E, Pierce J, Province M, Rao D, Campbell EJ. Variability of pulmonary function in alpha-1-antitrypsin deficiency: clinical correlates. Ann. Intern. Med. 1989; 111:982–91. 54. Mautino G, Henriquet C, Jaffuel D, Bousquet J, Capony F. Tissue inhibitor of metalloproteinase-1 levels in bronchoalveolar lavage fluid from asthmatic subjects. Am. J. Respir. Crit. Care Med. 1999; 160:324–30.
55. Vignola A, Riccobono L, Mirabella A. Sputum metalloproteinase-9/ tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med. 1998; 158:1945–50. 56. Hoshino M, Takahashi M, Takai Y, Sim J. Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression is asthma [see coments]. J. Allergy Clin Immunol 1999; 104:356–63. 57. Clark SD, Kobioshi DK, Welgus HG. Regulation of the expression of tissue inhibitor of metalloproteinases and collagenase by retinoids and glucocorticoids in human fibroblasts. J. Clin. Invest. 1987; 80:1280–8. 58. Lemjabbar H, Gosset P, Lamblin C et al. Contribution of 92 kDa gelatinase/type IV collagenase in bronchial inflammation during status asthmaticus. Am. J. Respir. Crit. Care Med. 1999; 159(4 Pt 1):1298–307. 59. Mackarel A, Cottell D, Russell K, FitzGerald M, O’Connor C. Migration of neutrophils across human pulmonary endothelial cells is not blocked by matrix metalloproteinase or serine protease inhibitors. Am. J. Respir. Cell Mol. Biol. 1999; 20(6):1209–19. 60. Okada S, Kita H, George T, Gleich G, Leiferman K. Migration of eosinophils through basement membrane components in vitro: role of matrix metalloproteinase-9. Am. J. Respir. Cell Mol. Biol. 1997; 17:519–28. 61. Kumagai K, Ohno I, Okada S et al. Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma. J. Immunol. 1999; 162:4212–19. 62. Akers I, Parsons M, Hill M et al. Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000; 278:L193–201. 63. Cairns J, Walls A. Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. J Clin Invest 1997; 99:1313–21. 64. Johnson S, Knox A. Autocrine production of matrix metalloproteinase-2 is required for human airway smooth muscle proliferation. Am. J. Physiol. 1999; 277(6 Pt 1):L1109–17.
Chapter
Growth Factors
30
Martin Kolb, Zhou Xing, and Jack Gauldie Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
R E PA I R A N D R E M O D E L I N G It has long been recognized that, after acute injury to the lung, the tissue repair process is engaged to return the organ to normal functioning. In chronic tissue injury, it appears the process of repair loses many of the control mechanisms, and continued repair results in remodeling of the tissue with alteration of normal structure and compromised normal lung function. The remodeling process involves excess and distorted matrix synthesis and deposition and the appearance of altered tissue cell phenotypes, most notably that of the myofibroblast. These cells are derived from existing fibroblasts under the influence of cytokines and growth factors, such as TGF-b or possibly from circulating (stemcell like) precursors that have migrated into the tissue injury site. Given the morphology seen in lung disorders, asthma is mostly associated with minor, primarily peribronchial, matrix deposition, while chronic obstructive pulmonary disease (COPD) has wide evidence of remodeling, primarily at the alveolar level. Many cytokines and growth factors can be found at the site of tissue remodeling through the use of immunohistochemistry, in-situ hybridization, and gene expression assessments – so much so that it is difficult to determine causative versus secondary presence. However, some have recently been shown to play more of a primary role of induction, in comparison with others, and thus represent more likely targets for developing therapeutic interventions. Transgenic and gene knockout models in mice point to possible primary targets in growth factors, such as TGF-b, while others implicate factors such as IL-1b or TNF-a. The presence of acute inflammation such as in acute respiratory distress syndrome (ARDS) or more chronic inflammation states such as COPD and usual interstitial pneumonia are usually associated with the sequelae of tissue remodeling. However, there may be situations involving structural cell phenotype alterations that can propagate the remodeling process through autocrine pathways independent of the state of inflammation that may have preceded the alteration. Thus identification of growth factors known to modulate the
synthesis and deposition of matrix may be crucial in defining the therapy that halts remodeling and induces the tissue to return to normal structure and function.
G R O W T H FA C T O R S I N H U M A N L U N G A N D A I R WAY D I S E A S E A large number of studies have investigated the role of growth factors in human lung disease in which tissue remodeling is a prominent feature. Most of them are based on immunohistochemical analysis of bronchial and pulmonary tissue and on analysis of bronchoalveolar lavage (BAL) fluid and cells. Unfortunately there is minimal information available about growth factors in airway disease. Three different factors are considered to play a prominent role: EGF, GM-CSF, and TGF-b.1,2 Increased EGF and EGF receptors are present in the submucosa of asthmatic airways,3,4 and it is suggested that the epithelium does not respond adequately to EGF after damage in asthma.2 GMCSF expression is increased in asthmatic epithelium and lymphocytes after allergen challenge,3 and GM-CSF can mediate airway remodeling through its survival effect on eosinophils1 and release of profibrotic cytokines.5 TGF-b has received particular interest. In one study,TGF-b expression in airways was shown to correlate with the degree of subepithelial fibrosis in asthma, although the data are controversial.3,6 More telling is the presence of TGF-b in BAL fluid after segmental allergen challenge.4 TNF-a and IL-1 are elevated in acutely inflamed asthmatic airways;3 and as both cytokines are able to trigger profibrotic tissue reactions,7 this strongly suggests a role in airway remodeling. Other growth factors detected like PDGF,1 IGF-1, and bFGF2 could also participate in the repair process in airways. Most knowledge about growth factors has accumulated for parenchymal lung disease, such as asbestosis, sarcoidosis, or idiopathic pulmonary fibrosis (IPF). These disorders are included in this discussion to provide a perspective on the potential biological actions of these factors.
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The presence of two key profibrotic growth factors, TGF-b and PDGF, has been demonstrated in various fibrosing disorders. In idiopathic pulmonary fibrosis, TGF-b was shown to be elevated in BAL fluid8,9 and can be expressed by bronchial and alveolar epithelial cells, alveolar macrophages, and fibroblast foci.10-12 Two studies have reported on the predictive value of elevated TGF-b plasma levels for the development of pulmonary fibrosis following bone marrow transplantation and thoracic radiotherapy.13,14 PDGF mRNA was shown to be upregulated in BAL cells retrieved from patients with IPF and in fibrotic areas of the lung.15 Increased PDGF was detected in BAL fluid from patients with IPF, pneumoconiosis, or scleroderma,8,16 while lungs affected by asbestosis and silicosis express increased TGF-b mRNA.15 In human diseases with more inflammatory components, such as ARDS and active sarcoidosis, TNF-a and IL-1 have been shown to be present in BAL fluid or BAL cell supernatants.17 In lungs with progressive pulmonary fibrosis, TNF-a, MIP-1a, and G-CSF are upregulated.17,18
S P E C I F I C G R O W T H FA C T O R S See Table 30.1 and Fig. 30.1. Tumor necrosis factor-a TNF-a is a peptide secreted as membrane-bound form and released after cleavage by TNF-a-converting enzyme.19 The cytokine is not constitutively present in the lung, but is secreted rapidly upon a variety of stimuli, mainly by alveolar macrophages and type II epithelial cells.15 TNF-a can bind to two different types of receptors, which are expressed on most cells and signals through various intracellular pathways.19 It is a potent proinflammatory cytokine and exerts a variety of effects, which may contribute to the process of remodeling and fibrosis: TNF-a induces inflammatory cell
TNF
INJURY IL-I
REMODELING
Myofibroblast GM-CSF FGF TGF-α
TGF-β PDGF CTGF
Matrix
Fig. 30.1. Locally released growth factors cause proliferation of mesenchymal cells and differentiation to myofibroblasts, with enhanced matrix deposition resulting in tissue remodeling.
migration and adhesion, initiates a cytokine cascade, and regulates apoptosis.19 Further, it is mitogenic for mesenchymal cells and influences collagen metabolism, being either pro- or antifibrotic.15,20 Numerous studies have demonstrated that TNF-a is involved in acute and chronic tissue changes seen after bleomycin, asbestos, silica, and irradiation damage. Animal strains that do not develop fibrosis following exposure to these agents show less TNF-a upregulation. Transient overexpression of TNF-a in the lung induces a limited fibrosis, likely to be by upregulation of TGF-b.21 Others have shown that TNF-a can act also through PDGF pathways.15 TNF-a was detected in BAL fluid and biopsies of patients with IPF, bronchiolitis obliterans with organizing pneumonitis (BOOP), and asbestosis.15 In asthma, TNF-a can amplify the inflammatory process and have indirect influence on airway remodeling through induction of growth factors.3 It has been detected in BAL fluid of asthmatics, in alveolar macrophages after allergen challenge, and in bronchial mucosa of asthma patients.3 It can be rapidly released from mast cells on degranulation.22
Table 30.1. Growth factors in pulmonary tissue remodeling
Induce fibroblast accumulation In vitro In vivo TNF IL-1b GM-CSF PDGF IGF FGF TGF-a TGF-b CTGF
/ / / /
? ? ?
Induce myofibroblasts In vitro In vivo
? ? ? ?
? ? ?
Induce matrix expression In vitro In vivo / /
? ? ?
TNF, tumor necrosis factor; IL, interleukin; GM-CSF, granulocyte/macrophage colony stimulating factor; PDGF, platelet-derived growth factor; IGF, insulin-like growth factor; FGF, fibroblast growth factor; TGF; transforming growth factor; CTGF, connective tissue growth factor.
Growth Factors
Interleukin-1b Two forms of IL-1 are known with almost identical biological properties. IL-1a is bound to cell membranes, while IL-1b is secreted and released.23 In the lung, many cells are able to produce IL-1b, but the major sources are activated macrophages.3 IL-1 binds to two receptors, but only IL-1 receptor I transduces signal, whereas IL-1 receptor II acts as a sink for IL-1, and the presence of a naturally occurring IL-1 receptor antagonist contributes to regulation of IL-1 activity.23 IL-1 is a pleiotropic proinflammatory cytokine, often acting synergistically with TNF-a24 In remodeling and fibrosis, several actions of IL-1 are important. IL-1 stimulates fibroblasts to secrete other cytokines, including IL-1b, IL-8, MCP-1, PDGF, and TGF-b.25,26 It stimulates collagen production in skin fibroblasts,27 but conversely appears to reduce extracellular matrix (ECM) synthesis in lung fibroblasts.20 The effect on fibroblast proliferation is also controversial.24 In vivo, IL-1 is elevated in BAL fluid and alveolar macrophages of patients with ARDS, but not in IPF,17,25 while in animal studies IL-1 is involved in the early stage of pulmonary bleomycin injury,25 and IL-1 receptor antagonist ameliorates the fibrotic response following silica and bleomycin administration.28 Studies by the authors’ group show that transient transgene expression of IL-1 in the lung causes marked alveolar damage, induction of TGF-b, and fibroblast foci with progressive fibrosis.29 IL-1b was found in BAL fluid and macrophages of asthma patients.3 Its role in airway disease is probably similar to that of TNF-a, perpetuating primarily acute inflammatory processes and affecting remodeling indirectly via induction of growth factors, such as PDGF and TGF-b. Granulocyte/macrophage–colony stimulating factor GM-CSF is a colony-stimulating factor that regulates growth and differentiation of hematopoietic cells. The lung is a major source of GM-CSF, and most pulmonary cells are able to synthesize this cytokine in response to various stimuli.3,30 In the context of tissue remodeling and fibrosis, the effects of GM-CSF in the local environment of the lung depend on dose and time of expression and on concomitant epithelial cell damage. In the model of transient transgene overexpression, low levels of GM-CSF induce little peribronchial inflammation and facilitate allergic reactions to exogenous allergen.30 At higher levels, GM-CSF in the airways results in sustained eosinophilia and macrophage accumulation with developing tissue fibrosis.5 This effect is mediated by induction of TGF-b.31 In the bleomycin model, early upregulation of GM-CSF in pulmonary cells is present and followed by enhanced TGF-b expression.32 However, others have demonstrated a reduction of GM-CSF in lungs 1 week after bleomycin injury and a protective effect of GM-CSF on the development of fibrosis in rats33 and mice.34 The profibrotic response may be due to stimulation and enhanced survival of macrophages and eosinophils, both cells major sources for TGF-b.3,5,31,32 In the setting of damaged bronchial and alveolar epithelium, as in bleomycin
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injury, the proliferative response of epithelium to GM-CSF stimulation might result in a more protective effect.33 GM-CSF is present in asthmatic airways of humans and increases in BAL after allergen challenge. Significant levels of GM-CSF are found in plasma of patients with severe asthma.3 These observations indicate that GM-CSF contributes to airway remodeling, and plays a major role in the pathogenesis of asthma.1 Platelet-derived growth factor PDGF is a glycoprotein dimer composed of A or B chains, existing in the form of AA, BB, or AB. In the lung, it is secreted by macrophages, by epithelial and endothelial cells, and by fibroblasts. PDGF-A chains can bind to PDGFreceptor a and b, whereas PDGF-B bind only to PDGFreceptor b.35 Signal transduction proceeds through tyrosine kinases, a major pharmacological target.36 PDGF isoforms are chemoattractive not only for fibroblasts, but also for neutrophils and macrophages, and they upregulate fibronectin and procollagen gene expression and synthesis. PDGF can induce TGF-b expression, suggesting that some of the long-term effects are partly mediated through this cytokine. On the other hand, PDGF and PDGF-receptor expression is stimulated by TGF-b, IL-1b, TNF-a and bFGF, indicating that parts of the profibrotic activities are due to PDGF-dependent pathways.15 In animals exposed to asbestos, both PDGF and its receptors are upregulated in bronchial bifurcations with developing fibroproliferative lesions.37 Lung macrophages and fibroblasts stimulated with asbestos fibers express PDGF in vitro. Mice that overexpress PDGF-BB in the lung tissue have thickened alveolar septae and develop emphysema. PDGF-A knockout mice die because of pulmonary emphysema, apparently because of impaired alveolar development and lack of myofibroblasts.38 Interference with PDGF activity, either through transgene overexpression of a truncated receptor or through inhibition of tyrosine kinase, resulted in amelioration of the fibrotic response in the bleomycin model and a model of bronchiolitis obliterans.15 In human fibrotic disorders of the lung, such as IPF, scleroderma, and bronchiolitis obliterans, PDGF genes were shown to be upregulated in BAL cells or in affected tissues.15 In asthma and airway remodeling, a contribution of PDGF to the pathogenesis is likely, but available data are controversial. Eosinophils in biopsies of asthmatic airways have been shown to produce PDGF-B chain.3 Bronchial fibroblasts from asthma patients show enhanced responsiveness to the mitogenic effects of PDGF, but increased levels of PDGF in BAL fluid are either not present or do not correlate with airway fibrosis.1 Insulin-like growth factor IGF-I and -II are single-chain peptides with structural homology to pro-insulin.39 In the lung, the major sources of IGFs are macrophages, but mesenchymal and bronchial epithelial cells are also able to produce IGF.3,40 IGFs can bind to two receptors, types I and II. IGF receptor type I is
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responsible for growth factor signaling, is homologous to the insulin receptor and transphosphorylates through tyrosine kinase. Biological activity is mainly determined by IGFbinding protein that releases IGF.41 IGFs regulate proliferation and differentiation of a variety of cells,39 being a strong mitogen for fibroblasts and causing enhanced collagen synthesis.40 In the bleomycin mouse model, IGF-1 has been shown to be upregulated together with PDGF.40 The authors’ group has used an adenovector to overexpress IGF-II in the lungs of mice and rats, resulting only in minor inflammatory changes without significant effects on the pulmonary collagen content – in contrast to other growth factors such as TGF-b or IL-1b (unpublished observation). In humans, IGF-I protein was found in BAL fluid of various fibroproliferative diseases.8 Alveolar macrophages of IPF patients secrete enhanced IGF-I, and are present in the interstitium of IPF patients, apparently correlating with the degree of collagen deposition and functional impairment.40 In patients with lung transplantation, IGF-I was exclusively expressed by those who developed bronchiolitis obliterans.42 Little information is available about the role of IGF in asthma. IGFs are present in airways and stimulate the proliferation of airway smooth muscle cells. It has also been suggested that IGF-I may be involved in airway fibrosis, with reduced expression on inhaled corticosteroid therapy.3 Fibroblast growth factor FGFs are a group of nine heparin binding peptides, amongst them acidic and basic FGF (now FGF-1 and -2) and keratinocyte growth factor (KGF or FGF-7).39,43 FGF-1 and -2 have been shown to accelerate granulation tissue formation, fibroblast proliferation, and collagen synthesis.39 They are strong mitogens for angiogenesis and endothelial cell migration.3 FGF-1 and -2 are not present at significant levels in normal lungs, but are produced after tissue injury by alveolar macrophages, epithelial cells, and fibroblasts.44 Major sources for FGF-2 in the lung are mast cells.45 In animal models, FGF-1 and -2 are upregulated after bleomycin and paraquat injury of the lung,44,45 and in humans FGF-2 was found in BAL fluid and serum of patients with IPF and scleroderma.46 In human airway smooth muscle cells, FGF2 increases the expression of PDGF-receptor a and therefore indirectly stimulates proliferation.3 KGF is primarily produced by fibroblasts and is mitogenic mainly for alveolar type-II epithelial cells.43 In rats, intratracheal administration of KGF reduced acute morphological tissue changes and fibrosis after experimental aspiration of hydrochloric acid and in a bleomycin model of fibrosis, indicating a protective healing role for this factor.47,48 In humans with ARDS, KGF in BAL fluid was a marker for the severity of tissue injury and correlated with poor prognosis.43 Epidermal growth factor The EGF family is a growing group of related proteins and includes EGF and transforming growth factor a (TGF-a). Both factors have potential roles in wound healing and
remodeling. They share 42% homology and signal through the EGF-receptor that activates tyrosine kinase.36,49 EGFs are important in the repair of epithelial injury. It has been shown in damaged bronchial epithelial cells that EGF receptors become phosphorylated and consequently the defect is repaired; supplementation with exogenous EGF further enhances this process.2 In asthma, EGF receptor is highly expressed in airway epithelium, but epithelial cell proliferation is still impaired,2 and impaired reepithelialization induces the formation of granulation tissue.50 This suggests that an abnormal response of the epithelium to growth factors could be a central factor in the pathogenesis of asthma and airway remodeling. In humans, EGF and EGF receptor are present in the submucosa of asthmatic airways.2,3 Similar to EGF, TGF-a is able to promote wound epithelialization.39 However, TGF-a also elicits mitogenic effects on mesenchymal cells and stimulates collagen synthesis. EGF receptor activation has been shown to stimulate TGF-b gene expression and TGF-a is present in bleomycininjured lungs.49 Tissue-specific overexpression of TGF-a in the lungs of mice leads to alveolar enlargement and interstitial and pleural fibrosis, while elimination of the TGF-a gene significantly decreased the fibrogenic tissue response to bleomycin.49 In another model, administration of a tyrosine kinase antagonist that specifically blocks the EGF receptor, reduced pulmonary fibrosis induced by vanadium pentoxide by 50%, which was considerable but less than blockade of PDGF receptor activation in a second treatment arm.36 In humans, TGF-a protein is elevated in BAL fluid of patients with ARDS and IPF,51 and TGF-a and EGF receptor expression is seen in biopsy material in IPF.52 Transforming growth factor-b The TGF-b family includes five isoforms, of which mammalian cells express three. The isoforms TGF-b 1–3 reveal considerable sequence homology, and their biological properties in wound healing and tissue remodeling are similar. Most studies have been performed with TGFb-1, which is the most abundant and best-characterized isoform.53 TGF-b is profibrotic by various effects on extracellular matrix (ECM) turnover and stromal cell biology. The immunomodulatory activities of TGF-b are crucial and aim mainly at the limitation of inflammatory processes. Many different cells secrete TGF-b, in the lung mainly macrophages, epithelial cells, and fibroblasts. The secreted molecule is inactive and has to be activated by cleavage of the latency associated peptide (LAP) through acid hydrolysis, oxygen radicals, or proteases (e.g. thrombospondin or plasmin).54 TGF-b binds to two receptors, types I and II, and signals are transduced by serine/threonine kinases to different intracellular pathways.53 In the context of tissue remodeling, the Smad pathway is the most prominent and a potential target for pharmacological intervention in fibrotic disorders.55 TGF-b stimulates ECM production, predominantly collagen and fibronectin, and reduces matrix degradation by
Growth Factors
changing the balance of collagenases and collagenase inhibitors (TIMP-1).54 It can be antiproliferative for epithelial cells, which could be an important factor in airway remodeling and formation of granulation tissue.1,56 The mitogenic effect on fibroblasts is not uniform, but it is apparent that TGF-b induces the transformation of fibroblasts into myofibroblasts.57 Myofibroblasts are contractile cells and synthesize most matrix proteins, both important factors in the final step of wound healing, but potentially a pathogenic process in fibrosis. In the remodeling process, TGF-b acts in concert with many other cytokines and growth factors. On the afferent, it can be upregulated by TNF-a, IL-1, GM-CSF, PDGF, and TGF-b itself. On the effector, TGF-b does not only act through direct interference with collagen metabolism, but may induce the expression and secretion of FGF, PDGF, and CTGF, as well as its own upregulation.7,15,57 The role of TGF-b in pulmonary remodeling and fibrosis has been investigated mainly in interstitial lung disease, where the key role of this growth factor is widely accepted. Evidence comes from a large number of animal models and human studies.15,39,53 In models using chemical agents such as bleomycin, asbestos, silica, or irradiation to induce progressive tissue damage,TGF-b was shown to be upregulated at the sites of developing fibrosis. In the authors’ own studies, in which transient overexpression of active TGF-b1 was achieved by adenoviral gene transfer, severe and diffuse pulmonary fibrosis developed in rats and mice.54 Fibrosis seen in animals overexpressing GM-CSF and TNF-a in the lung by a similar process was at least partly mediated by induction of TGF-b.21,31 The importance of TGF-b in tissue remodeling after pulmonary injury is highlighted by several experimental settings that demonstrate the beneficial effect of antiTGF-b agents on the course of fibrosis. Neutralizing antibodies, dominant negative TGF-b receptors, or natural antagonists such as the proteoglycan decorin have all been able to reduce fibrotic reactions in the lung.58–60 Other agents with antifibrotic properties are niacin, taurin, and pirfenidone, which again reduce TGF-b tissue expression.15 TGF-b was shown to be present in a variety of human lung diseases. It is present in BAL fluid and/or tissue of interstitial diseases associated with fibrosis, such as silicosis, asbestosis, scleroderma, and IPF.8,9,15,16 The importance of TGF-b in pulmonary remodeling is not only restricted to the interstitium, but is also present in airways. TGF-b genes are upregulated in bronchial walls in a model of chronic airway disease, where Aspergillus administration induced changes consistent with airway remodeling.61 In a cytokine gene transfer model the authors found that, with reduced amount of transgene TGF-b1 expressed from bronchial epithelium, the fibrogenic responses were more restricted to subepithelial areas of airways and similar to morphological changes seen in airway remodeling (unpublished observations). Interestingly, TGF-b1 and TGF-b3 appear to have opposite effects on connective tissue synthesis in cultured airway smooth muscle cells,
287
suggesting a protective role for TGF-b3 in airway remodeling.62 In asthma patients, TGF-b was found in airway walls and correlated with the degree of subepithelial fibrosis,6 but others have failed to find a correlation to disease severity.63 Further, asthmatic airways contain more TGF-b producing neutrophils than normal,64 and TGF-b is released into BAL fluid after endobronchial allergen challenge.2 Connective tissue growth factor Connective tissue growth factor has similar activities on collagen metabolism to TGF-b. It is a cysteine-rich peptide produced by fibroblasts and endothelial cells, but not by leucocytes or epithelial cells.15,65 CTGF is constitutively expressed in human lung fibroblasts and is stimulated by TGF-b, but not by TNF-a or IL-1b.66 In mouse lung, TGF-b and CTGF are upregulated following bleomycin injury.66 It has been suggested that TGF-b exerts its profibrotic effects in part through PDGF pathways and through a PDGF-independent pathway using CTGF.15 Little is known about CTGF in airway remodeling. However, the association with TGF-b makes it likely that CTGF might have similar effects in the airway. Indeed, it has been recently shown that TGF-b stimulates expression of CTGF in cultured airway smooth muscle cells.67
ANIMAL MODELS Chronic airway challenge Airway remodeling in human chronic airway disease is a concept not yet clearly defined.1 The principal morphological features are subepithelial fibrosis, myofibroblast hyperplasia, airway smooth muscle hypertrophy, mucous gland and goblet cell hyperplasia, and epithelial disruption.68 The mechanisms leading to persistent airway changes are poorly characterized because of a lack of simple and suitable animal models. An impaired response of asthmatic bronchi to EGF after epithelial injury seems to be important to initiate the process, while other growth factors, such as TGF-b isoforms, PDGF, and bFGF, might be responsible for the proliferative response.2 A recently described animal model using Aspergillus antigens to sensitize and subsequently challenge mice intratracheally produced changes similar to features characterizing airway remodeling; airway fibrosis was accompanied by upregulation of TGF-b.61 Transgene animal models In transgenic animal models certain genes are deleted (knockout animal), overexpressed, or mutated. Transgenic animals, either developed by gene insertion (or deletion) in embryonic stem cells, or by transient transgene expression in adult animals by gene transfer (e.g. adenoviral vectors) have proven useful to answer questions about the role of specific molecules in the pathogenesis of disease. Animals transiently overexpressing IL-1, TNF-a, TGF-b, or GM-CSF develop fibrotic lesions in the lung, probably through induction of TGF-b.21,29,31,54 On the other hand,
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TNF-a-receptor and TGF-a knockout mice are resistant to bleomycin-induced pulmonary fibrosis.15,49 Also implicated by transgenic studies are IL-11 and IL-13, not previously known to be factors involved in tissue remodeling and repair.69
S U M M A RY Of the many cytokines and growth factors that are found within the tissue or surrounding fluids in COPD and asthma, only a few can be shown to have direct impact on the process of tissue remodeling. In-vitro and in-vivo studies outlined above indicate that factors such as TGF-b, which induces chronic repair without accompanying tissue injury, and IL-1b, which induces tissue injury and chronic repair, most likely through induction of TGF-b, may be considered the critical targets for intervention. The fact that these growth factors act mainly at a local site in association with matrix helps explain the restricted and tissuerestricted nature of remodeling. Development of potent inhibitors of these growth factors or of genes activated downstream of them could prove beneficial in modifying the altered tissue in asthma and COPD – allowing conjoint therapy, preferably delivered to the local remodeled site, with anti-inflammatory drugs to halt the destructive process and return the lung to normal function.
REFERENCES 1. Fish JE, Peters SP. Airway remodeling and persistent airway obstruction in asthma. J.Allergy Clin. Immunol. 1999; 104:509–16. 2. Holgate ST. Epithelial damage and response. Clin. Exp. Allergy 2000; 30(Suppl. 1):37–41. 3. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54:825–57. 4. Redington AE et al. Transforming growth factor-beta 1 in asthma: measurement in bronchoalveolar lavage fluid. Am. J. Respir. Crit. Care Med. 1997; 156:642–7. 5. Xing Z et al. Transfer of GM-CSF gene to rat lung induces eosinophilia, monocytosis and fibrotic reactions. J. Clin. Invest. 1996; 97:1102–10. 6. Minshall EM et al. Eosinophil-associated TGF-beta-1 mRNA expression and airways fibrosis in bronchial asthma. Am. J. Respir. Cell Mol. Biol. 1997; 17:326–33. 7. Xing Z et al. Cytokines and pulmonary inflammatory and immune diseases. Histol. Histopathol. 1999; 14:185–201. 8. Vanhee D et al. Mechanisms of fibrosis in coal workers pneumoconiosis: increased production of PDGF, IGF-1 and TGFb and relationship to disease severity. Am. J. Respir. Crit. Care Med. 1994; 150:1049–55. 9. Hiwatari N et al. Significance of elevated procollagen III peptide and TGFb of bronchoalveolar lavage fluids from idopathic pulmonary fibrosis patients. Tohoku J. Exp. Med. 1997; 181:285–95. 10. Broekelmann TJ et al. TGFb1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc. Natl Acad. Sci. 1991; 88:6642–6. 11. Khalil N et al. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 1991; 5:155–62.
12. Corrin B et al. Immunohistochemical localization of TGFb1 in the lungs of patients with systemic sclerosis, cryptogenic fibrosing alveolitis and other lung disorders. Histopathology 1994; 24:145–50. 13. Anscher MS et al. TGFb as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer. N. Engl. J. Med. 1993; 328:1592–8. 14. Anscher MS et al. Changes in plasmaTGFb levels during pulmonary radiotherapy as a predictor of the risk of developing radiation pneumonitis. Int. J. Radiat. Oncol. Biol. Phys. 1994; 30:671–6. 15. Lasky JA, Brody AR. Interstitial fibrosis and growth factors. Environ. Hlth Perspect. 2000; 108(Suppl 4):751–62. 16. Ludwicka A et al. Elevated levels of PDGF and TGFß in bronchoalveolar lavage fluid from patients with scleroderma. J. Rheumatol. 1995; 22:1876–83. 17. Ziegenhagen MW et al. Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis. J Invest. Med. 1998; 46:223–31. 18. Ashitani J et al. Granulocyte-colony stimulating factor levels in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis. Thorax 1999; 54:1015–20. 19. Sporn MB, Roberts AR. Peptide Growth Factors and Their Receptors. New York: Springer-Verlag, 1991. 20. Tufvesson E, Westergren-Thorsson G. Alteration of proteoglycan synthesis in human lung fibroblasts induced by interleukin1beta and tumor necrosis factor-alpha. J. Cell Biochem. 2000; 77:298–309. 21. Sime PJ et al. Transfer of TNFa to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of TGFb1 and myofibroblasts. Am. J. Pathol. 1998; 153:825–932. 22. Kendall JC et al. Promotion of mouse fibroblast proliferation by IgE-dependent activation of mouse mast cells: role for mast cell tumor necrosis factor-alpha and transforming growth factorbeta 1. J. Allergy Clin. Immunol. 1997; 99:113–23. 23. Dinarello CA. Interleukin-1. Cytokine Growth Factor Rev. 1997; 8:253–65. 24. Rochester CL et al. Cytokines and cytokine networking in the pathogenesis in interstitial and fibrotic lung disorders. Semin. Respir. Crit. Care Med. 1994; 14:389–416. 25. Sime PJ, Gauldie J. Mechanisms of scarring. In: Evans TW, Haslett C, (eds.), ARDS: Acute Respiratory Distress in Adults, pp. 215–31. London: Chapman & Hall Medical, 1996. 26. Boyle JE et al. Prostaglandin-E2 counteracts interleukin-1betastimulated upregulation of platelet-derived growth factor alphareceptor on rat pulmonary myofibroblasts. Am. J. Respir. Cell Mol. Biol. 1999; 20:433–40. 27. Postlethwaite AE et al. Modulation of fibroblast functions by interleukin 1: increased steady-state accumulation of type I procollagen messenger RNAs and stimulation of other functions but not chemotaxis by human recombinant interleukin-1a and b. J. Cell Biol. 1988; 106:311–18. 28. Piguet PF et al. Interleukin-1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica. Cytokine 1993; 5:57–61. 29. Kolb M et al. Transient expression of IL-1b induces acute lung injury and chronic repair leading to pulmonary fibrosis. J. Clin. Invest. 2001; 107:1529–36. 30. Stämpfli MR et al. GM-CSF transgene expression in the airway allows aerosolized ovalbumin to induce allergic sensitization in mice. J. Clin. Invest. 1998; 102:1704–14. 31. Xing Z et al. Overexpression of GM-CSF induces pulmonary granulation tissue formation and fibrosis by induction of TGFb1 and myofibroblast accumulation. Am. J. Pathol. 1997; 150:59–66. 32. Andreutti D, Gabbiani G, Neuville P. Early granulocytemacrophage colony-stimulating factor expression by alveolar inflammatory cells during bleomycin-induced rat lung fibrosis. Lab. Invest. 1998; 78:1493–502.
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33. Christensen PJ et al. Role of diminished epithelial GM-CSF in the pathogenesis of bleomycin-induced pulmonary fibrosis. Am. J. Physiol. 2000; 279:L487–95. 34. Piguet PF, Grau GE, de Kossodo S. Role of granulocytemacrophage colony-stimulating factor in pulmonary fibrosis induced in mice by bleomycin. Exp. Lung Res. 1993; 19:579–87. 35. Fabisiak JP, Kelley J. Platelet derived growth factor. In: Kelley J (ed.), Cytokines of the Lung, pp. 3–39. New York: Marcel Dekker, 1992. 36. Rice AB et al. Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. Am. J. Pathol. 1999; 155: 213–21. 37. Lasky JA et al. Upregulation of the PDGF-alpha receptor precedes asbestos-induced lung fibrosis in rats. Am. J. Respir. Crit. Care Med. 1998; 157:1652–7. 38. Bostrum H et al. PDGF-A signalling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 1996; 58:863–76. 39. Mutsaers SE et al. Mechanisms of tissue repair: from wound healing to fibrosis. Int. J. Biochem. Cell Biol. 1997; 29:5–17. 40. Uh ST et al. Morphometric analysis of insulin-like growth factor-I localization in lung tissues of patients with idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 1998; 158:1626–35. 41. Bayes-Genis A, Conover CA, Schwartz RS. The insulin-like growth factor axis: a review of atherosclerosis and restenosis. Circ. Res. 2000; 86:125–30. 42. Charpin JM et al. Insulinlike growth factor-1 in lung transplants with obliterative bronchiolitis. Am. J. Respir. Crit. Care Med. 2000; 161:1991–8. 43. Stern JB et al. Keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients. Crit. Care Med. 2000; 28:2326–33. 44. Barrios R et al. Upregulation of acidic fibroblast growth factor during development of experimental lung fibrosis. Am. J. Physiol. 1997; 273:L451–8. 45. Liebler JM, Picou MA, Qu Z, Powers MR, Rosenbaum JT. Altered immunohistochemical localization of basic fibroblast growth factor after bleomycin-induced lung injury. Growth Factors 1997; 14:25–38. 46. Kadono T et al. Serum concentrations of basic fibroblast growth factor in collagen diseases. J. Am. Acad. Dermatol. 1996; 35:392–7. 47. Yano T et al. Keratinocyte growth factor reduces lung damage due to acid instillation in rats. Am. J. Respir. Cell Mol. Biol. 1996; 15:433–42. 48. Sugahara K et al. Double intratracheal instillation of keratinocyte growth factor prevents bleomycin-induced lung fibrosis in rats. J. Pathol. 1998; 186:90–8. 49. Madtes DK et al. Transforming growth factor-alpha deficiency reduces pulmonary fibrosis in transgenic mice. Am. J. Respir. Cell Mol. Biol. 1999; 20:924–34. 50. Khalil N et al. Regulation of type II alveolar epithelial cell proliferation by TGF-beta during bleomycin-induced lung injury in rats. Am. J. Physiol. 1994; 267:L498–507. 51. Madtes DK et al. Elevated transforming growth factor-alpha levels in bronchoalveolar lavage fluid of patients with acute respiratory
52.
53. 54.
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distress syndrome. Am. J. Respir. Crit. Care Med. 1998; 158:424–30. Baughman RP et al. Overexpression of transforming growth factoralpha and epidermal growth factor-receptor in idiopathic pulmonary fibrosis. Sarcoid.Vasc. Diff. Lung Dis. 1999; 16:57–61. O’Kane S, Ferguson MW. Transforming growth factor beta s and wound healing. Int. J. Biochem. Cell Biol. 1997; 29:63–78. Sime PJ et al. Adenovector mediated gene transfer of active TGFb1 induces prolonged severe fibrosis in rat lung. J. Clin. Invest. 1997; 100:768–76. Nakao A et al. Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J. Clin. Invest. 1999; 104:5–11. Bousquet J et al. Asthma: from bronchoconstriction to airways inflammation and remodeling. Am. J. Respir. Crit. Care Med. 2000; 161:1720–45. Gauldie J et al. TGFb gene transfer to the lung induces myofibroblast presence and pulmonary fibrosis. In: Desmouliere A, Tuchweber B (eds.), Tissue Repair and Fibrosis: Current Topics in Pathology, pp. 35–45. Berlin: Springer-Verlag, 1999. Giri SN, Hyde DM, Hollinger MA. Effect of antibody to TGFb on bleomycin-induced accumulation of lung collagen in mice. Thorax 1993; 48:959–66. Giri SN et al. Antifibrotic effect of decorin in a bleomycin hamster model of lung fibrosis. Biochem. Pharmacol. 1997; 54:1205–16. Kolb M et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am. J. Respir. Crit. Care Med. 2001; 163:770–7. Hogaboam CM et al. Chronic airway hyperreactivity, goblet cell hyperplasia, and peribronchial fibrosis during allergic airway disease induced by Aspergillus fumigatus. Am. J. Pathol. 2000; 156:723–32. Coutts A et al. TGF-beta3 inhibits connective tissue synthesis by airway smooth muscle cells. Am. J. Respir. Crit. Care Med. 2000; 161:A699. Chu HW et al. Collagen deposition in large airways may not differentiate severe asthma from milder forms of the disease. Am. J. Respir. Crit. Care Med. 1998; 158:1936–44. Chu HW et al. Peripheral blood and airway tissue expression of transforming growth factor beta by neutrophils in asthmatic subjects and normal control subjects. J. Allergy Clin. Immunol. 2000; 106:1115–23. Grotendorst GR. Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev. 1997; 8:171–9. Lasky JA et al. Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis. Am. J. Physiol. 1998; 275:L365–71. Douglas DA et al. TGFb stimulates the expression of CTGF by human bronchial smooth muscle cells. Am. J. Respir. Crit. Care Med. 2000; 161:A699. Redington AE. Fibrosis and airway remodeling. Clin. Exp. Allergy 2000; 30(Suppl. 1):42–5. Zhu Z et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 1999; 103:779–88.
Other Mediators of Airway Disease
Chapter
31
Peter J. Barnes National Heart & Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
Many mediators have been implicated in asthma1 and by implication in chronic obstructive pulmonary disease (COPD).2 Several mediators are discussed in earlier chapters, so the purpose of this chapter is to consider the role of some additional mediators.
H I S TA M I N E Histamine was one of the first mediators implicated in asthma as it was found to cause bronchoconstriction in animals, and later in asthmatic patients. Histamine mimics many of the pathophysiological features of asthma. There is no evidence that it is involved in COPD, as mast cell activation is not a feature of that disease. Synthesis and release of histamine Histamine is formed by the decarboxylation of the amino acid histidine by L-histidine decarboxylase, and is stored in granules of mast cells and basophils. Histamine is released from these cells by IgE-dependent mechanisms but also by some physical stimuli such as hypo- and hyperosmolality. Released histamine is metabolized predominantly by histamine N-methyltransferase (HMT) to N-methylhistamine, which is itself metabolized by monoamine oxidase to Nmethylimidazole acetic acid, the major urinary metabolite. The remaining histamine is metabolized by diamine oxidase to imidazole acetic acid, which is excreted in the urine. HMT is the most important enzyme contributing to the degradation of histamine in the airways. Blockers of HMT, such as SKF 91488, increase the bronchoconstrictor action of histamine in vitro and in vivo and increase the plasma exudation induced by histamine.3,4 HMT is expressed in airway epithelial cells and may therefore be responsible for the local metabolism of histamine released from airway mast cells. Certain virus infections and air pollutants may reduce HMT expression and thus increase airway responsiveness to histamine.
Histamine receptors There are three subtypes of histamine receptor, all of which are involved in airway responses to histamine5 (Table 31.1). H1 receptors mediate contraction of airway smooth muscle, plasma exudation, and activation of sensory nerves, and are the target for antihistamines. H2 receptors may mediate mucus secretory and vasodilator responses to histamine, but H2-receptor antagonists, such as ranitidine, do not have a measurable effect on airway function. H3 receptors are localized to cholinergic and sensory nerve endings and may act as feedback inhibitory receptors.6 They may also act as inhibitory autoreceptors on mast cells.7 Effects of histamine on airways Histamine exerts multiple effects on airway function (Fig. 31.1; Table 31.1). Histamine constricts airway smooth muscle from large and small airways. It also induces proliferation of airway smooth muscle cells through a mechanism involving activation of c-fos.8 In some species H2-receptors mediate bronchodilatation, but this does not appear to be the case in humans. Histamine causes plasma exudation and bronchial vasodilatation and this is largely mediated via H1 receptors, although there may be some involvement of H2 receptors.9 Histamine may activate sensory nerves via H1 receptors, resulting in coughing and reflex bronchoconstriction. This is relatively insignificant in asthmatic patients, as anticholinergics have little effect against histamine-induced bronchoconstriction. Histamine may cause mucus secretion predominantly via H2 receptors. Histamine has several effects on inflammatory cells, although the clinical significance of this is not certain. Histamine activates macrophages and enhances eotaxininduced chemotaxis of eosinophils.10 It increases the expression of ICAM-1 in epithelial and endothelial cells.11 The role of histamine in airway disease Histamine levels are increased in the plasma after exercise and after allergen challenge in asthmatic patients.12 Levels are also increased in bronchoalveolar lavage (BAL) fluid of
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Table 31.1. Histamine effects on airways
H1 receptors
H2 receptors
H3 receptors
Airway smooth muscle
Constriction
Relax (some species)
No effect
Airway vessels
Dilatation and constriction
Dilatation (some species)
No effect
Nerves
Afferent nerve stimulation
No effect
Inhibit sensory neuropeptide release Inhibit cholinergic ganglia/ nerves
Facilitation of cholinergic nerves Epithelium
Increased ion transport Increased IL-6, fibronectin release Increased ICAM-1, HLA-DR expression
Increase PGE2 release
No effect
Mucous glands
No effect
Increased glycoprotein secretion
?
Mast cell/basophils
No effect
Inhibit basophils
Inhibit mast cells
Eosinophils
Chemotaxis? Increased survival?
Bronchoconstriction
Plasma leak Mast cell
Vasodilatation
HISTAMINE Basophil
Inflammatory cell activation
Mucus secretion
Neural activation
Fig. 31.1. Effects of histamine on airway function.
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Other Mediators of Airway Disease
asthmatic patients at baseline and after allergen challenge.13 As histamine release is increased in patients with asthma, and histamine mimics many of the pathophysiological features of asthma, most of which are mediated via H1receptors, it has long been implicated in asthma. However, even potent antihistamines provide little or no clinical benefit in patients with asthma, suggesting that histamine plays little role.14 However, it is possible that histamine release from mast cells is involved in acute exacerbations of asthma and in acute responses to allergens and to exercise.
SEROTONIN Serotonin (5-hydroxytryptamine, 5-HT) causes bronchoconstriction in most animal species, but there has been little interest in this mediator as it is not a constrictor of human airways and its relevance in asthma and COPD is doubtful. Synthesis and metabolism of serotonin Serotonin is formed by decarboxylation of tryptophan in diet and is stored in secretory granules. Serotonin is present in mast cell granules of rodents, but not in humans. The major source of serotonin in humans is platelets, but it is also found in neuroendocrine cells of the respiratory tract and is also localized to occasional peripheral nerves. Serotonin receptors Multiple serotonin receptors have now been recognized, based on the development of selective antagonists and molecular cloning.15 There are over seven types of 5-HT receptor, each with several subtypes. Selective antagonists have now become available for clinical use, but few have been used in human airway cells or in patients with asthma.16
Effects of serotonin on airways Serotonin does not constrict human airway smooth muscle in vitro and may even have bronchodilator effects, although pulmonary vessels are constricted as expected17 (Fig. 31.2). Serotonin increases acetylcholine release from airway nerves, and this has also now been demonstrated in human airways and mediated via 5HT3 and 5HT4 receptors.18 In guinea-pig airways, serotonin inhibits NANC constriction due to tachykinin release via a 5HT1like receptor localized to sensory nerve endings.19,20 In humans, infused serotonin has no effect on airway function but may have an inhibitory effect on cough reflexes, possibly mediated via receptors on airway sensory nerves.21 Serotonin is a potent inducer of microvascular leakage in rodent airways, but it is not certain whether it has this property in human airways. The role of serotonin in airway disease Plasma serotonin levels are reported to be elevated in asthma and are significantly related to asthma severity.22 The source of serotonin is likely to be platelets, but the clinical relevance of this observation is uncertain. In animals, serotonin constricts airways via activation of 5HT2-receptors on airway smooth muscle cells. The 5HT2-receptor antagonist ketanserin had no effect on airway function but a small inhibitory effect on methacholine-induced bronchoconstriction in asthmatic patients.23 Inhaled ketanserin has no effect on histamineinduced bronchoconstriction, but a small inhibitory effect on adenosine-induced bronchoconstriction, indicating a possible action on mast cells.24 Tianeptine, which enhances serotonin uptake by platelets, lowers the elevated plasma serotonin levels reported in patients with asthma and is associated with a reduction on asthmatic symptoms.25
Plasma leak?
Platelet
SEROTONIN
Vasodilatation
Neural activation
Fig. 31.2. Effects of serotonin on airway function.
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ADENOSINE Adenosine is a ubiquitous mediator which is produced under conditions of stress. It has several effects that are relevant to asthma and COPD (Fig. 31.3; Table 31.2). Synthesis and metabolism of adenosine Adenosine is a purine nucleoside which arises following the dephosphorylation of 5′-adenosine monophosphate (AMP), by the membrane-associated enzyme 5′-nucleotidase, and is liberated intracellularly by the cleavage of the high energy bonds of the adenosine phosphates, adenosine 5′-tri- and
di-phosphate (ATP and ADP) and 5′-AMP. However, during hypoxia or even excessive cell stimulation where the utilization of energy and oxygen exceeds its supply, 5′AMP is metabolized to adenosine by the extracellular enzyme 5′-nucleotidase.26 Adenosine release was originally demonstrated during myocardial hypoxia,26 although there is now evidence that all cells are capable of producing adenosine in times of energy deficit. Adenosine can be released by lung tissue in times of hypoxia, such as following allergen-induced bronchoconstriction when circulating levels of adenosine have been shown to be three times higher than baseline
(A
ni
m
al
s)
Bronchoconstriction
Mast cell
ADENOSINE
Mast cell activation
Eosinophil activation
Plasma leak Inflammatory cells
Vasodilatation
Neural activation
Fig. 31.3. Effects of adenosine on airway function. Table 31.2. Adenosine effects on airways
Cell
Effect
Receptor
Airway smooth muscle Vessels
Bronchoconstriction (some species) Vasodilatation Plasma extravasation No effect No effect on cholinergic transmission (human) Sensory nerve activation? Mast cell activation Eosinophil inhibition
A1 A2a A2a
Secretions Nerves Inflammatory cells
A1? A2b A3
Other Mediators of Airway Disease
concentrations.27 Mast cells are a likely source of adenosine in this situation as these cells have been shown to be capable of releasing adenosine in response to IgE cross-linking and other stimuli for mast cell activation.28 Hypoxia-induced release of adenosine may also be relevant in COPD. Adenosine receptors Three distinct classes of receptor have been characterized, based on biochemical, functional, and more recent cloning studies; they include the A1, A2a, A2b and A3 receptor subtypes.29 The A1 receptor is expressed in lung tissue,30 and in particular A1 receptors have been identified on human epithelial cells.31 The classification of adenosine receptors into A2a and A2b subtypes is based on distinct rank orders of potency of a range of agonists and antagonists and distinct nucleotide sequences of the two complementary deoxyribonucleic acids (cDNA), with A2a, A2b, and A3 receptors being expressed in a number of tissues, including lungs and in mast cells and fibroblasts.32 Human mast cells predominantly express both A2a and A2b receptors without evidence of A3 receptors as in rodents.33,34 However in airways from asthmatic patients in vitro, the contractile response to adenosine appears to be mediated via A1 receptors.35 Effects of adenosine on airways The effect of adenosine on airway smooth muscle differs between species. In rabbits, adenosine causes direct constriction of airway smooth muscle via A1 receptors and this is associated with activation of phospholipase C and an increase in IP3.36 Adenosine elicits little or no contraction of human bronchi from nonasthmatic subjects, but potently constricts asthmatic airways in vitro via A1 receptors.35 This constriction is indirect as it is blocked by histamine and leukotriene antagonists and is therefore likely to be due to the release of mediators from mast cells in asthmatic airways. Comparable results have been observed in vivo where adenosine and AMP are able to elicit bronchoconstrictor effects in atopic and asthmatic subjects, but have also no effect in normal subjects.37 Furthermore, dipyridamole, an inhibitor of adenosine uptake into tissues, enhances adenosine-induced bronchospasm in asthmatic subjects,38 an effect that can be inhibited by theophylline, a nonselective adenosine antagonist.39 The receptor mediating the bronchoconstrictor effect of adenosine in asthma is not yet certain. In rabbits the A1 receptor is a likely candidate as tracheal strips from rabbits immunized with house dust mite are more responsive to adenosine and the adenosine A1-selective agonist cyclopentyl-adenosine (CPA) than tracheal strips isolated from naive animals.40 Furthermore, immunized animals are considerably more responsive to the bronchoconstrictor effects of adenosine and CPA in vivo.41 No bronchoconstrictor effect of the A3-selective agonist aminophenylethyladenosine (APNEA) have been found in the rabbit or guinea-pig.41,42 It is likely that the bronchoconstrictor effects of adenosine may be indirect as a result of the activation of mast cell degranulation, as adenosine will cause histamine
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release from mast cells, an effect that may involve the A2b receptor as this effect is sensitive to enprofylline, an A2b receptor antagonist.43 There is evidence for elevated levels of histamine in bronchoalveolar lavage following the instillation of AMP directly into the airways.44 Furthermore, the H1 receptor antagonist terfenadine has a protective effect against adenosine-induced bronchoconstriction in asthmatic subjects.45 Another possible explanation for adenosine-induced bronchoconstriction is that it occurs secondary to the activation of a neuronal reflex. Adenosine and related molecules have long been known to modulate synaptic transmission, although in human trachea adenosine does not influence cholinergic responses.46 Adenosine is a potent activator of airway sensory C (nonmyelinated) nerve fibers, acting via A1 receptors.47 AMP-induced effects in the airway may be secondary to the activation of C fibers, a suggestion supported by clinical observations showing that the airway effects induced by inhaled adenosine or AMP can be inhibited by sodium cromoglycate and nedocromil sodium, drugs that can attenuate C-fiber.48 Adenosine is a potent mediator of mast cell degranulation as described above, and therefore may contribute to the inflammatory changes observed in asthma. Adenosine increases the release of histamine from BAL mast cells from asthmatic patients,49 and this effect is likely to be mediated via A2b receptors.50 Adenosine increases the release of IL-8 from human mast cells, an effect that is mediated via the activation of p38 MAP kinase.51 On the other hand, adenosine inhibits eosinophil and neutrophil degranulation via A2 receptors,52 and activation of these receptors by adenosine inhibits eosinophil migration, degranulation, and release of oxygen-derived free radicals.53 The role of adenosine in airway disease Increased levels of adenosine have been found in BAL fluid obtained from asthmatic subjects when compared with normal subjects;54 and, as discussed above, adenosine concentrations in plasma are higher in allergic patients minutes after allergen provocation.27 A3 receptor expression is increased in asthmatic lung compared to normal subjects, although since the A3 receptor is expressed predominantly in eosinophils this may be a reflection of eosinophil infiltration.52 No specific receptor antagonists for adenosine have been evaluated in man against adenosine-induced bronchoconstriction. Dipyridamole, an inhibitor of adenosine uptake, enhances adenosine-induced bronchospasm in asthmatics when administered intravenously or by inhalation,38 an effect that can be inhibited by theophylline, an adenosine receptor antagonist.39 Adenosine-induced bronchospasm can also be inhibited by a variety of other drugs, including the H1 antagonist terfenadine, the cycloxygenase inhibitor indomethacin, and by sodium cromoglycate, although this does not provide direct evidence for the involvement of adenosine in asthma. The fact that theophylline has other actions that may contribute to its anti-asthma effect (including non-selective phosphodiesterase inhibition) cannot be
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taken as evidence for a role of theophylline, and studies with more selective adenosine antagonists are needed. The role of endogenous adenosine in allergic response has not been evaluated because of the lack of suitable drugs to test. However, the recent recognition that enprofylline is a selective A2b receptor antagonist has now provided a possible tool to evaluate the role of adenosine in allergic responses.55 This observation also raises the distinct possibility that some of the therapeutic activity of enprofylline and other xanthines such as theophylline may in part be related to inhibition of adenosine receptors.56,57 Furthermore, recent studies using an anti-sense oligonucleotide against the A1 receptor showed that a reduction in A1 receptors had a very significant effect on allergen-induced bronchospasm and bronchial hyperresponsiveness to inhaled histamine in an allergic rabbit model.58
P L AT E L E T- A C T I VAT I N G FA C T O R Platelet-activating factor (PAF) is an ether-linked phospholipid (1-0-alkyl-sn-gycero-3-phosphocholine) first described as a substance released from IgE-stimulated basophils. It is generated from membrane phospholipids by phospholipase A2.
Synthesis and metabolism of PAF PAF is synthesized in a wide variety of inflammatory cells, including platelets, neutrophils, basophils, macrophages, and eosinophils59 (Fig. 31.4). The synthesis of PAF in inflammatory cells is generally via a two-step enzymatic pathway involving initially the activation of phospholipase A2 to form lyso-PAF, which is then acetylated to PAF by acetyl transferase. PAF is not a single biologically active molecule, but a number of molecular species of PAF with significant biological activity exist.60 For example, the ester-linked [1-acyl] species 1-palmitoyl-2-acetoyl-sn-glyceryl-3-phosphocholine (PAGPC), is synthesized by a wide range of cells including endothelial cells, basophils, mast cells, and lymphocytes. The major enzyme responsible for the catabolism of PAF is PAF-acetylhydrolase, a PAF specific esterase that cleaves the acetyl group at sn-2 position producing lyso-PAF. PAFacetylhydrolase is abundant in human plasma associated with low-density lipoproteins, and intracellular acetylhydrolase is in the cytoplasm of inflammatory cells, including mast cells, macrophages, and platelets. An acetylhydrolase in BAL fluid appears to be distinct from plasma acetylhydrolase and is present in lower amounts in BAL fluid from patients with asthma. A deficiency of PAF acetylhydrolase in Japanese children is an autosomal recessive syndrome due to a missense mutation that abolishes enzymatic activity,61 and
Membrane lipids Mast cell
Eosinophil
Macrophage
Neutrophil
Epithelial cells
PLA2 Lyso-PAF
PLF acetyl transferase
Neutrophils
PAF PAF Macrophages
PAF acetyl hydrolase
PAF-receptor Eosinophils
B/C
Ep cells
Mucus secretion
Vasodilatation
Fig. 31.4. Generation and effects of platelet-activating factor (PAF).
Plasma exudation
AHR
Other Mediators of Airway Disease
this appears to be associated with severe asthma.62 Recombinant human PAF-acetylhydrolase reduces the inflammatory responses in the airways.63 PAF receptors A PAF-receptor has been cloned in human platelets and leucocytes and shown to be a typical GTP-binding protein with seven transmembrane spanning domains.64 PAF-receptors are expressed in animal and human lung.65 Overexpression of the PAF receptor in transgenic mice results in airway hyperresponsiveness, which is attenuated by thromboxane, leukotriene, and muscarinic antagonists.66 There may be heterogeneity of PAF receptors.67,68 Only a small part of the total amount of PAF generated by cells is actually released from cells, and intracellular PAF may exert some functional effect and may even activate intracellular receptors. Effect of PAF on airways PAF exerts many effects on the airways that closely mimic the pathophysiology of asthma (Fig. 31.4). PAF has little direct effect on human airway smooth muscle contraction in vitro, but may elicit constriction through the release of mediators.69 PAF elicits acute bronchoconstriction when inhaled by patients with asthma.70 PAF-induced bronchoconstriction is not inhibited by the H1-receptor antagonist ketotifen or a thromboxane antagonist GR32191B. However, PAFinduced bronchoconstriction can be inhibited by leukotriene antagonists, including zafirlukast,71 suggesting the involvement of LTD4 in this response. PAF has potent effects on vascular smooth muscle and elicits hypotension in a number of species. In the context of asthma, PAF is a potent inducer of airway plasma exudation,72 mediated mainly via release of thromboxane.73 Inhalation of PAF by mild asthmatics induces arterial hypoxemia due to V˙ /Q˙ imbalance.74 PAF elicits mucus secretion from isolated human airways that may depend in part on the generation of cysleukotrienes, but that is independent of acetylcholine release.75 PAF is a potent activator of inflammatory cells. For example, PAF stimulates the adhesion of eosinophils and neutrophils in vitro.76,77 In addition, PAF can act as a priming agent for eosinophils.78 After allergen challenge in asthmatic patients, PAF induces a greater activation of circulating eosinophils in vitro, indicating an interaction between PAF and other priming factors, such as IL-5 and GM-CSF.79 PAF also has a greater activating effect on the neutrophils of asthmatic patients compared to normal control subjects.80 In vivo, PAF elicits a marked eosinophil infiltrate into lung tissue following both IV and aerosol administration to guinea-pigs81 and rabbits.82 In primates, single and multiple exposure to aerosolized PAF elicits an increase in the number of eosinophils and neutrophils in BAL fluid, accompanied by an increased bronchial responsiveness to inhaled methacholine.83 Whilst inhalation of PAF has been reported to elicit bronchial hyperresponsiveness in humans,84,85 this has not been universal.86
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The role of PAF in airway disease Measurements of PAF in BAL fluid of asthmatic patients has produced conflicting results, with some groups reporting elevated levels, although all have found an increase in concentrations of lyso-PAF which may indicate formation of PAF.87,88 After segmental allergen challenge in asthmatic patients, high levels of lyso-PAF were correlated with increased acetylhydrolase and PLA2 activity.89 PAF has also been detected in the plasma of patients exhibiting a late asthmatic response.90 Despite the circumstantial evidence that PAF may play an important pathophysiological role in asthma, PAF antagonists have proved to be very disappointing in asthma, as discussed in Chapter 52. There is no evidence that PAF is involved with COPD, although the fact that it may be released in hypoxia means that it could play a role in that disease.
ENDOTHELINS Endothelins (ET) are potent constrictor peptides originally described as vasoconstrictors released from endothelial cells.There is now considerable circumstantial evidence that they are involved in the pathophysiology of asthma.91,92 Synthesis and metabolism of endothelins Endothelins may be stored within cells or synthesized on cell activation; secretion of endothelins is therefore regulated at the level of peptide synthesis. Although ET-1 was first described in endothelial cells, it is now apparent that endothelins may be synthesized by many different cell types, including several types of airway cell. ET-3 is relatively abundant in neuronal tissues and may be a neuronal form of endothelin. ET-like immunoreactivity is localized to airway epithelium in human airways, with intense staining in goblet and Clara cells, but only intermittent staining of ciliated epithelial cells.93 Specific antibodies have localized ET-1, proET-1, ET-3, and proET-3 to airway epithelial cells and submucosal glands in human lung.94 Endothelin-converting enzyme (ECE) has been reported in bovine lung membranes, and guinea-pig lung is reported to synthesize and degrade ET-1.95 The presence of proendothelins and mRNA for preproendothelins in lung suggests that they are synthesized locally. Furthermore, ET-1 is detectable in cultured human epithelial cells.96 ET-1 synthesis and release from epithelial cells is stimulated by endotoxin, and several proinflammatory cytokines which may be released from macrophages (IL-1b, TNF-a, IL-6).97 Human alveolar macrophages have also been identified as a source of endothelins,98 and these cells may be activated in asthmatic patients by exposure to allergens via low-affinity IgE receptors. Each ET peptide is encoded by a distinct gene,99 which codes for a precursor peptide. Preproendothelin-1 (mapped to chromosome #6 in humans) is cleaved to a 38 amino acid intermediate form called big ET-1 or pro-ET-1 (Fig. 31.5).
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1
203
N
Preproendothelin-1
C
Dibasic endopeptidases 1
39
N
Proendothelin-1
C
Endothelin converting enzyme (ECE-1) 1 N
21 Endothelin-1
C
Neutral endopeptidase (EC 3.4.24.11) Inactive peptides Fig. 31.5. Synthesis of endothelin.
Pro-ET-1 is rapidly cleaved by a specific enzyme ECE-1 to form mature ET-1. ECE-1 is a neutral metalloendopeptidase and is inhibited by phosphoramidon. ECE-1 is expressed in human epithelial cell lines.100 Mast cell chymase may also cleave pro-ET-1.101 Several proinflammatory cytokines, including TGF-b,TNF-a and IL-1b may increase expression of ET-1. Endothelins are metabolized by neutral endopeptidase (NEP: EC 3.4.24), which is localized to several cells in the airways, especially airway epithelium. Inhibition of NEP with phosphoramidon increases the potency of endothelins in guinea-pigs in vivo and in human airways in vitro.102 Endothelin receptors Two distinct receptors with the typical structure of Gprotein coupled receptor have been cloned with approximately 60% homology.103 For the ETA receptor, the rank order of potency is ET-1>ET-2>>ET-3 and the affinity of binding of ET-1 is approximately 100 times greater than for ET-3. ETB receptors show a similar affinity for all three endothelins and for the related sarafotoxins. The distinction between ETA and ETB receptors has been confirmed by the development of selective agonists and antagonists. Although the existence of a third ET receptor which is selective for ET-3 (ETC receptor) has been proposed, there is little conclusive evidence for this in human tissues. Radioligand binding studies and in-situ hybridization studies with cDNA receptor probes have demonstrated that ET receptors are widely distributed, in keeping with the multiple actions of these peptides. ETA and ETB receptors are expressed in lung and are differentially distributed.104 Autoradiographic studies with [125I]ET-1 and selective antagonists have shown a widespread distribution of ETA and ETB receptors in human airways, with a predominance of ETB receptors in airway smooth muscle.105 There is no
difference in receptor distribution in asthmatic airways compared to normal airways,106 although there is an increase in the ratio of ETB:ETA receptor mRNA in asthmatic airways.107 Effects of endothelins on airways ET-1 and ET-2 are potent constrictors of human airway smooth muscle in vitro, being even more potent than LTD4106,108,109 (Fig. 31.6, Table 31.3). The contractile response is slow in onset and sustained, and ET-1 appears to cause a maximal contractile response. The contractile response in human airways is unaffected by calcium antagonists and, in contrast to other species, cycloxygenase inhibitors or leukotriene antagonists,110 suggesting a direct effect on airway smooth muscle. This is consistent with the demonstration of ET-binding sites on human airway smooth muscle using autoradiography.105,106 ET-3 is less potent than ET-1 or ET-2,111 but the potency differences are complicated by differential metabolism. Mechanical removal of airway epithelium potentiates the constrictor effects of endothelins, but the effect is greater for ET-3 than for ET-1.102 After epithelial removal or phosphoramidon, the potencies of ET-1, ET-2, and ET-3 are similar, suggesting that any differences in previous studies were due to more rapid degradation of ET-3 by epithelial NEP. The constrictor response to ET-1 is enhanced by the nitric oxide synthase inhibitor L-NAME, suggesting that ET-induced release of nitric oxide normally counteracts its constrictor actions.112 ET-3-mediated contraction of human airways is partly reduced by cycloxygenase inhibition.110 The ETA antagonists BQ-123, FR-139317, and PD 145065 have no inhibitory effect on ET-induced constriction, suggesting that ETB receptors mediate the direct constrictor response; this is supported by the constrictor response to ETB-selective agonists BQ-3020 and
299
Other Mediators of Airway Disease
Bronchoconstriction Proliferation Vasodilatation Macrophage
Mucus secretion
ENDOTHELINS Epithelial cell
Cholinergic facilitation
Fibroblast activation Collagen deposition Fig. 31.6. Effects of endothelins on airway function. Table 31.3. Endothelin effects on airways
Cell
Effect
Receptor
Airway smooth muscle
Bronchoconstriction Proliferation (synergistic) Vasoconstriction Plasma extravasation? Increased mucus Increased cholinergic transmission Activates fibroblasts to increase collagen Probably no effect on human inflammatory cells
ETB ETA ETA
Vessels Secretions Nerves Inflammatory cells
IRL1620.109,111 Asthmatic airways show a similar, or even reduced, response to ETB-selective agonists than normal airways.106 Interestingly, the release of prostanoids (predominantly PGD2 and PGE2) induced by ET-1 in human airways appears to be mediated via an ETA receptor, since this is effectively inhibited by BQ-123.111 Inhaled ET-1 is a potent bronchoconstrictor (approximately 100-fold more potent than methacholine) in asthmatic patients and causes a bronchoconstrictor response that lasts for over an hour, whereas it has no effect in normal subjects.113 ET-1 increases proliferation of rabbit and sheep cultured airway smooth muscle cells,114,115 and this appears to be via the stimulation of the extracellular regulated kinase (ERK) MAP kinase pathway.116 However, ET-1 alone has no effect on cultured human airway smooth muscle cells, but
ETA ETA ETB ETA
markedly amplifies the proliferative effect of growth factors, such as epidermal growth factor and this is mediated via an ETA receptor.117 ET-1 constricts human bronchial arteries in vitro,118 but its effect on airway microvascular leakage is conflicting. In rat trachea, ET-1 causes an increase in plasma extravasation,119 and this response is dependent on leucocytes; in guinea-pig, ET-1 is without effect on plasma extravasation.120 This may reflect relative vasoconstrictor effects on precapillary arterioles versus direct effects on endothelial cells of postcapillary venules. ET-1 is a potent constrictor of pulmonary vessels, and as it may be released by hypoxia it has been implicated in pulmonary hypoxic vasoconstriction via an inhibitory action on ATP-dependent potassium channels.121,122
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Asthma and Chronic Obstructive Pulmonary Disease
ET-1, but not ET-2 or ET-3, stimulates mucus glycoprotein secretion from feline airway submucosal glands via a direct mechanism which involves calcium ion influx, suggesting that ETA receptors are involved.123 Endothelins bind to parasympathetic ganglia and nerves in rat and rabbit airways,124 suggesting that ET-3 may have an effect on cholinergic neurotransmission. ET-3 enhances neurotransmission in postganglionic cholinergic nerves in rabbit airways via a direct effect on prejunctional receptors.125 This would suggest that endothelins may potentiate cholinergic reflex bronchoconstriction, and this effect is mediated via an ETB receptor. The ETB-selective agonist sarafotoxin S6C enhances cholinergic nerveinduced contraction of human airways in vitro, indicating the presence of ETB receptors on cholinergic nerves as well as airway smooth muscle;126 and ET-1-induced enhancement of cholinergic contractions are inhibited by combined ETA and ETB receptor antagonists, indicating the presence of prejunctional ETA and ETB receptors.127 ET-1 has no effect on tachykinin release from normal sensory nerves.128 It is not yet certain whether endothelins have inflammatory effects in the airways. Intravenous or inhaled ET-1 has no effect on inflammatory cell influx in guinea-pigs,120 and there is no increase in airway responsiveness to other spasmogens.129 Similarly, in asthmatic patients inhaled ET-1 has no effect on inflammatory cells in induced sputum, or on the concentrations of IL-1b, TNF-a, or nitrite.130 Endothelins may increase the release of inflammatory mediators from a variety of cells. Thus ET-1 increases the release of lipid mediators from cultured human nasal mucosa,131 and increases superoxide formation and TNF-a release in alveolar macrophages.132 In a cultured human epithelial cell line, ET-1 induces the release of cytokines IL-6, IL-8, and GMCSF.133 ET-1 potently stimulates collagen secretion from pulmonary fibroblasts,134 and may therefore be involved in the increased collagen formation observed in asthmatic airways. ET-1 is reported to increase fibronectin gene expression and release in human airway epithelial cells.135 The role of endothelins in airway disease There is increased formation of endothelins in asthma. Elevated concentrations of ET-1 have been detected in bronchoalveolar lavage of asthmatic patients,136 and are reduced after treatment with steroids.137 ET-1 is present in induced sputum, but the levels are not elevated in asthmatic compared to normal subjects.138 An increase in concentration of plasma ET-1 has been reported in asthmatic children and adults and is related to asthma severity,139 although another study showed no increase in plasma ET-1 in patients with mild asthma.138 There is a significant increase in expression of ET-1 immunoreactivity in the epithelial layer in fiberoptic bronchial biopsies from asthmatic patients.140 It is tempting to speculate that this is due to the action of proinflammatory cytokines (IL-1b, TNF-a, IL-6) released from activated macrophages in asthmatic
airways. Anti-CD23 also induces release of ET-1 in epithelial cells from asthmatic patients, suggesting that allergen acting via low-affinity IgE receptors (FceRII) may be a mechanism for releasing ET-1 in asthma.141 There is also an increase in ET-1 content of alveolar macrophages from asthmatic patients compared with normal subjects, although no increase in its release after stimulation with lipopolysaccharide.132 An increase in the expression of ETB-receptor mRNA has been reported in patients with asthma. Endothelins are potent and long-lasting bronchoconstrictors in human airways via direct activation of ETB receptors on human airway smooth muscle and via the activation of cholinergic nerves. There is little evidence for proinflammatory actions of endothelins in humans, however. Perhaps their most relevant action in asthma is on airway remodeling, with stimulation of fibroblasts and proliferation of airway smooth muscle. Endothelins may also play an important role in COPD. There is evidence for increased expression of ET-1 in patients with COPD who have secondary pulmonary hypertension, thus implicating this mediator in its pathophysiology.142 ET-1 levels are increased in induced sputum of patients with COPD143 and increase further during acute exacerbations.144 Several nonpeptide antagonists have now been developed for clinical use,145 but they have not yet been tested in asthmatic or COPD patients. Potent nonpeptide antagonists, such as SB217242, have now been developed. If the major effect of endothelins is in tissue remodeling, it may be difficult to test the efficacy of such compounds as very prolonged studies may be needed. ET antagonists might also be indicated in the treatment of pulmonary hypertension that is secondary to COPD.
COMPLEMENT Synthesis of complement The complement system is a series of 30 distinct circulating proteins that include proteolytic proenzymes, nonenzymatic components that form functional enzymes once activated, and receptors.146,147 The proenzymes become sequentially activated in a cascade that finally leads to the formation of the so-called terminal attack sequence that can promote cell lysis and which is central to defense against invading microorganisms. However, there are a number of by-products generated during the activation of the complement cascade that have proinflammatory activity and have the potential therefore to be involved in asthma. The larger fragments of C3 and C4 (e.g. C3b and C4b) are involved in a range of biological activities including opsonization, phagocytosis, and immunomodulation.There are also a number of smaller fragments generated during the activation of the third and fifth component of complement, such as C3a and C5a which have been referred to as anaphylatoxins and have several airway effects.146
Other Mediators of Airway Disease
Complement receptors There are distinct receptors for C3a and C5a, which have now been cloned.146 Both C3a and C5a receptors are expressed in epithelial and airway and pulmonary vascular smooth muscle cells of human lung.148 There is increased expression of complement receptors after exposure to allergen and lipopolysaccharide.148 Effects of complement on airway function C3a and C5a induce airway smooth muscle contraction and chemotaxis of leucocytes, including eosinophils.149,150 Aerosolization of C5a into the airways induces a transient hyperresponsiveness to inhaled histamine,151 an effect that is partially inhibited by pretreatment with indomethacin.152 Both C3a and C5a are potent stimulants of eosinophil degranulation,153 and the response of circulating eosinophils to C5a is enhanced after the late response to inhaled allergen in asthmatic patients.154 C5a is also a potent chemoattractant of human monocytes and may therefore be involved in recruitment of macrophages into asthmatic airways.155 The role of complement in airway disease There have been conflicting reports about changes in the complement cascade in asthmatic patients. An increased amount of C3a has been demonstrated in the circulation of asthmatics during exercise-induced bronchoconstriction,156 and increased levels of C3a and C5a have been demonstrated in BAL fluid obtained from some, but not all asthmatics.157,158 In asthmatic patients the neutrophil chemotactic activity of bronchoalveolar lavage is largely explained by C5a,159 suggesting that this is an important mediator of neutrophil infiltration in asthmatic airways. Evaluating the contribution of endogenous activation of complement to the allergic asthmatic response is difficult as there are no selective inhibitors for the various complement components. However, in experimental animals treatment with the soluble complement receptor 1 (sCR1), the normal regulator of circulating C1, reduces allergen-induced bronchoconstriction.160 Treatment of animals with cobra venom factor to deplete circulating complement components does not inhibit allergen-induced eosinophil infiltration into lungs, however.161 Mice with deletion of the C5a receptor have a marked reduction in AHR, suggesting that complement may play a role in asthma.158 Similarly a strain of mice with defective function of C3a receptor also have reduced airway responsiveness.162 In a murine model of asthma, a susceptibility locus was identified as defective complement factor 5 and its mechanism of action linked to a deficiency in IL-12 secretion from macrophages.163
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3. Sekizawa K, Nakazawa H, Ohrui T et al. Histamine Nmethyltransferase modulates histamine and antigen-induced bronchoconstriction in guinea pigs in vivo. Am. Rev. Respir. Dis. 1993; 147:92–6. 4. Sekizawa K, Nakazawa H, Morikawa M et al. Histamine Nmethyltransferase inhibitor potentiates histamine- and antigeninduced airway microvascular leakage in guinea pigs. J. Allergy Clin. Immunol. 1995; 96:910–16. 5. Hill SJ. Distribution, properties and functional characteristics of three classes of histamine receptor. Pharmacol. Rev. 1990; 42:45–83. 6. Ichinose M, Barnes PJ. Inhibitory histamine H3-receptors on cholinergic nerves in human airways. Eur. J. Pharmacol. 1989; 163:383–6. 7. Ichinose M, Barnes PJ. Histamine H3-receptors modulate antigeninduced bronchoconstriction in guinea pigs. J. Allergy Clin. Immunol. 1990; 86:491–5. 8. Panettieri RA, Yadish PA, Rubinstein VA, Kelly AM, Kotlikoff MI. Histamine induces proliferation and c-fos transcription in cultured airway smooth muscle. Am. J. Physiol. 1990; 259:L365–71. 9. Liu SF, Yacoub M, Barnes PJ. Effect of histamine on human bronchial arteries in vitro. Naunyn Schmied Arch. Pharmacol. 1990; 342:90–3. 10. Das AM, Flower RJ, Perretti M. Eotaxin-induced eosinophil migration in the peritoneal cavity of ovalbumin-sensitized mice: mechanism of action. J. Immunol. 1997; 159:1466–73. 11. Miki I, Kusano A, Ohta S et al. Histamine enhanced the TNFalpha-induced expression of E-selectin and ICAM-1 on vascular endothelial cells. Cell Immunol. 1996; 171:285–8. 12. Ind PW, Barnes PJ, Brown MJ, Causen R, Dollery CT. Measurement of plasma histamine. Clin. Allergy 1983; 13:61–7. 13. Liu MC, Hubbard WC, Proud D et al. Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics: cellular, mediator and permeability changes. Am. Rev. Respir. Dis. 1991; 144:51–8. 14. van Ganse E, Kaufman L, Derde MP, Yernault JC, Delaunois L. Effects of antihistamines in adult asthma: a meta-analysis of clinical trials. Eur. Respir. J. 1997; 10:2216–24. 15. Saxena PR. Serotonin receptors: subtypes, functional responses and therapeutic relevance. Pharmacol.Ther. 1995; 66:339–68. 16. Dupont LJ, Pype JL, Demedts MG et al. The effects of 5-HT on cholinergic contraction in human airways in vitro. Eur. Respir. J. 1999; 14:642–9. 17. Raffestin B, Cerrina J, Boullet C et al. Response and sensitivity of isolated human pulmonary muscle preparations to pharmacological agents. J. Pharm. Exp.Ther. 1985; 233:186–94. 18. Takahashi T, Ward JK, Tadjkarimi S et al. 5-Hydroxytryptamine facilitates cholinergic bronchoconstriction in human and guinea pig airways. Am. J. Respir. Crit. Care Med. 1995; 152:377–80. 19. Ward JK, Fox AJ, Barnes PJ, Belvisi MG. Activation of a 5HT1-like receptor inhibits excitatory non-adrenergic non-cholinergic bronchoconstriction in guinea-pig airways in vitro. Br. J. Pharmacol. 1994; 111:1095–102. 20. Dupont LJ, Meade CJ, Demedts MG, Verleden GM. Epinastine (WAL 801CL) modulates the noncholinergic contraction in guinea-pig airways in vitro by a prejunctional 5-HT1-like receptor. Eur. Respir. J. 1996; 9:1433–8. 21. Stone RA, Worsdell Y-M, Fuller RW, Barnes PJ. Effects of 5hydroxytryptamine and 5-hydroxytryptophan infusions on the human cough reflex. J. Appl. Physiol. 1993; 74:396–401. 22. Lechin F, van der Dijs B, Orozco B, Lechin M, Lechin AE. Increased levels of free serotonin in plasma of symptomatic asthmatic patients. Ann. Allergy Asthma Immunol. 1996; 77:245–53. 23. Cazzola M, Assogna G, Lucchetti G, Cicchitto G, D’Amato G. Effect of ketanserin, a new blocking agent of the 5-HT2 receptor, on airway responsiveness in asthma. Allergy 1990; 45:151–3.
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Chapter
Nitric Oxide
32
Aaron Deykin Pulmonary Division, Brigham and Women’s Hospital, Boston, MA, USA
Sergei A. Kharitonov National Heart and Lung Institute, Imperial College, London, UK
Until the latter part of the 1980s nitric oxide (NO) was perceived to have a health-related role only as a by-product of the combustion of fossil fuels and its subsequent contribution to air pollution. This view was significantly altered in 1987 when it was discovered that this free radical was the previously uncharacterized endothelial-derived relaxing factor.1,2 At the present time, it has become clear that NO plays a central role in the physiology and pathophysiology of many human organ systems, including the respiratory tract. Within the respiratory system, NO promotes vascular and bronchial dilation, is a key mediator of the coordinated beating of ciliated epithelial cells, promotes mucus secretion, and is an important neurotransmitter for nonadrenergic, noncholinergic neurons which run in the bronchial wall.3–9 Additionally, NO is a mediator of inflammatory phenomena within the lung by virtue of its ability to influence the phenotype of inflammatory cells and its contribution to the formation of reactive nitrogen products.10–14 Given its wide distribution within the lung and airway, it is not surprising that NO can be detected in exhaled gas in levels that we now know vary in health and disease. This chapter reviews the formation of NO, the technical aspects of its measurement, and its role in the pathobiology of asthma and chronic obstructive pulmonary disease (COPD).
ⴙ
H2N NH
ⴙ
In vivo, NO is formed by the action of one of the isoforms of the enzyme nitric oxide synthase (NOS, EC1.13.13.39). These enzymes, in the presence of molecular oxygen and nicotinamide adanine dinucleotide phosphate (NADPH), catalyze the oxidation of the guanido nitrogen moiety of Larginine, resulting in the formation of L-citrulline and NO (Fig. 32.1). Flavin mononucleotide (FMN), flavin-adanine dinucleotide (FAD), tetrahydrobiopterin, and heme are other cofactors necessary for this reaction.16–19 Three isoforms of this enzyme are known to exist, and these have been characterized according to a number of classification schemes: a system based on their pattern of activity (inducible or constitutively active), one based on the
ⴚ
COO H3N L-arginine O2 1NADPH H2N
H4 biopterin
N-OH NH
NOS THIOL FAD FMN
ⴙ
ⴚ
H3N
COO
Nω-OH-L-Arginine 0.5 NADPH H2N
H2 biopterin O
NH
NO
THIOL RS-NO S-nitrosothiol
ⴙ
F O R M AT I O N O F N I T R I C O X I D E
NH2
ⴚ
COO H 3N L-citrulline Nitric oxide Fig. 32.1. Enzymatic formation of nitric oxide by NOS. Reproduced from reference 15, with permission.
requirement for calcium, and another based on the initial cellular site of identification (neural tissue, inflammatory cells, vascular endothelium). More recently, these isoforms have been cloned and mapped to distinct regions of the human genome; the current and most widely accepted nomenclature identifies them on this basis as type I, type II, and type III NOS.20,21 Table 32.1 indicates the relationship among the various designations. Types I and III NOS were originally identified as constitutively present in brain and vascular endothelium, respectively. In contrast, type II is
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Table 32.1. Characteristics of the three nitric oxide synthase (NOS) isoforms
Enzyme designation
Gene designation
Chromosomal location and gene size (kbp)
Cell type where first identified
Regulated by Ca2 flux
Type I (ncNOS) Type II (iNOS) Type III (ecNOS)
nos1 nos2 nos3
12q (100) 17cen-q (37) 7q (21)
Nerve Macrophage Vascular endothelium
Yes No Yes
normally not expressed (or expressed in very low levels) in most tissues but can be induced in inflammatory, endothelial, epithelial, and smooth muscle cells. Regulation of NOS isoforms The isoforms of NOS are regulated by distinct mechanisms. The constitutive isoforms, types I and III NOS, require free calcium and calmodulin in order to produce NO.22,23 This activity is potentially regulated by calcium-sensitive protein kinases that have the capacity to phosphorylate the NOS isoenzymes.24 Factors that can influence intracellular calcium concentration, and thus rapidly change NO formation by types I and III NOS, include excitatory amino acids, electrical stimulation, bradykinin, leukotrienes, platelet-activating factor, and lipopolysaccarides.16,25 Additional regulation of type I NOS activity occurs through the genetic variation of NOS I. In contrast to types I and III, type II NOS binds calmodulin so avidly that its activity is independent of calcium fluxes within the physiological range and is dependent on transcriptional induction by cytokines and other immunological stimuli, including TNF-a, IL1-b, and INF-c.26–28 Corticosteroids inhibit the transcription of type II NOS message and decrease type II NOS activity, probably through known NF-jB sites in the 5-flanking region of the iNOS gene.29 While there are no clearly established posttranscriptional regulatory mechanisms for type II NOS, additional regulation of this enzyme, as well as of the type I and III isoforms, likely occurs via cytokine induction of GTP-cyclohydrolase, the rate limiting enzyme in the synthesis of biopterin.30 Detailed reviews of these aspects of NOS regulation have recently been published.21,31–33 Cellular distribution of NOS Each of the three isoforms of NOS has the potential to contribute NO gas to the expirate, since all three are distributed widely throughout the airways of humans and other mammals. Schmidt et al.34 used an antibody specific for rat type I NOS to demonstrate the presence of this NOS isoform in rat airway epithelial cells. Similarly, Kobzik et al.35 documented cNOS (i.e. type I or type III) epithelial staining in rat airways. Subsequently, other groups have demonstrated low levels of calcium-independent NOS activity (i.e. type II) and patchy type II NOS immunostaining in rat airway epithelium and inflammatory cells.36–38
A similar distribution of NOS within the normal human airway has been documented by several investigative groups, including the authors’ own, using immunohistochemical techniques or in-situ hybridization.39–44 In addition, Kobzik et al.35 observed type II NOS in vascular endothelium and in alveolar macrophages obtained from regions of the lung with airway inflammation. Rosbe et al.45 used similar immunohistochemical techniques to demonstrate strong staining for type II NOS, but no staining with a nonspecific type I–III antibody in human nasal epithelium, an anatomical compartment characterized by high NO levels. These findings indicate that, within the human airway, all three isoforms of NOS are present and can generate NO that may contribute to that recovered in the expirate. The cellular locations of the various NOS isoforms in the lung are summarized in Table 32.2. Nonenzymatic formation of NO The amount of NO in exhaled air is not a direct measure of NOS activity in the lower respiratory tract. NO reacts with thiol-containing molecules, such as cysteine and glutathione, to form S-nitrosoproteins and S-nitrosothiols.50 Approximately 70–90% of NO is released by Snitrosothiols, which therefore provide a major source of NO in tissues.51 S-nitrosothiols are potent relaxants of human airways and may play an important role in sequestration, releasing, and transportation of NO to the site of action.50 Table 32.2. Pulmonary cellular location of the three NOS isoforms
NOS Cellular location isoform
References
Type I
Bronchial submucosal nerves
35
Type II
Bronchial epithelieal cells Alveolar macrophages Nasal vascular endothelial cells Nasal ciliated epithelial cells
8,35,41,46 35,44,47,48 49 45,49
Type III Pulmonary vascular endothelium Bronchial epithelium Nasal epithelium Nasal vascular endothelium
35,40 40 49 49
Nitric Oxide
Nitric oxide in exhaled air may also be derived from nitrite protonation to form nitrous acid which releases NO gas with acidification.52 This pH-related pathway has been implicated in acute asthma which is associated with low pH in expired condensate.53
309
A specific role for NO in allergic disorders is suggested by the finding that it may promote the preferential proliferation of Th2 lymphocytes (over Th1 lymphocytes) and thus foster overproduction of IL-4 and IL-5, a condition which is associated with asthma.60 An additional permissive effect on the Th2 phenotype is further suggested by data indicating that NO inhibits apoptosis of eosinophils in vitro.61
P R O I N F L A M M AT O RY P R O P E R T I E S O F NITRIC OXIDE In addition to its role as a homeostatic molecule, NO functions in a proinflammatory capacity within the lung (Fig. 32.2). For example, alveolar macrophages synthesize NO after stimulation by endotoxin and cytokines, and there is considerable evidence that this elaboration of NO is integral to host defense.10,38,54 In addition, through its role as a vasodilator, NO has been shown in an animal model to be a potent mediator of neurogenic edema.4,5 In this regard, NO has the potential to worsen airflow obstruction directly and to facilitate the migration of inflammatory cells to the airway. A direct toxic role for NO in airway disease is supported by the fact that NO is easily oxidized in biological systems to peroxynitrite (OONO-). This potent epithelial toxin is found in increased concentrations in the asthmatic airway following allergen exposure.55–58 Furthermore, peroxynitrite has been shown to enhance airway hyperresponsiveness and eosinophil activation in a rodent model.59 Therefore, NO generated in the lung may directly propagate the epithelial damage which characterizes severe asthma and other airway diseases.
Pulmonary NO sources Inflammatory cells Macrophages Eosinophils Mast cells Airway epithelium Vascular endothelium NANC nerves
NO•
Deleterious NO effects Formation of peroxynitrite Airway epithelial toxicity Airway hyperresponsiveness Increased microvascular leak Increased mucus secretion Inhibition of Th1 lymphocytes Reduced eosinophil apoptosis Fig. 32.2. The proinflammatory properties of NO include formation of peroxynitrite, promotion of vascular leak, mucus production, and expression of Th2-like phenotype.
MEASUREMENT OF NITRIC OXIDE IN T H E E X P I R AT E In 1991, Gustafsson et al.62 first reported NO concentrations in the range of 3–20 parts per billion (ppb) in the expirate of animals and humans using the technique of chemiluminescence analysis.62 This measures NO concentration in the gas phase by reacting NO in the sample with ozone, producing nitrogen dioxide in an excited state. As nitrogen dioxide moves to a lower energy state, photons are emitted in a stochiometric relationship with the amount of NO present in the gas sample. The preponderance of reports found in the literature use chemiluminescence to measure expired NO concentrations; additional studies have used gas chromatography and mass spectroscopy to confirm that the molecule detected by chemiluminescence is in fact NO.63 In general, expired gas is collected for NO determinations using either an “on-line” or an “off-line” technique: • The on-line technique involves sampling gas from a subject exhaling into tubing connected directly to the NO analyzer. • Off-line measurements refer to collection where the expirate is collected into a reservoir such as a NOimpermeable Mylar balloon. This reservoir is sealed and subsequently transported to the analyzer for NO measurement. Whichever technique is used, the expiratory flow rate must be controlled, as NO levels vary inversely with expiratory flow.64 In addition, the resistance of the expiratory limb of the circuit must be such that the subject develops an orapharnygeal pressure of 5 cmH2O; at this pressure the vellum is closed, preventing contamination of the expirate with high NO gas derived from the nasopharynx.65 Standards for the collection and measurement of exhaled NO have been published.66,67
NITRIC OXIDE IN ASTHMA Many investigative groups have demonstrated that asthmatic individuals have higher exhaled NO concentrations than those encountered in normals; this finding has been confirmed using both on-line and off-line techniques. For example, Kharitonov et al.68 demonstrated peak expired NO levels of 283 16 ppb in asthmatics, compared with 101 7 ppb in nonasthmatic controls.68 Similarly,
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Massaro et al.69 reported mixed fraction of expired nitric oxide (FENO) of 13.9 1.7 ppb in nonsteroid-treated asthmatic subjects, in contrast to 6.2 0.6 ppb in controls (Fig. 32.3). It appears that the elevated FENO encountered in asthma is not simply related to bronchial tone per se, since neither bronchoconstriction (with methacholine or histamine) nor bronchodilation with a short-acting b-agonist produce significant changes in FENO.69–71 The subsequent observation that the elevated FENO in asthma is reduced by the administration of corticosteroids suggests that exhaled NO levels may reflect ongoing airway inflammation, potentially mediated by induction of type II NOS by proinflammatory cytokines.46,68,69,72,73 This widely held hypothesis is supported by the observation that FENO is elevated following other inflammatory stimuli such as inhalation of allergen or cold, dry air and the occurrence of viral upper respiratory infection.74,75 Further evidence for a relationship between airway inflammation in asthma and FENO is the finding reported by Jatakanon et al.76 that FENO correlates with the numbers of eosinophils in induced sputum (Fig. 32.4). Indeed, elevations in FENO have been reported to discriminate asthmatics from nonasthmatics in a population of individuals with chronic cough.77 In this way, elevated FENO may be considered part of the usual asthmatic phenotype.
70 Subjects tested (%)
50
60 50 40 30
40 30 20 r 0.48 P 0.003
10 0 0
5
10 15 Sputum eosinophils (%)
20
Fig 32.4. In asthmatic subjects not being treated with inhaled corticosteroids, mixed expired NO content is closely correlated with the percentage of eosinophils in induced sputum. Reproduced from reference 76, with permission.
50 Changes in exhaled NO (ppb)
The role of exhaled NO in asthma monitoring Exhaled NO has been used to monitor the effect of corticosteroid treatment in asthma72,78 and asthma exacerbations, both spontaneous69 and induced by steroid reduction.73,79 Notably, FENO is extremely sensitive to steroid treatment; it is significantly reduced 6 hours following a single administration of a nebulized corticosteroid, or within several days after inhaled corticosteroids (Fig. 32.5).72,80 This reduction appears to be maximal after 2–4 weeks of treatment.72,73,81–85
The ability of corticosteroids to suppress FENO has been suggested to allow titration of these medicines to the lowest effective dose as changes in FENO parallel improvement in asthma symptoms during inhaled corticosteroid treatment in mild-to-moderate asthma.85 In contrast, another study indicated that doses of inhaled steroids that reduced FENO in moderate asthma were not sufficient to reduce sputum eosinophils or to improve asthma symptoms.82 However, Jatakanon et al.79 have reported that exhaled NO levels were increased by 40% and 100% after 2 and 4 weeks, respectively, following a reduction in inhaled corticosteroid treatment. This increase in exhaled NO levels was accompanied by worsened lung function and asthma symptoms. In this study, the baseline high number of eosinophils in sputum of patients who eventually
Exhaled NO (ppb)
310
25 Placebo 0
25
20 10 0 0–3 4–6 7–9 10–12 13–15 >16 Mixed expired NO concentration (ppb)
Fig. 32.3. Distribution of mixed expired NO in a group of 90 nonsmoking normal subjects (light bars, 58 female; age range 19–65) and 43 patients with asthma (dark bars, 27 female; age range 20–88). The mean mixed expired NO content in the normal subjects was 6.2 0.6 ppb ( SEM) which was significantly less than the mean mixed expired NO content in the patients with asthma, 13.9 1.7 ppb (P 0.001). Reproduced from reference 69, with permission.
*
50
*
0
1
2
7
14
*
1600 µg budesonide
21
Days Fig. 32.5. In subjects with mild asthma, treatment with budesonide 1600 lg/day reduces mixed expired NO content within one week. *P 0.05 vs baseline and placebo. Reproduced from reference 72, with permission.
311
Nitric Oxide
Alternative sources of NO in asthma It is important to note that several lines of evidence challenge the view that the elevated FENO in asthma is solely the result of type II NOS induction by airway cytokines. First, Deykin et al.74 have shown that, after allergen challenge, the relative rise in FENO (as compared to sham challenge) occurs within 15 minutes of allergen inhalation; this time course is too brief to account for induction of transcription and translation of the type II NOS gene product and suggests that a constitutively active NOS (type I or III, or perhaps an atypical, constitutively active type II) may be important. In addition, De Sanctis et al.86 have reported that in mice lacking functional nos1, expired NO is 40% lower than that in wild-type animals.86 In humans, Wechsler has demonstrated that asthmatic individuals homozygous for NOS I alleles with large numbers of a specific intronic trinucleotide repeat have a lower FENO than asthmatics with the wild-type allele. This finding suggests that the type I NOS gene product, or the product of a gene linked to this locus, influences the levels of exhaled NO in asthmatics.86a Finally, it has recently been suggested that a large portion of the FENO encountered in asthma may be the result of nonenzymatic formation of NO occurring in the acid milieu of the asthmatic airway.
NITRIC OXIDE IN COPD Exhaled NO levels in stable COPD and chronic bronchitis are lower than in either smoking or nonsmoking asthmatics and are not different from in normal subjects.87–91 This relative reduction in exhaled NO may be due to the effect of tobacco smoking, which has been shown to downregulate NOS and reduce exhaled NO.91–93 In addition to the effects of cigarette smoking, a relatively low value of exhaled NO in COPD may reflect alternative sites of inflammation as compared to asthma, low NOS type II expression, and possibly increased oxidative stress that may consume NO in the formation of peroxynitrite.89,94 Patients with unstable COPD, however, have high NO levels compared with stable smokers or ex-smokers with COPD95 (Fig. 32.6). An important factor promoting increased FENO in exacerbated COPD may be the predominance of neutrophilic inflammation encountered in this condition.96
PERSPECTIVES Exhaled nitric oxide is simple to collect and, apart from the expense of the analyzer, relatively easy to quantify. A large
P < 0.0001 P < 0.0001 P < 0.01 Exhaled NO (ppb)
developed exacerbations was a good predictor of asthma deterioration, while the change in eosinphils following the steroid reduction was a more slowly responsive marker. Long-term serial studies of exhaled NO, together with other markers of airway inflammation in sputum, lung function, and symptoms are under way.
30
P < 0.02 P < 0.01
20
P < 0.05 10 0
Normal smokers
Stable COPD
Unstable COPD
with chronic Smoking Ex-smoking bronchitis Fig 32.6. Mixed expired NO content is higher in subjects with COPD than in subjects with chronic bronchitis and no airflow obstruction. Exacerbation of COPD is associated with a further increase in FENO. Active smoking has an independent suppressive effect on FENO. Reproduced from reference 95, with permission.
body of evidence confirms that NO is produced enzymatically in the airways at higher levels in subjects with asthma than in normals, and that reductions in these levels correlate with clinical improvements induced by anti-inflammatory therapy. The precise inflammatory pathways and cells, NOS enzyme isoforms, and anatomical compartments responsible for production of the NO captured in the expirate are areas of active investigation. In addition, the role of nonenzymatically formed NO in asthma has just begun to be explored. Nonetheless, it is possible that once the technical aspects of ambulatory NO assessment are simplified, measurement of this molecule will have a role in routine asthma monitoring.
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51. Sheu FS, Zhu W, Fung PC. Direct observation of trapping and release of nitric oxide by glutathione and cysteine with electron paramagnetic resonance spectroscopy. Biophys. J. 2000; 78:1216–26. 52. Klebanoff SJ. Reactive nitrogen intermediates and antimicrobial activity: role of nitrite. Free Radic. Biol. Med. 1993; 14:351–60. 53. Hunt JF, Fang K, Malik R et al. Endogenous airway acidification. Implication for asthma pathophysiology. Am. J. Respir. Crit. Care Med. 2000; 161(3 Pt 1):694–9. 54. Robbins RA, Springall DR, Warren JB et al. Inducible nitric oxide synthase is increased in murine lung epithelial cells by cytokine stimulation. Biochem. Biophys. Res. Commun. 1994; 198:835–43. 55. Calhoun WJ, Reed HE, Moest DR et al. Enhanced superoxide production by alveolar macrophages and air-space cells, airway inflammation, and alveolar macrophage density changes after segmental antigen bronchoprovocation in allergic subjects. Am. Rev. Respir. Dis. 1992; 145(2 Pt 1):317–25. 56. Brunelli L, Crow JP, Beckman JS.The comparative toxicity of nitric oxide and peroxynitrite to Escherichia coli. Arch. Biochem. Biophys. 1995; 316:327–34. 57. Wizemann TM, Gardner CR, Laskin JD et al. Production of nitric oxide and peroxynitrite in the lung during acute endotoxemia. J. Leukoc. Biol. 1994; 56:759–68. 58. Heiss LN, Lancaster JR, Corbett JA et al. Epithelial autotoxicity of nitric oxide: role in the respiratory cytopathology of pertussis. Proc. Natl Acad. Sci. USA 1994; 91:267–70. 59. Sadeghi-Hashjin G, Folkerts G, Henricks PA et al. Peroxynitrite induces airway hyperresponsiveness in guinea pigs in vitro and in vivo. Am. J. Respir. Crit. Care Med. 1996; 153:1697–701. 60. Barnes PJ, Liew FY. Nitric oxide and asthmatic inflammation. Immunol.Today 1995; 16(3):128–30. 61. Hebestreit H, Dibbert B, Balatti I et al. Disruption of fas receptor signaling by nitric oxide in eosinophils. J. Exp. Med. 1998; 187:416–25. 62. Gustafsson LE, Leone AM, Persson MG et al. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem. Biophys. Res. Commun. 1991; 181:852–7. 63. Leone AM, Gustafsson LE, Francis PL et al. Nitric oxide is present in exhaled breath in humans: direct GC-MS confirmation. Biochem. Biophys. Res. Commun. 1994; 201:883–7. 64. Silkoff PE, McClean PA, Slutsky AS et al. Marked flowdependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide. Am. J. Respir. Crit. Care Med. 1997; 155:260–7. 65. Kharitonov SA, Barnes PJ. Nasal contribution to exhaled nitric oxide during exhalation against resistance or during breath holding. Thorax 1997; 52:540–4. 66. Kharitonov S, Alving K, Barnes PJ. Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force. Eur. Respir. J. 1997; 10:1683–93. 67. Recommendation for the standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children. Am. J. Respir. Crit. Care Med. 1999; 160:2104–17. 68. Kharitonov SA,Yates D, Robbins RA et al. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343:133–5. 69. Massaro AF, Gaston B, Kita D et al. Expired nitric oxide levels during treatment of acute asthma. Am. J. Respir. Crit. Care Med. 1995; 152:800–3. 70. Garnier P, Fajac I, Dessanges JF et al. Exhaled nitric oxide during acute changes of airways calibre in asthma. Eur. Respir. J. 1996; 9:1134–8. 71. Deykin A, Belostotsky O, Hong C et al. Exhaled nitric oxide following leukotriene E4 and methacholine inhalation in patients with asthma. Am. J. Respir. Crit. Care Med. 2000; 162:2043–7. 72. Kharitonov SA, Yates DH, Barnes PJ. Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am. J. Respir. Crit. Care Med. 1996; 153:454–7.
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73. Kharitonov SA,Yates DH, Chung KF et al. Changes in the dose of inhaled steroid affect exhaled nitric oxide levels in asthmatic patients. Eur. Respir. J. 1996; 9:196–201. 74. Deykin A, Halpern O, Massaro AF et al. Expired nitric oxide after bronchoprovocation and repeated spirometry in patients with asthma. Am. J. Respir. Crit. Care Med. 1998; 157:769–75. 75. Kharitonov SA, Yates D, Barnes PJ. Increased nitric oxide in exhaled air of normal human subjects with upper respiratory tract infections. Eur. Respir. J. 1995; 8:295–7. 76. Jatakanon A, Lim S, Kharitonov SA et al. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 1998; 53:91–5. 77. Chatkin JM, Ansarin K, Silkoff PE et al. Exhaled nitric oxide as a noninvasive assessment of chronic cough. Am. J. Crit. Care Med. 1999; 159:1810–13. 78. Gustafsson LE. Exhaled nitric oxide as a marker in asthma. Eur. Respir. J. 1998; 26:49S–52S. 79. Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am. J. Respir. Crit. Care Med. 2000; 161:64–72. 80. Kharitonov SA, Barnes PJ, O’Connor BJ. Reduction in exhaled nitric oxide after a single dose of nebulized budesonide in patients with asthma. Am. J. Respir. Crit. Care Med. 1996; 153:A799. 81. Lim S, Jatakanon A, John M et al. Effect of inhaled budesonide on lung function and airway inflammation: assessment by various inflammatory markers in mild asthma. Am. J. Respir. Crit. Care Med. 1999; 159:22–30. 82. Jatakanon A, Kharitonov S, Lim S et al. Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Thorax 1999; 54:108–14. 83. van Rensen EL, Straathof KC, Veselic-Charvat MA et al. Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Thorax 1999; 54:403–8. 84. Silkoff PE, McClean PA, Slutsky AS et al. Exhaled nitric oxide and bronchial reactivity during and after inhaled beclomethasone in mild asthma. J. Asthma 1998; 35:473–9. 85. Kharitonov SA, Donnelly LE, Corradi M et al. Dose-dependent onset and duration of action of 100/400 mcg budesonide on exhaled nitric oxide and related changes in other potential markers of airway inflammation in mild asthma. Am. J. Respir. Crit. Care Med. 2000; 161:A186. 86. De Sanctis GT, Mehta S, Kobzik L et al. Contribution of type I (neuronal) nitric oxide (NO) synthase to expired gas NO and bronchial responsiveness in mice. Am. J. Physiol. Lung Cell Mol. Physiol. 1997; 17:L883–8. 86a. Wechsler ME, Grasemann H, Deykin A et al. Exhaled nitric oxide in patients with asthma: association with NOS1 genotype. Am. J. Respir. Crit. Care Med. 2000; 162(6):2043–7. 87. Kharitonov SA, Robbins RA, Yates D et al. Acute and chronic effects of cigarette smoking on exhaled nitric oxide. Am. J. Respir. Crit. Care Med. 1995; 152:609–12. 88. Robbins RA, Floreani AA, Von Essen SG et al. Measurement of exhaled nitric oxide by three different techniques. Am. J. Respir. Crit. Care Med. 1996; 153:1631–5. 89. Rutgers SR, van der Mark TW, Coers W et al. Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease. Thorax 1999; 54:576–80. 90. Von Essen SG, Scheppers LA, Robbins RA et al. Respiratory tract inflammation in swine confinement workers studied using induced sputum and exhaled nitric oxide. J.Toxicol. Clin.Toxicol. 1998; 36:557–65. 91. Verleden GM, Dupont LJ, Verpeut AC et al. The effect of cigarette smoking on exhaled nitric oxide in mild steroid-naive asthmatics. Chest 1999; 116:59–64.
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92. Su Y, Han W, Giraldo C et al. Effect of cigarette smoke extract on nitric oxide synthase in pulmonary artery endothelial cells. Am. J. Respir. Cell Mol. Biol. 1998; 19:819–25. 93. Robbins RA, Millatmal T, Lassi K et al. Smoking cessation is associated with an increase in exhaled nitric oxide. Chest 1997; 112:313–18. 94. Eiserich JP, Hristova M, Cross CE et al. Formation of nitric oxidederived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 1998; 391:393–7.
95. MaziakW, Loukides S, Culpitt S et al. Exhaled nitric oxide in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 157(3 Pt 1):998–1002. 96. Kanazawa H, Shoji S, Yoshikawa T et al. Increased production of endogenous nitric oxide in patients with bronchial asthma and chronic obstructive pulmonary disease. Clin. Exp. Allergy 1998; 28:1244–50.
Transcription Factors
Chapter
33
Ian M. Adcock and Gaetano Caramori National Heart & Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
INTRODUCTION Inflammation is a central feature of asthma and chronic obstructive pulmonary disease (COPD). The specific characteristics of the inflammatory response in each disease and the site of inflammation differ, but both involve the recruitment and activation of inflammatory cells and changes in the structural cells of the lung. Asthma and COPD are characterized by an increased expression of components of the inflammatory cascade. These inflammatory proteins include cytokines, chemokines, growth factors, enzymes, receptors, and adhesion molecules.1 The increased expression of these proteins seen in asthma and COPD is the result of enhanced gene transcription since many of the genes are not expressed in normal cells but are induced in a cell-specific manner during the inflammatory process. Changes in gene transcription are regulated by transcription factors, which are proteins that bind to DNA and modulate the transcriptional apparatus. Transcription factors regulate the expression of many genes, including inflammatory genes, and may play a key role in the pathogenesis of asthma and COPD since they regulate the increased gene expression that may underlie the acute and chronic inflammatory mechanisms that characterize these diseases.2 Transcription factors may amplify and perpetuate the inflammatory process, so it is possible that abnormal functioning of transcription factors may determine disease severity and response to treatment. The increased understanding of the role of transcription factors in the pathogenesis of asthma and COPD has also opened an opportunity for the development of new potential anti-inflammatory drugs. Several new compounds based on interacting with specific transcription factors or their activation pathways are now in development for the treatment of asthma and COPD, and some drugs already in clinical use (such as glucocorticoids) are thought to work via transcription factors. Glucocorticoids are effective therapy in the long-term control of asthma. One of their mechanisms of action in asthmatic airways is by inhibiting the action of transcription factors that regulate inflammatory gene expression.3 Glucocorticoids may also have a beneficial effect in COPD during
exacerbations, although this is less marked than in asthma, indicating that different genes and transcription factors are involved and emphasizing the importance of cell-specific transcription factors. One concern about this approach is the specificity of such drugs, but it is clear that transcription factors have selective effects on the expression of certain genes and this may make it possible to be more selective. In addition, there are cellspecific transcription factors that may be targeted for inhibition, which could provide selectivity of drug action. One such example is GATA-3, which has been reported to have a restricted cellular distribution.4 In asthma it may be possible to target drugs to the airways by inhalation, as is currently done for inhaled glucocorticoids, to systemic effects. Despite the fact that many transcription factors have now been discovered there is still a paucity of data concerning the regulation of transcription factors in the human lungs. This chapter briefly reviews the physiological function of the transcription factors in the normal cells and the role of some transcription factors that may be relevant in the pathogenesis of asthma and COPD.
T R A N S C R I P T I O N FA C T O R S Transcription factors are proteins that bind to DNAregulatory sequences (enhancers and silencers), usually localized in the 5 upstream region of target genes, to modulate the rate of gene transcription. This may result in increased or decreased gene transcription, protein synthesis, and subsequent altered cellular function. Many transcription factors have now been identified and a large proportion of the human genome appears to code for these proteins. Several families of transcription factors exist and members of each family may share structural characteristics. These families include: • helix-turn-helix (e.g. Oct-1), • helix-loop-helix (e.g. E2A), • zinc finger (e.g. glucocorticoid receptors, GATA proteins),
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• basic protein-leucine zipper (cyclic AMP response element binding factor [CREB], activator protein-1 (AP-1]) • b-sheet motifs (e.g. nuclear factor-jB [NF-jB]).5 (Table 33.1). Many transcription factors are common to several cell types (ubiquitous), such as AP-1 and NF-jB, and may play a general role in the regulation of inflammatory genes, whereas others are cell-specific and may determine the phenotypic characteristics of a cell. Transcription factor activation is complex and may involve multiple intracellular signal transduction pathways, including the kinases PKA, MAPKs, JAKs, and PKCs, stimulated by cell-surface receptors.6 Transcription factors may also be directly activated by ligands such as glucocorticoids and vitamins A and D. Transcription factors may therefore convert transient environmental signals at the cell surface into long-term changes in gene transcription, thus acting as “nuclear messengers”. Transcription factors may be activated within the nucleus, often with the transcription factor already bound to DNA, or within the cytoplasm, resulting in exposure of nuclear localization signals and targeting to the nucleus.3 Cross-talk One of the most important concepts to have emerged is the demonstration that transcription factors may physically interact with each other to form homodimers or heterodimers, resulting in inhibition or enhancement of transcriptional activity at a site distinct from the consensus target for a particular transcription factor (Fig. 33.1). This then allows cross-talk between different signal transduction pathways at the level of gene expression. Generally it is necessary to have coincident activation of several transcription factors in order to have maximal gene expression. This may explain how transcription factors that are ubiquitous may regulate particular genes in certain types of cells. The complexity of the activation pathways and their ability to engage in cross-talk enables cells to overcome inhibition of one pathway and retain a capacity to activate specific transcription factors. This cross-talk and redundancy may Table 33.1. Transcription factor families involved in the pathogenesis of asthma and COPD
GR NF-jB AP-1 CREB STATs
NF-ATs GATA HIF-1 C/EBP SP-1
GR, glucocorticoids receptor; NF-jB, nuclear factor-kappa B; AP-1, activator protein 1; CREB, cyclic AMP response element binding protein; STATs, signal transducers and activators of transcription; NF-ATs, nuclear factors of activated T cells (NF-AT); GATA, GATA binding proteins; HIF-1, hypoxiainducible factor-1.
also hinder the search for novel anti-inflammatory agents targeted towards transcription factor activation. Binding of transcription factors to their specific binding motifs in the promoter region may alter transcription by interacting directly with components of the basal transcription apparatus or via cofactors that link the transcription factor to the basal transcription apparatus.7 Large proteins that bind to the basal transcription apparatus bind many transcription factors and thus act as integrators of gene transcription. These coactivator molecules include CREB-binding protein (CBP), and the related p300, thus allowing complex interactions between different signaling pathways. Histone acetylation DNA is wound around histone proteins to form nucleosomes and the chromatin fiber in chromosomes.8 It has long been recognized at a microscopic level that chromatin may become dense or opaque owing to the winding or unwinding of DNA around the histone core.9 CBP, p300, and other coactivators have histone acetylase activity (HAT) which is activated by the binding of transcription factors, such as AP-1, NF-jB and STATs (Fig. 33.2). Acetylation of histone residues results in unwinding of DNA coiled around the histone core, thus opening up the chromatin structure, allowing increased transcription. Histone deacetylation by specific histone deacetylases (HDACs) reverses this process, leading to gene repression.8
T R A N S C R I P T I O N FA C T O R S I N A S T H M A Asthma is a complex chronic inflammatory disease of the airways that involves the activation of many inflammatory and structural cells, all of which release inflammatory mediators that result in the typical clinico-pathological changes of asthma. The chronic airway inflammation of asthma is unique in that the airway wall is infiltrated by T lymphocytes of the T-helper (Th) type 2 phenotype, eosinophils, macrophages/monocytes, and mast cells. In addition, an “acute-on-chronic” inflammation may be observed during exacerbations, with an increase in eosinophils and sometimes also neutrophils. The role of transcription factors in differentiation of Th1/Th2 cells CD4 T-helper (Th) cells can be divided into three major subsets, termed Th1, Th2, and Th0 based on the pattern of cytokines they produce.10 Th1 cells produce predominantly IL-2 and interferon gamma (IFN-c) and predominantly promote cell-mediated immune responses. Th2 cells, which produce mainly interleukins (IL-4, IL-5, and IL-13), augment certain B cell responses. IL-4 in particular is the major inducer of B cell switching to immunoglobulin E production, and therefore plays a crucial role in allergic reactions involving IgE and mast cells. Th cells producing cytokines typical of both Th1 and Th2 clones have also been described and they have been named Th0.
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Fig. 33.1. Multiple pathways mediating transcription factor modulation of inflammatory genes. (a) Inflammatory mediator signal transduction activation. The binding of cytokines, growth factors, or chemokines to their respective receptors sets in train the activation of a number of signal transduction pathways, including the receptor tyrosine kinases, mitogen-activated protein kinases (MAPKs including MEKK1 and JNK), Janus kinases (JAKs), and other kinase pathways involved in NF-jB activation. Activation of nuclear factor-jB involves phosphorylation of the inhibitory protein IjB by specific kinase(s), with subsequent ubiquitination and proteolytic degradation by the proteasome. The free NF-jB then translocates to the nucleus, where it binds to jB sites in the promoter regions of inflammatory genes. Activation of the IjB gene results in increased synthesis of IjB to terminate the activation NF-jB. (b) JAK–STAT pathways. Cytokine binding to its receptor results in activation of Janus kinases (JAK) which phosphorylate intracellular domains of the receptor, resulting in phosphorylation of signal transduction-activated transcription factors (STATs). Activated STATs dimerise and translocate to the nucleus where they bind to recognition elements on certain genes. (c,d) Nuclear factor of activated T cells (NF-AT) is activated via dephosphorylation by calcineurin and translocates to the nucleus where it interacts with AP-1 to induce gene transcription. (e) Classical mechanism of steroid action. Glucocorticoids are lipophilic molecules which diffuse readily through cell membranes to interact with cytoplasmic receptors. Upon ligand binding receptors are activated and translocate into the nucleus where they bind to specific DNA elements. The foregoing pathways can interact so that the final signal may be amplified or altered depending upon the exact combination of stimuli. The final response to each stimulus or combination of stimuli by a particular cell depends upon the receptors present in a particular cell along with the exact intracellular transduction pathway activated.
Evidence indicates that Th1 and Th2 cells differentiate from a common precursor, naive T cells. This appears to be a multistep process, in which naive T cells pass through an intermediate stage (Th0) at which both Th1 and Th2 cytokines are produced (Fig. 33.3). Recent evidence suggests that many transcription factors, including GATA3 and STAT6, are involved in the molecular mechanisms by which Th1 and Th2 cells differentially express the Th1 and Th2 cytokines.11,12 However, most of these studies were conducted on murine T cells, and the situation in human T cells, in physiological and pathological conditions (e.g. bronchial asthma) remain largely unknown. Determination of asthma severity Activation of NF-jB leads to the coordinated induction of multiple genes that are expressed in inflammatory and immune responses. Many of these genes are induced in inflammatory and structural cells and play an important role in the inflammatory process.
NF-jB While NF-jB is not the only transcription factor involved in regulation of the expression of these genes, it often appears to have a decisive regulatory role. NF-jB often functions in cooperation with other transcription factors, such as AP-1 and C/EBP, which are also involved in regulation of inflammatory and immune genes.13 Genes induced by NF-jB include those for the proinflammatory cytokines IL-1b, TNF-a, and GM-CSF and the chemokines IL-8, macrophage inflammatory protein-1a (MIP-1a), macrophage chemotactic protein-1 (MCP-1), RANTES, and eotaxins, that are largely responsible for attracting inflammatory cells into sites of inflammation.5 NF-jB also regulates the expression of inflammatory enzymes, including the inducible form of nitric oxide synthase (NOS2) that produces large amounts of NO. NF-jB also plays an important role in regulating expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), that are expressed on
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IFN-γ
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IL-4R Fig. 33.2. Histone acetylation by proinflammatory transcription factors. In response to stress and other stimuli, such as cytokines, various second messenger systems are upregulated, leading to activation of signaldependent transcription factors (TF) such as CREB, NF-jB, AP-1, and STAT proteins. Binding of these factors leads to recruitment of CBP and/or other coactivators to signal-dependent promoters and acetylation of histones by an intrinsic acetylase activity (HAT). Induction of histone acetylation allows the formation of a more loosely packed nucleosome structure which enables access to TATA-box binding protein (TBP) and associated factors (TAFs) and the recruitment of further remodeling factors including switch/sucrose nonfermentable (SWI/SNF). Remodeling thereby allows RNA polymerase II recruitment and the activation of inflammatory gene transcription.
endothelial and epithelial cells at inflammatory sites and play a key role in the initial recruitment of inflammatory cells.5 Recent data have also suggested that NF-jB may be activated by many of the stimuli that exacerbate asthmatic inflammation (e.g rhinovirus infection, allergen exposure, proinflammatory cytokines, oxidants).14–17 There is also evidence for activation of NF-jB in bronchial epithelial cells of patients with asthma.18 NF-jB is an amplifying and perpetuating mechanism that exaggerates the disease-specific inflammatory process through the coordinated activation of multiple inflammatory genes. AP-1 AP-1 is a collection of related transcription factors belonging to the Fos (c-Fos, FosB) and Jun (c-Jun, JunB, JunD) families which dimerise in various combinations through their leucine zipper region. Fos/Jun form heterodimers with high affinity and are the predominant form of AP-1 in most cells, whereas Jun/Jun homodimers bind with low affinity and are less abundant.19 AP-1 may be activated by various cytokines, including TNF-a and IL-1b, via several types of protein tyrosine kinase (PTK) and mitogenactivated protein (MAP) kinases, which themselves activate a cascade of intracellular kinases.6 AP-1, like NF-jB, regulates many of the inflammatory and immune genes that are overexpressed in asthma. Indeed many of these genes require the simultaneous activation of both transcription factors that work together cooperatively. There is evidence for increased expression of c-Fos in bronchial epithelial cells
c-Maf GATA3 STAT6 NFATc
Th2 cell
IL-4, 5, 6, 9, 10, 13 Fig. 33.3. Differentiation of T cell subtypes depends upon the action of a number of transcription factors. Th0 cells can differentiate into Th1 and Th2 cells following IL-12 or IL-4 stimulation. Stimulation through the IL-12 receptor (IL-12) activates the transcription factor STAT4 and the MAPK pathways JNK2 and p38 and drives Th1 cell differentiation, leading to cells capable of releasing IFN-c. In contrast, activation of the IL4R in concert with T cell receptor (TCR) stimulation leads to activation of the transcription factors STAT6, GATA3, c-Maf, and NFATc, and drives Th2 cell differentiation. Th2 cells can release a number of cytokines including interleukins 4, 5, 6, 9, 10, and 13. In addition, activation of JNK1, NFATp, and NFAT4 can prevent Th2 cell differentiation.
in asthmatic airways,20 and many of the stimuli relevant to asthma that activate NF-jB will also activate AP-1. STATs STAT6 also provides a target as a potential treatment for allergic asthma. STAT6 knockout mice have no response to IL-4, do not develop Th2 cells in response to IL-4, and fail to produce IgE, bronchial hyperresponsiveness or bronchoalveolar lavage eosinophilia after allergen sensitization indicating the critical role of STAT6 in allergic responses.21 At present there are no published data detailing the expression of STAT6 in asthma or COPD, but evidence does exist for enhanced expression of STAT1 in the airways of asthmatic, but not COPD, subjects.22 Sp1 is a ubiquitous transcription factor that binds to GCboxes and related motifs, which are frequently occurring DNA-elements present in many promoters and enhancers. Modification of these sites within the IL-10 and IL-4 and the 5-lipoxygenase promoters has been associated with altered expression of these genes in distinct patient groups.23–26 Transcription factors and glucocorticoid action Glucocorticoids belong to the family of nuclear steroid hormone receptors and are important anti-inflammatory agents used in the treatment of chronic inflammatory diseases such as asthma.27 Functionally they act by suppressing airway
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hyper-responsiveness, reducing airway edema and the infiltration of inflammatory cells from the blood to the airway and thereby reducing the airway inflammatory response.28 Glucocorticoid receptors (GR) are predominantly localized to the airway epithelium, alveolar macrophages and endothelium,29 which are, therefore, probably important sites for the anti-inflammatory action of steroids, especially those delivered by the inhaled route. Airway epithelial cells act as important regulators of the inflammatory reaction, responding to various inflammatory mediators, such as cytokines, by the production of a wide range of cytokines, chemokines, and other inflammatory mediators.30 Glucocorticoids bind to and activate a cytosolic receptor (GR) which then translocates to the nucleus. Within the nucleus two GR subunits form a dimer and bind to specific DNA elements (GREs) in the promoter regions of glucocorticoid responsive genes, resulting in modulation of transcription.31 Several genes are upregulated by glucocorticoids, including the b2-receptor and serum leukoprotease inhibitor (SLPI). However, in inflammation the major role of glucocorticoids appears to be gene repression. Evidence accumulated over the past few years has suggested that a major mechanism of glucocorticoids is repression of the actions of AP-1 and NF-jB.32 It has recently been reported that the activated GR is able to inhibit AP-1 mediated transcription through an effect on reducing CBP activity.33 It is now clear that a major action of glucocorticoids is to inhibit histone H4 acetylation on lysine 8 and 12 induced by IL-1b and TNF-a for example. This is achieved by a direct inhibition of CBP-associated histone acetylation and by recruitment of histone deacetylases (HDACs) to the activated complex34 (Fig. 33.4). Of interest is that oxidative stress that modulates HDAC activity is able to markedly alter glucocorticoid responsiveness,35 and targeting of these enzymes may provide another novel target for future drug discovery. A very small number of asthmatic patients are steroidresistant and fail to respond to even high doses of oral glucocorticoids (so called steroid-resistant asthma). This defect is also present in their peripheral blood mononuclear cells (PBMCs) and T lymphocytes.36 Although ligand binding data show no change in GR number in these patients, immunohistochemistry indicates a reduced GR nuclear translocation which may account for the reduced binding to DNA seen in these patients.37 Altered nuclear translocation is affected by GR phosphorylation status,38 which may also be a target for long-acting b-agonists.39 In the same patients there is a reduced inhibitory effect of glucocorticoids on AP-1 activation, but not on NF-jB. Furthermore, there is an increase in the baseline activity of AP-1 which appears to be due to excessive activation of JUN N-terminal kinase (JNK).40,41 This resistance will be seen at the site of inflammation where AP-1 is activated but not at uninflamed sites. This may explain why patients with steroid-resistant asthma are not resistant to the endocrine and metabolic effects of glucocorticoids, and thus develop the drug’s systemic side-effects.
CBP
ⴚ
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ex
pl
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Nucleosomes Fig. 33.4. The actions of the dexamethasone/GR complex on inhibition of IL-1b-stimulated histone acetylation. DNA-bound p65 induces histone acetylation via activation of CBP and a CBP-associated HAT complex to occur. This causes local unwinding of DNA and increased gene transcription. GR, acting as a monomer, interacts with CBP causing an inhibition of CBP-mediated HAT activity. In addition, GR also recruits HDAC2 to the p65/CBP complex, further reducing local HAT activity, leading to enhanced nucleosome compaction and repression of transcription.
T R A N S C R I P T I O N FA C T O R S I N C O P D In contrast to the enormous increase in our understanding of the pathogenesis of asthma, little is known about the molecular pathogenesis of COPD.42 Transcription factors and disease susceptibility The etiology of COPD appears to be due to interactions between environmental factors (particularly cigarette smoking) and genetic factors. Chronic heavy cigarette smoking is currently the cause of more than 90% of cases of COPD in Westernized countries, so environmental factors are clearly very important. However it is important to identify the factors that determine why only 15–20% of chronic heavy cigarette smokers develop symptomatic COPD. So far, this is little understood, although it is likely that genetic factors are important. There is convincing evidence that several genes influence the development of COPD. In a complex polygenic disease such as COPD, it is likely that multiple genes are operating and that the influence of each gene in isolation may be relatively weak. The susceptibility to develop COPD with smoking is likely to depend on the coincidence of several gene polymorphisms that act together. The only clearly established, but rare, genetic risk factor for COPD is a1-antitrypsin deficiency (a1-AT). Approximately 95% of cases of clinical a1-AT deficiency are caused by a single amino acid substitution at position 342 (lysine for glutamic acid) in the coding region of the a1-AT gene (Z allele). This genotype is uncommon, but a Taq1 polymorphism in the 3-flanking region of the a1-AT gene has been reported to be present in 18% of COPD patients but in only 5% of the general population in the United
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Kingdom.43 Although this mutation is not associated with an abnormal a1-AT protein expression, this genetic variant is within an enhancer sequence (which contains C/EBP binding sites) and may impair the acute-phase increase in a1-AT gene expression in response to IL-6.44 Transcription factors and clinical manifestations of COPD The chronic airflow obstruction in tobacco smoking-related COPD results from a combination of airway disease, which particularly affects small airways, and loss of lung elasticity because of destruction of the lung parenchyma.The modulation of the inflammatory response in COPD by genetic factors associated to transcription factors may be in part the cause of the different clinical phenotypes of the patients with COPD. Recently it has been suggested that in patients with COPD and symptoms of chronic bronchitis there is an increased prevalence of a common polymorphism in the 5-flanking region of theTNF-a gene, which was previously found to be associated with high baseline and induced TNF-a expression.45 It is tempting to speculate that, despite the relationship between structural remodeling of the pulmonary artery walls and chronic hypoxia not being well understood, it could be linked to the induction or repression of some transcription factors (such as hypoxia-inducible factor-1) in these cell types. COPD is characterized by alveolar destruction and enlarged alveolar spaces. Elegant work by Massaro and colleagues46 has indicated that treatment with all-trans retinoic acid induces septation in both immature and adult animals, offering the possibility of a similar effect in adults. Retinoic acid activates retinoid receptors which function as transcription factors and may interact with other transcription factors.
CONCLUSION In the future the role of transcription factors and the genetic regulation of their expression in asthma and COPD may be an increasingly important aspect of research, as this may be one of the critical mechanisms regulating the expression of clinical phenotypes and their responsiveness to therapy. Despite recent advances in the knowledge of the pathogenesis of asthma and COPD, much more research on the molecular mechanisms of asthma and COPD are needed to aid the logical development of new therapies for these common and important diseases, particularly in COPD where no effective treatments currently exist.
REFERENCES 1. Barnes PJ. Mechanisms in COPD: differences from asthma. Chest 2000; 117:10S–14S. 2. Barnes PJ, Chung KF, Page CP. Inflammatory mediators of asthma: an update. Pharmacol. Rev. 1998; 50:515–96. 3. Adcock IM. Molecular mechanisms of glucocorticosteroid actions. Pulm. Pharmacol.Ther. 2000; 13:115–26.
4. Caramori G, Tomita K, Lim S et al. GATA family of transcription factors in T-cells, monocytes and bronchial biopsies of normal and asthmatic subject. Eur. Respir. J. 2001; 18:466–73. 5. Barnes PJ, Adcock IM. Transcription factors and asthma. Eur. Respir. J. 1998; 12:221–34. 6. Karin M. Mitogen-activated protein kinase cascades as regulators of stress responses. Ann. NY Acad. Sci. 1998; 851:139–46. 7. Janknecht R, Hunter T. Transcription: a growing coactivator network. Nature 1996; 383:22–3. 8. Imhof A, Wolffe AP. Transcription: gene control by targeted histone acetylation. Curr. Biol. 1998; 8:R422–4. 9. Allfrey VG, Faulkner R, Mirsky AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl Acad. Sci. USA 1964; 51:786–94. 10. Romagnani S. The Th1/Th2 paradigm. Immunol. Today 1997; 18:263–6. 11. Zheng W, Flavell RA.The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 1997; 89:587–96. 12. Zhang S, Lukacs NW, Lawless VA et al. Cutting edge: differential expression of chemokines in Th1 and Th2 cells is dependent on Stat6 but not Stat4. J. Immunol. 2000; 165:10–14. 13. Baldwin AS. The NF-kappa B and I-kappa B proteins: new discoveries and insights. Annu. Rev. Immunol. 1996; 14:649–83. 14. Papi A, Johnston SL. Respiratory epithelial cell expression of vascular cell adhesion molecule-1 and its up-regulation by rhinovirus infection via NF-kappaB and GATA transcription factors. J. Biol. Chem. 1999; 274:30041–51. 15. Rahman I. Regulation of nuclear factor-kappa B, activator protein1, and glutathione levels by tumor necrosis factor-alpha and dexamethasone in alveolar epithelial cells. Biochem. Pharmacol. 2000; 60:1041–9. 16. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54:825–57. 17. Ten RM, McKinstry MJ, Bren GD, Paya CV. Signal transduction pathways triggered by the Fc-epsilonRIIb receptor (CD23) in human monocytes lead to nuclear factor-kappaB activation. J. Allergy Clin. Immunol. 1999; 104:376–87. 18. Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF. Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am. J. Respir. Crit. Care Med. 1998; 158:1585–92. 19. Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. Phil. Trans. Roy. Soc. Lond. B: Biol. Sci. 1996; 351:127–34. 20. Demoly P, Basset SN, Chanez P et al. c-Fos proto-oncogene expression in bronchial biopsies of asthmatics. Am. J. Respir. Cell Mol. Biol. 1992; 7:128–33. 21. Tomkinson A, Kanehiro A, Rabinovitch N et al. The failure of STAT6-deficient mice to develop airway eosinophilia and airway hyperresponsiveness is overcome by interleukin-5. Am. J. Respir. Crit. Care Med. 1999; 160:1283–91. 22. Sampath D, Castro M, Look DC, Holtzman MJ. Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma. J. Clin. Invest. 1999; 103:1353–61. 23. Hobbs K, Negri J, Klinnert M, Rosenwasser LJ, Borish L. Interleukin-10 and transforming growth factor-beta promoter polymorphisms in allergies and asthma. Am. J. Respir. Crit. Care Med. 1998; 158:1958–62. 24. In KH, Asano K, Beier D et al. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J. Clin. Invest. 1997; 99:1130–7. 25. Lim S, Crawley E,Woo P, Barnes PJ. Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet 1998; 352:113. 26. Burchard EG, Silverman EK, Rosenwasser LJ et al. Association between a sequence variant in the IL-4 gene promoter and
Transcription Factors
27. 28. 29.
30. 31.
32.
33.
34.
35.
36. 37.
FEV(1) in asthma. Am. J. Respir. Crit. Care Med. 1999; 160:919–22. Barnes PJ. Molecular mechanisms of antiasthma therapy. Ann. Med. 1995; 27:531–5. Barnes PJ. Inhaled glucocorticoids for asthma. N. Engl. J. Med. 1995; 332:868–75. Adcock IM, Gilbey T, Gelder CM, Chung KF, Barnes PJ. Glucocorticoid receptor localization in normal and asthmatic lung. Am. J. Respir. Crit. Care Med. 1996; 154:771–82. Levine SJ. Bronchial epithelial cell–cytokine interactions in airway inflammation. J. Investig. Med. 1995; 43:241–9. Truss M, Beato M. Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. Endocr. Rev. 1993; 14:459–79. McEwan IJ, Wright AP, Gustafsson JA. Mechanism of gene expression by the glucocorticoid receptor: role of protein–protein interactions. Bioessays 1997; 19:153–60. Kamei Y, Xu L, Heinzel T et al. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 1996; 85:403–14. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits IL-1b-induced histone H4 acetylation on lysines 8 and 12. Mol. Cell. Biol. 2000; 12:6891–903. Ito K, Lim S, Caramori G et al. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. 2001; 15:1110–12. Adcock IM. Steroid resistance in asthma: molecular mechanisms. Am. J. Respir. Crit. Care Med. 1996; 154:S58–61. Matthews JG, Ito K, Barnes PJ, Adcock IM. Corticosteroidresistant and corticosteroid-dependent asthma: two clinical phenotypes can be associated with the same in-vitro defects in
38.
39.
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41.
42. 43.
44.
45.
46.
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GR nuclear translocation and acetylation of histone H4. Am. J. Respir. Crit. Care Med. 2000; 161, A189. Bodwell JE, Webster JC, Jewell CM et al. Glucocorticoid receptor phosphorylation: overview, function and cell cycle-dependence. J. Steroid Biochem. Mol. Biol. 1998; 65:91–9. Eickelberg O, Roth M, Lorx R et al. Ligand-independent activation of the glucocorticoid receptor by beta2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells. J. Biol. Chem. 1999; 274:1005–10. Lane SJ, Adcock IM, Richards D et al. Corticosteroid-resistant bronchial asthma is associated with increased c-Fos expression in monocytes and T lymphocytes. J. Clin. Invest. 1998; 102:2156–64. Sousa AR, Lane SJ, Soh C, Lee TH. In-vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of JUN N-terminal kinase and failure of prednisolone to inhibit JUN N-terminal kinase phosphorylation. J. Allergy Clin. Immunol. 1999; 104:565–74. Barnes PJ. Chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343:269–80. Kalsheker NA, Morgan K. Regulation of the alpha 1-antitrypsin gene and a disease-associated mutation in a related enhancer sequence. Am. J. Respir. Crit. Care Med. 1994; 150:S183–9. Morgan K, Scobie G, Marsters P, Kalsheker NA. Mutation in an alpha1-antitrypsin enhancer results in an interleukin-6 deficient acute-phase response due to loss of cooperativity between transcription factors. Biochim. Biophys. Acta 1997; 1362:67–76. Huang SL, Su CH, Chang SC. Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis. Am. J. Respir. Crit. Care Med. 1997; 156:1436–9. Massaro GD, Massaro D. Retinoic acid treatment partially rescues failed septation in rats and in mice. Am. J. Physiol. 2000; 278:L955–60.
Neural and Humoral Control
Chapter
34
Peter J. Barnes and Neil C. Thomson National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
Airway nerves and circulating hormones regulate the caliber of the airways and have an influence on airway smooth muscle tone, airway blood flow, and mucus secretion. They may also influence the inflammatory process and play an integral role in host defense.There is increasing evidence that neural and humoral mechanisms may play a role in the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD), and several of the treatments used interact with neural or humoral control.
CHOLINERGIC
ACh
Muscarinic receptors
B/C
NA
α-receptors
B/C?
A
β-receptors
B/D
VIP NO
VIP-receptor Guanylyl cyclase
B/D
SP/NKA
NK-receptor
B/C
ADRENERGIC
NANC
NEURAL CONTROL Overview of airway innervation Neural control of airway function is more complex than previously thought. Many neurotransmitters are now identified and these act on a multitude of autonomic receptors. Three types of airway nerve are recognized: • parasympathetic nerves which primarily release acetylcholine (ACh); • sympathetic nerves which primarily release noradrenaline (norepinephrine); • afferent (sensory nerves) whose primary transmitter may be glutamate. In addition to these classical transmitters, multiple neuropeptides have now been localized to airway nerves and may have potent effects on airway function.1 All of these neurotransmitters act on autonomic receptors that are expressed on the surface of target cells in the airway. It is increasingly recognized that a single transmitter may act on several subtypes of receptor, which may lead to different cellular effects mediated via different second messenger systems. Several neural mechanisms are involved in the regulation of airway caliber, and abnormalities in neural control may contribute to airway narrowing in disease (Fig. 34.1). Neural mechanisms may be involved in the pathophysiology of airway diseases, such as asthma and COPD, contributing to the symptoms and possibly to the inflammatory response.2 There is a close interrelationship between inflam-
Fig. 34.1. Autonomic control of airway smooth muscle tone: neural mechanisms resulting in bronchoconstriction (B/C) and bronchodilatation (B/D). ACh, acetylcholine; NA, noradrenaline; A, adrenaline; VIP, vasoactive intestinal peptide; NO, nitric oxide; i-NANC, inhibitory nonadrenergic noncholinergic nerves; e-NANC, excitatory nonadrenergic noncholinergic nerves; NK, neurokinin.
mation and neural responses in the airways, since inflammatory mediators may influence the release of neurotransmitters via activation of sensory nerves leading to reflex effects, and via stimulation of prejunctional receptors that influence the release of neurotransmitters3 (Fig. 34.2). In turn neural mechanisms may influence the nature of the inflammatory response, either reducing inflammation or exaggerating the inflammatory response. Neural interactions Complex interactions between various components of the autonomic nervous system are now recognized. Adrenergic nerves may modulate cholinergic neurotransmission in the airways, and sensory nerves may influence neurotransmission in parasympathetic ganglia and at postganglionic nerves. This means that changes in the function of one neural pathway may have effects on other pathways. Cotransmission Almost every nerve contains multiple transmitters.Thus airway parasympathetic nerves, in which the primary transmitter is ACh, also contain the neuropeptides vasoactive
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Inflammatory mediators
Inflammatory cells
Airway nerves
Neurotransmitters Neuropeptides Neurogenic inflammation Fig. 34.2. Interaction between airway nerves and inflammatory cells.
intestinal polypeptide (VIP), peptide histidine isoleucine/ methionine (PHI/M), pituitary adenylate cyclase activating peptide (PACAP), helodermin, galanin, and nitric oxide (NO) (Fig. 34.3). These cotransmitters may have either facilitatory or antagonistic effects on target cells, or may influence the release of the primary transmitter via prejunctional receptors. Thus VIP modulates the release of ACh from airway cholinergic nerves. Sympathetic nerves, which release noradrenaline, may also release neuropeptide Y (NPY) and enkephalins, whereas afferent nerves may contain a variety of peptides including substance P (SP), neurokinin A (NKA), calcitonin gene-related peptide (CGRP), galanin, VIP, and cholecystokinin. The physiological role of neurotransmission may be in “fine tuning” of neural control. Neuropeptides may be preferentially released by high-frequency firing of nerves, and
• PARASYMPATHETIC Acetylcholine
• SYMPATHETIC Noradrenaline
• AFFERENT Glutamate
VIP, PHM, PHV PACAP-27 Helospectin, I, II Helodermin Galanin (SP, CGRP)
NPY (Enkephalin)
SP, NKA, NPK CGRP GRP Secretoneurin Galanin? Somatostatin? CCK-8? Nociceptin, endomorphins?
Fig. 34.3. Neurotransmitters and cotransmitters in airway nerves. SP, substance P; NKA, neurokinin A; CGRP, calcitonin gene-related peptide; VIP, vasoactive intestinal peptide; PHI/PHM/PHV, peptide histidine isoleucine/methionine/valine; PACAP, pituitary adenylate cyclase activating peptide; NPY, neuropeptide Y.
their effects may therefore become manifest only under the condition of excessive nerve stimulation. Neuropeptide neurotransmitters may also act on target cells different from the primary transmitter, resulting in different physiological effects. Thus in airways ACh causes bronchoconstriction, but VIP which is coreleased may have its major effect on bronchial vessels, thus increasing blood flow to the airways. In chronic inflammation the role of cotransmitters may be increased by alterations in the expression of their receptors or by increased synthesis of transmitters via increased gene transcription. Afferent nerves The sensory innervation of the respiratory tract is mainly carried in the vagus nerve. The neuronal cell bodies are localized to the nodose and jugular ganglia and input to the solitary tract nucleus in the brain stem. A few sensory fibers supplying the lower airways enter the spinal cord in the upper thoracic sympathetic trunks, but their contribution to respiratory reflexes is minor and it is uncertain whether they are represented in humans. There is a tonic discharge of sensory nerves that has a regulatory effect on respiratory function and also triggers powerful protective reflex mechanisms in response to inhaled noxious agents, physical stimuli, or certain inflammatory mediators. At least three types of afferent fiber have been identified in the lower airways4 (Fig. 34.4). Most of the information on their function has been obtained from studies in anesthetized animals, so it is difficult to know how much of the information can be extrapolated to human airways. Slowly adapting receptors Myelinated fibers associated with smooth muscle of proximal airways are probably slowly adapting (pulmonary stretch) receptors (SAR), that are involved in reflex control of breathing. Activation of SARs reduces efferent vagal discharge and mediates bronchodilatation. During tracheal constriction, the activity of SARs may serve to limit the bronchoconstrictor response.4 SARs may play a role in the
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325
Capsaicin, bradykinin cigarette smoke, SO2, water, hyperosmolar solutions
Mechanical stimuli (bronchocontriction), water, low Cl
Airway epithelium RAR Aδ fiber
NP release SP, NKA, CGRP
Airway smooth muscle
C fiber
Bronchial vessel
Cough Cholinergic reflex
SAR Fig. 34.4. Afferent nerves in airways. Slowly adapting receptors (SAR) are found in airway smooth muscle, whereas rapidly adapting myelinated (RAR) and unmyelinated C fibers are present in the airway mucosa.
cough reflex since, when these receptors are destroyed by exposure to high concentration of SO2, the cough response to mechanical stimulation is lost. Rapidly adapting receptors Myelinated fibers in the epithelium, particularly at the branching points of proximal airways, show rapid adaptation. Rapidly adapting receptors (RAR) account for 10–30% of the myelinated nerve endings in the airways. These endings are sensitive to mechanical stimulation and to mediators such as histamine. The response of RARs to histamine is partly due to mechanical distortion consequent on bronchoconstriction, although if this is prevented by pretreatment with isoprenaline the RAR response is not abolished, indicating a direct stimulatory effect of histamine. It is likely that mechanical distortion of the airway may amplify irritant receptor discharge. RARs with widespread arborizations are very numerous in the area of the carina, where they have been termed “cough receptors” as cough can be evoked by even the slightest touch in this region. RARs respond to inhaled cigarette smoke, ozone, serotonin, and prostaglandin F2a, although it is possible that these responses are secondary to the mechanical distortion produced by the bronchoconstrictor response to these irritants. Neurophysiological studies using an in-vitro preparation in guinea-pig trachea and bronchi show that a majority of afferent fibers are myelinated and belong to the Ad fiber group. Although these fibers are activated by mechanical stimulation and low pH, they are not sensitive to capsaicin, histamine, or bradykinin.5,6 C fibers There is a high density of unmyelinated (C fibers) in the airways and they greatly outnumber myelinated fibers. In the bronchi, C fibers account for 80–90% of all afferent fibers in cats. C fibers play an important role in the defense of the
lower respiratory tract.7 C fibers contain neuropeptides, including SP, NKA, and CGRP, that confer a motor function on these nerves.8 Bronchial C fibers are insensitive to lung inflation and deflation, but typically respond to chemical stimulation. In-vivo studies suggest that bronchial C fibers in dogs respond to the inflammatory mediators histamine, bradykinin, serotonin, and prostaglandins.7 They are selectively stimulated by capsaicin given either intravenously or by inhalation, and are also stimulated by SO2 and cigarette smoke. Since these fibers are relatively unaffected by lung mechanics, it is likely that these agents act directly on the unmyelinated endings in the airway epithelium. In the in-vitro guinea-pig trachea preparation, C fibers are stimulated by capsaicin and by bradykinin, but not by histamine, serotonin, or prostaglandins (with the possible exception of prostacyclin).5 Both RARs and C fibers are sensitive to water and hyperosmotic solutions, with RARs showing a greater sensitivity to hypotonic and C fibers to hypertonic saline. In the in-vitro guinea-pig trachea preparation, Ad fibers and C fibers are stimulated by water and by hyperosmolar solutions; a small proportion of Ad fibers are also stimulated by low-chloride solutions, whereas the majority of C fibers are.9 Cough Cough is an important defense reflex, which may be triggered from either laryngeal or lower airway afferents.10 There is debate about which are the most important afferents for initiation of cough and this may be dependent on the stimulus. Thus RARs are activated by mechanical stimuli (e.g. particulate matter), bronchoconstrictors, and hypotonic saline and water, whereas C fibers are more sensitive to hypertonic solutions, bradykinin, and capsaicin. In normal humans, inhaled capsaicin is a potent tussive stimulus and this is associated with a transient bronchoconstrictor reflex that is abolished by an anticholinergic drug. It is not certain whether this is due to stimulation of C fibers in the larynx,
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but as these are very sparse it is likely that bronchial C fibers are also involved. Citric acid is commonly used to stimulate coughing in experimental challenges in human subjects; it is likely that it produces cough by a combination of low pH (which stimulates C fibers) and low chloride (which may stimulate laryngeal and lower airway afferents). Inhaled bradykinin causes coughing and a raw sensation retrosternally which may be due to stimulation of C fibers in the lower airways. Bradykinin appears to be a relatively pure stimulant of C fibers.5 Prostaglandins E2 and F2a are potent tussive agents in humans and also sensitize the cough reflex.11,12 Afferent nerves in airway disease Airway afferent nerves may become sensitized in inflammatory airway diseases, resulting in increased symptoms, such as cough and chest tightness (Fig. 34.5). Cough is a prominent symptom of asthma and COPD, and there is evidence that cough sensitivity is increased.13 This may be due to sensitization of afferent nerves in the airways as a result of inflammatory mediators produced during asthma and COPD. PGE2 is a potent sensitizer of airway sensory nerves and is increased in asthma and COPD. Bradykinin is also a potent afferent nerve sensitizer.6 Chronic inflammation may lead to neural hyperesthesia through mechanisms that may involve cytokines and neurotrophins.14 Neurotrophins, such as nerve growth factor and ciliary neurotrophic factor, may result in proliferation of airway sensory nerves and a change in the nerve phenotype, with a reduced threshold of activation and increased expression of neuropeptides.15 The role of neurotrophins in airway diseases has not yet been explored.16
Cholinergic nerves Cholinergic nerves are the major neural bronchoconstrictor mechanism in human airway, and are the major determinant of airway caliber. Cholinergic control of airways Cholinergic nerve fibers arise in the nucleus ambiguous in the brain stem and travel down the vagus nerve and synapse in parasympathetic ganglia which are located within the airway wall. From these ganglia, short postganglionic fibers travel to airway smooth muscle and submucosal glands (Fig. 34.6). In animals, electrical stimulation of the vagus nerve causes release of ACh from cholinergic nerve terminals, with activation of muscarinic cholinergic receptors on smooth muscle and gland cells, which results in bronchoconstriction and mucus secretion. Prior administration of a muscarinic receptor antagonist, such as atropine, prevents vagally induced bronchoconstriction. A novel aspect of cholinergic control is the demonstration that human airway epithelial cells may release Ach as a result of upregulation of choline acetyltransferase in response to inflammatory stimuli.17 The contribution of extraneuronal ACh to cholinergic responses in the airways is currently unknown. Muscarinic receptors Of the five know subtypes of muscarinic receptor, four have been identified by binding studies and pharmacologically in lung.18 The muscarinic receptors that mediate bronchoconstriction in human and animal airways belong to the M3receptor subtype, whereas mucus secretion appears to be mediated by M1 and M3 receptors. M1 receptors are also
INFLAMMATION
Prostaglandins PGE2, PGI2
Cytokines IL-1β, TNF-α
Neurotrophins NGF, CNTF, BDNF
Bradykinin B1, B2 receptors
H
Activation Sensitization
Symptoms Cough Chest tightness
C fiber Aδ fiber
Neurogenic inflammation
SP, CGRP Fig. 34.5. Airway hyperesthesia. Increased sensitivity of airway nerves induced by inflammation as a result of sensitization and activation of airway sensory nerves, resulting in increased symptoms and possibly neurogenic inflammation through the release of neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP).
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Neural and Humoral Control
CNS Nodose ganglion Vagus nerve Laryngeal and esophageal afferents
Parasympathetic nerve ACh C fiber A fiber
Parasympathetic ganglion Inflammatory cell
C fiber receptors Irritant receptors
Submucosal gland
ACh
ACh Mediators
Airway epithelium
Irritants (e.g. cigarette smoke) Fig. 34.6. Cholinergic control of airway smooth muscle. Preganglionic and postganglionic parasympathetic nerves release acetylcholine (ACh) and can be activated by airway and extrapulmonary afferent nerves.
localized to parasympathetic ganglia, where they facilitate the neurotransmission mediated via nicotinic receptors (Fig. 34.7). Inhibitory muscarinic receptors (autoreceptors) have been demonstrated on cholinergic nerves of airways in animals in vivo, and in human bronchi in vitro.19 These prejunctional receptors inhibit ACh release and may serve to limit vagal bronchoconstriction. Autoreceptors in human airways belong to the M2 receptor subtype, whereas those on airway smooth muscle and glands belong to the M3 receptor subtype.20 Drugs such as atropine and ipratropium bromide, which block both prejunctional M2 receptors and postjunctional M3 receptors on smooth muscle with equal efficacy, therefore increase ACh release which may then overcome the postjunctional blockade.This means that such drugs will not be as effective against vagal bronchoconstriction as against cholinergic agonists, and it may be necessary to reevaluate the contribution of cholinergic nerves when drugs which are selective for the M3 receptors are developed for clinical use. The presence of muscarinic autoreceptors has been demonstrated in human subjects in vivo.21 A cholinergic agonist, pilocarpine, which selectively activates M2 receptors, inhibits cholinergic reflex bronchoconstriction induced by sulfur dioxide in normal subjects; such an inhibitory mechanism does not appear to operate in asthmatic subjects, suggesting that there may be dysfunction of these
autoreceptors. Such a defect in muscarinic autoreceptors may then result in exaggerated cholinergic reflexes in asthma, since the normal feedback inhibition of ACh release may be lost. This might also explain the sometimes catastrophic
Preganglionic nerve
Parasympathetic ganglion
ACh
N (+) M1 (+)
M2 ()
Postganglionic nerve ACh
Airway smooth muscle
M3 ()
Fig. 34.7. Muscarinic receptor subtypes in the airways. Acetylcholine (ACh) from preganglionic vagal nerves activates nicotinic receptors (N) and may be facilitated by M1 receptors. ACh release from preganglionic nerves activates M3 receptors on airway smooth muscle and feeds back to activate prejunctional M2 receptors (autoreceptors) which inhibit further ACh release.
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Asthma and Chronic Obstructive Pulmonary Disease
bronchoconstriction which occurs with P-blockers in asthma which, at least in mild asthmatics, appears to be mediated by cholinergic pathways.^^ Antagonism of inhibitory P-receptors on cholinergic nerves would result in increased release of ACh which could not be switched off in the asthmatic patient (Fig. 34.8). This explains why anticholinergics prevent P-blocker-induced asthma. The mechanisms which lead to dysfunction of prejunctional M2 receptors in asthmatic airways are not certain, but it is possible that M j receptors may be more susceptible to damage by oxidants or other products of the inflammatory response in the airways. Experimental studies have demonstrated that influenza virus infection and eosinophils in guinea-pigs may result in a selective loss of M2 receptors compared with M3 receptors, resulting in a loss of autoreceptor function and enhanced cholinergic bronchoconstriction. Cholinergic innervation is greatest in large airways and diminishes peripherally, although in humans muscarinic receptors are localized to airway smooth muscle in all airways.^^ In humans, studies which have tried to distinguish large and small airway effects have shown that cholinergic bronchoconstriction predominantly involves larger airways, whereas P-agonists are equally effective in large and small airways. This relative diminution of cholinergic control in small airways may have important clinical implications, since anticholinergic drugs are likely to be less useful than P-agonists when bronchoconstriction involves small airways. Normal human subjects also have resting bronchomotor tone, since atropine causes bronchodilatation. Cholinergic reflexes A wide variety of stimuli are able to elicit reflex cholinergic bronchoconstriction through activation of sensory receptors in the larynx or lower airways. Activation of cholinergic reflexes may result in bronchoconstriction and an increase in airway mucus secretion through the activation of muscarinic receptors on airway smooth muscle cells and sub-
NORMAL Vagus —H nerve ^
0i
0
1 1 1 1 1
Vagal "tone" 1 1 1 1 1 1 1 1 1
ANTICHOLINERGIC 1 1 1 1 1 1
COPD
JL ACh
1
V^
U
Resistance oc1/r''
Fig. 34.8. Cholinergic control of airways in COPD. The normal vagal cholinergic tone has a greater effect in COPD airways because of the geometric relationship between airway diameter and resistance, so that anticholinergics are effective bronchodilators in COPD.
mucosal glands. Cholinergic reflexes may also be activated from extrapulmonary afferents and these reflexes may also contribute to airway defenses. Esophageal reflux may be associated with bronchoconstriction in asthmatic patients. In some patients this may be due to aspiration of acid into the airways; in other cases, acid reflux into the esophagus activates a reflex cholinergic bronchoconstriction (the "reflux reflex") ?'^ Modulation of cholinergic neurotransmission Many agonists may modulate cholinergic neurotransmission via prejunctional receptors on postganglionic nerves.^ Some receptors increase (facilitate), whereas others inhibit, the release of ACh. Inflammatory mediators may influence cholinergic neurotransmission via prejunctional receptors. For example, thromboxane and prostaglandin (PG)D2 facilitate ACh release from postganglionic nerves in the airways. Facilitation may also occur at parasympathetic ganglia in the airways; these structures are surrounded by inflammatory cells and have an afferent neural input. Electrophysiological recordings show a prolonged potentiation of neurotransmission in ganglia after allergen exposure in sensitized guinea-pigs.^^ The role of cholinergic nerves in asthma Many of the stimuli which produce bronchospasm in asthma activate sensory nerves and reflex bronchoconstriction in animals, so it was logical to suggest that asthma may be due to exaggerated cholinergic reflex mechanisms. There is some evidence that cholinergic tone is increased in asthmatic airways. There are several mechanisms by which cholinergic tone might be increased in asthma. An increase in cholinergic tone could arise via several mechanisms: •
There may be increased afferent receptor stimulation by inflammatory mediators, such as histamine or prostaglandins, which may be released from mast cells and other inflammatory cells in the asthmatic airway or from bradykinin formed from precursors in exuded plasma. • There may be increased release of ACh from cholinergic nerve terminals by an action on cholinergic nerve endings themselves, or by an increase in nerve traffic through cholinergic ganglia (the local airway reflex).^ • There may be abnormal muscarinic receptor expression, either via an increase in M3 receptors or reduction in M j receptors. There is no evidence for increased Mj or M3 receptor expression in asthmatic lungs,^* but there is functional evidence for a defect in M j receptor function that may be secondary to the inflammatory process, as discussed above. • There may be a decrease in the neuromodulators (VIP, NO) that have a "braking" effect on neurotransmission (see below). The effect of ACh on asthmatic airways is exaggerated, as a manifestation of nonspecific hyperresponsiveness of the
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Neural and Humoral Control
airways which is so characteristic of asthma. However, asthmatic airways are hyperresponsive to many spasmogens in addition to ACh; mediators such as histamine, leukotrienes, and prostaglandins have a direct contractile effect on bronchial smooth muscle which is not blocked by anticholinergic drugs. Anticholinergic agents will only counteract the cholinergic reflex component of bronchoconstriction, which may be less prominent in human airways than animal studies have indicated. By contrast, b2-agonists reverse bronchoconstriction irrespective of the mechanism, since they act as functional antagonists. In patients with chronic asthma which has been poorly controlled, there is a progressive decline in lung function over the years,27 which presumably results from chronic inflammation. Vagal tone increases the airway narrowing further, and for geometric reasons will have a greater effect on airway resistance in narrowed airways. This may explain why anticholinergics are often of greater use in chronic asthmatics with a major element of fixed airway obstruction. The role of cholinergic nerves in COPD The structural narrowing of the airways in COPD means that even normal vagal tone will exert a greater effect on airway caliber than in normal airways (Fig. 34.9). This may account for the efficacy of anticholinergics as bronchodilators in COPD, as cholinergic tone is the only reversible element. In addition, cholinergic mechanisms may account for the mucus hypersecretion of chronic bronchitis. Adrenergic control The airways are also under adrenergic control, which includes sympathetic nerves (which release noradrenaline), circulating catecholamines (predominantly adrenaline – see below) and a- and b-adrenoceptors (Fig. 34.10). The fact that b-adrenergic antagonists cause bronchoconstriction in asthmatic patients, but not in normal individuals, suggests that adrenergic control of airway smooth muscle may be abnormal in asthma.
Sympathetic innervation Although sympathetic bronchodilator nerves have been demonstrated in several species, including cats, dogs, and guinea-pigs, most evidence suggests that adrenergic nerves do not control human airway smooth muscle directly. Sympathetic nerves may, however, influence cholinergic tone of airway smooth muscle via adrenoceptors localized to parasympathetic ganglia and prejunctionally on postganglionic nerves.3 Sympathetic nerves may also play an important role in the regulation of airway blood flow and in mucus secretion. Beta-adrenoceptors Beta-adrenoceptors regulate many aspects of airway function, including airway smooth muscle tone, mast cell mediator release, and plasma exudation.28 The possibility that b-receptors are abnormal in asthma has been extensively investigated.The suggestion that there is a primary defect in ß-receptor function in asthma has not been substantiated; any defect in b-receptors is likely to be secondary to the disease, perhaps as a result of inflammation or as a consequence of adrenergic therapy. Some studies have demonstrated that airways from asthmatic patients fail to relax normally to isoprenaline, suggesting a possible defect in b-receptor function in airway smooth muscle.29 Whether this is due to a reduction in b-receptors, a defect in receptor coupling, or some abnormality in the biochemical pathways leading to relaxation, is not yet known, although the density of b-receptors in airway smooth muscle appears to be normal30 and there is no reduction in the density of b1- or b2-receptors in asthmatic lung, either at the receptor or mRNA level.26 There is some evidence that proinflammatory cytokines may affect b2-receptor function. IL-1b reduces the bronchodilator effect of isoprenaline in vitro and in vivo, and this appears to be due to uncoupling of b2-receptors due to increased expression of the inhibitory G protein, Gi.31,32 However, studies of b2-receptor expression in asthmatic airways obtained by biopsy have demonstrated only small defects in coupling after local allergen challenge.33
Normal
Asthma
Adrenaline
Adrenaline
β-blocker β2
Cholinergic nerve
M2
β-blocker
No effect
ACh
ACh
Bronchoconstriction
M3 Autoreceptor dysfunction
Cholinergic hyperresponsiveness
Fig. 34.9. Possible mechanism of b-blocker-induced asthma. Blockade of prejunctional b2 receptors on cholinergic nerves in normal individuals results in increased release of acetylcholine (ACh), but this is compensated by stimulation of prejunctional muscarinic M2 receptors to inhibit any increase in ACh. In patients with asthma prejunctional M2 receptors are dysfunctional, so that there is a net release of ACh, and ACh also has a greater bronchoconstrictor effect on the airways due to airway hyperresponsiveness.
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Asthma and Chronic Obstructive Pulmonary Disease
M3 receptors β2 receptors α receptors
CNS
Sympathetic ganglion
Vagus nerve
Parasympathetic nerve Sympathetic nerve NA
Adrenal medulla
NA
A
Parasympathetic ganglion NA
Bronchial vessel
ACh
Airway smooth muscle
Fig. 34.10. Adrenergic control of airway smooth muscle. Sympathetic nerves release noradrenaline (NA), which may modulate cholinergic nerves at the level of the parasympathetic ganglion or postganglionic nerves, rather than directly at smooth muscle in human airways. Circulating adrenaline (A) is more likely to be important in adrenergic control of airway smooth muscle.
Alpha-adrenoceptors Alpha-receptors which mediate bronchoconstriction have been demonstrated in airways of several species, and may only be demonstrated under certain experimental conditions. There is now considerable doubt about the role of a-receptors in the regulation of tone in human airways, however, since it has proved difficult to demonstrate their presence functionally or by autoradiography,34 and a-blocking drugs do not appear to be effective as bronchodilators. It is possible that a-receptors may play an important role in regulating airway blood flow, which may indirectly influence airway responsiveness, and there is some evidence that aagonists may reduce airway narrowing in exercise-induced asthma.35 NANC nerves and neuropeptides Neural responses that are not blocked by a combination of adrenergic and cholinergic antagonists are known as nonadrenergic noncholinergic (NANC) nerves. These NANC responses appear to be due to the release of neurotransmitters from classical autonomic nerves, which include neuropeptides, nitric oxide (NO), and adenosine triphosphate (ATP). In the airways both inhibitory NANC (bronchodilator) and excitatory NANC (bronchoconstrictor) nerves have been described. i-NANC nerves i-NANC nerves which mediate bronchodilatation have been described in many species, including humans, in whom they are of particular importance in the absence of any direct sympathetic innervation of airway smooth muscle.36 The
neurotransmitter for these nerves in some species, including guinea-pigs and cats, is vasoactive intestinal polypeptide (VIP) and related peptides. The i-NANC bronchodilator response is blocked by a-chymotrypsin, an enzyme which very efficiently degrades VIP, and by antibodies to VIP. However, although VIP is present in human airways and VIP is a potent bronchodilator of human airways in vitro, there is no evidence that VIP is involved in neurotransmission of iNANC responses in human airways, and a-chymotrypsin that completely blocks the response to exogenous VIP has no effect on neural bronchodilator responses.37 It is likely that VIP and related peptides may be more important in neural vasodilatation responses and may result on increased blood flow to bronchoconstricted airways. The predominant neurotransmitter of human airways is NO. Nitric oxide synthase inhibitors, such as NG-L-arginine methyl ester, virtually abolish the i-NANC response.38 This effect is more marked in proximal airways, consistent with the demonstration that nitrergic innervation is greatest in proximal airways. Nitric oxide appears to be a cotransmitter with ACh, and it acts as a “braking” mechanism for the cholinergic system by acting as a functional antagonist to ACh at airway smooth muscle39 (Fig. 34.11). Airway neuropeptides Many neuropeptides are localized to sensory, parasympathetic, and sympathetic neurones in the human respiratory tract. These peptides have potent effects on bronchomotor tone, airway secretions, the bronchial circulation, and inflammatory and immune cells.1 Although the precise physiological roles of each peptide are not yet fully
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Neural and Humoral Control
Normal
Inflammation Cholinergic
ACh NO
ⴚ
Cholinergic
NO EFS
iNANC
Bronchoconstriction ONOO
Parasympathetic nerve
EFS
ACh
Airway smooth muscle cell
O2
Inflammatory cells Fig. 34.11. Nitric oxide (NO) and vasoactive intestinal peptide (VIP) may modulate cholinergic neural effects mediated via acetylcholine (ACh). In inflammation, NO may be removed by superoxide anions (O2) generated from inflammatory cells and VIP by mast cell tryptase, therefore diminishing their “braking” effects, resulting in exaggerated cholinergic bronchoconstriction.
understood, clues are provided by their localization and functional effects. Recently the development of specific neuropeptide receptor antagonists has provided important new insights into the roles of these neurotransmitters. Many of the inflammatory and functional effects of neuropeptides are relevant to asthma, and there is compelling evidence for the involvement of neuropeptides in the pathophysiology and symptomatology of asthma and COPD. Although classically neuropeptides are released from autonomic nerves, there is increasing evidence that these peptides may be synthesized and released from inflammatory and non-neural structural cells, particularly in disease. Inflammatory cytokines may increase the expression of neuropeptide genes in inflammatory cells, so becoming a major source of the neuropeptide at the inflammatory site. For example, both VIP and substance P have been localized to human eosinophils, and substance P to macrophages.40,41 Neuropeptides and airway inflammation Neuropeptides have multiple inflammatory and immune effects on the airways, thereby intensifying the ongoing inflammation.42 In turn, inflammatory mediators may amplify or sometimes dampen neuropeptide effects. Inflammatory mediators may increase the release of neuropeptides from sensory and other nerves, may increase the expression of neuropeptide genes in neural and inflammatory cells, may increase the expression of neuropeptide receptors, and may decrease the degradation of neuropeptides (Fig. 34.12). Vasoactive intestinal peptide and related peptides VIP-immunoreactive nerves are widely distributed throughout the respiratory tract in humans, and there is also evidence for the presence of several closely related peptides (peptide histidine methionine, peptide histidine valine, helodermin, helospectins I and II, and pituitary adenylate cyclase activating peptides [PACAP-38 and PACAP-27]) which have
similar functional effects. VIP may be localized to parasympathetic and sensory nerves. It is a potent vasodilator, a bronchodilator, increases mucus secretion, and may have anti-inflammatory effects. In some species it is a mediator of neurogenic bronchodilatation, but this is not the case in human airways. A defect inVIP has been proposed in asthma but there is little evidence to support this contention.43 Tachykinins Substance P (SP) and neurokinin A (NKA), but not NKB, are localized to C fibers; they are abundant in rodent airways but are sparse in human airways.44 Tachykinins are also expressed by human macrophages, which also express tachykinin receptors. Tachykinins have many different effects on the airways which may be relevant to asthma, and these effects are mediated via NK1 receptors (preferentially activated by SP) and NK2 receptors (activated by NKA) (Table 34.1). Tachykinins constrict smooth muscle of human airways in vitro via NK2-receptors. Tachykinin receptors are widely distributed in human airways, with localization predominantly to airway smooth muscle, mucus-secreting cells, and bronchial cells.45 NKA causes bronchoconstriction after both intravenous and inhaled administration in asthmatic subjects. Mechanical removal of airway epithelium potentiates the bronchoconstrictor response to tachykinins, largely because the neutral endopeptidase (NEP), which is a key enzyme in the degradation of tachykinins in airways, is strongly expressed on epithelial cells.46 Substance P stimulates mucus secretion from submucosal glands in human airways in vitro and is a potent stimulant to goblet cell secretion in guinea-pig airways via activation of NK1 receptors. NK1 receptors also mediate the increased plasma exudation and the vasodilator response to tachykinins. Tachykinins may also interact with inflammatory and immune cells, although whether this is of pathophysiological
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Asthma and Chronic Obstructive Pulmonary Disease
Eosinophils Epithelial shedding Sensory nerve activation
Plasma exudation Vasodilatation Mucus secretion
Neuropeptide release SP, NKA, CGRP, ...
Bronchoconstriction
Cholinergic activation
Cholinergic facilitation
Fig. 34.12. Axon reflex mechanisms. Possible neurogenic inflammation in asthmatic airways via retrograde release of peptides from sensory nerves via an axon reflex. Substance P (SP) causes vasodilatation, plasma exudation, and mucus secretion, whereas neurokinin A (NKA) causes bronchoconstriction and enhanced cholinergic reflexes and calcitonin gene-related peptide (CGRP) vasodilatation. Table 34.1. Effects of tachykinins on airways
Effect
Neurokinin receptors
Bronchoconstriction (small > large airways) Plasma exudation Bronchial vasodilatation ↑ Neurotransmission (ganglia, cholinergic nerves) Cough (peripheral and central mechanisms) Mucus secretion (submucosal glands and goblet cells) ↑ Adhesion molecules (ICAM-1, E-selectin) Activation of inflammatory cells (macrophages, T lymphocytes, eosinophils) Angiogenesis Fibroblast activation
NK2, NK1 NK1 NK1, NK1, NK1 NK1 NK1, NK1 NK1,
significance remains to be determined.47 Substance P degranulates skin mast cells and eosinophils through a nonreceptor-mediated mechanism. Tachykinins also enhance eosinophil chemotaxis. Tachykinins may activate alveolar macrophages and monocytes to release inflammatory cytokines, such as IL-6. Substance P stimulates proliferation of blood vessels (angiogenesis) and may therefore be involved in the new vessel formation that is found in asthmatic airways. SP and NKA also stimulate the proliferation and chemotaxis of human lung fibroblasts, suggesting that tachykinins may contribute to the fibrotic process in chronic
NK1
NK2, NK3 NK2, NK3
NK2 NK2
asthma.48 Tachykinins also enhance cholinergic neurotransmission by facilitating acetylcholine release at cholinergic nerve terminals and by enhancing ganglionic transmission. Tachykinins are subject to degradation by at least two enzymes, angiotensin converting enzyme (ACE) and NEP. The former is predominantly localized to vascular endothelial cells and therefore degrades intravascular peptides, whereas NEP is important for degrading tachykinins in the airways. The activity of NEP may therefore determine tachykinin responsiveness in the airways (Fig. 34.13). Inhibition of NEP by phosphoramidon or thiorphan markedly
333 potentiates bronchoconstriction in vitro in animal and h u m a n airways, and after inhalation in vivo^'^ The activity of N E P is reduced by mechanical removal of the epithelium, some virus infections, cigarette smoke, and hypertonic saline. Several of the stimuli known to induce bronchoconstrictor responses in asthmatic patients have been found to reduce the activity of airway NEP.^° Calcitonin gene-related peptide CGRP-immunoreactive nerves are abundant in the respiratory tract of several species and are costored and colocalized with SP in afferent nerves. C G R P is a potent vasodilator, which has long-lasting effects and potently dilates bronchial vessels in vitro and in vivo. It is possible that C G R P may be the predominant mediator of arterial vasodilatation and increased blood flow in response to sensory nerve stimulation in the bronchi. C G R P may be an important mediator of airway hyperemia in asthma. C G R P has variable effects on airway smooth muscle tone and appears to act indirectly through the relapse of other constrictors, such as endothelin. Like tachykinins, C G R P is chemotactic for eosinophils. Neurogenic inflammation in airway disease Sensory nerves may be involved in inflammatory responses through the antidromic release of neuropeptides from nociceptive nerves or C fibers via a local (axon) refiex^^ (Fig34.12). The phenomenon is well documented in several organs, including skin, eye, gastrointestinal tract, and bladder.^^ There is increasing evidence that neurogenic inflammation occurs in the respiratory tract and that it may contribute to the inflammatory response in asthma. Neurogenic inflammation has been well documented in the air-
NORMAL
ways of rodents, and there is good evidence that tachykinins contribute to the airway hyperresponsiveness in several animal models of asthma, using capsaicin depletion or specific tachykinin antagonists. However, although it was proposed several years ago that neurogenic inflammation and peptides released from sensory nerves might be important as an amplifying mechanism in asthmatic inflammation, there is little evidence to date to support this idea, despite the extensive work in rodent models. There is some evidence in support of a role for tachykinins in asthma: • An increase in SP-immunoreactive nerves has been described in patients with severe asthma.^^ • Substance P and N K A levels are increased in bronchoalveolar lavage (BAL) fluid of asthmatic patients^^ and in induced sputum of patients with asthma.^^ • There is increased expression of NKj and N K j receptors in asthmatic lungs and airways.^^>^^ • A tachykinin antagonist inhibits bradykinin-induced bronchoconstriction and cough in asthmatic patients.^^ However, there is also evidence against a role for tachykinins: •
SP-immunoreactive nerves are sparse in h u m a n airways and are not increased in lungs and biopsies from asthmatic patients.^^ • Capsaicin has no effect on h u m a n airways in vitro, whereas it potently constricts guinea-pig airways. Similarly, inhaled capsaicin causes cough and transient bronchoconstriction, but not prolonged bronchoconstriction as in rodents.^^
ASTHMA
Shedding Cytokines (IL-1p) Virus infection Cig smoke Hypotonic saline
NEP
C fiber
Postcapillary venule
Airway smooth muscle Fig. 34.13. Neutral endopeptidase and neurogenic inflammation in airways.
Plasma exudation
C fiber
Bronchoconstriction
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Asthma and Chronic Obstructive Pulmonary Disease
• NEP inhibitors have no different effects in patients with asthma than in normal subjects.60 • Tachykinin antagonists that are NK1-selective have so far been found to be ineffective in asthma.61,62 It is possible that it will be important to block NK2 receptors in addition, and several nonselective tachykinin antagonists are now in development. It is possible that some effect might be seen in more severe asthma or in patients with virally induced exacerbations, but such studies have not yet been reported. Neurogenic inflammation may also be important in COPD. SP levels are elevated in induced sputum of patients with COPD.55 Cigarette smoke activates C fibers in airways and may result in mucus hypersecretion and goblet cell discharge,63 and tachykinins are potent stimuli of mucus secretion in human airways.64 Other neuropeptides Several other neuropeptides have been identified in human airways65 (Table 34.2), but their function is even less well defined than the neuropeptides discussed above.
Table 34.2. Neuropeptides in the respiratory tract
Neuropeptide
Localization
Vasoactive intestinal peptide Peptide histidine isoleucine/ methionine Peptide histidine valine-42 Helodermin Helospectins I and II PACAP-27 Galanin
Parasympathetic ( afferent)
Substance P Neurokinin A Neuropeptide K Calcitonin gene-related peptide Gastrin-releasing peptide Secretoneurin? Nociceptin
Afferent (C fibers)
Neuropeptide Y Opioids?
Sympathetic
Somatostatin Enkephalin Afferent/uncertain Endomorphins Cholecystokinin octapeptide
HUMORAL MECHANISMS Airway function can be altered by vasoactive peptides and hormones that reach the lungs from the bloodstream, as well as by neurotransmitters released from nerve endings and by molecules released locally from other cells within the airway.66 Vasoactive peptides Circulating catecholamines Circulating adrenaline (epinephrine) is released from the adrenal medulla into the circulation. It may reduce bronchial smooth muscle tone directly by stimulating b2adrenergic receptors on airway smooth muscle, or indirectly by reducing acetylcholine release from cholinergic nerves. The lack of a bronchoconstrictor effect of b-antagonists in normal subjects suggests that in this group, basal concentrations of circulating adrenaline are probably not important in the regulation of resting bronchomotor tone. In contrast, b2-antagonists cause bronchoconstriction in some asthmatics; in the absence of an important sympathetic nerve supply to airway smooth muscle, this suggests that basal concentrations of circulating adrenaline are important in the maintenance of airway tone. The controlling influence of circulating adrenaline on airway tone might operate particularly in those asthmatic patients in whom resting airway caliber is already reduced. In patients with nonasthmatic COPD, however, b2-antagonists do not normally cause bronchoconstriction. This finding would suggest that basal concentrations of circulating adrenaline are not important in the maintenance of airway tone in COPD. Basal adrenaline concentrations and the circadian variation in adrenaline concentrations in asthmatic patients appear to be similar to those found in normal subjects.67–69 Although Bates et al.70 reported that plasma adrenaline levels at 10 pm were lower in patients with nocturnal asthma than in a non-nocturnal asthma group;70 correction of the nocturnal fall in plasma adrenaline does not alter the peak flow rate values of patients with nocturnal asthma.71 These findings, taken together with the report of nocturnal asthma occurring in a patient after adrenalectomy,72 suggest that a fall in plasma adrenaline at night is not a dominant factor in nocturnal asthma. Adrenaline is not released in response to allergen- or pharmacological-induced bronchoconstriction per se, and so does not appear to have an important homeostatic role in the regulation of airway caliber during bronchoconstriction to these stimuli.73,74 Even during acute exacerbations of asthma there may be no elevation in plasma adrenaline level,75,76 although very high adrenaline concentrations have been found in some patients with acute severe asthma. The elevated adrenaline concentrations achieved after strenuous exercise77 cause bronchodilation in both normal and asthmatic subjects,67,69,78 and may counteract bronchospasm induced by exercise in asthma.79 Although a blunted catecholamine response to exercise in asthmatic patients has been reported by some investigators,80 other studies have
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Neural and Humoral Control
An intravenous infusion of exogenous ANP has important actions on airway function, including bronchodilation and the modification of bronchial reactivity to inhaled histamine and to fog challenge.89–93 The rise in plasma ANP levels during exercise is similar to these obtained during the lowest rates of ANP infusion; these results suggest that these elevations may lead to an attenuation of bronchospasm82 (Fig. 34.15). Plasma ANP levels are elevated in patients with cardiac failure94 and pulmonary hypertension secondary to COPD;95 under these circumstances ANP may also play a protective role on the airways. Circulating ANP at physiological concentrations, however, appears unlikely to have any influence on bronchomotor tone in normal subjects.91
Natriuretic peptides Natriuretic peptides are a family of hormones that have an important role in salt and water homeostasis.84,85 The human natriuretic peptides include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin. Most natriuretic peptides are produced primarily in the heart but are released also in other tissues, including the kidneys, lungs, and central nervous system. Specific ANP receptors have been localized to lung (including airway smooth muscle), of which some may be the ANP-C or clearance receptor subtype,86 although the receptor subtype(s) in human airway smooth muscle is unknown. In isolated human airway tissue, ANP has a direct relaxant effect and confers protection against agonistinduced contraction.87,88 Two principal mechanisms have been proposed for the inactivation of ANP: degradation by NEP, and binding to a non-guanylyl cyclase clearance receptor (ANP-C receptor). NEP is widely distributed within the airways and plays a role in modulating the effect of ANP on airway smooth muscle.87,88
Angiotensin II The renin–angiotensin system plays an important role in fluid and electrolyte homeostasis through the actions of the octapeptide angiotensin II. Angiotensin II is formed from angiotensinogen by the action of renin and then angiotensin-converting enzyme (ACE), 60–80% occurring within the pulmonary vascular endothelium. An alternative ACE-independent pathway, possibly mediated by several inflammatory proteases,96 may also cause the formation of angiotensin II. The effect of physiological concentrations of angiotensin II on basal bronchial tone of normal individuals is not know, whereas infusion of angiotensin II in mild asthmatic patients to plasma levels found in acute asthma causes bronchoconstriction97 (Fig. 34.16). Angiotensin II, although causing only weak contraction of isolated human and bovine bronchial rings, potentates the effects of methacholine and endothelin-1 in vitro.98,99 In patients with mild asthma, angiotensin II at subthreshold concentrations potentates methacholine-induced bronchoconstriction,99 but has no
3.5
30
3.0
25
Plasma ANP (pmol/L)
Plasma adrenaline (nmol/L)
found no significant difference in either the peak plasma catecholamine level between normal and asthmatic subjects nor in the response to increasing levels of exercise77,81,82 (Fig. 34.14). Noradrenaline, which has b1- and weak b2-adrenergic activity in addition to a-adrenergic effects, acts as a neurotransmitter in the sympathetic nervous system but overspills into the circulation. The infusion of noradrenaline, producing circulating concentrations within the physiological and pathophysiological range, has no effect on airway caliber in either normal or asthmatic subjects.67,69 The third catecholamine present in the blood, dopamine, has no influence on bronchomotor tone in humans.83
2.5 2.0 1.5 1.0
20 15 10 5
0.5
0
0.0 Base
1
2
3
4
Stage Bruce protocol
5
2
5
10
20
Time post-exercise (minutes)
Fig. 34.14. Plasma adrenaline concentrations during the course of and for 20 minutes after maximal treadmill exercise in normal subjects (broken line) and asthmatic subjects (solid) (no significant difference). Reproduced from reference 82, with permission.
Base
1
2
3
4
Stage Bruce protocol
5
2
5
10
20
Time post-exercise (minutes)
Fig. 34.15. Plasma atrial natriuretic peptide (ANP) concentrations during exercise after maximal treadmill exercise in normal subjects (broken line) and asthmatic subjects (solid) (no significant difference). Reproduced from reference 82, with permission.
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Asthma and Chronic Obstructive Pulmonary Disease
Plasma All (pg/mL)
140
A-11
120 100 80 60 40
*
Placebo
Adrenomedullin Adrenomedullin is a 52-amino-acid peptide that possesses vasodilator and natriuretic properties.110 The chemical structure of adrenomedullin is similar to calcitonin gene-related peptide (CGRP). Immunoreactivity to adrenomedullin is found in tissues throughout the body, including the lung.111 Adrenomedullin has a long-lasting bronchodilator action in guinea-pig trachea112 and inhibits IL-8 secretion from alveolar macrophages.113 Plasma levels of adrenomedullin are elevated in hypoxic patients with COPD.114 Its role in the control of airway smooth tone and inflammation in asthma or COPD is uncertain.115
*
*
20 0
Absolute change in systolic BP (mmHg)
35 *
*
25 15
*
Urotensin II Urotensin II is an 11-amino-acid cyclic peptide which activates specific receptors that are widely distributed in smooth muscle.116 It is a potent vasoconstrictor and a more potent constrictor of airway smooth muscle than endothelins.117 Its role in regulating airway smooth muscle and vascular tone in asthma and COPD are currently unknown.
5 5
Change in FEV1 (%)
5 0 5
*
10
*
15 20 0
20
40 60 Time (min)
80
100
Fig. 34.16. Effect of infused angiotensin II (A-11) on plasma levels of AII, changes in systolic blood pressure (BP) and change in FEV1 from baseline values in 8 asthmatic patients. *P 0.05 versus placebo. Reproduced from reference 97, with permission.
effect on endothelin- or histamine-evoked bronchoconstriction in vivo.100,101 Angiotensin II receptor antagonists reduce methacholine-induced bronchoconstriction in asthma102 and allergen-induced airway hyperresponsiveness and eosinophil accumulation in guinea-pigs.103 These results suggest a role for angiotensin II as a putative mediator in asthma. The renin–angiotensin system is activated in acute severe asthma, but not in stable chronic asthma.76,97 The mechanism of activation is unclear, but nebulized b2-agonists cause elevation of renin and angiotensin II in normal and mild asthmatic subjects through an ACE-dependent pathway.104,105 This may occur via stimulation of b-adrenoceptors on juxtaglomerular cells, but the levels of angiotensin II seen in acute severe asthma are higher, suggesting the existence of an alternative pathway of angiotensin II formation. Exercise activates the renin–angiotensin system,106,107 raising the possibility that elevated angiotensin II levels during exercise could contribute to exercise-induced bronchospasm. The renin–angiotensin system is also activated in patients with COPD and edema.108,109
Hormones Cortisol Pharmacological doses of intravenous cortisol have no short-term effect on airway caliber in normal subjects.118 Although glucocorticoids can potentate the response to catecholamines in isolated bronchial tissue, the effect occurs only at supraphysiological concentrations.119 These results suggest that endogenous cortisol is unlikely to have an important direct effect on airway tone in normal individuals. In asthma the role of physiological concentrations of circulating cortisol in airway function is uncertain. In nocturnal asthma, the nadir in the circadian variation in plasma cortisol occurs 4 hours before maximal bronchoconstriction,120 although the delayed action of cortisol means that it could still have an influence on airway caliber. Kallenbach et al.121 found a reduced nadir of plasma cortisol in patients with nocturnal asthma compared to a group without nocturnal asthma, but this finding may have been influenced by previous corticosteroid therapy. Other studies have found no direct association between plasma cortisol concentrations and nocturnal asthma.67 Furthermore, the infusion of physiological concentrations of hydrocortisone, eliminating the fall in plasma cortisol at night, does not prevent the nocturnal fall in peak flow rate in most asthmatic patients,120 suggesting that the circulating cortisol level is not the only factor in determining nocturnal asthma. Endogenous glucocorticoids rise following allergen challenge in allergic asthmatic subjects and may play a role in the modulation of allergen-induced bronchoconstriction.122 Local metabolism of circulating cortisol by 11b hydroxysteroid dehydrogenase in the lungs may have an influence on the inflammatory response in the airways, and this enzyme may be affected by various inflammatory mediators.123
Neural and Humoral Control
Thyroid hormones The relationship between asthma and thyroid disease provides indirect evidence of a role for thyroid hormones in maintaining airway function. The development of hyperthyroidism can be associated with deterioration in asthma control, with subsequent improvement in symptoms following appropriate treatment.124,125 Conversely the occurrence of hypothyroidism has been reported to be associated with improvement in asthma control, which relapses following subsequent thyroxine replacement.126 The possible mechanisms by which thyroid hormones could influence airway smooth muscle tone and responsiveness are unclear.66 Sex hormones Progesterone has an important role in reducing the contractility of uterine smooth muscle during pregnancy, and this effect may be due to its influence on gap junction formation between smooth muscle cells. It has been suggested that progesterone might cause similar effects on bronchial smooth muscle. Progesterone could influence airway smooth muscle tone by other mechanisms indirectly by potentating the effect of catecholamines119 or through its immunosuppressive properties. Progesterone levels and airway responsiveness do not show a clear relationship during either pregnancy or the menstrual cycle, although changes in the levels of other hormones may obscure an effect of progesterone on the airways.127,128 It is of interest that intramuscular progesterone has a beneficial effect in some women with severe menstrual asthma.129 Estrogen possesses both immunostimulatory and immunosuppressive properties and causes increased acetylcholine activity in the lungs of animals,130 which could result in an increase or decrease in airway tone. A preliminary report suggested that estrogen treatment might have steroidsparing effects in postmenopausal asthmatic women,131 although conversely hormone replacement therapy has been associated with an increased risk of developing asthma.132 Glucagon Glucagon has bronchodilator actions, but whether it has a role in the control of airway smooth tone in humans has not been investigated.133 The role of humoral mechanisms in asthma and COPD Circulating hormones and vasoactive peptides appear to play a minor role in the physiological regulation of airway tone in normal individuals. Adrenaline is the only hormone known to influence bronchomotor tone, and it is only during strenuous exercise that concentrations are elevated sufficiently to cause bronchodilation. Humoral mechanisms play a more important role in the regulation of airway tone in diseased states of the airways such as asthma and possibly in other disorders such as COPD, cor pulmonale, congestive cardiac failure, respiratory failure, and thyroid disease. Circulating adrenaline has a role in the maintenance of resting airway tone in asthma,
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perhaps particularly in those patients in whom resting airway caliber is already reduced. The elevated adrenaline and ANP concentrations achieved after vigorous exercise may act to counteract exercise-induced asthma. It has not been established in asthma whether elevated circulating angiotensin II achieved during exercise, or more particularly in acute severe asthma, contributes to the bronchospasm.
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21. Minette PAH, Lammers J, Dixon CMS, McCusker MT, Barnes PJ. A muscarinic agonist inhibits reflex bronchoconstriction in normal but not in asthmatic subjects. J. Appl. Physiol. 1989; 67:2461–5. 22. Ind PW, Dixon CMS, Fuller RW, Barnes PJ. Anticholinergic blockade of beta-blocker induced bronchoconstriction. Am. Rev. Respir. Dis. 1989; 139:1390–4. 23. Mak JCW, Baraniuk JN, Barnes PJ. Localization of muscarinic receptor subtype mRNAs in human lung. Am. J. Respir. Cell Mol. Biol. 1992; 7:344–8. 24. Herve P, Denjean A, Jian R, Simmoneau G, Duroux P. Intraesophageal perfusion of acid increases the bronchomotor response to methacholine and to isocapnic hyperventilation in asthmatic subjects. Am. Rev. Respir. Dis. 1986; 139:986–9. 25. Undem BJ, Riccio MM, Weinreich D, Ellis JL, Myers AC. Neurophysiology of mast cell-nerve interactions in the airways. Int. Arch. Allergy Immunol. 1995; 107:199–201. 26. Haddad E-B, Mak JCW, Barnes PJ. Expression of b-adrenergic and muscarinic receptors in human lung. Am. J. Physiol. 1996; 270:L947–53. 27. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year followup study of ventilatory function in adults with asthma. N. Engl. J. Med. 1998; 339:1194–200. 28. Barnes PJ. Beta-adrenergic receptors and their regulation. Am. J. Respir. Crit. Care Med. 1995; 152:838–60. 29. Bai TR. Abnormalities in airway smooth muscle in fatal asthma: a comparison between trachea and bronchus. Am. Rev. Respir. Dis. 1991; 143:441–3. 30. Spina D, Rigby PJ, Paterson JW, Goldie RG. Autoradiographic localization of beta-adrenoceptors in asthmatic human lung. Am. Rev. Respir. Dis. 1989; 140:1410–15. 31. Hakonarson H, Herrick DJ, Serrano PG, Grunstein MM. Mechanism of cytokine-induced modulation of b-adrenoceptor responsiveness in airway smooth muscle. J. Clin. Invest. 1996; 97:2593–600. 32. Koto H, Mak JCW, Haddad E-B et al. Mechanisms of impaired b-adrenergic receptor relaxation by interleukin-1b in vivo in rat. J. Clin. Invest. 1996; 98:1780–7. 33. Penn RB, Shaver JR, Zangrilli JG et al. Efects of inflammation and acute b-agonist inhalation on b2-AR signaling in human airways. Am. J. Physiol. 1996; 271:L601–8. 34. Spina D, Rigby PJ, Paterson JW, Goldie RG. a-adrenoceptor function and autoradiographic distribution in human asthmatic lung. Br. J. Pharmacol. 1989; 97:701–8. 35. Dinh-Xuan AT, Chaussain M, Regnard J, Lockart A. Pretreatment with an inhaled a1-adrenergic agonist, methoxamine, reduces exercise-induced asthma. Eur. Respir. J. 1989; 2:409–14. 36. Lammers JWJ, Barnes PJ, Chung KF. Non-adrenergic, noncholinergic airway inhibitory nerves. Eur. Respir. J. 1992; 5:239–46. 37. Belvisi MG, Stretton CD, Miura M et al. Inhibitory NANC nerves in human tracheal smooth muscle: a quest for the neurotransmitter. J. Appl. Physiol. 1992; 73:2505–10. 38. Belvisi MG, Ward JR, Mitchell JA, Barnes PJ. Nitric oxide as a neurotransmitter in human airways. Arch. Int. Pharmacodyn. Ther. 1995; 329:111–20. 39. Ward JK, Belvisi MG, Fox AJ et al. Modulation of cholinergic neural bronchoconstriction by endogenous nitric oxide and vasoactive intestinal peptide in human airways in vitro. J. Clin. Invest.1993; 92:736–43. 40. Ho WZ, Lai JP, Zhu XH, Uvaydova M, Douglas SD. Human monocytes and macrophages express substance P and neurokinin-1 receptor. J. Immunol. 1997; 159:5654–60. 41. Germonpre PR, Bullock GR, Lambrecht BN et al. Presence of substance P and neurokinin 1 receptors in human sputum macrophages and U-937 cells. Eur. Respir. J. 1999; 14:776–82. 42. Barnes PJ. Neurogenic inflammation in the airways. Respir. Physiol. 2001; 125:145–54.
43. Lilly CM, Bai TR, Shore SA, Hall AE, Drazen JM. Neuropeptide content of lungs from asthmatic and nonasthmatic patients. Am. J. Respir. Crit. Care Med. 1995; 151:548–53. 44. Joos GF, Germonpre PR, Pauwels RA. Role of tachykinins in asthma. Allergy 2000; 55:321–37. 45. Mapp CE, Miotto D, Braccioni F et al. The distribution of neurokinin-1 and neurokinin-2 receptors in human central airways. Am. J. Respir. Crit. Care Med. 2000; 161:207–15. 46. Frossard N, Rhoden KJ, Barnes PJ. Influence of epithelium on guinea pig airway responses to tachykinins: role of endopeptidase and cyclooxygenase. J. Pharmacol. Exp. Ther. 1989; 248:292–8. 47. Daniele RP, Barnes PJ, Goetzl EJ et al. Neuroimmune interactions in the lung. Am. Rev. Respir. Dis. 1992; 145:1230–5. 48. Harrison NK, Dawes KE, Kwon OJ et al. Effects of neuropeptides in human lung fibroblast proliferation and chemotaxis. Am. J. Physiol. 1995; 12:L278–83. 49. Cheung D, Bel EH, den Hartigh J, Dijkman JH, Sterk PJ. An effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responses to neurokinin A in normal humans in vivo. Am. Rev. Respir. Dis. 1992; 145:1275–80. 50. Di Maria GU, Bellofiore S, Geppetti P. Regulation of airway neurogenic inflammation by neutral endopeptidase. Eur. Respir. J. 1998; 12:1454–62. 51. Barnes PJ. Asthma as an axon reflex. Lancet 1986; i:242–5. 52. Maggi CA, Patacchini R, Santicioli P et al. The “efferent” function of capsaicin-sensitive nerves: ruthenium red discriminates between different mechanisms of activation. Eur. J. Pharmacol. 1989; 170:167–77. 53. Ollerenshaw SL, Jarvis D, Sullivan CE, Woolcock AJ. Substance P immunoreactive nerves in airways from asthmatics and nonasthmatics. Eur. Resp. J. 1991; 4:673–82. 54. Nieber K, Baumgarten CR, Rathsack R et al. Substance P and b-endorphin-like immunoreactivity in lavage fluids of subjects with and without asthma. J. Allergy Clin. Immunol. 1992; 90:646–52. 55. Tomaki M, Ichinose M, Miura M et al. Elevated substance P content in induced sputum from patients with asthma and patients with chronic bronchitis. Am. J. Respir. Crit. Care Med. 1995; 151:613–17. 56. Adcock IM, Peters M, Gelder C et al. Increased tachykinin receptor gene expression in asthmatic lung and its modulation by steroids. J. Mol. Endocrinol. 1993; 11:1–7. 57. Bai TR, Zhou D, Weir T et al. Substance P (NK1)- and neurokinin A (NK2)-receptor gene expression in inflammatory airway diseases. Am. J. Physiol. 1995; 269:L309–17. 58. Ichinose M, Nakajima N, Takahashi T et al. Protection against bradykinin-induced bronchoconstriction in asthmatic patients by a neurokinin receptor antagonist. Lancet 1992; 340:1248–51. 59. Fuller RW, Dixon CMS, Barnes PJ. The bronchoconstrictor response to inhaled capsaicin in humans. J. Appl. Physiol. 1985; 85:1080–4. 60. Cheung D, Timmers MC, Zwinderman AH et al. Neonatal endopeptidase activity and airway hyperesponsiveness to neurokinin A in asthmatic subjects in vivo. Am. Rev. Respir. Dis. 1993; 148:1467–73. 61. Fahy J, Wong HH, Geppetti P et al. Effect of an NK1 receptor antagonist (CP-99,994) on hypertonic saline-induced bronchoconstriction and cough in male asthmatic subjects. Am. J. Resp. Crit. Care Med. 1995; 152:879–84. 62. Ichinose M, Miura M, Yamauchi H et al. A neurokinin 1-receptor antagonist improves exercise-induced airway narrowing in asthmatic patients. Am. J. Respir. Crit. Care Med. 1996; 153:936–41. 63. Kuo H-P, Rohde JAL, Barnes PJ, Rogers DF. Cigarette smoke induced goblet cell secretion: neural involvement in guinea pig trachea. Eur. Respir. J. 1990; 3:1895. 64. Rogers DF, Aursudkij B, Barnes PJ. Effects of tachykinins on mucus secretion on human bronchi in vitro. Eur. J. Pharmacol. 1989; 174:283–6.
Neural and Humoral Control
65. Uddman R, Hakanson R, Luts A, Sundler F. Distribution of neuropeptides in airways. In: Barnes PJ (ed.), Autonomic Control of the Respiratory System, pp. 21–37. London: Harwood Academic, 1997. 66. Thomson NC, Dagg KD, Ramsay SG. Humoral control of airway tone. Thorax 1996; 51:461–4. 67. Barnes P, FitzGerald G, Brown M, Dollery C. Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol. N. Engl. J. Med. 1980; 303:263–7. 68. Berkin KE, Inglis GC, Ball SG, Thomson NC. Effect of low dose adrenaline and noradrenaline infusions on airway calibre in asthmatic patients. Clin. Sci. 1986; 70:347–52. 69. Berkin KE, Inglis GC, Ball SG, Thomson NC. Airway responses to low concentrations of adrenaline and noradrenaline in normal subjects. Q. J. Exp. Physiol. 1985; 70:203–9. 70. Bates ME, Clayton M, Calhoun W et al. Relationship of plasma epinephrine and circulating eosinophils to nocturnal asthma. Am. J. Respir. Crit. Care Med. 1994; 149:667–72. 71. Morrison JFJ, Teale C, Pearson GB et al. Adrenaline and nocturnal asthma. Br. Med. J. 1990; 301:473–6. 72. Morice A, Sever P, Ind PW. Adrenaline, bronchoconstriction and asthma. Br. Med. J. 1986; 293:539–40. 73. Arvidsson P, Larsson S, Löfdahl CG et al. Formoterol, a new longacting bronchodilator for inhalation. Eur. Resp. J. 1989; 2:325–30. 74. Larsson K, Gronneberg R, Hjemdahl P. Bronchodilatation and inhibition of allergen-induced bronchoconstriction by circulating epinephrine in asthmatic subjects. J. Allergy Clin. Immunol. 1985; 75:586–93. 75. Ind PW, Causon RC, Brown MJ, Barnes PJ. Circulating catecholamines in acute asthma. Br. Med. J. 1985; 290:267–9. 76. Ramsay SG, Dagg KD, McKay IC et al. Investigations on the renin–angiotensin system in acute severe asthma. Eur. Respir. J. 1997; 10:2766–71. 77. Berkin KE, Walker G, Inglis GC, Ball SG, Thomson NC. Circulating adrenaline and noradrenaline concentrations during exercise in patients with exercise induced asthma and normal subjects. Thorax 1988; 43:295–9. 78. Warren JB, Dalton N. A comparison of the bronchodilator and vasopressor effects of exercise levels of adrenaline in man. Clin. Sci. 1983; 64:475–9. 79. Knox AJ, Campos-Gongora H, Wisniewski A, MacDonald IA, Tattersfield AE. Modification of bronchial reactivity by physiological concentrations of plasma epinephrine. J. Appl. Physiol. 1992; 73:1004–7. 80. Barnes PJ, Brown MJ, Silverman M, Dollery CT. Circulating catecholamines in exercise and hyperventilation induced asthma. Thorax 1981; 36:435–40. 81. Gilbert IA, Lenner KA, McFadden ERJ. Sympathoadrenal response to repetitive exercise in normal and asthmatic subjects. J. Appl. Physiol. 1988; 64:2667–74. 82. Hulks G, Mohammed AF, Jardine AG, Connell JM, Thomson NC. Circulating plasma concentrations of atrial natriuretic peptide and catecholamines in response to maximal exercise in normal and asthmatic subjects. Thorax 1991; 46:824–8. 83. Thomson NC, Patel KR. Effect of dopamine on airways conductance in normals and extrinsic asthmatics. Br. J. Clin. Pharmacol. 1978; 5:421–4. 84. Ruskoaho H. Atrial natriuretic peptide: synthesis, release, and metabolism. Pharmacol. Rev. 1992; 44:479–602. 85. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N. Engl. J. Med. 1998; 339:321–8. 86. James S, Burnstock G. Atrial and brain natriuretic peptides share binding sites on cultured cells from the rat trachea. Cell Tissue Res. 1991; 265:555–65. 87. Angus RM, Nally JE, McCall R et al. Modulation of the effect of atrial natriuretic peptide in human and bovine bronchi by phosphoramidon. Clin. Sci. Colch. 1994; 86:291–5.
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88. Nally JE, Clayton RA, Thomson NC, McGrath JC. The interaction of a-human atrial natriuretic peptide (ANP) with salbutamol, sodium nitroprusside and isosorbide dinitrate in human bronchial smooth muscle. Br. J. Pharmacol. 1994; 113:1328–32. 89. Hulks G, Jardine AG, Connell JMC, Thomson NC. Bronchodilator effect of atrial natriuretic peptide in asthma. Br. Med. J. 1989; 292:1081–2. 90. Chanez P, Mann C, Bousquet J et al. Atrial natriuretic factor (ANF) is a potent bronchodilator in asthma. J. Allergy Clin. Immunol. 1990; 86:321–4. 91. Hulks G, Jardine AG, Connell JM, Thomson NC. Effect of atrial natriuretic factor on bronchomotor tone in the normal human airway. Clin. Sci. 1990; 79:51–5. 92. McAlpine LG, Hulks G, Thomson NC. Effect of atrial natriuretic peptide given by intravenous infusion on bronchoconstriction induced by ultrasonically nebulized distilled water (fog). Am. Rev. Respir. Dis. 1992; 146:912–15. 93. Angus RM, Mecallaum MJA, Hulks G, Thomson NC. Bronchodilator, cardiovascular and cyclic guanylyl monophosphate response to high dose infused atrial natriuretic peptide in asthma. Am. Rev. Respir. Dis. 1993; 147:1122–5. 94. Raine AE, Erne P, Burgisser E et al. Atrial natriuretic peptide and atrial pressure in patients with congestive heart failure. N. Engl. J. Med. 1986; 315:533–7. 95. Burghuber OC, Hartter E, Punzengruber C, Weissel M, Woloszczuk W. Human atrial natriuretic peptide secretion in precapillary pulmonary hypertension: clinical study in patients with COPD and interstitial fibrosis. Chest 1988; 93:31–7. 96. Husain A. The chymase-angiotensin system in humans. J. Hypertens. 1993; 11:1155–9. 97. Millar EA, Angus RM, Hulks G et al. Activity of the renin–angiotensin system in acute severe asthma and the effect of angiotensin II on lung function. Thorax 1994; 49:492–5. 98. Nally JE, Clayton RA, Wakelam MJ, Thomson NC, McGrath JC. Angiotensin II enhances responses to endothelin-1 in bovine bronchial smooth muscle. Pulm. Pharmacol. 1994; 7:409–13. 99. Millar EA, Nally JE, Thomson NC. Angiotensin II potentiates methacholine-induced bronchoconstriction in human airway both in vitro and in vivo. Eur. Respir. J. 1995; 8:1838–41. 100. Chalmers GW, Millar EA, Little SA, Shepherd MC, Thomson NC. Effect of infused angiotensin II on the bronchoconstrictor activity of inhaled endothelin-1 in asthma. Chest 1999; 115:352–6. 101. Ramsay SG, Clayton RA, Dagg KD et al. Effect of angiotensin II on histamine-induced bronchoconstriction in the human airway both in vitro and in vivo. Respir. Med. 1997; 91:609–15. 102. Myou S, Fujimura M, Kamio Y et al. Effect of losartan, a type 1 angiotensin II receptor antagonist, on bronchial hyperresponsiveness to methacholine in patients with bronchial asthma. Am. J. Respir. Crit. Care Med. 2000; 162:40–4. 103. Myou S, Fujimura M, Kurashima K et al. Type 1 angiotensin II receptor antagonism reduces antigen-induced airway reactions. Am. J. Respir. Crit. Care Med. 2000; 162:45–9. 104. Millar EA, McInnes GT, Thomson NC. Investigation of the mechanism of b2-agonist-induced activation of the renin–angiotensin system. Clin. Sci. 1995; 88:433–7. 105. Millar EA, Connell JM, Thomson NC. The effect of nebulized albuterol on the activity of the renin–angiotensin system in asthma. Chest 1997; 111:71–4. 106. Kosunen KJ, Pakarinen AJ, Kuoppasalmi K, Adlercreutz H. Plasma renin activity, angiotensin II, and aldosterone during intense heat stress. J. Appl. Physiol. 1976; 41:323–7. 107. Milledge JS, Catley DM. Renin, aldosterone, and converting enzyme during exercise and acute hypoxia in humans. J. Appl. Physiol. 1982; 52:320–3. 108. Reihman DH, Farber MO, Weinberger MH et al. Effect of hypoxemia on sodium and water excretion in chronic obstructive lung disease. Am. J. Med. 1985; 78:87–94.
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109. Anand IS, Chandrashekhar Y, Ferrari R et al. Pathogenesis of congestive state in chronic obstructive pulmonary disease: studies of body water and sodium, renal function, hemodynamics, and plasma hormones during edema and after recovery. Circulation 1992; 86:12–21. 110. Jougasaki M, Burnett JCJ. Adrenomedullin: potential in physiology and pathophysiology. Life Sci. 2000; 66:855–72. 111. Ichiki Y, Kitamura K, Kangawa K et al. Distribution and characterization of immunoreactive adrenomedullin in human tissue and plasma. FEBS Lett. 1994; 338:6–10. 112. Kanazawa H, Kurihara N, Hirata K et al. Adrenomedullin, a newly discovered hypotensive peptide, is a potent bronchodilator. Biochem. Biophys. Res. Commun. 1994; 205:251–4. 113. Kamoi H, Kanazawa H, Hirata K et al. Adrenomedullin inhibits the secretion of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, from rat alveolar macrophages. Biochem. Biophy. Res. Commun. 1995; 211:1031–5. 114. Cheung B, Leung R. Elevated plasma levels of human adrenomedullin in cardiovascular, respiratory, hepatic and renal disorders. Clin. Sci. 1997; 92:59–62. 115. Nishimura J, Seguchi H, Sakihara C et al. The relaxant effect of adrenomedullin on particular smooth muscles despite a general expression of its mRNA in smooth muscle, endothelial and epithelial cells. Br. J. Pharmacol. 1997; 120:193–200. 116. Ames RS, Sarau HM, Chambers JK et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 1999; 401:282–6. 117. Hay DW, Luttmann MA, Douglas SA. Human urotensin-II is a potent spasmogen of primate airway smooth muscle. Br. J. Pharmacol. 2000; 131:10–12. 118. Ramsdell JW, Berry CC, Clausen JL. The immediate effects of cortisol on pulmonary function in normals and asthmatics. J. Allergy Clin. Immunol. 1983; 72:69–74. 119. Foster PS, Goldie RG, Paterson JW. Effect of steroids on betaadrenoceptor-mediated relaxation of pig bronchus. Br. J. Pharmacol. 1983; 78:441–5. 120. Soutar CA, Costello J, Ijaduola O, Turner-Warwick M. Nocturnal and morning asthma: relationship to plasma corticosteroids and response to cortisol infusion. Thorax 1975; 30:436–40.
121. Kallenbach JM, Panz VR, Joffe BI et al. Nocturnal events related to “morning dipping” in bronchial asthma. Chest 1988; 93:751–7. 122. Stokes Peebles R, Togias A, Bickel CA et al. Endogenous glucocorticoids and antigen-induced acute and late phase pulmonary responses. Clin. Exp. Allergy 2000; 30:1257–65. 123. Schleimer RP. Potential regulation of inflammation in the lung by local metabolism of hydrocortisone. Am. J. Respir. Cell Mol. Biol. 1991; 4:166–73. 124. Ayres J, Clark TJH. Asthma and the thyroid. Lancet 1981; ii:1110–1. 125. Lipworth BJ, Dhillon DP, Clark RA, Newton RW. Problems with asthma following treatment of thyrotoxicosis. Br. J. Dis. Chest. 1988; 82:310–14. 126. Bush RK, Ehrlich EN, Reed CE. Thyroid disease and asthma. J. Allergy Clin. Immunol. 1977; 59:398–401. 127. Juniper EF, Daniel EE, Roberts RS et al. Improvement in airway responsiveness and asthma severity during pregnancy: a prospective study. Am. Rev. Respir. Dis. 1989; 140:924–31. 128. Tan KS, Thomson NC. Asthma in pregnancy. Am. J. Med. 2000; 109:727–33. 129. Beynon HLC, Garbett ND, Barnes PJ. Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone. Lancet 1988; ii:370–2. 130. Abdul-Karim RW, Marshall LD, Nesbitt REJ. Influence of estradiol-17b on the acetylcholine content of the lung in the rabbit neonate. Am. J. Obstet. Gynecol. 1970; 107:641–4. 131. Celedon JC, Sherman CB, Myers J et al. Estrogens as steroidsparing agents in postmenopausal asthmatic women. Am. J. Resp. Crit. Care Med. 1995; 151:A675. 132. Troisi RJ, Speizer FE, Willett WC, Trichopoulos D, Rosner B. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma: a prospective cohort study. Am. J. Respir. Crit. Care Med. 1995; 152:1183–8. 133. Sherman MS, Lazar EJ, Eichacker P. A bronchodilator action of glucagon. J. Allergy Clin. Immunol. 1988; 81:908–11.
Pathophysiology of Asthma
Chapter
35
Peter J. Barnes National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
Jeffrey M. Drazen Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
INTRODUCTION This chapter aims to provide a brief overview of disease mechanisms to integrate some of the detailed information provided in earlier chapters into a framework with clinical relevance. Asthma and chronic obstructive pulmonary disease (COPD) are highly complex; many different inflammatory cells and multiple mediators with complex acute and chronic effects on the airways are part of the syndromes. We now appreciate that these changes may vary among patients because of genetic variance in susceptibility. There have been important advances in our understanding of asthma pathogenesis, resulting from the application of new molecular, cell biological and genetic techniques, and with the development of new specifically targeted drugs to dissect the complex interacting pathways that are activated in asthma; the same has not been true of COPD. Even though we have made considerable advances in understanding asthma, there are many fundamental questions about the disease that remain to be answered. Our understanding of COPD is far less well developed; we understand some of the cellular elements, but how they are integrated to produce the disease phenotype is not known. Our views on asthma and COPD have continued to evolve. Although it is recognized that chronic inflammation underlies the clinical syndromes, it has been hard to define the precise nature of this inflammation, much less its primary etiology. Nevertheless it is appreciated that the final consequence of this chronic inflammatory response is an abnormal control of airway caliber in vivo in asthma. In contrast, the evolution of understanding in COPD has been much slower; key insights are sought which will open up the understanding of this complex disorder.
A S T H M A A S A N I N F L A M M AT O RY DISEASE It had been recognized for many years that patients who die of asthma attacks have grossly inflamed airways. The airway lumen is occluded by a tenacious mucus plug composed of plasma proteins exuded from airway vessels and mucus glycoproteins secreted from surface epithelial cells. The airway wall is edematous and infiltrated with inflammatory cells, which are predominantly eosinophils and T lymphocytes.1 The airway epithelium is invariably shed in a patchy manner and clumps of epithelial cells are found in the airway lumen. Occasionally there have been opportunities to examine the airways of asthmatic patients who die in accidents thought to be unrelated to their asthma. In this setting inflammatory changes have been observed but they are less marked than those observed in patients with active asthma.2 These studies also reveal that the inflammation in asthmatic airways involves not only the trachea and bronchi, but extends to the terminal bronchioles;3 some investigators have shown inflammatory cells in the parenchyma.4 It has also been possible to examine the airways of asthmatic patients by fiberoptic and rigid bronchoscopy, by bronchial biopsy, and by bronchoalveolar lavage. Direct bronchoscopic examination reveals that the airways of asthmatic patients are often erythematous and swollen, indicating acute inflammation. Lavage of the airways has revealed an increase in the numbers of lymphocytes, mast cells, and eosinophils and evidence for activation of macrophages in comparison with nonasthmatic controls. Biopsies have provided evidence for increased numbers and activation of mast cells, macrophages, eosinophils, and T lymphocytes. These changes are found even in patients with mild asthma who have few symptoms,5 suggesting that inflammation may be found in all asthmatic patients who are symptomatic. Indeed, inflammation may even be present in episodic asthmatics at a time when there are no symptoms, or in atopic
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individuals who are not asthmatic. This suggests that the inflammation needs to reach a certain threshold to result in symptoms.
A I R WAY H Y P E R R E S P O N S I V E N E S S The relationship between inflammation and clinical symptoms of asthma is not clear. There is evidence that the degree of inflammation is loosely related to airway hyperresponsiveness (AHR), as measured by histamine or methacholine challenge. The degree of inflammation does not clearly correspond to asthma severity, however. This suggests that other factors, such as structural changes in the airway wall, are important. The increased airway responsiveness in asthma is a striking physiological abnormality that is present even when airway function is normal. It is likely that there are several factors that underlie this increased responsiveness to constrictor agents, particularly those that act indirectly by releasing bronchoconstrictor mediators from airway cells. AHR may be due to increased release of mediators (such as histamine and leukotrienes from mast cells), abnormal behavior of airway smooth muscle, thickening of the airway wall by reversible (edema) and irreversible (airway smooth muscle thickening, fibrosis) elements. Airway sensory nerves may also contribute importantly to symptoms, such as cough and chest tightness, as the nerves become sensitized by the chronic inflammation in the airways. In hyperresponsive airways, triggers which would not normally narrow the airways, such as exercise, have a bronchoconstrictor effect (Fig. 35.1). However, there is reason to believe that products of the inflammatory response may also directly lead to an increase in asthma symptoms, such as cough and chest tightness. These effects, which are the
Allergens Sensitizers Viruses Air pollutants??
AIRWAY HYPERRESPONSIVENESS
INFLAMMATION ‘Chronic eosinophillic bronchitis’
Triggers Allergens Exercise Cold air SO2 Particulates
Symptoms Cough Wheeze Chest Dyspnea tightness
Fig. 35.1. Inflammation in the airways of asthmatic patients leads to airway hyperresponsiveness and symptoms.
equivalent of pain in other inflammatory diseases, may be mediated by sensitization and activation of airway sensory nerve endings. Although most attention has been focused on the acute inflammatory changes seen in asthmatic airways (bronchoconstriction, plasma exudation, mucus secretion), asthma is a chronic disease, persisting over many years in most patients. Superimposed on this chronic inflammatory state are acute inflammatory episodes, which correspond to exacerbations of asthma. It is clearly important to understand the mechanisms of acute and chronic inflammation in asthmatic airways and to investigate the long-term consequences of this chronic inflammation on airway function.
I N F L A M M AT O RY C E L L S Many different inflammatory cells are involved in asthma, although the precise role of each cell type is not yet certain (Fig. 35.2). It is evident that no single inflammatory cell is able to account for the complex pathophysiology of asthma, but some cells predominate in asthmatic inflammation. The inflammation in asthmatic airways differs strikingly from that observed in COPD, where there is a predominance of macrophages, cytotoxic (CD8) T lymphocytes, and neutrophils, although both of these common diseases may coexist in some patients.6,7 Mast cells Mast cells are clearly important in initiating the acute bronchoconstrictor responses to allergen and probably to other indirect stimuli, such as exercise and hyperventilation (via osmolality or thermal changes) and fog. We now appreciate that mast cell numbers are increased in sensitized human airway smooth muscle.8 Treatment of asthmatic patients with prednisone results in a decrease in the number of tryptase-only positive mast cells.9 Furthermore, the number of mast cells in induced sputum in patients with seasonal allergic rhinitis is related to the degree of methacholine responsiveness.10 Finally there are data implicating mast cell tryptase as an important component of airway remodeling as this mast cell product stimulates human lung fibroblast proliferation.11 Mast cells also secrete certain cytokines, such as interleukin (IL)-4 that may be involved in maintaining the allergic inflammatory response.12 However, there are questions about the role of mast cells in more chronic inflammatory events, and it seems more probable that other cells, such as macrophages, eosinophils, and T lymphocytes, are more important in the chronic inflammatory process, including AHR. Classically mast cells are activated by allergens through an IgE-dependent mechanism. The importance of IgE in the pathophysiology of asthma has been highlighted by recent clinical studies with humanized anti-IgE antibodies, which inhibit IgE-mediated effects. Although anti-IgE antibody results in a reduction in circulating IgE to undetectable levels, this treatment results in minimal clinical improvement in patients with severe
Pathophysiology of Asthma
345
Inflammatory cells Mast cells Eosinophils Th2 cells Basophils Neutrophils Platelets
Structural cells Epithelial cells Sm muscle cells Endothelial cells Fibroblast Nerves
Mediators Histamine Leukotrienes Prostanoids PAF Kinins Adenosine Endothelins Nitric oxide CYTOKINES CHEMOKINES
Effects Bronchospasm Plasma exudation Mucus secretion AHR Structural changes
Fig. 35.2. Many cells and mediators are involved in asthma and lead to several effects on the airways.
steroid-dependent asthma.13 Interestingly, treatment with the anti-IgE monoclonal did allow reduction of the dose of steroids required for asthma control. This suggests that the mechanisms whereby IgE leads to airway obstruction are steroid-sensitive. Macrophages Macrophages, which are derived from blood monocytes, may traffic into the airways in asthma and may be activated by allergen via low-affinity IgE receptors (FceRII).14 The enormous immunological repertoire of macrophages allows these cells to produce many different products, including a large variety of cytokines that may orchestrate the inflammatory response. Macrophages have the capacity to initiate a particular type of inflammatory response via the release of a certain pattern of cytokines. Macrophages may both increase and decrease inflammation, depending on the stimulus. Alveolar macrophages normally have a suppressive effect on lymphocyte function, but this may be impaired in asthma after allergen exposure.15 Macrophages may therefore play an important anti-inflammatory role, preventing the development of allergic inflammation. Macrophages may also act as antigen-presenting cells which process allergen for presentation to T lymphocytes, although alveolar macrophages are far less effective in this respect than macrophages from other sites, such as the peritoneum.16 Dendritic cells By contrast, dendritic cells (which are specialized macrophage-like cells in the airway epithelium) are very effective antigen-presenting cells,16,17 and may therefore play a very important role in the initiation of allergen-induced responses in asthma. Dendritic cells take up allergens, process them to peptides, and migrate to local lymph nodes where they present the allergenic peptides to uncommitted T lymphocytes, to program the production of allergenspecific T cells. Immature dendritic cells in the respiratory tract promote Th2 cell differentiation and require cytokines such as IL-12 and TNF-a to promote the normally preponderant Th1 response.18
Eosinophils Eosinophil infiltration is a characteristic feature of asthmatic airways and differentiates asthma from other inflammatory conditions of the airway. Indeed, asthma might more accurately be termed “chronic eosinophilic bronchitis” (a term first used as early as 1916). Allergen inhalation results in a marked increase in eosinophils in bronchoalveolar lavage (BAL) fluid at the time of the late reaction, and there is a correlation between eosinophil counts in peripheral blood or bronchial lavage and AHR. Eosinophils are linked to the development of airway hyperresponsiveness through the release of basic proteins and oxygen-derived free radicals.19 An important area of research is now concerned with the mechanisms involved in recruitment of eosinophils into asthmatic airways. Eosinophils are derived from bone marrow precursors. After allergen challenge eosinophils appear in BAL fluid during the late response, and this is associated with a decrease in peripheral eosinophil counts and with the appearance of eosinophil progenitors in the circulation. The signal for increased eosinophil production is presumably derived from the inflamed airway. Eosinophil recruitment initially involves adhesion of eosinophils to vascular endothelial cells in the airway circulation, their migration into the submucosa, and their subsequent activation. The role of individual adhesion molecules, cytokines, and mediators in orchestrating these responses has been extensively investigated. Adhesion of eosinophils involves the expression of specific glycoprotein molecules on the surface of eosinophils (integrins) and their expression of such molecules as intercellular adhesion molecule-1 (ICAM-1) on vascular endothelial cells. An antibody directed at ICAM-1 markedly inhibits eosinophil accumulation in the airways after allergen exposure and also blocks the accompanying hyperresponsiveness.20 However, ICAM-1 is not selective for eosinophils and cannot account for the selective recruitment of eosinophils in allergic inflammation. The adhesion molecules VLA4 expressed on eosinophils and VCAM-1 appear to be more selective for eosinophils,21 and IL-4 increases the expression of VCAM-1 on endothelial cells.22 Eosinophil
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migration may be due to the effects of lipid mediators, such as leukotrienes23 and possibly PAF, to the effects of cytokines, such as GM-CSF and IL-5 which may be very important for the survival of eosinophils in the airways and may “prime” eosinophils to exhibit enhanced responsiveness. Eosinophils from asthmatic patients show exaggerated responses to PAF and phorbol esters, compared with eosinophils from atopic nonasthmatic individuals.24 This is further increased by allergen challenge,25 suggesting that they may have been primed by exposure to cytokines in the circulation. There are several mediators involved in the migration of eosinophils from the circulation to the surface of the airway. The most potent and selective agents appear to be chemokines, such as RANTES, eotaxin, and MCP-4, that are expressed in epithelial cells.26,27 There appears to be a co-operative interaction between IL-5 and chemokines, so that both cytokines are necessary for the eosinophilic response in airways.28 Once recruited to the airways, eosinophils require the presence of various growth factors, of which GM-CSF and IL-5 appear to be the most important.29 In the absence of these growth factors eosinophils undergo programmed cell death (apoptosis). Recently a humanized monoclonal antibody to IL-5 has been administered to asthmatic patients;30 and, as in animal studies, there is a profound and prolonged reduction in circulating eosinophils. Although the infiltration of eosinophils into the airway after inhaled allergen challenge is completely blocked, there is no effect on the response to inhaled allergen and no reduction in AHR. These data question the pivotal role of eosinophils in asthma. Neutrophils The eosinophil has been the recipient of current attention as an effector cell in asthma, but attention has been returning to the role of neutrophils.31 Although neutrophils are not a predominant cell type observed in the airways of patients with mild-to-moderate chronic asthma, they appear to be a more prominent cell type in airways and induced sputum of patients with more severe asthma.32 Also in patients who die suddenly of asthma, large numbers of neutrophils are found in the airways,33 although this may reflect the rapid kinetics of neutrophil recruitment compared to eosinophil inflammation. Whether the selective recruitment of neutrophils occurs as a result of high doses of inhaled corticosteroids or reflects the pathophysiology of severe asthma is currently unknown. Our appreciation of the importance of neutrophils as effector cells in more severe forms of asthma is just beginning; in the future we can expect a more complete understanding of the role of neutrophils in the asthmatic diathesis. T lymphocytes T lymphocytes play a very important role in coordinating the inflammatory response in asthma through the release of specific patterns of cytokines, resulting in the recruitment and survival of eosinophils and in the maintenance of mast cells in the airways. T lymphocytes are coded to express a
distinctive pattern of cytokines, which are similar to that described in the murine Th2 type of T lymphocytes, which characteristically express IL-4, IL-5, and IL-13.34 This programming of T lymphocytes is presumably due to antigen presenting cells such as dendritic cells, which may migrate from the epithelium to regional lymph nodes or which interact with lymphocytes resident in the airway mucosa. The naive immune system is skewed to express theTh2 phenotype; data now indicate that children with atopy are more likely to retain this skewed phenotype than are normal children.35 There is some evidence that early infections or exposure to endotoxins might promote Th1-mediated responses to predominate and that a lack of infection or a clean environment in childhood may favour Th2 cell expression and thus atopic diseases.36–38 Indeed, the balance between Th1 cells and Th2 cells is thought to be determined by locally released cytokines, such as IL-12, which tip the balance in favor of Th1 cells, or IL-4 or IL-13 which favor the emergence of Th2 cells (Fig. 35.3). There is some evidence that steroid treatment may differentially effect the balance between IL12 and IL-13 expression.39 Data from murine models of asthma40–42 have strongly suggested that IL-13 is both necessary and sufficient for induction of the asthmatic phenotype. One of the most important areas of asthma research in the next few years will be to establish the importance of IL-13 in the induction of the Th2 phenotype and asthma in humans. Basophils The role of basophils in asthma is uncertain, as these cells have previously been difficult to detect by immunocytochemistry.12 Using a basophil-specific marker, a small increase in basophils has been documented in the airways of asthmatic patients, with an increased number after allergen challenge. However, these cells are far outnumbered by eosinophils.43 Allergen
Antigen presenting cell Dendritic cell, macrophage MHCI Allergent peptide TCR
B7-2 CD28
Mast cell
Thp IL-12 IL-18 Th1
IL-4 IFN-γ
Th2
IL-4 IL-13
IgE
IL-5 IL-2 IFN-γ
Eosinophil
Fig. 35.3. Asthma is characterized by a preponderance of Th2 over Th1 cells.
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Pathophysiology of Asthma
Structural cells Structural cells of the airways, including epithelial cells, fibroblasts, and even airway smooth muscle cells may also be an important source of inflammatory mediators, such as cytokines and lipid mediators in asthma.''''"''* Indeed, because structural cells far outnumber inflammatory cells they may become the major source of mediators driving chronic inflammation in asthmatic airways. In addition, epithelial cells may have a key role in translating inhaled environmental signals into an airway inflammatory response and are probably a major target cell for inhaled glucocorticoids (Fig. 35.4).
INFLAMMATORY MEDIATORS Many different mediators have been implicated in asthma. They may have a variety of effects on the airways, which could account for the pathological features of asthma'"'''* (Fig. 35.2). Mediators such as histamine, prostaglandins, and leukotrienes contract airway smooth muscle, increase microvascular leakage, increase airway mucus secretion, and attract other inflammatory cells. Because each mediator has many effects the role of individual mediators in the pathophysiology of asthma is not yet clear. Although the multiplicity of mediators makes it unlikely that preventing the synthesis or action of a single mediator will have a major impact in clinical asthma, recent clinical studies with antileukotrienes suggest that cysteinyl-leukotrienes have a clinically important effect. The cysteinyl-leukotrienes LTC4, LTD4, and LTE4 are potent constrictors of human airways and have been
Allergens
Viruses O2, NO2
FCERII
reported to increase A H R and may play an important role in asthma''''^" (see Chapter 24). T h e recent development of potent specific leukotriene antagonists has made it possible to evaluate the role of these mediators in asthma. Potent LTD4 antagonists protect (by about 50%) against exerciseand allergen-induced bronchoconstriction,^'"^^ suggesting that leukotrienes contribute to bronchoconstrictor responses. Combined treatment with an antihistamine and an antileukotriene is particularly effective.^* Chronic treatment with antileukotrienes improves lung function and symptoms in asthmatic patients, although the degree of lung function improvement is not as great as that seen with an inhaled glucocorticoid. It is only through the use of specific antagonists that the role of individual mediators of asthma may be defined. In the future, pharmaceuticals with specific targets of action will be of special value in providing pathobiological insights into the basic mechanisms of asthma; their potential role in the treatment of asthma remains to be determined. For example, platelet-activating factor (PAF) is a potent inflammatory mediator that mimics many of the features of asthma, including eosinophil recruitment and activation and induction of AHR; yet even potent PAF antagonists, such as modipafant, do not control asthma symptoms, at least in chronic asthma.^'"*" However, genetic studies in Japan, where there is a high frequency of a genetic mutation which disables the PAF metabolizing enzyme, PAF acetyl hydrolase, have shown that there is an association between the presence of the mutant form of the enzyme and severe asthma.*''*^ These data suggest that there may be certain conditions associated with a significant role for PAF in asthma.
Viruses
° •= - > Macrophage
TNF-a, IL-ip, IL-6
^P<MiMiMi^ Airway epithelial cells GM-CSF Eotaxin RANTES MCP-4
Eosinophil survival chemotaxis
PDGF RANTES IL-16
Lymphocyte activation
Smooth muscle hyperplasia
Fibroblast activation
Fig. 35.4. Airway epithelial cells may play an active role in asthmatic inflammation through the release of many inflammatory mediators and cytokines.
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Asthma and Chronic Obstructive Pulmonary Disease
Cytokines Cytokines are increasingly recognized to be important in chronic inflammation and play a critical role in orchestrating the type of inflammatory response63 (Fig. 35.5). Many inflammatory cells (macrophages, mast cells, eosinophils, and lymphocytes) are capable of synthesizing and releasing these proteins, and structural cells such as epithelial cells and endothelial cells may also release a variety of cytokines and may therefore participate in the chronic inflammatory response.64 While inflammatory mediators like histamine and leukotrienes may be important in the acute and subacute inflammatory responses and in exacerbations of asthma, it is likely that cytokines play a dominant role in chronic inflammation. Almost every cell is capable of producing cytokines under certain conditions. Research in this area is hampered by a lack of specific antagonists, although important observations have been made using specific neutralizing antibodies. The cytokines which appear to be of particular importance in asthma include the lymphokines secreted by T lymphocytes: • IL-3, which is important for the survival of mast cells in tissues; • IL-4, which is critical in switching B-lymphocytes to produce IgE and for expression of VCAM-1 on endothelial cells; • IL-13, which acts similarly to IL-4 in IgE switching; • IL-5 which is of critical importance in the differentiation, survival and priming of eosinophils.
There is increased gene expression of IL-5 in lymphocytes in bronchial biopsies of patients with symptomatic asthma.65 The role of an IL-5 in eosinophil recruitment in asthma has been confirmed in a study in which administration of an anti-IL-5 antibody to asthmatic patients was associated with a decrease in eosinophil counts in the blood and BAL fluid.30 Interestingly in this small study there was no effect on the physiology of the allergen-induced asthmatic response; although this is not the last word on eosinophils in asthma, it provides evidence that the eosinophil, as recruited by IL-5, is not the major pathogenetic cell in asthma. Another Th2 cytokine, IL-9, may play a critical role is sensitizing responses to the cytokines IL-4 and IL-5.66–68 Other cytokines, such as IL-1b, IL-6, TNF-a, and GMCSF, are released from a variety of cells, including macrophages and epithelial cells, and may be important in amplifying the inflammatory response. TNF-a may be an amplifying mediator in asthma and is produced in increased amounts in asthmatic airways.69 Inhalation of TNF-a increased airway responsiveness in normal individuals.70 TNF-a and IL-1b both activate the proinflammatory transcription factors, nuclear factor-jB (NF-jB) and activator protein-1 (AP-1) which then switch on many inflammatory genes in the asthmatic airway. Complement Although the role of complement has been largely discounted in asthma, studies in mice harboring a targeted deletion of the C5a receptor had diminished bronchial hyperresponsiveness induced after allergen challenge.71
Allergen GM-CSF, IL-6, IL-11 Eotaxin, RANTES, IL-8
Epithelial cell IL-1β
Dendritic cell
TNF-α IL-12
Macrophage
ⴚ IL-10
MCP-1 GM-CSF
Monocyte IL-3
TNF-α IL-4 IL-5
Smooth muscle
Th0 cell IL-4 IL-13
GM-CSF RANTES
Th2 cell IL-4 IL-13
IL-5
IL-5, GM-CSF
IgE
Mast cell
B lymphocyte
Eosinophil
Fig. 35.5. The cytokine network in asthma. Many inflammatory cytokines are released from inflammatory and structural cells in the airway and orchestrate and perpetuate the inflammatory response.
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Pathophysiology of Asthma
Genetic linkage studies in mice have linked regions of the mouse genome containing the gene for C5a to the phenotype of airway hyperresponsivenes.72 Furthermore, the complement peptide C5a has been recovered from BAL fluid of patients after allergen challenge.71 Oxidative stress As in all inflammatory diseases, there is increased oxidative stress in asthma as activated inflammatory cells, such as macrophages and eosinophils, produce reactive oxygen species. Evidence for increased oxidative stress in asthma is provided by the increased concentrations of 8-isoprostane (a product of oxidized arachidonic acid) in exhaled breath condensates,73 and increased ethane (a product of oxidative lipoid peroxidation) in exhaled breath of asthmatic patients.74 Increased oxidative stress is related to disease severity and may amplify the inflammatory response and reduce responsiveness to corticosteroids. Endothelins Endothelins are potent peptide mediators that are vasoconstrictors and bronchoconstrictors.75 Endothelin-1 levels are increased in the sputum of patients with asthma; these levels are modulated by allergen exposure and steroid treatment.76–78 Endothelins also induce airway smooth muscle cell proliferation and promote a profibrotic phenotype and may therefore play a role in the chronic inflammation of asthma. Endothelin has an inhibitory effect on the expression
of inducible nitric oxide synthase (NOS) and thus may modify the primary microenvironment of the asthmatic airway. Nitric oxide Nitric oxide (NO) is produced by several cells in the airway by NO synthases.79 Although the cellular source of NO within the lung is not known, inferences based on mathematical models suggest that it is the large airways which are the source of NO.80 Current data indicate that the level of NO in the exhaled air of patients with asthma is higher than the level of NO in the exhaled air of normal subjects.81–83 The elevated levels of NO in asthma are more likely reflective of an as yet to be identified inflammatory mechanism than of a direct pathogenetic role of this gas in asthma.84,85 Current data suggest that the level of NO in exhaled air reflects local airway pH which may be the primary factor modified by the inflammatory processes of asthma.86 The combination of increased oxidative stress and NO may lead to the formation of the potent radical peroxynitrite, that may result in nitrosylation of proteins in the airways.87
E F F E C T S O F I N F L A M M AT I O N O N T H E A I R WAY S The chronic inflammatory response has several effects on the target cells of the airways, resulting in the characteristic pathophysiological changes associated with asthma (Fig. 35.6).
Allergen Macrophage /dendritic cell
Mast cell
Neutrophil Th2 cell Eosinophil Mucus plug
Epithelial shedding Nerve activation Subepithelial fibrosis
Myofibroblast Plasma leak Edema Mucus hypersecretion Hyperplasia
Vasodilatation New vessels
Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy/hyperplasia
Fig. 35.6. The pathophysiology of asthma is complex, with participation of several interacting inflammatory cells which result in acute and chronic inflammatory effects on the airway.
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Asthma may be regarded as a disease with continuous inflammation and repair proceeding simultaneously. Important advances continue to be made in our understanding of these changes; but despite these new insights, the relationship between chronic inflammatory processes and asthma symptoms is often not clear. Airway epithelium Airway epithelial shedding may be important in contributing to airway hyperresponsiveness and may explain how several different mechanisms, such as ozone exposure, certain virus infections, chemical sensitizers and allergen exposure can lead to its development, since all these stimuli may lead to epithelial disruption. Epithelium may be shed as a consequence of inflammatory mediators, such as eosinophil basic proteins and oxygen-derived free radicals, together with various proteases released from inflammatory cells. Epithelial cells are commonly found in clumps in the BAL fluid or sputum (Creola bodies) of asthmatics, suggesting that there has been a loss of attachment to the basal layer or basement membrane. Epithelial damage may contribute to AHR in a number of ways, including: • loss of its barrier function to allow penetration of allergens; • loss of enzymes (such as neutral endopeptidase) which normally degrade inflammatory mediators; • loss of a relaxant factor (so called epithelial-derived relaxant factor); • exposure of sensory nerves which may lead to reflex neural effects on the airway. Fibrosis The basement membrane in asthma appears on light microscopy to be thickened; on closer inspection by electron microscopy it has been demonstrated that this apparent thickening is due to subepithelial fibrosis with deposition of type III and V collagen below the true basement membrane. Data from a number of investigative groups show that the thickness of the deposited collagen is related to airway obstruction and airway responsiveness.88–90 The mechanism of the collagen deposition is not known. However, it is known that several profibrotic cytokines, including TGF-b and PDGF, and mediators such as endothelin-1, can be produced by epithelial cells or macrophages in the inflamed airway.64 There are novel findings which indicate that even simple mechanical manipulations can alter the phenotype of airway epithelial cells in a profibrotic fashion.91 The role of fibrosis in asthma is unclear, as subepithelial fibrosis has been observed even in mild asthmatics at the onset of disease; it is not certain whether the collagen deposition has any functional consequences. Nevertheless, substantial attention has been paid to these histological changes. Some investigators suggest that the changes are the key pathogenetic changes leading to irreversible loss of lung function in patients with asthma, while others argue that the findings are of little consequence.92,93 This is an area of active
research and greater understanding of these changes is likely over the next few years. Airway smooth muscle There is still debate about the role of abnormalities in airway smooth muscle in asthmatic airways. In vitro, airway smooth muscle from asthmatic patients usually shows no increased responsiveness to spasmogens. Reduced responsiveness to b-agonists has also been reported in postmortem or surgically removed bronchi from asthmatics, although the number of b-receptors is not reduced, suggesting that b-receptors have been uncoupled.94 These abnormalities of airway smooth muscle may be a reflection of the chronic inflammatory process. For example, it is established that chronic exposure to inflammatory cytokines, such as IL-1b, can downregulate the response to b2-adrenergic agonists.95 Interestingly, steroid treatment prevents the effects of IL-1b on the effects of b-agonists.96 Furthermore, the reduced b-adrenergic responses in airway smooth muscle could be due to phosphorylation of the stimulatory G protein coupling b-receptors to adenylyl cyclase, resulting from the activation of protein kinase C by the stimulation of airway smooth muscle cells by inflammatory mediators and to increased activity of the inhibitory G protein (Gi) induced by proinflammatory cytokines.97,98 Inflammatory mediators may modulate the ion channels that serve to regulate the resting membrane potential of airway smooth muscle cells, thus altering the level of excitability of these cells. Furthermore, modulation of the activation kinetics of other ion channels by key inflammatory mediators can lead to altered contractile characteristics of smooth muscle. In asthmatic airways there is also a characteristic hypertrophy and hyperplasia of airway smooth muscle,99 which is presumably the result of stimulation of airway smooth muscle cells by various growth factors, such as PDGF, or endothelin-1 released from inflammatory cells. Vascular responses Vasodilatation occurs in inflammation, yet little is known about the role of the airway circulation in asthma. This is partly because of the difficulties involved in measuring airway blood flow. Recent studies using an inhaled absorbable gas have demonstrated an increased airway mucosal blood flow in asthma.100 The bronchial circulation may play an important role in regulating airway caliber, since an increase in the vascular volume may contribute to airway narrowing. Increased airway blood flow may be important in removing inflammatory mediators from the airway, and may play a role in the development of exercise-induced asthma.101 Increased shear stress due to high expiratory pressures may lead to gene transduction and enhanced production of nitric oxide by type III (endothelial) NO synthase.102,103 There may also be an increase in the number of blood vessels in asthmatic airways as a result of angiogenesis.104,105 Microvascular leakage is an essential component of the inflammatory response and many of the inflammatory
Pathophysiology of Asthma
mediators implicated in asthma produce this leakage.106,107 There is good evidence for microvascular leakage in asthma, and it may have several consequences on airway function, including increased airway secretions, impaired mucociliary clearance, formation of new mediators from plasma precursors (such as kinins), and mucosal edema which may contribute to airway narrowing and increased airway hyperresponsiveness.108,109 Mucus hypersecretion Mucus hypersecretion is a common inflammatory response in secretory tissues. Increased mucus secretion contributes to the viscid mucus plugs which occlude asthmatic airways, particularly in fatal asthma. There is evidence for hyperplasia of submucosal glands which are confined to large airways, and of increased numbers of epithelial goblet cells. This increased secretory response may be due to inflammatory mediators acting on submucosal glands and due to stimulation of neural elements. Two of the critical cytokines thought to be of importance in creating the immune environment of asthma, IL-4 and IL-13, have been shown to participate in mucus hypersecretion in experimental models of asthma.42,110 The role of hypertrophy and hyperplasia of the mucosecretory apparatus in asthma is not known, but these recent findings should stimulate a reassessment of both the anatomic changes in the mucus-secreting cells as well as the study of the secreted mucus itself in asthma. Neural effects There has recently been a revival of interest in neural mechanisms in asthma.111 Autonomic nervous control of the airways is complex; in addition to classical cholinergic and adrenergic mechanisms, nonadrenergic noncholinergic (NANC) nerves and several neuropeptides have been identified in the respiratory tract.112–114 Several studies have investigated the possibility that defects in autonomic control may contribute to AHR in asthma, and abnormalities of autonomic function, such as enhanced cholinergic and aadrenergic responses or reduced b-adrenergic responses, have been proposed. Current thinking suggests that these abnormalities are likely to be secondary to the disease, rather than primary defects.111 It is possible that airway inflammation may interact with autonomic control by several mechanisms. Inflammatory mediators may act on various prejunctional receptors on airway nerves to modulate the release of neurotransmitters.115,116 Thus thromboxane and PGD2 facilitate the release of acetylcholine from cholinergic nerves in canine airways, whereas histamine inhibits cholinergic neurotransmission at both parasympathetic ganglia and postganglionic nerves via H3 receptors. Inflammatory mediators may also activate sensory nerves, resulting in reflex cholinergic bronchoconstriction or release of inflammatory neuropeptides. Inflammatory products may also sensitize sensory nerve endings in the airway epithelium, so that the nerves become hyperalgesic. Hyperalgesia and pain (dolor) are cardinal signs of inflammation, and in the
351
asthmatic airway may mediate cough and chest tightness, which are such characteristic symptoms of asthma. The precise mechanisms of hyperalgesia are not yet certain, but mediators such as prostaglandins, certain cytokines, and neurotrophins may be important. Neurotrophins, which may be released from various cell types in peripheral tissues, may cause proliferation and sensitization of airway sensory nerves.117 Bronchodilator nerves which are nonadrenergic are prominent in human airways, and it has been suggested that these nerves may be defective in asthma.118 In animal airways, vasoactive intestinal peptide (VIP) has been shown to be a neurotransmitter of these nerves, and a striking absence of VIP-immunoreactive nerves has been reported in the lungs from patients with severe fatal asthma.119 However, it is likely that this loss of VIP immunoreactivity is due to degradation by tryptase released from degranulating mast cells in the airways of asthmatics. In human airways, the bronchodilator neurotransmitter appears to be nitric oxide.120 In guinea-pigs, VIP administration can lead to NO release,121 thus there may be a link between VIP and NO in humans. Airway nerves may also release neurotransmitters which have inflammatory effects. Thus neuropeptides such as substance P (SP), neurokinin A, and calcitonin-gene related peptide may be released from sensitized inflammatory nerves in the airways which increase and extend the ongoing inflammatory response.122 There is evidence for an increase in SP-immunoreactive nerves in airways of patients with severe asthma,123 which may be due to proliferation of sensory nerves and increased synthesis of sensory neuropeptides as a result of nerve growth factors released during chronic inflammation – although this has not been confirmed in milder asthmatic patients.124 There may also be a reduction in the activity of enzymes, such as neutral endopeptidase, which degrade neuropeptides such as SP.125 There is also evidence for increased gene expression of the receptor which mediates the inflammatory effects of SP.126 Thus chronic asthma may be associated with increased neurogenic inflammation, which may provide a mechanism for perpetuating the inflammatory response even in the absence of initiating inflammatory stimuli. Acute and chronic inflammation Asthma is characterized by acute inflammatory episodes, which may occur after upper respiratory tract virus infections or exposure to a large amount of inhaled allergen, resulting in bronchoconstriction, plasma exudation, edema, and mucus secretion. However, asthma is also a chronic inflammatory process, partly driven by exposure to low-level environmental allergens such as house dust mite and molds, and this may result in structural changes in the airway walls (remodeling) that lead to progressive narrowing of airways. This may account for the accelerated decline in airway function seen in asthmatic patients over several years.127,128 These changes include:
352 • • • •
Asthma and Chronic Obstructive Pulmonary Disease
increased thickness of airway smooth muscle; fibrosis (which is predominantly subepithelial); increased mucus-secreting cells; increased numbers of blood vessels (angiogenesis).
It is not known if these changes are reversible with therapy. These changes may occur in some patients to a greater extent than others and may be increased by other factors such as concomitant cigarette smoking. It is likely that genetic factors will influence the extent of remodeling that occurs in individual patients.
T R A N S C R I P T I O N FA C T O R S The chronic inflammation of asthma is due to increased expression of multiple inflammatory proteins (cytokines, enzymes, receptors, adhesion molecules). In many cases these inflammatory proteins are induced by transcription factors, DNA binding factors that increase the transcription of selected target genes129,130 (Fig. 35.7). One transcription factor that may play a critical role in asthma is nuclear factor-kappa B (NF-jB) which can be activated by multiple stimuli, including protein kinase C activators, oxidants, and proinflammatory cytokines (such as IL-1b and TNF-a).131 There is evidence for increased activation of NF-jB in asthmatic airways, particularly in epithelial cells
and macrophages.132 NF-jB regulates the expression of several key genes that are overexpressed in asthmatic airways, including proinflammatory cytokines (IL-1b, TNF-a, GMCSF), chemokines (RANTES, MIP-1a, eotaxin), adhesion molecules (ICAM-1, VCAM-1), and inflammatory enzymes (cycloxygenase-2, iNOS). The c-fos component of AP-1 is also activated in asthmatic airways and often cooperates with NF-jB in switching on inflammatory genes.133
A N T I - I N F L A M M AT O RY M E C H A N I S M S I N ASTHMA Although most emphasis has been placed on inflammatory mechanisms, there may be important anti-inflammatory mechanisms that may be defective in asthma, resulting in increased inflammatory responses in the airways (Fig. 35.8). Endogenous cortisol may be important as a regulator of the allergic inflammatory response, and nocturnal exacerbation of asthma may be related to the circadian fall in plasma cortisol. Blockade of endogenous cortisol secretion by metyrapone results in an increase in the late response to allergen in the skin.134 Cortisol is converted to the inactive cortisone by the enzyme 11b-hydroxysteroid dehydrogenase which is expressed in airway tissues.135 It is possible that this enzyme functions abnormally in asthma or may determine the severity of asthma.
INFLAMMATORY PROTEINS Cytokines, enzymes, receptors, adhesion molecules
INFLAMMATORY STIMULI Allergens, viruses, cytokines
Receptor
Inactive transcription factor
Kinases
mRNA
P
Activated transcription factor (NF-κB, AP-1, STATs)
Nucleus
Inflammatory gene
Promoter
Coding region
Fig. 35.7. Transcription factors play a key role in amplifying and perpetuating the inflammatory response in asthma. Transcription factors, including nuclear factor kappa-B (NF-jB), activator protein-1 (AP-1), and signal transduction-activated transcription factors (STATs), are activated by inflammatory stimuli and increase the expression of multiple inflammatory genes.
Pathophysiology of Asthma
ANTIINFLAMMATORY MEDIATORS
INFLAMMATORY MEDIATORS
IL-10 IL-1ra IFN-γ, IL-12, IL-18 PGE2
Lipid mediators Cytokines Peptides Oxidants
Fig. 35.8. There may be an imbalance between increased proinflammatory mediators and a deficiency in anti-inflammatory mediators.
Various cytokines have anti-inflammatory actions.136 IL-1 receptor antagonist (IL-1ra) inhibits the binding of IL-1 to its receptors and therefore has anti-inflammatory potential in asthma. It is reported to be effective in an animal model of asthma.137 IL-12 and interferon-c (IFN-c) enhance Th1 cells and inhibit Th2 cells, and there is some evidence that IL-12 expression may be impaired in asthma.39 IL-10, which was originally described as cytokine synthesis inhibitory factor, inhibits the expression of multiple inflammatory cytokines (TNF-a, IL-1b, GM-CSF) and chemokines, as well as inflammatory enzymes (iNOS, COX-2).138 It may
353
produce this widespread anti-inflammatory action by inhibiting NF-jB.139 There is evidence that IL-10 secretion and gene transcription are defective in macrophages and monocytes from asthmatic patients;140,141 this may lead to enhancement of inflammatory effects in asthma and may be a determinant of asthma severity (Fig. 35.9). Other mediators may also have anti-inflammatory and immunosuppressive effects. PGE2 has inhibitory effects on macrophages, epithelial cells, and eosinophils. Exogenous PGE2 inhibits allergen-induced airway responses, and its endogenous generation may account for the refractory period after exercise challenge.142 However, it is unlikely that endogenous PGE2 is important in most asthmatics since nonselective cycloxygenase inhibitors worsen asthma only in a minority of patients (aspirin-induced asthma). Other lipid mediators may also be anti-inflammatory, including 15HETE that is produced in high concentration by airway epithelial cells. 15-HETE and lipoxins may inhibit cysteinylleukotriene effects on the airways.143 Lipoxins are known to have strong anti-inflammatory effects, most likely through modulation of the trafficking of key intracellular proinflammatory intermediates.144,145 The peptide adrenomedullin, which is expressed in high concentrations in lung, has bronchodilator activity146 and also appears to inhibit the secretion of cytokines from macrophages.147 Its role in asthma is currently unknown. Airway and alveolar macrophages have a predominantly suppressive effect in asthma and inhibit T cell proliferation.148,149 The mechanism of macrophage-induced immunosuppression is not yet certain, but PGE2 and IL-10 secretion may contribute. There is some evidence that the immunosuppressive effect of macrophages is reduced in asthmatic patients after allergen challenge in vitro, thus favoring T cell proliferation.15
Inflammatory stimuli LPS
IL-10
ⴚ
ⴙ
ⴙ NF-κB NF-κB
late
ⴙ
Macrophage
early
Corticosteroids Theophylline? PDE4 inhibitors
ⴙ
Inflammatory proteins iNOS, COX-2 IL-1β, TNF-α, GM-CSF MIP-1α, RANTES
Fig. 35.9. Interleukin-10 is an anti-inflammatory cytokine that may inhibit the expression of inflammatory mediators from macrophages. IL-10 secretion is deficient in macrophages from patients with asthma, resulting in increased release of inflammatory mediators.
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GENETIC INFLUENCES There is now extensive research on the genetics of asthma, although most of this research relates to the genetics of atopy, which provides little insight into the mechanisms of asthma.150 Atopy is clearly determined by genetic factors and several genes appear to be involved, although there are marked differences between different populations. There is evidence for linkage between markers on chromosome 11q13 which may relate to polymorphism of the gene coding for the b-chain of the high-affinity IgE receptor (FceRI), and 5q31, which codes for a cytokine cluster IL-3, IL-4, IL5, IL-9, IL-13, and GM-CSF. There are also associations between these linkages and airway hyperresponsiveness, although it is difficult to dissociate changes in airway reactivity from atopy. Atopy is the most important risk factor for the development of asthma; but while understanding the genetics of atopy will shed light on the nature of allergic inflammation, it may not be very informative in understanding asthma. It is likely that environmental factors (viral/bacterial infections, allergen exposure, diet) may be more important in determining whether an atopic individual becomes an asthmatic patient. However, once asthma is established, genetic factors may be important in determining the severity of the disease and its response to therapy (Fig. 35.10). Polymorphisms have been described in many genes involved in the inflammatory process and may occur in coding and promoter regions, resulting in increased production of inflammatory mediators, such as cytokines, for example. It is likely that a combination of multiple single-nucleotide polymorphisms (SNP) will help predict the natural history and outcome of asthma, but this idea has not yet been reduced to practice.
Environment Allergens Infections Diet, etc. Pollutants?
Atopy AHR
ASTHMA
Mild
UNANSWERED QUESTIONS Although our understanding of asthma has advanced very rapidly in recent years and this has led to a fundamental change in the approach to therapy, many important questions remain unanswered.162
GENES AND ASTHMA
Genes
An area of importance is the relationship between clinical responses to anti-asthma treatments and genotype at various drug targets. For example there are known to be a number of SNPs in the b2-adrenoceptor gene that result in structural changes in the b2-receptor structure associated with functional changes in isolated cell systems.151 These are related to the acute response to bronchodilator aerosols acting via this receptor,152,153 and with deleterious effects of chronic use of salbutamol.154,155 Similarly, there are genetically based functional variants in the regulation of the ALOX-5 gene156–158 which modify the clinical response to these treatments.159 Thus genetics may have its greatest impact on understanding the variance in asthma treatment responses. It is currently unclear why some patients develop severe asthma while others remain with mild disease throughout their lives. It is likely that genetic factors are important. An example of genetic polymorphism that is associated with asthma severity is the haplotypes of the IL-10 gene promoter that are linked to different expression of the IL-10 gene. Haplotypes that are associated with increased IL-10 production are significantly more commonly associated with mild asthma, whereas haplotypes associated with decreased production are more commonly associated with severe asthma.160 Another polymorphism of significance to the phenotype of severe asthma is the SNP in the promoter of the IL-4 gene.161 When present this SNP results in the creation of a binding site for NFAT gene; this SNP has been associated with lower FEV1 values among patients with a diagnosis of asthma.
Severe
Genes Environment
Fig. 35.10. There is an interaction between genetic and environmental factors in asthma.
Why is the prevalence of asthma increasing throughout the world as a consequence of Westernization? It is not clear what environmental factors are most important for the increase in atopic diseases, but it is likely that several factors are operating together. These factors include diet (reduced intake of antioxidants, reduced unsaturated fats), lack of early childhood infections (with consequent tendency to develop Th2-driven responses), greater exposure to allergens in the home (tight housing, mattresses, central heating providing more favorable environment), cigarette smoking (pregnancy and early childhood exposure) and possibly air pollution due to road traffic. Why does asthma once established become chronic in some individuals but remain intermittent and episodic in others? For example, occupational asthma due to chemical sensitizers, such as toluene diisocyanate, may remit if the patient is removed from exposure to the sensitizer within 6 months of development of asthma symptoms, whereas longer
Pathophysiology of Asthma
exposure is often associated with persistent asthma even when avoidance of exposure is complete.163 This suggests that once inflammation is established it may continue independently of a causal mechanism. In contrast, numerous patients with asthma due to environmental exposures, such as dust mites, can become asthma-free when removed from the exposure. Are there different types of asthma, each characterized by a common genetic background with its attendant immunological and inflammatory response? Intrinsic asthma, where there is no identifiable atopy, looks very similar to allergic asthma clinically and immunocytochemically, yet there are likely to be immunological differences. Can we develop genetic or biochemical criteria which would allow identification of phenotypically uniform patient cohorts? How does inflammation of the airways translate into clinical symptoms of asthma? Airway thickening, as a consequence of the inflammatory response, may contribute to increased responsiveness to spasmogens.164,165 However, there is no obvious relationship between the inflammatory response in airways and asthma severity; patients with mild asthma may have a similar eosinophil response to patients with severe asthma, suggesting that there are other factors that determine clinical severity. The nature of these “factors” remains elusive, but we must identify them if we are to make true scientific progress. How important are genetic factors (genetic polymorphisms) in determining the phenotype of asthma? Disease is of differing severity and varying responsiveness to steroids, b2-agonists and other therapies. By determining the profile of genetic polymorphisms in an individual patient, using novel gene-chip technology, it may be possible to predict who is at risk for asthma, to predict the severity of asthma, or to predict the response to treatment. Are asthma and atopy causally related or just closely linked? Much of our understanding of asthma derives from study of models of allergy. Although these models are of great value in defining the pathobiology of asthma, how closely will they relate to the human disease?
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114. Joos GF, Germonpre PR, Pauwels R. Role of tachykinins in asthma. Allergy 2000; 55:321–37. 115. Canning BJ, Undem BJ. Evidence that antidromically stimulated vagal afferents activate inhibitory neurones innervating guineapig trachealis. J. Physiol. London 1994; 480:613–25. 116. Barnes PJ. Modulation of neurotransmission in airways. Physiol. Rev. 1992; 72:699–729. 117. Braun A, Lommatzsch M, Lewin GR, Virchow JC, Renz H. Neurotrophins: a link between airway inflammation and airway smooth muscle contractility in asthma? Int. Arch. Allergy Immunol. 1999; 118:163–5. 118. Lammers JW, Barnes PJ, Chung KF. Nonadrenergic, noncholinergic airway inhibitory nerves. Eur. Respir. J. 1992; 5:239–46. 119. Ollerenshaw S, Jarvis D, Woolcock A, Sullivan C, Scheibner T. Absence of immunoreactive vasoactive intestinal polypeptide in tissue from the lungs of patients with asthma. N. Engl. J. Med. 1989; 320:1244–8. 120. Belvisi MG, Stretton CD,Yacoub M, Barnes PJ. Nitric oxide is the endogenous neurotransmitter of bronchodilator nerves in humans. Eur. J. Pharmacol. 1992; 210:221–2. 121. Lilly CM, Martins MA, Drazen JM. Peptidase modulation of vasoactive intestinal peptide pulmonary relaxation in tracheal superfused guinea pig lungs. J. Clin. Invest. 1993; 91:235–43. 122. Barnes PJ. Sensory nerves, neuropeptides, and asthma. Ann. NY Acad. Sci. 1991; 629:359–70. 123. Ollerenshaw SL, Jarvis D, Sullivan CE, Woolcock AJ. Substance P immunoreactive nerves in airways from asthmatics and nonasthmatics. Eur. Respir. J. 1991; 4:673–82. 124. Howarth PH, Springall DR, Redington AE et al. Neuropeptidecontaining nerves in endobronchial biopsies from asthmatic and nonasthmatic subjects. Am. J. Respir. Cell Mol. Biol. 1995; 13:288–96. 125. Nadel JA. Neutral endopeptidase modulates neurogenic inflammation. Eur. Respir. J. 1991; 4:745–54. 126. Adcock IM, Peters M, Gelder C et al. Increased tachykinin receptor gene expression in asthmatic lung and its modulation by steroids. J. Mol. Endocrinol. 1993; 11:1–7. 127. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N. Engl. J. Med. 1998; 339:1194–200. 128. Brown PJ, Greville HW, Finucane KE. Asthma and irreversible airflow obstruction. Thorax 1984; 39:131–6. 129. Barnes PJ, Adcock IM. Transcription factors and asthma. Eur. Respir. J. 1998; 12:221–34. 130. Barnes PJ, Adcock IM. Transcription factors. Clin. Exp. Allergy 1995; 25(Suppl. 2):46–9. 131. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 1997; 336:1066–71. 132. Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF. Activation and localization of transcription factor, nuclear factor-kappa B, in asthma. Am. J. Respir. Crit. Care Med. 1998; 158:1585–92. 133. Demoly P, Basset-Seguin N, Chanez P et al. c-fos proto-oncogene expression in bronchial biopsies of asthmatics. Am. J. Respir. Cell Mol. Biol. 1992; 7:128–33. 134. Herrscher RF, Kasper C, Sullivan TJ. Endogenous cortisol regulates immunoglobulin E-dependent late phase reactions. J. Clin. Invest. 1992; 90:596–603. 135. Schleimer RP. Potential regulation of inflammation in the lung by local metabolism of hydrocortisone. Am. J. Respir. Cell Mol. Biol. 1991; 4:166–73. 136. Barnes PJ, Lim S. Inhibitory cytokines in asthma. Mol. Med.Today 1998; 4:452–8. 137. Selig W, Tocker J. Effect of interleukin-1 receptor antagonist on antigen-induced pulmonary responses in guinea pigs. Eur. J. Pharmacol. 1992; 213:331–6. 138. Ho AS, Moore KW. Interleukin-10 and its receptor. Therap. Immunol. 1994; 1:173–85.
139. Wang P, Wu P, Siegel MI, Egan RW, Billah MM. Interleukin (IL)10 inhibits nuclear factor kappa B (NF-jB) activation in human monocytes. IL-10 and IL-4 suppress cytokine synthesis by different mechanisms. J. Biol. Chem. 1995; 270:9558–63. 140. Borish L, Aarons A, Rumbyrt J et al. Interleukin-10 regulation in normal subjects and patients with asthma. J. Allergy Clin. Immunol. 1996; 97:1288–96. 141. John M, Lim S, Seybold J et al. Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein1a, granulocyte–macrophage colony-stimulating factor, and interferon-c release from alveolar macrophages in asthma. Am. J. Respir. Crit. Care Med. 1998; 157:256–62. 142. Pavord ID, Tattersfield AE. Bronchoprotective role for endogenous prostaglandin E2. Lancet 1995; 345:436–8. 143. Lee TH. Lipoxin A4: a novel anti-inflammatory molecule? Thorax 1995; 50:111–12. 144. Levy BD, Fokin VV, Clark JM et al. Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a “stop” signaling switch for aspirin-triggered lipoxin A4. FASEB J. 1999; 13:903–11. 145. Levy BD, Petasis NA, Serhan CN. Polyisoprenyl phosphates in intracellular signalling. Nature 1997; 389:985–90. 146. Kanazawa H, Kurihara N, Hirata K et al. Adrenomedullin, a newly discovered hypotensive peptide, is a potent bronchodilator. Biochem. Biophys. Res. Commun. 1994; 205:251–4. 147. Kamoi H, Kanazawa H, Hirata K et al. Adrenomedullin inhibits the secretion of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, from rat alveolar macrophages. Biochem. Biophys. Res. Commun. 1995; 211:1031–5. 148. Holt PG. Regulation of antigen-presenting cell function(s) in lung and airway tissues. Eur. Respir. J. 1993; 6:120–9. 149. Upham JW, Strickland DH, Bilyk N, Robinson BW, Holt PG. Alveolar macrophages from humans and rodents selectively inhibit T-cell proliferation but permit T-cell activation and cytokine secretion. Immunology 1995; 84:142–7. 150. Sandford A, Weir T, Paré P. The genetics of asthma. Am. J. Respir. Crit. Care Med. 1996; 153:1749–65. 151. Liggett SB. Polymorphisms of the beta(2)-adrenergic receptor and asthma. Am. J. Respir. Crit. Care Med. 1997; 156:S156–62. 152. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the b2adrenoceptor and response to albuterol in children with and without a history of wheezing. J. Clin. Invest. 1997; 100:3184–8. 153. Hall IP, Wheatley A, Christie G et al. Association of CCR5 del 32 with reduced risk of asthma. Lancet 1999; 354:1264–5. 154. Hancox RJ, Sears MR, Taylor DR. Polymorphism of the beta(2)adrenoceptor and the response to long-term b2-agonist therapy in asthma. Eur. Resp. J. 1998; 11:589–93. 155. Israel E, Drazen JM, Boushey HA et al. Effect of polymorphisms of the b2-adrenergic receptor on the response to regular use of albuterol in asthma. Am. J. Respir. Crit. Care Med. 2000; 162: 75–80. 156. In KH, Asano K, Beier D et al. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J. Clin. Invest. 1997; 99:1130–7. 157. Silverman ES, Du J, Desanctis GT et al. Egr-1 and Sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. Am. J. Respir. Cell Molec. Biol. 1998; 19:316–23. 158. Silverman ES, Du J, Williams AJ et al. cAMP-response-elementbinding protein (CBP) and p300 are transcriptional coactivators of early growth response factor-1 (Egr-1). Biochem. J. 1998; 336:183–9. 159. Drazen JM, Yandava C, Dube L et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Gen. 1999; 22:170–2.
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160. Lim S, Crawley E, Woo P, Barnes PJ. Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet 1998; 352:113. 161. Burchard EG, Silverman EK, Rosenwasser LJ et al. Association between a sequence variant in the IL-4 gene promoter and FEV1 in asthma. Am. J. Respir. Crit. Care Med. 1999; 160:919–22. 162. Woolcock AJ, Barnes PJ. Asthma: the important questions 3. Am. J. Respir. Crit. Care Med. 2000; 161:S157–230.
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163. Chan-Yeung M, Malo JL. Occupational asthma. N. Engl. J. Med. 1995; 333:107–12. 164. Paré PD, Bai TR. The consequences of chronic allergic inflammation. Thorax 1995; 50:328–32. 165. Shore SA, Laporte J, Hall IP, Hardy E, Panettieri RAJ. Effect of IL-1 beta on responses of cultured human airway smooth muscle cells to bronchodilator agonists. Am. J. Respir. Cell Mol. Biol. 1997; 16:702–12.
Pathogenesis of COPD
Chapter
36
Stephen I. Rennard University of Nebraska Medical Center, Omaha, NE, USA
Peter J. Barnes National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
INTRODUCTION Chronic obstructive pulmonary disease (COPD), recently redefined in the GOLD Guideline,1 is a clinical entity which includes a collection of disorders sharing the common physiological feature of progressively worsening expiratory airflow limitation.2–4 The various conditions included under the rubric COPD have different risk factors and pathophysiological mechanisms. COPD has been a useful term, however, as both chronic bronchitis and emphysema are often the result of cigarette smoking and therefore often coexist. Use of the all-inclusive term “COPD” simplifies the need for a more precise diagnosis. As therapies advance from general supportive care and become based on specific pathophysiological processes, however, it is likely that more accurate diagnoses will be essential. Moreover, while it is convenient to have a single term that includes multiple processes which have similar clinical and physiological features, current usage has tended to focus attention on cigarette smoking while discounting the importance of other exposures. Airflow limitation (see Chapter 5 on Respiratory Physiology and Chapter 6 on Airway Pathology) in COPD likely results from several distinct lesions.5 In emphysema, alveolar destruction is associated with a loss of elastic recoil of the lung. As a result, there is little intra-alveolar pressure driving exhalation. Patency of small airways depends on both intraluminal pressure generated by elastic recoil and on the tethering effect of the walls of adjacent alveoli. Both the decrease in intraluminal pressure and the loss of adjacent alveoli in emphysema can lead to the collapse of small airways and can limit expiratory airflow. It is possible that IV drug abuse induces emphysema through a vascular mechanism (see below), and that cadmium may have adverse effects on repair processes. It is likely, therefore, that the many etiological agents associated with the development of
COPD will be acting through a number of distinct mechanisms. Peribronchial fibrosis also leads to fixed airflow limitation by causing narrowing of small airways. It is likely that these two lesions, alveolar destruction with loss of elastic recoil and peribronchial fibrosis with small airway narrowing, interact functionally to exacerbate further reduced expiratory flows. Clinical features of COPD are not solely related to airflow limitation.2 Excessive cough and production of secretions, for example, are the defining features of chronic bronchitis. For many patients, these symptoms may be the most troubling feature of the disease, and may be present in the absence of airflow limitation. Patients with COPD, moreover, have a variety of nonpulmonary problems which often affect their clinical course. These include, among other conditions, lung cancer,6,7 skeletal muscle dysfunction,8–10 osteoporosis and bone fracture,11 abdominal aortic aneurysm,12–14 and an increased incidence of cardiac mortality.15,16 While these comorbid conditions are related to the same risk factors as COPD, e.g. cigarette smoking, patients with COPD appear to be at increased risk for these illnesses independent of an effect related to smoking.The mechanistic basis for this increased shared susceptibility remains unknown. This chapter will review the pathophysiological mechanisms which are believed to underlie the development of COPD. Many of the cells and mediators believed to be involved in these processes are discussed in greater detail in other chapters. The focus in this chapter will be to review the evidence on which a role for specific cells and mediators in the COPD process is based, to review how these mediators are believed to lead to the anatomical and functional alterations which characterize COPD and to outline how understanding of the pathophysiological basis for COPD may direct future attempts to develop and utilize novel therapies.
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E T I O L O G I C A L FA C T O R S Exposures The most important etiological risk factors for the development of COPD are inhalational exposures. Cigarette smoke is the most important of these, as has been consistently observed in numerous studies.17–24 Exposures other than cigarette smoking, however, also contribute to the risk of COPD.25,26 Such exposures can both cause COPD independently of cigarette smoking and can increase the risk for COPD in the presence of concurrent cigarette smoking.27 Exposures leading to COPD include a range of both occupational28–30 and environmental fumes and dusts.31,32 Coal dust, for example, alone can lead to airflow limitation.33,34 Use of biomass for home cooking can result in significant inhalational exposure and a marked increased risk for the development of COPD.35–37 Such exposure is currently a major risk factor for COPD in parts of the developing world.35,37–39 Passive cigarette smoke exposure is also related to symptoms of cough and sputum production and is likely a risk factor for the development of airflow limitation.25,40,41 Some exposures which represent risk factors for the development of COPD, e.g. IV drug abuse42 and cadmium43 may act through pathways distinct from the more common inhalational exposures. Intravenous drug abuse may lead to the development of COPD by a vascular mechanism, and cadmium may act by altering the repair response (see below). These rare causes of COPD are particularly instructive as they indicate that a variety of mechanisms may lead to altered lung structure and function. To what degree such mechanisms are involved in the more common etiologies of COPD remains to be determined. It is likely that the varied inhalational exposures which lead to COPD share the ability to initiate some of the same pathogenetic mechanisms.This may account for some of the similarities of the disease induced by cigarette smoke and other environmental exposures. Most exposures, however, are complex and contain many candidate toxins. Importantly, not all exposed individuals will develop COPD. Genetic factors, most of which remain to be defined (see below), can affect risk. Infections Infections play a key role in COPD exacerbations. Up to two-thirds of exacerbations can be associated with a potential infectious pathogen, about half being bacterial and half being viral.44 Individuals with frequent exacerbations have been demonstrated to have an inferior quality of life as assessed by the St. George’s Respiratory Questionnaire.45 The suggestion has also been made that individuals with frequent exacerbations experience a more rapid decline in lung function. Damage induced by infections and the ensuing inflammatory process may make the airways more susceptible to subsequent infection.46 Infections have also been related to increased risk for the development of COPD. A history of severe childhood viral
infection has been associated with reduced lung function and with increased respiratory symptoms.25,47 There are several, non-exclusive, possible explanations for this association. First, there might be an increased diagnosis of severe infections in children who have underlying airway responsiveness which itself may be a risk factor. Second, viral infections may be related to another factor such as socioeconomic status or birthweight, which is itself related to COPD. Viral infections, moreover, may directly contribute to the development of COPD. In this regard, viral infections may result in incorporation of viral DNA into airway cells, which could alter the response to subsequent exposures increasing the risk of COPD. Animal studies suggest the incorporation of adenoviral DNA can amplify the inflammatory response induced when airway epithelial cells are exposed to cigarette smoke48,49 and increased levels of adenoviral DNA have been detected in the lungs of patients with COPD compared with control patients.50 In addition, HIV infection has also been related to the development of emphysema.51 HIV-induced pulmonary inflammation may play a role, although weight loss associated with HIV infection has also been suggested as a possible mechanism.52 Nutrition Nutritional status, independent of concurrent viral infection, is also probably a risk factor for the development of COPD. The famine and resulting starvation in the Warsaw ghetto in World War II was associated with the development of emphysema.53 Reduced bodyweight, often expressed as body mass index, is a poor prognostic sign in individuals with established COPD.54,55 Underweight individuals with COPD, moreover, appear to be at risk for the development of emphysema.56 The association of starvation and anabolic/ catabolic status with the development of COPD, particularly with emphysema, is also supported by experimental studies in animals (see below). Birthweight, lung growth, and development Low birthweight has been associated with the development of COPD in one study,57 although these results were not observed in another study.58 Low birthweight has also been associated with increased risk for asthma59,60 and with reduced lung function in both childhood61 and young adulthood.62 In this regard, reduced maximal attained lung function may identify individuals who are at increased risk for the development of COPD.63 While some of these results are controversial,58 it remains possible that developmental problems associated with low birthweight represent a risk factor for the development of COPD. Reactive airways Asthma and increased airways reactivity have been identified as risk factors for the development of COPD. This relationship was originally proposed by Orie and colleagues64 and termed the Dutch hypothesis. Asthmatics, as a group, experience accelerated loss of lung function65,66 as do
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smokers with increased airways reactivity (Fig. 36.1).67 Whether airways reactivity results from an inflammatory process which, in turn, also leads to loss of lung function in COPD or the airways reactivity directly causes COPD remains undetermined.
within families with COPD probands. Some of this risk may be due to shared environmental factors, but several studies in diverse populations also suggest shared genetic risk.68–70 To date the only well-defined genetic risk factor is deficiency of alpha-1 protease inhibitor.71–73 Severe deficiency in this major circulating inhibitor of serine proteases is associated with development of emphysema in nonsmokers, although not all deficient individuals are affected. In smokers, alpha-1 PI deficiency is associated with the accelerated development of emphysema and mortality.
Genetics It is likely that many genetic factors interact with and increase (or decrease) the risk of developing COPD. Family studies have demonstrated an increased risk of COPD
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Intermediate levels are present in heterozygotes and persons with mixed phenotypes. Individuals with intermediate levels may also be at increased risk of developing COPD or, if COPD is present, of developing COPD at a more rapid rate, but these possibilities are controversial.74,75 Polymorphisms in untranslated regions of the alpha-1 gene have been associated with an increased prevalence of COPD in some studies,76,77 but these association studies must be interpreted with caution.78 It is likely that many other genes will also be identified as being associated with risk of COPD. Several genetic associations have been suggested. Candidate genes include ABO secretor status,79,80 microsomal epoxide hydrolase,81 glutathione S-transferase,82 alpha-1 antichymotrypsin,83 the complement component GcG,84 the cytokine tumor necrosis factor-a (TNF-a),85 and microsatellite instability,86 although inconsistent results have often been reported when several studies are available. Several of the reported polymorphisms are in genes likely related to the inflammatory process believed to underlie the development of COPD and, therefore, to potential pathogenetic mechanisms related to COPD. Pathogenesis: integrating concepts Taken together, the currently available data suggest that the majority of COPD results from exposures to noxious agents. These, in turn, lead to activation of inflammatory processes within the lower respiratory tract. Damage to lung structures results from both the exposures and, more importantly, from the ensuing inflammatory responses. Inflammation and injury also activate repair responses. Some individuals, either on a genetic or developmental basis, appear to be particularly sensitive to the injurious effects of exposures and inflammation. Similarly, individuals likely differ in their ability to repair lung injury, differences which reflect both genetic and acquired (e.g. nutritional) heterogeneity. The following sections will review briefly the cells and mediators believed to play a role in COPD.
M E A S U R E M E N T O F I N F L A M M AT I O N I N COPD The inflammatory response in COPD has been assessed by several approaches. Pathology Studies of the pathology of COPD (see also Chapter 6) have been limited by the availability of specimens. Post-mortem specimens, samples obtained during surgical lobectomy or lung volume reduction surgery, have been used to demonstrate inflammatory changes in the airways and lung parenchyma in patients with COPD.87,88 In the airway mucosa of large and small airways, there is an increase in macrophages and T lymphocytes, particularly CD8 T cells (see also Chapter 6). Similar changes are found in lung parenchyma in association with emphysema.
Increases in parenchymal lymphocytes have been associated with increasing severity of emphysema.87 Emphysema has also been associated with focal deposition of collagen, consistent with the concept that there are ongoing attempts at repair of the emphysematous lesions.89 Bronchoalveolar lavage can sample the intraluminal contents of the airways and alveolar structure The first fluid returned from a wedged lavage is relatively enriched in airways material and characteristically demonstrates increased neutrophils in COPD patients.90,91 Subsequent returns may reflect inflammation in the lung periphery and are characterized by a marked increase in the numbers of macrophages and neutrophils.90,92–94 The increase in neutrophils recovered from the alveolar portions of airways lavage correlates with an increase in neutrophil elastase, quantifiable in bronchoalveolar lavage fluid. In one study, the severity of emphysema assessed by CT scan and by diffusion capacity was correlated with neutrophils and neutrophil elastase, and inversely correlated with elastase inhibitory capacity.95 Bronchial biopsy Fiber-optic bronchial biopsies have been restricted to proximal airways and show an increase in macrophages and T cells, particularly CD8 cells, thus reflecting the changes in peripheral airways assessed on surgical and autopsy specimens.96 In smokers and patients with mild COPD, neutrophils do not appear to be increased in the airway wall, contrasting with results noted above in the airway lumen,96,97 but are increased in patients with severe COPD.97 The inflammatory changes in bronchial biopsies are also present in ex-smokers with COPD, suggesting that the inflammatory response in COPD may persist, at least to a degree, even in the absence of causal mechanisms.98,99 Prospective studies evaluating endobronchial biopsies in COPD patients following smoking cessation will be required to determine if inflammatory changes are at least partially reversible. Such studies have not yet been reported. Studies using bronchoalveolar lavage (see above) have been reported in normal smokers.100 In such individuals, rapid decreases in the number of recovered macrophages have been reported, although it took as long as 2 years for the macrophages to be free of autofluorescent particles. A prospective study has also been reported using induced sputum (see below) in patients with bronchitis.101 In these individuals, improvement was also noted in sputum neutrophils following smoking cessation. Whether the intraluminal changes noted in these studies will be paralleled by changes within the airway wall, however, remains to be determined. Increased numbers of eosinophils have also been reported in the airways of some patients with COPD, although these patients may have coexisting asthma,92,102 and in other studies no increase in the numbers of airway eosinophils has been reported.96 Increased numbers of eosinophils have been reported in the airways during acute exacerbations of COPD.103,104
Pathogenesis of COPD
Induced sputum Induction of sputum with nebulized hypertonic saline can be safely performed even in patients with severe COPD (FEV1 40% predicted) and is a useful means of investigating airway inflammation in COPD. Taken as a group, induced sputum in COPD patients shows an increase in total cell numbers, indicating an increase in macrophages. There is also an increase in the proportion of neutrophils but not eosinophils.105,106 This is matched by an increase in myeloperoxidase (MPO) and human neutrophil lectin (HNL), reflecting neutrophil activation.107 There is, however, considerable individual variation. Whether this represents heterogeneity among COPD patients or reflects temporal variations in inflammation remains undetermined. In normal cigarette smokers there is an increase in the proportion of neutrophils compared with age-matched nonsmoking subjects, but, on average, this is less than seen in COPD patients. There is an inverse correlation between the proportion of neutrophils and the percentage of predicted FEV1.105,106 Although the numbers of eosinophils are not increased in sputum in stable COPD, there is an increase in both eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO), suggesting that eosinophils may have been degranulated.107 It is possible that neutrophil elastase derived from activated neutrophils in sputum may be responsible for degranulating these eosinophils.108 Exhaled markers With a need to develop noninvasive markers of airway inflammation, there has been particular interest in measurement of volatile markers of inflammation in the breath and exhaled condensates. Exhaled nitric oxide (NO) has been most extensively investigated and is clearly elevated in patients with asthma. Exhaled NO levels are much lower in COPD than in asthma and have been reported to be only slightly increased or normal in stable COPD109–111 and increased during exacerbations.109 This is partly because cigarette smoking itself reduces exhaled NO levels.112 Smoking cessation is associated with an increase in exhaled NO levels.113 Levels of exhaled carbon monoxide (CO) are increased in patients with COPD, although this measurement is affected by cigarette smoking. However, the levels of exhaled CO are increased even in ex-smokers with COPD.114 Markers of oxidative stress, including hydrogen peroxide (H2O2), ethane and 8-isoprostane are increased in expired condensates of patients with COPD.115–117
I N F L A M M AT O RY C E L L S (Each of the cell types discussed below is discussed in detail in another chapter.) Many inflammatory cells are increased and/or activated in COPD, but their contribution to disease progression is largely unknown. There are clearly interactions between the inflammatory cells involved in COPD (Fig. 36.2).
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Mediators LTB4 IL-8, GRO-α MCP-1, MIP-1α Cells GM-CSF Effects Macrophages ROS, NO Mucus hypersecretion Neutrophils Endothelin Fibrosis CD8 lymphocytes Substance P Alveolar wall Eosinophils destruction Epithelial cells Endoth cells Proteinases Fibroblasts Neutrophil elastase Cathepsins Proteinase-3 MMPs
Fig. 36.2. Cellular mechanisms in COPD. Activation of macrophages leads to recruitment of neutrophils and both cells release proteinases which may result in emphysema and chronic bronchitis if not counteracted by anti-proteinases.
Neutrophils Increased numbers of activated neutrophils are found in sputum and BAL fluid of patients with COPD,90,93,105,106 yet are little increased in the airways or lung parenchyma.87,118 This may reflect their rapid transit through the airways and parenchyma. Alternatively, this may reflect degranulation of neutrophils, making their subsequent recognition on histologic specimens difficult. Neutrophils secrete several proteinases, including neutrophil elastase (NE), cathepsin G and proteinase-3, which may contribute to parenchymal destruction. NE and proteinase-3 are potent mucus stimulants.119 Consistent with a role for neutrophils in the parenchyma in COPD, NE can be observed in the extracellular milieu in COPD. In particular, elastase has been found in association with elastin, consistent with its potential role in contributing to lung destruction,120,121 although these results have not been uniformly confirmed.122 Neutrophil recruitment to the airways and parenchyma involves adhesion to endothelial cells, and the adhesion molecule E-selectin is up-regulated on endothelial cells in the airways of COPD patients (Fig. 36.3).123 Circulating neutrophils show up-regulation of Mac-1 (CD11b/CD18) in stable COPD patients. Circulating neutrophils in smokers, moreover, are retained longer within the pulmonary circulation and, therefore, have increased potential to induce lung damage from within the intravascular space.124 Adherent neutrophils can migrate into the respiratory tract under the direction of neutrophil chemotactic factors, which include the chemokine interleukin (IL)-8 and leukotriene B4 (LTB4). Neutrophil survival in the respiratory tract may be increased by cytokines, such as granulocyte–macrophage colony-stimulating factor (GM-CSF). Although the role of neutrophils in COPD is not yet entirely clear, neutrophil numbers in bronchial biopsies and induced sputum are correlated with COPD disease severity97,105,125 and the numbers of neutrophils in BAL fluid and
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Fig. 36.3. Mechanism of neutrophil inflammation in COPD. Neutrophils derived from promyeloblasts in the bone marrow adhere to endothelial cells in the bronchial and pulmonary circulations, then move into the airways or parenchyma, where they survive and become activated to release serine proteinases.
sputum are markedly increased during acute exacerbations of COPD.126 BAL neutrophils, moreover, are increased in patients with COPD who have never smoked, whereas macrophage numbers are not increased, emphasizing the importance of neutrophils in COPD.127 However, while neutrophils have the capacity to cause elastolysis, this is not a prominent feature of other pulmonary diseases where chronic airway neutrophilia is prominent, including cystic fibrosis and bronchiectasis. This suggests that additional factors must be involved. One potential feature may be the distinction between intraluminal and parenchymal activation of neutrophils. In this regard, elastase released within the airway lumen may not be able to induce tissue destruction.128 It is, moreover, likely that neutrophilia is linked to mucus hypersecretion in chronic bronchitis (see below). Macrophages There is an increase in the numbers of macrophages in airways, lung parenchyma, BAL fluid and sputum in patients with COPD. Furthermore, macrophages are localized to sites of alveolar wall destruction in patients with emphysema87 and in the epithelium of small airways.88 There is a correlation between macrophage numbers in the airways and severity of COPD.97 Macrophages may be activated by
cigarette smoke to release inflammatory mediators, including TNF-a, IL-8 and LTB4 (Fig. 36.4). Macrophages are heterogeneous, but little is yet understood about different types of macrophage in the respiratory tract. Alveolar macrophages are also likely to be an important cellular source of elastolytic enzymes, including cathepsins and matrix metalloproteinases. The mechanisms that result in macrophage accumulation in COPD are not yet understood. It is likely that chemokines such as monocyte chemotactic protein-1 (MCP-1) recruit macrophages from circulating monocytes, although local production of macrophages in the lung may also be important. Elastin degradation products may also be important as chemotactic stimuli for macrophages in the lung parenchyma.129 T lymphocytes There is an increase in the total numbers of T lymphocytes in lung parenchyma, peripheral and central airways of patients with COPD, with the greatest increase in CD8 (cytotoxic) cells.87,96,130 There is a correlation between the numbers of T cells and the amount of alveolar destruction and the severity of airflow obstruction.87,96 However, the role of T cells in pathophysiology is not yet certain. CD8 cells have the capacity to cause cytolysis and apoptosis of alveolar
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CXCR1 CXCR2 Neutrophil elastase Cathepsins Proteinase 3 Pulmonary/bronchial vessel Elastolysis Mucus hypersecretion
Fig. 36.4. Interaction between macrophages, neutrophils and epithelial cells. Cigarette smoke activates macrophages and epithelial cells to produce tumor necrosis factor-a (TNF-a) which in turn switches on the gene for interleukin-8 (IL-8), which recruits and activates neutrophils. This is via the activation of the transcription factor nuclear factor jB (NF-jB).
epithelial cells through release of perforin and granzyme-B and by the release of TNF-a.131 An increased number of natural killer (NK) cells has also been reported in patients with severe COPD.97 Eosinophils The role of eosinophils in COPD is uncertain. Reports of increased eosinophils in the airways of some patients with COPD might be due to coexisting asthma. However, an increase in eosinophils during exacerbations of COPD103,104 may be important. Surprisingly, as noted above, the levels of ECP and EPO in induced sputum are as elevated in COPD as in asthma despite the absence of visible eosinophils, suggesting that they may have degranulated and are no longer recognizable by light microscopy.107 Perhaps this is due to the high levels of NE that degranulate eosinophils.108 Epithelial cells Airway epithelial cells play a critical role in asthma and may be a major source of inflammatory mediators. The airway epithelium is characteristically altered in COPD patients. A normal pseudo-stratified columnar epithelium can undergo goblet cell metaplasia with an increase in the number of goblet cells at the expense of ciliated cells. More severe degrees of abnormality are associated with basal cell hyperplasia and loss of the pseudo-stratified morphology. Frank squamous metaplasia may develop. Cigarette smoke is capable of activating airway epithelial cells to release inflammatory mediators including IL-8.132
The activated complement component C5A can synergistically potentiate this effect.133 Airway epithelial cells are also sources of mediators which can drive both epithelial cell and mesenchymal cell participation in repair responses including fibronectin, endothelin 1, PDGF, IGF1 and transforming growth factor-b (TGF-b). The role of airway epithelial cells in producing these mediators in COPD, however, remains to be defined. The alveolar epithelium is also likely affected in COPD. While in-vitro culture models suggest alveolar epithelial cells can produce mediators similar to airway epithelial cells, the importance of these findings in COPD remains to be defined.
I N F L A M M AT O RY M E D I AT O R S While many inflammatory mediators have been identified in asthma,134 there is much less information about the production and role of mediators in COPD. It is likely that many mediators are involved and that mediator antagonists (see also related chapters) will have potential as new therapies for COPD. Inflammatory mediators are derived from several cell types in the respiratory tract, and these mediators are likely to mediate several inflammatory effects (Fig. 36.5). Leukotrienes LTB4 is a potent chemoattractant for neutrophils and is increased in the sputum and exhaled breath condensates of
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Cigarette smoke (and other irritants)
Alveolar macrophage MCP-1
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CD8 lymphocyte
Protease inhibitors
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ⴚ Alveolar wall destruction (Emphysema)
Neutrophil elastase Cathepsins MMPs
Mucus hypersecretion (chronic bronchitis)
Fig. 36.5. Multiplicity of cells and mediators involved in the inflammatory response in COPD.
patients with COPD.125,135 It is probably mainly derived from alveolar macrophages, which secrete greater amounts of LTB4 in patients with COPD. Several potent LTB4 receptor antagonists have been developed for clinical studies and should elucidate the role of this mediator in COPD. There is no evidence that cysteinyl-leukotrienes (LTC4, LTD4, LTE4) are involved in COPD and levels of LTE4 in exhaled breath condensates are not increased. Clinical studies with anti-leukotrienes in COPD are currently underway. Such studies should help delineate the role of leukotrienes in COPD. Prostaglandins The role of prostaglandins (see Chapter 23) in COPD is unknown. Macrophages, epithelial cells and fibroblasts are all potent sources of prostaglandin E in the airway. The cytokines TNF-a and IL-1 are potent inducers of PGE production acting by increasing the expression of cycloxygenase 2. Oxidative stress may result in the nonenzymatic formation of novel prostanoid mediators, isoprostanes, directly from arachidonic acid without the involvement of cycloxygenase. There is increased formation of 8isoprostane in COPD in urine and in expired condensate.136,137 8-isoprostane is a potent constrictor of human airways. PGE has been suggested to have important effects modulating repair and remodeling responses in vitro,138,139
although the in-vivo effects remain unknown. The levels of PGE2 are increased in exhaled breath condensates of patients with COPD.135 Platelet-activating factor PAF enhances the release of LTB4 from activated neutrophils, indicating that it might have an amplifying effect on neutrophilic inflammation.140 Whether PAF is released from alveolar macrophages in patients with COPD is not yet certain. Reactive oxygen species There is compelling evidence for increased oxidative stress in patients with COPD.141 Cigarette smoke contains a high concentration of reactive oxygen species (ROS) (1017 moles/puff) and inflammatory cells, such as activated macrophages and neutrophils, likely contribute even more oxidants. Evidence for increased oxidative stress in COPD is provided by demonstration of increased concentrations of H2O2 in expired condensates, particularly during exacerbations,115 and increased 8-isoprostane levels in urine and expired condensate.116,136 The increased oxidative stress in COPD may have several deleterious effects: oxidation of anti-proteinases, such as a1-antitrypsin and secretory leukoprotease inhibitor (SLPI), may reduce the anti-proteinase shield, and may directly activate matrix metalloproteinases,
Pathogenesis of COPD
resulting in increased proteolysis. H2O2 directly constricts airway smooth muscle in vitro and hydroxyl radicals (OH) potently induce plasma exudation in airways. Oxidants also activate the transcription factor nuclear factor-jB (NF-jB), which orchestrates the expression of multiple inflammatory genes, including IL-8 and TNF-a. Superoxide anions (O2) rapidly combine with NO to form the potent radical peroxynitrite, which itself generates OH. Peroxynitrite reacts with tyrosine residues in proteins to form stable 3-nitrotyrosine residues and there is evidence that 3-nitrotyrosine immunoreactivity is increased in inflammatory cells in induced sputum in patients with COPD.142 ROS also induce lipid peroxidation, resulting in the formation of additional mediators, such as isoprostanes and the volatile hydrocarbons pentane and ethane, as well as inducing DNA damage. Exhaled ethane levels are markedly elevated in patients with COPD.117 ROS are normally counteracted by endogenous (glutathione, uric acid, bilirubin) and exogenous (vitamin C and vitamin E from diet) antioxidants. There is evidence of a reduction in antioxidant defenses in patients with COPD.141 Chemokines IL-8 selectively chemoattracts to neutrophils and is present in high concentrations in induced sputum of patients with COPD.105,143 Indeed, there is a good correlation between the levels of IL-8 and the degree of neutrophilia in sputum.105,143 IL-8 concentrations are also increased in BAL fluid of normal smokers and in patients with COPD, and this is also correlated with neutrophil counts in both groups.94,132 IL-8 may be secreted by macrophages, neutrophils and by airway epithelial cells. Other related (CXC) chemokines, such as GRO-a and GRO-b, are also increased in COPD.144 The CC-chemokine MCP-1 is increased in BAL fluid of patients with COPD and healthy smokers, whereas another CC-chemokine, macrophage inflammatory protein-1b (MIP-1b), is increased in COPD compared with normal subjects and healthy smokers.145 MCP-1 is a potent chemoattractant for monocytes and may be involved in macrophage recruitment into the lungs in smokers. The CC-chemokine MIP-1a shows increased expression in airway epithelial cells and might contribute to the macrophage activation in COPD.97 Cytokines TNF-a has been reported to be present in high concentrations in the sputum of COPD patients105 and is detectable in bronchial biopsies from patients with COPD.102 TNF-a activates the transcription factor NF-jB, which switches on the transcription of the IL-8 gene in epithelial cells and macrophages. Increased levels of TNF-a may account for some of the systemic features of COPD (see below). TNFa, moreover, may directly contribute to the development of COPD. In an animal model, intraperitoneal injections of TNF-a have been demonstrated to lead directly to the development of air space enlargement.146 Whether this is
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due to a direct effect of TNF-a on the lung or is mediated through an inflammatory process is undetermined. The concentrations of GM-CSF in BAL fluid are increased in stable COPD but markedly elevated during exacerbations.126 The number of GM-CSF-immunoreactive macrophages is increased in the sputum of patients with COPD.147 GM-CSF is important for neutrophil survival and may play an enhancing role in neutrophilic inflammation. GM-CSF produced in the lung may account for the increased neutrophilia which characterizes smokers and is an independent risk factor for the development of COPD.148 Growth factors TGF-b and epidermal growth factor (EGF) show increased expression in epithelial cells and submucosal cells (eosinophils and fibroblasts) in patients with COPD and might play a role in the structural changes in the airways (see below).149 EGF may play an important role in amplifying mucus secretion in COPD (see below).150 It is likely that a number of other growth factors, including platelet-derived growth factor (PDGF), insulin-like growth factor 1, transforming growth factor-a and vascular endothelial growth factor (VEGF), to name but a few, will also play important roles in COPD. Endothelins There is an increased concentration of endothelin-1 (ET-1) in induced sputum of patients with COPD.151 ET-1 is released by airway epithelial cells.152 Plasma levels of ET-1 are elevated in patients with severe COPD and this is likely to be related to chronic hypoxia in these patients.153 There is increased expression of ET-1 in pulmonary endothelial cells of patients with COPD who have secondary pulmonary hypertension,154 suggesting that ET-1 may contribute to the vascular remodeling associated with hypoxic pulmonary hypertension. ET-1 can also stimulate fibroblast recruitment and proliferation and may, therefore, contribute to the structural alterations which characterize the airways disease in COPD. Neuropeptides Several neuropeptides have potent effects on vascular function and mucus secretion. An increase in the concentration of substance P (SP) is found in the sputum of patients with chronic bronchitis.155 However, no significant differences in the number of nerves immunoreactive for SP, calcitonin gene-related peptide or vasoactive intestinal peptide (VIP), are found in bronchial biopsies from patients with COPD,156 although there is a slight decrease in the expression of neuropeptide Y in airway smooth muscle. An increase in VIP-immunoreactive nerves in the vicinity of submucosal glands in bronchial biopsies of patients with chronic bronchitis has been reported, suggesting a role for VIP in mucous hypersecretion.157 Proteinases Several enzymes that degrade matrix proteins are released in COPD and appear to be the underlying mechanism for
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alveolar destruction in emphysema. It is likely that they also result in mucus hypersecretion in chronic bronchitis. Proteinases differ in their substrate specificity, but the combination of proteinases increased in COPD is capable of degrading collagens and elastin, and therefore destroying alveolar walls. Elastin may be the most important target for these enzymes as there is a loss of elasticity in the lung parenchyma. While elastin is not believed to be regenerated in an active form in adult tissues, recent in-vitro studies raise the possibility of elastin repair.158 Neutrophils secrete three major serine proteases with elastolytic activity: neutrophil elastase, cathepsin G and proteinase 3. As model studies suggest that any of these may result in the development of emphysema, prevention of neutrophil protease-induced emphysema may require inhibitors of all three proteases. In addition to these proteases, neutrophils also release cathepsins, enzymes which are also present in macrophages. Matrix metalloproteinases (MMP) are a group of over 20 closely related endopeptidases that are capable of degrading all of the components of the extracellular matrix of lung parenchyma, including elastin, collagen, proteoglycans, laminin and fibronectin. They are produced by neutrophils, alveolar macrophages, fibroblasts and airway epithelial cells.159 Increased levels of collagenase (MMP-1), gelatinase A (MMP-2) and gelatinase B (MMP-9) have been detected in BAL fluid and induced sputum of patients with COPD.160,161 Lavaged macrophages from patients with emphysema express more MMP-9 and MMP-1 than cells from control subjects, suggesting that these cells, rather than neutrophils, may be a major cellular source.162 Alveolar macrophages also express a unique MMP, macrophage metalloelastase (MMP-12).159 MMP-12 knockout mice do not develop emphysema and do not show the expected increases in lung macrophages after long-term exposure to cigarette smoke,163 although the role of MMP-12 in humans is undefined.162 An immunocytochemical study of emphysematous lungs indicated increased expression of MMP-9 and MMP2, but not NE at sites of alveolar destruction164 although, as noted above, NE in an association with elastic fibers has been reported. Pathogenetic mechanisms Emphysema Current concepts regarding the pathogenesis of COPD originate with the observation by Laurell and Eriksson71 that individuals deficient in the serum protein alpha-1 protease inhibitor are at increased risk of developing emphysema. This study led directly to the protease–anti-protease hypothesis in which activity of proteolytic enzymes in excess of their endogenous inhibitors is believed to lead to lung destruction. This basic concept has been extended to include proteases and anti-proteases in addition to alpha-1 protease inhibitor and NE, to include toxic moieties other than proteases, and to reflect the ability of the lung to repair following injury.
Damage Cigarette smoke leads to activation of inflammatory processes by a variety of mechanisms. Smoke can, for example, activate a variety of cell types within the lung. Both macrophages and epithelial cells within the lung are activated by cigarette smoke to produce pro-inflammatory cytokines.165,166 Smoke can, moreover, activate complement leading to the activation of pro-inflammatory mediators independent of cellular activity.167 As a result, cigarette smoke can lead to the accumulation of activated inflammatory cells in the lung where they can release mediators capable of damaging lung structures. These inflammatory cells, as noted above, include predominately neutrophils and macrophages, both of which are capable of releasing moieties which can lead to lung destruction. In this regard, a spectrum of potent proteases,168,169 oxidants170 and toxic peptides171 have all been suggested to play a role. Importantly, the damage induced by these moieties may further potentiate the inflammation by releasing chemotactic peptides from the extracellular matrix.172 Lung damage mediated by smoke may also result from circulating inflammatory cells within lung blood vessels. Smokers have increased numbers of circulating neutrophils which are more rigid than nonsmokers’ neutrophils.173 These cells are retained excessively in the lung, perhaps because of their stiffness, and/or because of alteration in the pulmonary vascular endothelium.124,174 It has been suggested that these intravascular effects can also contribute to smoke-induced lung disease. Although few data are available, it is likely that other exposures have similar effects. Grain dust, for example, is associated with lower respiratory tract inflammation.175 Similarly, a number of studies have demonstrated that a variety of particulates can initiate inflammatory responses.176–179 It seems likely that indoor air pollution derived from burning of biomass fuels will also have similar effects. The concept, therefore, is emerging that a key mechanism in the development of COPD is the initiation of an inflammatory response secondary to an inhaled toxin. The toxins involved are heterogeneous as are the responding cells. Individual responses, moreover, may vary based on genetic and other factors. These features may account, in part, for the heterogeneity of COPD. That there is a relatively limited number of responses, however, also likely accounts for the fact that the conditions which comprise COPD are relatively similar despite the myriad potential variations in initiating stimuli. Lung defense Cigarette smoke may also exacerbate lung damage by impairing lung defense mechanisms. Smoke, for example, inactivates the serine protease inhibitor alpha-1 antiprotease thereby augmenting the activity of enzymes such as NE, which can damage lung tissue.180,181 In addition, smoke inhibits the activity of chemotactic factor inactivator, a down-regulator of the complement system.182 Such an effect could contribute to an excessive inflammatory response.
Pathogenesis of COPD
Repair Altered repair mechanisms may contribute to the development of emphysema. In this context, the net tissue loss which characterizes emphysema may result from inadequate repair in the face of injury. Several lines of evidence support this concept. First, several animal models of emphysema have been developed in which lung destruction is induced either by exposure to large concentrations of NE, to cigarette smoke or to other similar insults.183 Such injury is characterized by a rapid loss of lung connective tissue consistent with tissue destruction taking place.184,185 These models, however, are also associated with a rapid onset of new connective tissue synthesis. In many cases, total tissue matrix macromolecule concentration is restored to normal or increased levels within a few weeks of tissue injury. Similarly, in mild human emphysema, lung collagen content has been reported to be increased consistent with initiation of matrix molecule production.186,187 The concept that repair processes initiated in model systems of emphysema serve to mitigate the severity of the resulting emphysema is supported by studies in which repair processes are disrupted. For example, starvation can greatly potentiate the development of emphysema following elastase exposure in rats.188 Similarly, inhibition of matrix macromolecule cross-linking (see also Chapter 22, Extracellular Matrix) can also exacerbate the development of emphysema.189 In this context, cigarette smoke can interfere with repair processes by a number of mechanisms. Smoke can inhibit parenchymal cell recruitment, proliferation, matrix production and tissue remodeling.190,191 Smoke can also interfere with matrix macromolecule cross-linking.192 It is possible, therefore, that smoke can lead to the development of emphysema by three interacting mechanisms: (1) by initiating an inflammatory response which causes tissue destruction; (2) by interfering with the defenses which normally protect tissues from injury during inflammation; and (3) by disrupting the repair processes which have the potential for restoring tissue architecture in the face of injury. Recent studies by Voelkel and colleagues extend the concept of repair in emphysema and support the role of endothelial cells in the maintenance of lung structure. Endothelial cell survival is dependent on the vascular endothelial growth factor. Absence of VEGF or interference with its activity can lead to endothelial cell apoptosis. If this occurs in the lungs, particularly in the alveolar structures where the endothelial cells represent a major component of total tissue structure, the net result might be loss of alveolar structures and the development of emphysema. Consistent with such a model, lungs from patients with emphysema have been noted to have an increase in apoptosis as judged histochemically together with a reduction in the expression of both VEGF and the VEGF receptor.193 In support of this model, treatment of rats with a blocker of theVEGF receptor leads to an increase in apoptosis and the development of emphysema.194 These effects, in turn, can be blocked by an inhibitor of caspase 3, an enzyme required for the apoptosis sequence. Taken together, these studies suggest that emphysema may
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result from apoptotic loss of endothelial cells due to interference with VEGF. Such a model is appealing as it suggests a number of potential novel therapeutic targets. Rare causes of emphysema Cadmium can induce emphysema. While a rare condition, this may develop without apparent inflammation.195 Cadmium has been reported to interfere with some potential fibroblast-mediated repair responses in vitro, suggesting a possible mechanism for the development of emphysema.196 Lower respiratory tract inflammation, however, may play a pathogenetic role in the small number of cases of emphysema which have been reported in association with a variety of other disorders. Bullous emphysema has been reported as a rare complication of sarcoidosis.197 In one study of patients undergoing pneumoreductive surgery, 14% had evidence of interstitial fibrosis and 11% had noncaseating granulomas.198 As noted above, HIV infection has been associated with the development of emphysema. HIV infection, moreover, is associated with alveolar inflammation.199 Chronic bronchitis Mucus hypersecretion: while the concepts of the pathogenesis of chronic bronchitis are less fully developed than those for emphysema, many of the same mechanisms are believed to be involved. The airways are exposed to most of the same inhaled toxins as the alveolar structures, and deposition of larger particles occurs preferentially in the airways.200 Airways inflammation (see Chapter 6) is a regular feature of chronic bronchitis associated with both cigarette smoking and with other inhalant exposures. Therefore, bronchitis likely results from many of the same mechanisms as emphysema (discussed above). Also supporting this concept are experimental studies which suggest that inhalational exposures lead to inflammation, which can lead to both acute mucus production and an increase in the secretory apparatus, setting the stage for chronic mucus hypersecretion. In this regard, inflammatory mediators including neutrophil elastase are potent mucus secretagogues.201 Neutrophil elastase can also lead to secretory cell metaplasia.202 In this context, many stimuli which can lead to activation of mucin expression and goblet cell hyperplasia in the airways may do so indirectly by driving the recruitment and activation of neutrophils.203 Neutrophils, in turn, lead to ligand-independent activation of the EGF receptor, which then drives goblet cell metaplasia. The dependence of goblet cell metaplasia on activation of the EGF receptor150 suggests potential therapeutic strategies. In this regard, blockade of EGF-receptor signaling can block neutrophil-induced mucin expression.203 Many animal studies2,204 show that irritants205 can lead to an increase in secretory cells and to mucus gland hyperplasia. While the mechanisms by which these varied stimuli lead to metaplasia of the airways is undefined, inflammation with subsequent inflammatory cell activation of the EGF receptor could represent a unifying concept. Both cholinergic and adrenergic agonists can also modify the secretory
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apparatus.206,207 It is possible, therefore, that interactions among inflammatory mediators and other host responses including neurogenic pathways can regulate mucus hypersecretion in vivo. Tissue remodeling Peribronchial fibrosis and narrowing contributes to airflow limitation in chronic bronchitis.208,209 The mechanisms which lead to this process are unknown. However, injury of the small airways, either directly by inhaled toxins such as cigarette smoke or indirectly by the action of inflammatory mediators likely initiates repair processes. In this regard, the airway epithelium has considerable capacity to mediate repair. Following mechanical injury, for example, airway epithelial cells from the edge of the wound rapidly flatten and migrate to cover the defect.210–212 In-vitro studies suggest that fibronectin and TGF-b produced by the epithelial cells present in the wound may help direct these processes.213,214 The newly recruited cells then replicate and undergo an orderly sequence of differentiation. It is likely that these processes can often restore both anatomic structure and airway function. In addition to the epithelial cells, mesenchymal cells, fibroblasts and myofibroblasts, are also activated in the repair response (Fig. 36.6). The wave of accumulation and replication of epithelial cells which occurs 24 hours after mechanical injury is followed about 2 days later by the accumulation and proliferation of mesenchymal cells.215 Under normal circumstances, these cells disappear over the next few weeks. However, as in many tissues, repair in the airways can result in the excessive deposition of fibrotic extracellular matrix, and like most scars, these contract.216 If this were to happen circumferentially around an airway, airway narrowing would result. In this context, airway epithelial cells can also produce factors which drive fibroblast recruitment,217 proliferation,218,219 matrix production,220 and remodeling.138 Interestingly, the fibrotic process may be driven by some of the same mediators which may also lead to epithelial repair, such as TGF-b and fibronectin. Consistent with a role for these mediators, both TGF-b and fibronectin have been
reported in the airways and BAL fluid in asthma and chronic bronchitis.149,221 While the processes which regulate airway repair following injury are only partly delineated, it seems likely that disordered repair processes can lead to tissue remodeling with altered structure and function. Measurements of peripheral airway resistance using collateral ventilation are consistent with narrowed and relatively noncompliant small airways in mild asthma.222 These findings were present even though overall airflow was normal, and are consistent with the concept that fibrosis of the small airways may take place in asthma as a process separate from bronchospasm. Such a process could account for development of progressive loss of lung function in asthma.65,66 The unifying concept, therefore, emerges that airways changes in COPD, like the alveolar changes which result in emphysema, are a result of injury due to environmental toxins and the inflammation which they incite. While not evaluated in as much detail as in emphysema, it is likely that these injurious processes depend on the balance between proteases and their inhibitors, between oxidants and antioxidants and between agents which induce cell proliferation, cellular loss, and cellular differentiation. These processes can lead to tissue distortion and loss of function. Systemic effects It is becoming increasingly clear that COPD has systemic manifestations. The classification of COPD patients into “pink puffers” and “blue bloaters” was an early attempt to base COPD classification on systemic responses. While the “pink puffer” may not accurately reflect patients with emphysema (as “pink puffers” may also have bronchitis) and, therefore, be contrasted with the “blue bloaters” who have bronchitis (but who also may have emphysema), these two characteristic body phenotypes must reflect distinct systemic responses. Weight loss in COPD is now well recognized as a poor prognostic feature (Fig. 36.7).55 Reduced weight is associated with increased mortality in COPD patients across all weight ranges.This differs somewhat from all-cause mortality
TGF-β Fn
Fn
TGF-β
Fig. 36.6. Schematic events during epithelial repair. Following injury, epithelial cells release mediators including TGF-b and fibronectin which can mediate both epithelial repair and the accumulation of subjacent mesenchymal cells. Other mediators present in the local milieu can modulate the process leading either to restoration of normal tissue structure and function or to abnormal structure and dysfunctional tissue.
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>29 1.0
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Fig. 36.7. Relationship between mortality and body mass index in COPD patients followed prospectively. Reproduced from Reference 55 with permission.
where mortality also increases with overweight patients. The reasons for weight loss in COPD are likely to be multiple. Increased oxygen consumption due to increased work of breathing and resting energy expenditure,223,224 and decreased caloric intake based on dyspnea and/or depression have both been suggested, although these have not uniformly been found to be present.225 Cytokines produced as part of the inflammatory response may also play a role. As noted above, TNF-a is a cytokine thought to play a role in the inflammatory response in COPD. TNF-a is a well-described cause of cachexia, one of its early names being “cachexin”, as it was believed to account for the marked cachexia sometimes observed with chronic infections. Circulating levels of TNF-a have been reported to be increased in patients with COPD.226 Peripheral blood mononuclear cells obtained from weight-losing COPD patients, moreover, have been noted to produce increased amounts of TNF-a in response to standard stimuli when compared with mononuclear cells from normals and nonweight-losing COPD patients.227 These findings are consistent with a schema in which some patients with COPD are over-producers of TNF-a and, as a result, experience systemic manifestations, including weight loss, as a result of high systemic TNF-a levels. Consistent with this schema are the genetic studies suggesting polymorphisms in TNF-a which may be related to TNF-a expression.85 Action of circulating factors in COPD may explain other systemic effects. Weakness is a characteristic feature of COPD.228 While undoubtedly some weakness is due to the
deconditioning which develops as dyspneic patients decrease their level of exercise, some muscle weakness in COPD appears to be due to abnormalities in skeletal muscle.229 In this regard, apoptosis of skeletal muscle has been reported in COPD.The factors involved in this process remain to be determined. Acute exacerbations of COPD are likely associated with altered systemic levels of circulating cytokines. IL-6 levels, for example, are increased during and following an exacerbation.230 IL-6 is a potent stimulator for liver production of acute-phase reactants. This can result in a number of secondary effects, including an increase in coagulation factors. Such an effect may account for the increased risk of both venous thrombosis and acute myocardial infarctions for which patients with COPD are at increased risk. Lungderived cytokines acting on the coagulation system may also account for the increased cardiac mortality which occurs during acute episodes of air pollution.231 Whether the cytokines released during acute exacerbations and acute exposures are also increased and contribute to increased thrombotic risk during chronic stable COPD remains to be determined. Patients with COPD are frequently depressed.232 In many cases, this may be a situational response as the COPD patient confronts their increasingly compromised health. It is also possible that individuals with an underlying depression are at increased risk of becoming smokers and, therefore, at increased risk of developing COPD. Smoking cessation can, in some cases, unmask this underlying
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depression, thus accounting for depression in patients after they develop COPD.233 The cytokines believed to play a role in COPD, moreover, may also have effects on the central nervous system including effects on mood. It is possible, therefore, that some of the depression experienced by COPD patients also represents a systemic manifestation of lung inflammation. Concepts regarding the pathogenesis of COPD are expanding rapidly. It is clear that a variety of noxious agents can initiate processes within the lung which can lead to inflammation and tissue injury. Individual patient responses to these injurious stimuli are varied based on both genetic predisposition and other individual factors. These responses, however, can lead to alterations in tissue structure which can compromise expiratory airflow by a variety of mechanisms. These responses can, in addition, have systemic manifestations which are also characteristic features of COPD. Undoubtedly, future studies will continue to increase the number of cells and, in particular, the number of mediators involved in these processes. Delineation of the mechanisms which underlie the development of COPD and its manifestations, however, promises both to define novel therapeutic targets and, eventually, to guide the clinician in the effective use of new treatments.
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160. Finlay GA, Russell KJ, McMahon KJ et al. Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients. Thorax 1997; 52:502–6. 161. Culpitt SV, Maziak W, Loukidis S, Nightingale JA, Matthews JL, Barnes PJ. Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1635–9. 162. Finlay GA, O’Driscoll LR, Russell KJ et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am. J. Crit. Care Med. 1997; 156:240–7. 163. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smokeinduced emphysema in mice. Science 1997; 277:2002–4. 164. Ohnishi K, Takagi M, Yoshimochi K, Satomi S, Konttinen YT. Matrix metalloproteinase mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab. Invest. 1998; 78:1077–87. 165. Mio T, Romberger DJ, Thompson AB, Robbins RA, Heires A, Rennard SI. Cigarette smoke induces interleukin-8 release from human bronchial epithelial cells. Am. J. Respir. Crit. Care Med. 1997; 155:1770–6. 166. Hunninghake GW, Gadek JE, Fales HM, Crystal RG. Human alveolar macrophage-derived chemotactic factor for neutrophils: stimuli and partial characterization. J. Clin. Invest. 1980; 66:473–83. 167. Robbins RA, Nelson KJ, Gossman GL, Koyama S, Rennard SI. Complement activation by cigarette smoke. Am. J. Physiol. 1991; 260:L254–9. 168. McElvaney NG, Crystal RG. Proteases and lung injury. In: Crystal RG, West JB (eds.), The Lung: Scientific Foundations, pp. 2205–18. Philadelphia: Lippincott-Raven, 1997. 169. Shapiro SD. Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Curr. Opin. Cell Biol. 1998; 10:602–8. 170. Warren JS, Ward PA. Consequences of oxidant injury. In: Crystal RG, Barnes PJ, West JB, Weibel ER (eds.), The Lung: Scientific Foundations, pp. 2279–88. Philadelphia: Lippincott-Raven, 1997. 171. Ganz T, Lehrer RI. Defensins. Curr. Opin. Immunol. 1994; 6:584–9. 172. Senior RM, Griffin GL, Meacham RP. Chemotactic activity of elastin-derived peptides. J. Clin. Invest. 1980; 66:859–62. 173. Drost EM, Selby C, Lannan S, Lowe GD, MacNee W. Changes in neutrophil deformability following in vitro smoke exposure: mechanism and protection. Am. J. Respir. Cell Mol. Biol. 1992; 6:287–95. 174. Selby C, Drost E, Wraith PK, MacNee W. In vivo neutrophil sequestration within lungs of humans is determined by in vitro “filterability”. J. Appl. Physiol. 1991; 71:1996–2003. 175. Von Essen SG, O’Neill DP, McGranagham S, Olenchock SA, Rennard SI. Neutrophilic respiratory tract inflammation and peripheral blood neutrophilia after grain sorghum dust extract challenge. Chest 1995; 108:1425–33. 176. Li XY, Brown D, Smith S, MacNee W, Donaldson K. Short-term inflammatory responses following intratracheal instillation of fine and ultrafine carbon black in rats. Inhal. Toxicol. 1999; 11:709–31. 177. Monn C, Becker S. Cytotoxicity and induction of proinflammatory cytokines from human monocytes exposed to fine (PM2.5) and coarse particles (PM10-2.5) in outdoor and indoor air. Toxicol. Appl. Pharmacol. 1999; 155:245–52. 178. Salvi S, Blomberg A, Rudell B et al. Acute inflammatory responses in the airways and peripheral blood after short-term exposure to diesel exhaust in healthy human volunteers. Am. J. Respir. Crit. Care Med. 1999; 159:702–9. 179. Von Essen SG, Robbins RA, Thompson AB, Ertl RF, Linder J, Rennard SI. Mechanisms of neutrophil recruitment to the lung by grain dust exposure. Am. Rev. Respir. Dis. 1988; 138:921–7.
180. Carp H, Miller F, Hoidal JR, Janoff A. Potential mechanism of emphysema: alpha-1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity. Proc. Natl Acad. Sci. 1979; 79:2041–5. 181. Janoff A. Reduction of the elastase in inhibitory capacity of alpha-1-antitrypsin by peroxides in cigarette smoke. An analysis of the brands and the filters. Am. Rev. Respir. Dis. 1982; 126:25–30. 182. Robbins RA, Gossman GL, Nelson KJ, Koyama S, Thompson AB, Rennard SI. Inactivation of chemotactic factor inactivator by cigarette smoke. A potential mechanism of modulating neutrophil recruitment to the lung. Am. Rev. Respir. Dis. 1990; 142:763–8. 183. Snider G, Lucey E, Stone P. Animal models of emphysema. Am. Rev. Respir. Dis. 1986; 133:149–69. 184. Senior RM, Tegner H, Kuhn C, Ohlsson K, Starcher BC, Pierce JA.The induction of pulmonary emphysema with human leukocyte elastase. Am. Rev. Resp. Dis. 1977; 116:469–75. 185. Karlinsky JB, Fredette J, Davidovits G. The balance of lung connective tissue elements in elastase-induced emphysema. J. Lab. Clin. Med. 1983; 102:151–62. 186. Pierce JA, Hocott JB, Ebert RV. The collagen and elastin content of the lung in emphysema. Ann. Intern. Med. 1961; 55:210–21. 187. Lang MR, Fiaux GW, Gillooly M, Stewart JA, Hulmes DJS, Lamb D. Collagen content of alveolar wall tissue in emphysematous and non-emphysematous lungs. Thorax 1994; 49:319–26. 188. Sahebjami H, Domino M. Effects of starvation and refeeding on elastase-induced emphysema. J. Appl. Physiol. 1989; 66:2611–16. 189. Osman M, Cantor JO, Roffman S, Keller S, Turino GM, Mandl I. Cigarette smoke impairs elastin resynthesis in lungs of hamsters with elastase-induced emphysema. Am. Rev. Respir. Dis. 1985; 132:640–3. 190. Nakamura Y, Romberger DJ, Tate L et al. Cigarette smoke inhibits lung fibroblast proliferation and chemotaxis. Am. J. Respir. Crit. Care Med. 1995; 151:1497–503. 191. Carnevali S, Nakamura Y, Mio T et al. Cigarette smoke extract inhibits fibroblast-mediated collagen gel contraction. Am. J. Physiol. 1998; 247:L591–8. 192. Laurent P, Janoff A, Kagan HM. Cigarette smoke blocks crosslinking of elastin in vitro. Am. Rev. Respir. Dis. 1983; 127:189–92. 193. Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am. J. Respir. Crit. Care Med. 2001; 163:737–44. 194. Kasahara Y,Tuder RM,Taraseviciene-Stewart L et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J. Clin. Invest. 2000; 106:1311–19. 195. Postlethwaite AE, Keski-Oja J, Balian G, Kang AH. Induction of fibroblast chemotaxis by fibronectin: Localization of the chemotactic region to a 140,000 molecular weight non-gelatin binding fragment. J. Exp. Med. 1980; 153:494–9. 196. Liu XD, Umino T, Zhu YK et al. A study on the effect of cadmium on human lung fibroblasts. Chest 2000; 117:247S. 197. Judson A, Strange C. Bullous sarcoidosis. Chest 1998; 114:1474–8. 198. Keller CA, Naunheim KS, Osterloh J, Espiritu J, McDonald JW, Ramos RR. Histopathologic diagnosis made in lung tissue resected from patients with severe emphysema undergoing lung volume reduction surgery. Chest 1997; 111:941–7. 199. Autran B, Mayaud CM, Raphael M et al. Evidence for a cytotoxic T-lymphocyte alveolitis in human immunodeficiency virusinfected patients. AIDS 1988; 2:179–83. 200. Clarke SW, Yeates DB. Deposition and clearance. In: Murray JF, Nadel JA (eds.), Textbook of Respiratory Medicine, vol. 1, pp. 345–69. Philadelphia: WB Saunders, 1994.
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201. Sommerhoff CP, Nadel JA, Basbaum CB, Caughey GH. Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J. Clin. Invest. 1990; 85:682–9. 202. Christensen TG, Korthy AL, Snider GL, Hayes JA. Irreversible bronchial goblet cell metaplasia in hamsters with elastaseinduced panacinar emphysema. J. Clin. Invest. 1977; 59:397–404. 203. Takeyama K, Dabbagh K, Jeong Shim J, Dao-Pick T, Ueki IF, Nadel JA. Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils. J. Immunol. 2000; 164:1546–52. 204. Snider GL. Animal models of chronic airways injury. Chest 1992; 101:74S–9S. 205. Rogers DF, Jeffery PK. Inhibition by oral N-acetylcysteine of cigarette smoke-induced “bronchitis” in the rat. Exp. Lung Res. 1986; 10:267–83. 206. Reid L, Jones R. Experimental chronic bronchitis. Int. Rev. Pathol. 1983; 24:335–82. 207. Sturgess J, Reid L. The effect of isoprenaline and pilocarpine on (a) bronchial mucous secreting tissue and (b) pancreas, salivary glands, heart, thymus, liver and spleen. Br. J. Exp. Pathol. 1973; 54:388–99. 208. Kuwano K, Bosken CH, Pare PD, Bai TR, Wiggs BR, Hogg JC. Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1993; 148:1220–5. 209. Matsuba K,Wright JL,Wiggs BR, Pare PD, Hogg JC.The changes in airways structure associated with reduced forced expiratory volume in one second. Eur. Respir. J. 1989; 2:834–9. 210. Erjefalt JS, Persson CG. Airway epithelial repair: breathtakingly quick and multipotentially pathogenic. Thorax 1997; 52:1010–12. 211. McDowell EM, Beals TF. Biopsy Pathology of the Bronchi pp. 140–91, Philadelphia: WB Saunders, 1987. 212. Lane BP, Gordon R. Regeneration of rat tracheal epithelium after mechanical injury. Proc. Soc. Exp. Biol. Med. 1974; 145:1139–44. 213. Shoji S, Ertl RF, Linder J, Romberger DJ, Rennard SI. Bronchial epithelial cells produce chemotactic activity for bronchial epithelial cells: Possible role for fibronectin in airway repair. Am. Rev. Respir. Dis. 1990; 141:218–25. 214. Sacco O, Romberger D, Rizzino A, Beckmann J, Rennard SI, Spurzem JR. Spontaneous production of transforming growth factor beta 2 by primary cultures of bronchial epithelial cells: effects on cell behavior in vitro. J. Clin. Invest. 1992; 90:1379–85. 215. Erjefalt JS, Erjefalt I, Sundler F, Persson GA. In vivo restitution of airway epithelium. Cell Tissue Res. 1995; 281:305–16. 216. Rennard SI. Repair of the airway epithelium: Potential opportunities for therapeutic intervention in airway disease. Allergol. Intl 1998; 47:91–7. 217. Shoji S, Rickard KA, Ertl RF, Robbins RA, Linder J, Rennard SI. Bronchial epithelial cells produce lung fibroblast chemotactic factor: Fibronectin. Am. J. Respir. Cell Mol. Biol. 1989; 1:13–20.
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Chapter
Allergens
37
D. W. Cockcroft University of Saskatchewan, Royal University Hospital, Saskatoon, Saskatchewan, Canada
H I S T O RY Allergy, i.e. type I IgE-mediated sensitization and sequelae to predominantly inhaled allergens, has become increasingly recognized as important in the pathogenesis of asthma. The development of this increased recognition is briefly outlined, focusing on identification of allergy and its mechanisms, on the relevance of allergen in the pathogenesis of asthma, and on increased prevalence of the condition(s). Allergy Although “rose catarrh” (likely actually due to grass pollen) had been known for some time, the first comprehensive clinical description of allergic rhinitis is attributed to John Bostock in 1819.1 The disease was given the medical name “catarrhus aestivus” (summer cold) but was recognized in the lay literature as “hay fever”, a label which persists to this day. This disease was felt to be limited to the middle and upper classes and a major prevailing hypothesis was that it was due to the effects of summer heat and/or sunshine.1 Grass pollen had been suggested as a potential cause but this was not confirmed until the elegant experiments of Charles Blackley in 1873.2 The term “allergy” (different from normal) was coined by Von Pirquet in 1906.3 In 1912, allergy skin testing was first used in the investigation of this type of hypersensitivity.4 With the mistaken belief that pollen contained a toxin, the concept of pollen immunization was introduced by Dunbar5 and popularized by Noon in 1911.6,7 Prausnitz and Kustner disproved the toxin hypothesis by the demonstration of passive transfer of allergic sensitivity using the injection of the serum of a sensitized individual into the skin of a nonsensitized subject8 – the basis of the so-called PK test. Coca demonstrated that a heat labile serum factor which could not be precipitated from serum by the usual methods was the case of this sensitivity and, in 1923, he coined the terms “atopy” (strange disease) and “atopic reagin” as the name for this serum factor.9 Reaginic antibody was eventually identified as IgE by Ishizaka in 1967.10 The complete allergen response, including allergen-presenting cells, lymphocytes (T helper 2 or Th2 and B cells), mast cells, basophils, and mediators is still being elucidated.
Allergy and asthma The recognition of allergens as potential causes of asthma parallels the recognition of allergy. Classic asthma symptoms were a major component of Bostock’s original description of catarrhus aestivus.1 Pollen, both ragweed11 and grass,2 was specifically shown to provoke attacks of asthma in the 1870s. Cat, horse, and house dust mites were identified as relevant asthma-producing allergens in the early part of the twentieth century,12 and more recently, fungal spore sensitivity has been identified as a risk factor for asthma.13 Asthma became lumped with the atopic diseases by many in the early part of the twentieth century. However, the very influential Osler’s textbook had stated that asthma was a “neurosis”,14 an opinion which continued to hold weight for many years. The opposing view, namely that asthma was primarily an atopic allergic disease, was argued by Cooke and colleagues.15 This controversy persisted well into the twentieth century. The identification of allergen-induced late asthmatic responses,16 allergen-induced airway hyperresponsiveness,17 and allergen-induced airway inflammation,18 i.e. features which define clinical asthma, has led to allergens becoming recognized as important in the pathogenesis of asthma. (The term “airway (hyper) responsiveness” throughout this chapter, unless otherwise stated, refers to the nonallergic (hyper) responsiveness to histamine, cholinergic agonists, exercise, etc. which is a characteristic feature of symptomatic asthma.) Although still a subject of some controversy,19 many investigators now regard the majority, i.e. 75 to 80%, of nonselected asthmatics, as being atopic.20,21 Prevalence There was a striking increase in the prevalence of allergic rhinitis from the beginning to the end of the nineteenth century.22 Within that time-frame, allergic disease went from rare and reportable in the early 1800s to a common disorder by 1900. A case can be made that this is, at least in part, related to earlier underrecognition of a condition whose symptoms (rhinitis, wheezing) resemble other conditions believed to have been more common, and whose symptoms are often so mild as potentially to go unreported at a time
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when there were many more serious diseases with which to be concerned. As early as 1873, Blackley noted the rising prevalence of allergic disease and felt that this could not adequately be explained by increased recognition, which he admitted did play a role.2 The prevalence of atopic disease and asthma, in particular, has continued to increase throughout the twentieth century with more objective data to support these trends. The reasons for the remarkable increase in the prevalence of atopy and asthma are not completely understood. Genetics play a role in determining the presence and severity of atopy, however, large changes in prevalence over a short period must be due to one or more environmental factors. One hypothesis is increased exposure to allergens, particularly indoor allergens in modern air-tight homes, may lead to increased atopy and asthma.23 This has been demonstrated prospectively in Papua New Guinea where blanket introduction was followed by house dust mites, house dust mite sensitivity, and an asthma epidemic.24 Another intriguing hypothesis is the “hygiene hypothesis”.25 This hypothesis suggests that early childhood infections drive the immune system towards the T helper 1 (Th1) paradigm which suppresses or reduces the Th2 arm of the immune system. Control/prevention of infections will remove this Th2 suppression and lead to an increased prevalence of Th2-related atopic disease. The evidence for this, including family-size studies and epidemiologic studies related to infection, is stronger for atopy than for asthma alone.25 Other factors related to lifestyle issues including diet and level of activity may be important.23
AT O P Y Atopy is the tendency to develop IgE antibodies to commonly encountered environmental allergens by natural exposure in which the route of entry of allergen is across intact mucosal surfaces.26 The recognized familial nature of atopy is due to complex (multiple gene) inheritance (genetic heterogeneity).21,27 The remarkable relatively short-term increase in atopic prevalence indicates that environmental factors are also important.22–25 The pathophysiological basis for subjects developing atopy is uncertain and is the topic of a recent symposium.28 An old hypothesis favoring allergen handling perhaps at the mucosal surface29 rather than increased capacity to produce IgE has not been excluded. The prevalence of atopy in random populations, defined as the presence of positive(s) on prick skin tests with a small battery of allergens, ranges from 30 to almost 50%.30–32 The peak period of sensitization is in the third decade; thereafter the prevalence falls.26 Our experience with a random young population would suggest that about 50% of atopic (skin test positive) subjects will have symptoms referable to atopy, which will include asthma in about 50%.32 Thus, atopy is common, affecting about one in three, with about one in six having symptomatic atopy and about one in 12 having atopic asthma; the prevalences will be proportionately higher in populations with a higher prevalence of atopy.
ALLERGENS Inhaled complete allergens which provoke asthma by IgEmediated mechanisms are soluble organic high molecular weight (20,000–40,000 MW) protein or protein-containing molecules, which may be derived from any phylum of either the plant or animal kingdoms (including bacteria).33,34 The structural characteristics which make a protein allergenic have been recently reviewed.35 In clinical nonoccupational settings, the important inhalant allergens fall into four groups: pollen, fungal spores, animal danders, and household mite/insects.36 Pollen allergens Pollen allergens which trigger asthma are predominantly from wind-pollinated plants, namely trees, grass, and weeds.36 The relevant allergens and seasonal fluctuations will vary with geography and climate, with tree pollens predominant in spring months, grasses in summer, and weeds in late summer and autumn.34 Although whole pollen grains may have limited access to the lower respiratory tract,37 the relationships of pollen to clinical asthma is convincing.36 Fungal spores Atmospheric fungal spores of many groups of fungi are smaller and more respirable than pollen, and are recognized as causing atopic sensitization.13 Their role in triggering asthma is less certain than pollen.34,36 Fungal spore types and seasons will also vary with geographic and climatic (temperature/humidity) conditions. Fungal spores are associated with decaying vegetation resulting in a late summer and autumn peak for common fungal spores, Alternaria, Cladosporium, Aspergillus, Sporobolomyces, etc.34 A spring peak for atmospheric fungal spores may be seen in some areas especially where late melting of snow cover leads to so-called “snow mold”.34 Thus, atmospheric fungal spores may be responsible for fall or spring–fall asthma symptoms. Fungi may also be present inside living areas in moist basements, food storage areas, and waste receptacles.34 Aspergillus may cause a distinct clinical syndrome, allergic bronchopulmonary aspergillosis, which will be covered separately. Animal danders Household animals,34 particularly cats and dogs, but also small animals (gerbils, hamsters, rabbits, etc.) and birds may release allergens in secretions (e.g. saliva) or excretions (e.g. urine, feces). Large animals, particularly horses, may also provoke atopic sensitivity. Household mites/insects House dust, due to its content of mite antigens from various Dermatophagoides species or insect antigens such as the cockroach,38 is an important source of atopic sensitization. Dermatophagoides spp., in particular, are likely the most important cause of atopic sensitization worldwide. Again,
385
Allergens
climatic conditions are important, since areas of low indoor relative humidity do not favor growth of house dust mites.34,39
4.5
Inhalation
4.0
Other allergens Other allergens are encountered less frequently, often in occupational settings, and include various plant parts (castor bean, cocoa bean, tobacco leaf, psyllium (laxative), vegetable gums, etc.), insect dusts, bacterial enzymes, and in the very highly sensitized even atmospheric molecular levels of foods (e.g. cooking fish).34
3.5
3.0
INHALED ALLERGENS Patterns of airway response Airway responses to inhaled allergens have been assessed by the somewhat artificial inhalation tests in the laboratory with aqueous allergen extracts.17,40,41 Nevertheless, the results of such challenges, especially the late sequelae, appear to be clinically relevant,42,43 and allergen inhalation tests allow study of both the pharmacology and pathophysiology of allergen-induced asthma. Airway responses to allergen can be divided into early and late sequelae. The early asthmatic response (EAR) is an episode of airflow obstruction which is maximal 10–20 minutes after allergen inhalation and resolves spontaneously in 1 to 2 hours.17,40,41,44 The late sequelae include the late asthmatic response (LAR),16,17,40,41,43–46 airway hyperresponsiveness,17,41,42 recurrent nocturnal asthma,46 and airway inflammation.18,47 The LAR is an episode of airflow obstruction which develops after spontaneous resolution of the EAR between 3 and 5 hours after exposure, occasionally earlier, rarely later.17,40,41,43–45 Resolution usually begins by 6 to 8 hours but may require in excess of 12 hours.41,43,44 Modest late responses respond well to bronchodilators;48 unpublished observations suggest bronchodilators may be required often (e.g. up to 2 hourly). More severe late airway obstruction is not always completely reversible by bronchodilator.44 Examples of early and late responses are shown in Fig. 37.1. Allergen-induced increase in airway responsiveness (e.g. to histamine/methacholine) occurs following both experimental17,41,42,47 and natural42,49,50 allergen exposure. This is correlated with the occurrence and severity of the late response, often appearing with small, previously ignored, late responses (5–15% FEV1 fall).17,41 Airway responsiveness develops between 251 and 3 hours52–54 after exposure, is present at 7–8 hours17,41,51 and may persist for days, occasionally worsening despite return of airway caliber to baseline41 (Fig. 37.2). As expected,55 the increased airway responsiveness is associated with symptoms of asthma,17,41 including recurrent nocturnal asthma.46 Both the late asthmatic response18,47 and the increased airway responsiveness47 are associated with increases in airway inflammation.The occurrence of seasonal increases in responsiveness42,49,50 and airway inflammation56 provide support both for the relevance of the bronchoprovocation
FEV1 (Liters)
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Fig. 37.1. Early and dual asthmatic responses to allergen. The top graph shows an isolated early asthmatic response following ragweed pollen inhalation and the bottom graph a dual asthmatic response (in another subject) following grass pollen inhalation. Modified and reproduced from Reference 136, with permission.
model and for the importance of the inflammation in the pathogenesis of the late sequelae. Pharmacology Pharmacological inhibition of airway responses to inhaled allergen has been studied both for its therapeutic relevance and for further understanding of the pathophysiology of the responses. Inhaled β2 agonists are the best inhibitors of the EAR45,57–60 due to a combination of effects on smooth muscle and on mediator release.61,62 Despite the latter, intermediate-acting inhaled β2 agonists (salbutamol, terbutaline, etc.) do not inhibit the LAR45,57,58,60 or the increased airway responsiveness.60 The long-acting inhaled β2 agonists, salmeterol and formoterol, completely inhibit or mask all aspects of the allergen-induced airway response,63,64 likely due to functional antagonism rather than anti-inflammatory
386
Asthma and Chronic Obstructive Pulmonary Disease
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Fig. 37.2. Allergen-induced increase in nonallergic airway responsiveness to inhaled histamine. A dual asthmatic response, with spontaneous recovery, occurred after a single inhalation of ragweed pollen extract. Airway responsiveness to inhaled histamine, expressed as the provocation concentration causing a 2 0 % FEV, fall (PC20), increased after allergen exposure, and was associated with asthma symptoms on exposure to nonallergic stimuli. Reproduced from Reference 135, with permission.
effect.*'' Regular use of inhaled P2 agonists for a week or more increases the EAR,*^"*' the LAR,*'"*' mast cell mediator release,*' and allergen-induced airway inflammation.*'"*' A larger dose of allergen can be administered after an inhaled P2 agonist and will lead to a larger LAR.'" These features, failure to inhibit the LAR, enhanced airway responses, and ability to tolerate a larger dose of allergen, may be relevant in P2 agonist worsened asthma control." Muscarinic blockers cause variable minor inhibition of the EAR5''''2-74 and no inhibition of the LAR.'^.'^ Allergeninduced airway hyperresponsiveness appears to be uninfluenced by anticholinergics.''' The enhanced airway responsiveness to histamine following allergen inhalation is no more responsive to atropine than it was prior to allergen inhalation.'^ Ingested theophylline offers partial protection against both the EAR and the LAR'*"" and variable protection against induced airway hyperresponsiveness.""" It is not clear whether this is a functional antagonist or an antiinflammatory effect. Inhaled sodium cromoglycate (SCG) given prior to allergen exposure inhibits both the EAR and LAR, 44,45,57,60,77,80 .
well as the allergen-induced responsiveness to both histamine*" and methacholine." Nedocromil sodium appears to have similar effects on allergen-induced asthmatic responses.*' S C G given after the EAR will slightly delay but not inhibit the LAR.**^ A single dose of inhaled corticosteroid, given prior to allergen, has no influence on the EAR but provides effective, often complete inhibition of the lJ^R_11,1s,^^,6o,ao-a6 ^ ^jj^gjg dose given after the EAR will inhibit the LAR.*^ Longer treatment periods with inhaled corticosteroids will partially inhibit the EAR as well.**'*^'** Corticosteroid-induced provides only improvement m airway responsiveness* partial explanation.** Reduction in mucosal mast cells*'"" is likely more important. Hi blockers partially inhibit the early portion of the EAR.''^'^'"'^"''' Newer Hj blockers may also show some inhibition of the LAR;''' further studies are necessary. Ingested anti-allergic drugs such as ketotifen and repirinast have produced variable effects on allergen-induced asthma.'^"'"^ Most studies have failed to show any significant protection.'^•'*'""'"'^ Nonsteroidal anti-inflammatory agents, particularly indomethacin, appear to have no effect or perhaps enhance the EAR;'"^ there is conflicing evidence regarding the late response.'"''"'"* Allergen-induced increase in airway responsiveness appears to be partially inhibited by indomethacin.'"* A thromboxane synthetase inhibitor had no effect on allergen-induced early or late responses or increased airway responsiveness.'"' Interference with the leukotriene pathway with leukotriene receptor antagonists," 5-lipoxygenase inhibitors"" or 5-lipoxygenaseactivating protein inhibitors'" produces modest inhibition of EAR and LAR. A platelet activating factor antagonist proved ineffective against allergen-induced asthma."^ Inhaled furosemide provides inhibition of both EAR and LAR."^ Allergen injection therapy has produced variable results in modulating the EAR"'''"^ but may be particularly effective versus the LAR."* A novel recombinant anti-IgE molecule directed against the Fc component of IgE is very effective at inhibiting both the E A R ' " and LAR."* Mechanisms The mechanisms of allergen-induced asthmatic responses have been studied in humans by indirect means. Animal studies, in-vitro studies on excised human tracheobronchial smooth muscle, drug-inhibition studies and, more recently, bronchoalveolar lavage and induced sputum, have all been used to assess mechanisms. The EAR is due to the allergenIgE-mast cell acute mediator release including histamine,'" prostaglandins,'^" and leukotrienes'^' and is primarily bronchospastic. Individual mediator blockers are only partially effective in inhibiting the EAR,'^''^''"*''"' however, an in-vitro study on human tracheal smooth muscle demonstrated complete inhibition of the EAR by combined Hj blocker, cycloxygenase inhibitor and lipoxygenase inhibitor. '^^ The pathogenesis of the LAR is not so clear. An outdated hypothesis that late responses were type III precipitinmediated responses,'''' controversial at that time,^' has been
Allergens
disproved since both cutaneous123,124 and pulmonary118,125 late responses are IgE-mediated. Animal studies have documented the requirement for inflammatory cells (eosinophils, neutrophils) in the LAR126,127 and induced airway hyperresponsiveness.128–130 This has been confirmed in humans using BAL18,131 and induced sputum.47,109 The precise role of the chemokines and their cellular origin in the recruitment of inflammatory cells is a topic of current research.132–134 Allergens as a cause of asthma The importance of allergens as a cause of asthma (i.e. symptomatic airway hyperresponsiveness and airway inflammation135) which was hypothesized several years ago136 (Fig. 37.3), is now generally accepted.137 The lines of reasoning include the high prevalence of atopy amongst asthmatics,20,21 the correlation of both airway hyperresponsiveness and asthma with atopy in epidemiological population studies32,138–143 (Fig. 37.4), the relationship of both seasonal42,49,50,144,145 and indoor23,24,146 allergen exposure to symptoms and airway hyperresponsiveness, and their reduction with allergen avoidance.147,148 It is speculated that, in sensitized individuals, the duration and magnitude of airways allergic exposure, if not suppressed pharmacologically, may lead not only to transient but also to persistent airway
Allergen IgE
387
hyperresponsiveness and clinical asthma.136 This is supported by parallel observations in animals149 and in human occupational asthma.150,151
INGESTED/INJECTED ALLERGENS Isolated asthma caused by allergens introduced via routes other than inhalation is uncommon but has been reported.152,153 Ingested allergens153 (foods, drugs) or injected allergens154 (hyposensitization injections, intradermal allergen tests, drugs, insect bites and stings) can produce IgE-mediated hypersensitivity reactions. Most often, these produce systemic allergic reactions152,154 (violent gastrointestinal upset, urticaria, angioedema, laryngeal edema, anaphylactic shock, with or without bronchospasm). However, occasionally such exposures produce reactions which appear to be centered primarily in the lung.153,155 It is likely that these represent systemic allergic reactions in subjects with preexisting asthma and high levels of airway hyperresponsiveness who develop disproportionately severe bronchospasm. Some cases of food/bite/sting-induced “asthma” may actually represent laryngeal spasm or edema which has been misdiagnosed. Although relatively uncommon, allergic (asthmatic or otherwise) responses to both ingested and injected allergens occur rapidly and can be exceedingly severe. We have seen subjects with sudden severe asthma due to foods (nuts, shellfish) and two subjects with sudden onset status asthmaticus circumstantially linked to unrecognized black fly bites.
C L I N I C A L F E AT U R E S Allergic reaction Early asthmatic response
Increased nonallergic bronchial reactivity
and
Late asthmatic response
Symptoms on exposure to nonallergic stimuli (irritants, exercise, etc.)
Fig. 37.3. Diagram of hypothesis explaining development and maintenance of perennial allergen-induced asthma. Reproduced from Reference 136, with permission.
Clinical presentation Allergic asthma usually begins at a young age, between about 2 and 20, but can develop at any time. A positive family history of asthma or atopy is common. Other atopic symptoms are often present and include food sensitivity (infancy), childhood eczema, urticaria, conjunctivitis and allergic rhinitis. Asthma or asthma exacerbations should correlate with allergen exposure or seasons. Spring, summer or fall exacerbations suggest fungal spore or pollen sensitivity whereas winter exacerbations are typical of indoor allergen sensitivity but may also occur in nonatopic asthmatics. The polyallergic subject may show little seasonal variability. Because of the gradual onset of airway inflammation and hyperresponsiveness, allergen-induced asthma exacerbations are usually of gradual onset often lagging behind and persisting beyond allergen exposure. An acute exposure– symptom relationship may be lacking. For these reasons, the patient and physician may miss the importance of allergens. When present, nonrespiratory, particularly ocular or cutaneous and, to a lesser extent, nasal symptoms will bear a much closer relationship to exposure and may provide an important historical clue to sensitization. Irritant- and exercise-induced bronchospasm are symptomatic of underlying
388
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Fig. 37.4. Degree of atopy (various scales) from nonatopic (0) to highly atopic (highest number) on the horizontal axis versus prevalence of airway hyperresponsiveness (%) on the vertical axis from four population studies.^^' i^s-i"! Reproduced from Reference 142, with permission.
airway hyperresponsiveness and, consequently, can be due to (often unrecognized) allergen exposure which may not be acutely temporally related. Sudden severe symptoms can occur following inhaled allergen exposure if the exposure is marked, if the individual is highly sensitized or if previous asthma symptoms/airflow obstruction have been either underperceived or ignored. However, genuinely sudden asthma exacerbations raise the possibility of ingested or injected allergen (food, drugs, bites, stings, allergen shots); this clinical scenario should prompt an aggressive historical review for relevant clues. Non-IgE-mediated responses to ASA and NSAIDs, p adrenergic blockers, food additives (e.g. metabisulfites), or choline ste rase-inhibiting insecticides are included in the differential diagnosis of sudden severe asthma. Diagnosis The diagnosis of allergic asthma rests predominantely on the historical features noted above. The inquiry into possible allergens should not stop with the home but must include work, school, social and recreational exposures. Because of the frequently subtle exposure-symptom relationships, nonrespiratory symptoms related to allergen exposure should be sought. Following completion of a complete history, allergen prick-skin testing with a small series of relevant allergens should be done. Treatment The treatment of allergen-induced asthma is the same as for asthma in general and is outlined elsewhere in this book. The pathophysiological and clinical features outlined above stress the importance of environmental control. The possibility
that chronic allergen exposure might lead to permanent pathology suggests that therapeutic strategies, which are largely effective by preventing the allergic response and sequelae (allergen avoidance, cromones, anti-IgE), will be less effective if their introduction is delayed. Allergic bronchopulnionm*y m y c o s e s A distinctive clinical syndrome occurs when atopic individuals have organisms, against which they have IgE antibodies, growing in their airways. The prototype and, by far the commonest of these "allergic bronchopulmonary mycoses", is allergic bronchopulmonary aspergillosis (ABPA) usually caused hy As Other fungi, including Helminthosporium^^''-'''^'^''-'^ Curvularia and Drechslera,^'^^'^'^^ Stemphylium,^^^ Candida,^^ Fusarium,^^^ and rarely bacteria such as Pseudomonas,^^-'^-' may cause a similar syndrome. The syndrome which these organisms can produce involves complex immunologic and mechanical pathogenesis. The pathogenesis of ABPA initially involves acquisition of IgE-mediated type I hypersensitivity to the fungus. Aspergillus fungal spores released from decaying vegetation, particularly in the autumn germinate and grow in the airway provoking reduced airway caliber and mucous hypersecretion leading to mucous plugs containing fungal hyphae producing "castlike" outlines of the bronchial tree. The chronic high-level allergen exposure leads to very high levels of both allergenspecific and total serum IgE, an intense peripheral and bronchial eosinophilia, and in most, but not all, to the development of IgG-precipitating antibodies. Other immunological responses including cell-mediated immunity may be stimulated. The continuous airways allergic reaction will lead to exacerbation of asthma while the other immunological
Allergens
reactions may be responsible for bronchial and parenchymal damage which includes (proximal) bronchiectasis and (upper lobe) interstitial pulmonary fibrosis. Fleeting or fixed pulmonary infiltrates may be produced by immunological reactions within the lung, by the mechanical effect of obstruction of major bronchi by mucous plugs, or both. ABPA is a fairly common condition in some areas; the precise prevalence is not certain. Among asthmatics, the prevalence of type I (IgE) sensitivity to Aspergillus may be approximately 25%,167–169 and the prevalence of type III (IgG) sensitivity to Aspergillus is approximately half this.170,171 By contrast, on the dry Canadian prairies, Aspergillus skin sensitivity is uncommon and we have seen no new cases of ABPA in over 20 years. Other organisms (e.g. Helminthosporium) are involved only rarely. The clinical picture is generally that of a subject with preexistent atopy, and usually previous asthma, presenting with exacerbation of asthma accompanied by the expectoration of characteristic firm brown plugs.156 Pulmonary infiltrates with eosinophils with or without fever may be seen. Chronic disease may manifest as bronchiectasis with chronic or recurrent pulmonary infection or pulmonary fibrosis with progressive dyspnea or both.156,157 The two features which must be present in all subjects with ABPA are type I hypersensitivity to Aspergillus and the presence of Aspergillus in the airways. However, it is not always possible to grow the organism.172 Specific IgGprecipitating antibodies are found in about 90% of cases.158 Other features which are commonly seen include intense peripheral and bronchial eosinophilia,172 marked elevations of total serum IgE,173 and transient pulmonary infiltrates;156–159 these all tend to correlate with activity of disease. Chronic changes in established or recurrent disease include radiographic demonstration of an unusual and essentially pathognomonic proximal bronchiectasis174 and, in more severe cases, progressive upper lobe interstitial pulmonary fibrosis similar to tuberculosis and other upper lobe scarring conditions.157 The computerized tomographic scan may be particularly helpful as an adjunct to the diagnosis of ABPA.175,176 ABPA is a common complication of cystic fibrosis;177 the 2% prevalence in one observational cohort was felt to represent underrecognition.178 Atopic skin testing has been suggested as a useful screen in this population,177 however, this may not be reliable;179 specific skin tests, allergen-specific IgE, total IgE and precipitins are recommended in this population.179 Allergic bronchopulmonary infestations with Aspergillus or other fungal organisms are not true infections; progression to invasive fungal infections or mycetoma formation is uncommon. Treatment is directed against the asthma and the immunological abnormalities; intensive asthma treatment with systemic corticosteroids in doses sufficient to suppress clinical and laboratory features of the disease is indicated.172,180,181 Total serum IgE may be useful to predict exacerbations.181 With such treatment, the prognosis is favorable; however, under-treatment can lead to substantial, even severe, permanent bronchopulmonary damage.
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Itraconazole has been reported to be effective in reducing corticosteroid requirements in ABPA,182 and may be useful in cystic fibrosis.177 However, a recent Cochrane Database report concludes there is insufficient information available to recommend the use of azoles (itraconazole, ketoconazole) in this condition.183
S U M M A RY • The majority of subjects with asthma are atopic. • Allergen-induced airway hyperresponsiveness and airway inflammation point to allergens as a cause of asthma (i.e. symptomatic airway hyperresponsiveness with inflammation). • The remarkable rise in the prevalence of atopy (“hygiene” hypothesis, airtight home/indoor allergen exposure hypothesis, other hypotheses or some combination) over the past 200 years may explain in whole or in part the rising prevalence of asthma. • Chronic/recurrent allergen exposure may lead to persistent asthma. • This provides a plausible basis to suggest that early prophylactically or actively anti-inflammatory therapeutic strategies should improve long-term outcomes in allergic asthma. • This also provides a rationale to speculate re primary prevention of (allergic) asthma.
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160. Dolan CT, Weed LA, Dines DE. Bronchopulmonary helminthosporiosis. Am. J. Clin. Pathol. 1970; 53:235–42. 161. Matthiesson AM. Allergic bronchopulmonary disease caused by fungi other than Aspergillus. Thorax 1981; 36:719. 162. McAleer R, Kroenert DB, Elder JL et al. Allergic bronchopulmonary disease caused by Curvularia lunata and Drechslera hawaiiensis. Thorax 1981; 36:338–44. 163. Benatar SR, Allan B, Hewitson RP et al. Allergic bronchopulmonary stemphyliosis. Thorax 1980; 35:515–18. 164. Voisin C, Tonnel AB, Jacob M et al. Infiltrats pulminaires avec grande eosinophilie sanguine associes a une candidose bronchique. Rev. Fr. Allergie Immunol. Clin. 1976; 16:279–81. 165. Saini SK, Boas SR, Jerath A et al. Allergic bronchopulmonary mycosis to Fusarium vasinfectum in a child. Ann. Allergy Asthma Immunol. 1998; 80:377–80. 166. Gordon DS, Hunter RG, O’Reilly RJ et al. Pseudomonas aeruginosa allergy and humoral antibody-mediated hypersensitivity pneumonia. Am. Rev. Respir. Dis. 1973; 108:127–31. 167. Longbottom JL, Pepys J. Pulmonary aspergillosis: diagnostic and immunologic significance of antigens and C-substance in Aspergillus fumigatus. J. Pathol. Bacteriol. 1964; 88:141–51. 168. Hendrick DJ, Davies RJ, D’Souza MF et al.An analysis of prick skin test reactions in 656 asthmatic patients. Thorax 1975; 30:2–8. 169. Malo JL, Paquin R. Incidence of immediate sensitivity to Aspergillus fumigatus in a North American asthma population. Clin. Allergy 1979; 9:377–84. 170. Hoehne JH, Reed CE, Dickie HA. Allergic bronchopulmonary aspergillosis is not rare. Chest 1973; 63:177–81. 171. Malo JL, Paquin R, Longbottom JL. Prevalence of precipitating antibodies to different extracts of Aspergillus fumigatus in a North American asthmatic population. Clin. Allergy 1981; 11:333–41. 172. McCarthy DS, Pepys J. Allergic bronchopulmonary aspergillosis. Clin. Allergy 1971; 1:261–86. 173. Patterson R, Fink JN, Pruzansky JJ et al. Serum immunoglobulin levels in pulmonary allergic aspergillosis and certain other lung disease, with special reference to immunoglobulin E. Am. J. Med. 1973; 54:16–22. 174. Scadding JG. The bronchi in allergic bronchopulmonary aspergillosis. Scand. J. Respir. Dis. 1967; 48:372–7. 175. Panchal N, Bhagat R, Pant C, Shah A. Allergic bronchopulmonary aspergillosis: the spectrum of computed tomography appearances. Respir. Med. 1997; 91:213–19. 176. Johkoh T, Muller NL, Akira M et al. Eosinophilic lung diseases: diagnostic accuracy of thin-section CT in 111 patients. Radiology 2000; 216:773–80. 177. Nepomuceno IB, Esrig S, Moss RB. Allergic bronchopulmonary aspergillosis in cystic fibrosis: role of atopy and response to itraconazole. Chest 1999; 115:364–70. 178. Geller DE, Kaplowitz H, Light MJ et al.Allergic bronchopulmonary aspergillosis in cystic fibrosis: reported prevalence, regional distribution, and patient characteristics. Scientific Advisory Group, Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Chest 1999; 116:639–46. 179. Skov M, Koch C, Reimert CM et al. Diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis. Allergy 2000; 55:50–8. 180. Safirstein BH, D’Souza MF, Simon G et al. Five year follow-up of allergic bronchopulmonary aspergillosis. Am. Rev. Respir. Dis. 1973; 108:450–9. 181. Wang JLF, Patterson R, Roberts M et al. The management of allergic bronchopulmonary aspergillosis. Am. Rev. Respir. Dis. 1979; 120:87–92. 182. Salez F, Brichet A, Desurmont S et al. Effects of itraconazole therapy in allergic bronchopulmonary aspergillosis. Chest 1999; 116:1665–8. 183. Wark P, Wilson AW, Gibson PG. Azoles for allergic bronchopulmonary aspergillosis (Cochrane review) (in process citation). Cochrane Database Syst. Rev. 2000; 3:CD001108.
Occupational Agents
Chapter
38
Jean-Luc Malo Department of Chest Medicine, Sacré-Coeur Hospital, Montreal, Canada
Moira Chan-Yeung Respiratory Division, Vancouver General Hospital, Vancouver, Canada
Susan Kennedy Occupational Hygiene Program, University of British Columbia, Vancouver, Canada
O C C U PAT I O N A L A S T H M A Definition A proposed definition of occupational asthma (OA) should take into account at least two essential aspects of the condition. First, it should reflect the fact that OA shares the clinical, functional and pathological features of asthma, that is variable, spontaneously or as a result of treatment, symptomatic airway caliber, hyperresponsiveness, and inflammation of the airways. Second, it should state that OA is caused by the workplace in which, in most cases, an agent has been identified. The definition of OA which has been retained in a textbook on OA reads as follows: “OA is a disease characterized by variable airflow limitation and/or airway hyperresponsiveness due to causes and conditions attributable to a particular occupational environment and not to stimuli encountered outside the workplace”.1 Within this definition, two types of OA are distinguished by whether they appear after or without a latency period. Agents that cause occupational asthma and the pathophysiological mechanisms Over 300 agents in the workplace have been implicated in causing asthma.2 Table 38.1 shows a list of the more common agents responsible for OA. The agents can be divided into two groups according to the pathogenic mechanisms: those that give rise to asthma by immunological mechanisms and those by nonimmunological mechanisms. Agents in the former group can cause asthma by immunoglobulin (Ig) E-dependent or IgEindependent mechanisms. Irritant-induced asthma (IIA) is a type of OA caused by an apparently nonimmunological mechanism.3
Agents that induce occupational asthma by immunological mechanisms Agents that induce asthma by IgE-dependent mechanisms: The agents causing OA by IgE-dependent mechanisms include both high molecular weight compounds (5 kDa) and some low molecular weight compounds (5 kDa). High molecular weight compounds are usually proteins or polysaccharides and induce specific IgE antibodies. Some low molecular weight agents such as platinum4 and acid anhydrides5 can also induce specific IgE antibodies by acting as haptens, which combine with a body protein to form complete antigens.There is evidence to support the fact that the asthmogenic potency of a compound is determined to a certain extent by its chemical structure.6,7 Often, agents such as trimellitic anhydride and isocyanates can modify body proteins, an important step towards becoming a hapten, and thus stimulate the immune system. These agents often affect atopic subjects. The inhaled occupational sensitizer can bind to specific IgE antibodies on the surface of mast cells, basophils, and possibly macrophages and eosinophils. The mechanism of asthma induction by these sensitizers is similar to nonoccupational allergens.8 Agents that induce asthma by IgE-independent mechanisms: The agents that give rise to OA through IgE-independent mechanisms are mostly low molecular weight compounds such as isocyanates and plicatic acid (the agent responsible for western red cedar asthma).8 In subjects with both isocyanate and western red cedar asthma, specific IgE antibodies have been found in only a small proportion proven to have the disease,9,10 although, if present in high concentrations, they appear specific for the disease.11 It is still uncertain whether the presence of specific IgG antibodies is a marker of the disease9 or merely of exposure. In western red
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Table 38.1. Agents that cause immunologically mediated occupational asthma
Common sources of exposure High molecular weight agents Animal-derived material Dander Excreta Secretions Serum
Animal, poultry and insect work, veterinary medicine, fishing and fish processing, laboratory work
Plant-derived material Flour Grain Castor bean Coffee bean Wood dust Vegetable gum Psyllium Latex
Bakery Grain elevator and terminal and feed mill Oil manufacture Food processing Sawmill, carpentry, furniture work Printing Health care Latex
Enzymes Alpha-amylase Papain Alcalase Bacillus subtilis-derived enzyme
Bakery Food processing Pharmaceutical industry Detergent enzyme industry
Low molecular weight agents Spray paints Toluene diisocyanate Dimethylphenyl diisocyanate Hexamethylene diisocyanate
Manufacture of plastic, foam Insulation Automobile spray paint
Wood dust Western red cedar
Sawmill worker, carpenter, furniture maker
Acid anhydride
Users of plastics, epoxy resins
Biocides Formaldehyde Glutaraldehyde Chloramine T
Health care workers
Colophny fluxes
Electronic workers
Irritant agents Chlorine Acetic acid Isocyanates
Pulp and paper mills Hospital setting Spray paint
For further information see Reference 2.
cedar asthma, the significance of the presence of specific IgE antibodies is not clear since anti-IgE antibodies failed to inhibit the release of histamine by plicatic acid from granulocytes of patients with the disease.12 Studies of both isocyanate and western red cedar asthma have demonstrated that T lymphocytes might play a direct role in mediating the inflammatory response in the air-
ways.13,14 In patients with isocyanate-induced asthma, the majority of T cell clones derived from bronchial mucosa of subjects were found to be CD8 T lymphocytes that produced IL-5.13 Among patients with western red cedar asthma, peripheral blood lymphocytes released IL-5 and IFN-c after stimulation with plicatic acid in sensitized subjects.14
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Agents that induce occupational asthma by nonimmunological mechanism Irritant-induced asthma is apparently a nonimmunologically induced type of asthma.There seems to be a dose-dependent relationship between exposure and the likelihood of permanent disability/impairment.3,15–17 Pathology Immunologically mediated occupational asthma There is no difference between the pathology of the airways of patients with occupational and those with nonoccupational asthma. Studies of bronchoalveolar lavage fluid have shown influx of eosinophils and neutrophils and a marked increase in albumin concentration during late asthmatic reaction after inhalation challenge with isocyanates.18 In patients with western red cedar asthma, increases in eosinophils, and epithelial cells, as well as in albumin, histamine and LTE4, have also been found in the BAL fluid.19 Irrespective of the sensitizing agent, the pathological features in the airways are similar. There is subepithelial fibrosis, hypertrophy of airway smooth muscle, edema of the airway wall, accumulation of inflammatory cells, mostly eosinophils, and obstruction of the airway lumen by exudate and/or mucus in patients with OA.20 Cessation of exposure to the sensitizing agent is associated with a decrease in the number of inflammatory cells in the airway mucosa.21 In isocyanate-induced asthma, some reversal of the subepithelial fibrosis has been found.22 Nonimmunologically induced asthma The mechanism of IIA is not known. IIA is a “big bang” phenomenon. Exposure to a high level of the irritant leads to acute sloughing of the epithelium.3 There are some differences between the pathological features of IIA and those of immuno-
logically mediated asthma. In general, subepithelial fibrosis is more evident in IIA.23 The airway epithelium is extensively damaged and the submucosa infiltrated by mononuclear cells.24 One study reported fewerT lymphocytes in the airway mucosa in IIA than in allergen-induced asthma.25 Epidemiology: frequency and determinants Frequency OA has become one of the two most common occupational lung diseases in developed countries (the other is mesothelioma).26 Estimates of incidence of OA have been made using registers based on mandated or voluntary physician reporting, medicolegal statistics and various national or disability registers. There are considerable between-country differences in the estimated incidence of OA ranging from 22 per million per year in the United Kingdom to 187 per million per year in Finland. The differences are likely due in part to the methods used to derive these estimates. However, community-based studies on population-attributable risk of occupational exposure for asthma carried out in countries involved in the European Community Respiratory Health Survey using similar methodology have shown considerable variation from 5% in Spain to 41% in New Zealand depending on the local industries, options for employment and the population’s susceptibility.27–30 Studies in the United States of adult patients with new-onset asthma have shown that about 8% reported a history of exposure to sensitizers at work and 13% when irritants were included.31,32 Table 38.2 summarizes the findings from selected studies for various workplaces.33–42 There is considerable variation in the prevalence of OA in different industries, ranging from 2% in latex-exposed workers to 50% among detergent-enzyme workers.33 While the between-workforce differences can be
Table 38.2. Prevalence and determinants of work-related asthma: results of selected studies
Exposure/Industry
No.
Latency (months)
Work-related asthma (%)
Prevalence Smoking (%)
Atopy (%)
High molecular weight compounds Enzyme/detergent33 Clam/Shrimp34 Snow-crab processor35 Laboratory animal worker36 Bakery37 Latex/Hospital workers38
98 59 303 238 344 289
N/A N/A number unknown 26 26 120
50 26 (8) 21 (16) 6 6 2 (3)
52 49 67 30 57 22
64 21 11 40 34 25
Low molecular weight compounds Platinum refinery39 Anhydrides, TCPA40 Toluene diisocyanate41 Plicatic acid/Red cedar sawmills42
91 329 241 652
12–24 Up to 24 Up to 36 N/A
54 3.2 9.5 4
63 50 51 38
33 22 35 19
For further information see Reference 1.
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due to varying data collection methodology, different definitions used for OA, and intensity of exposure, it is quite possible that the asthmogenic potential of the agents is different. Host determinants Atopy (defined as positive skin test to one or more common allergens) has been shown to be associated with sensitization to some high molecular weight agents33,36 but not others34,35 (Table 38.2). The positive predictive value of atopy in various studies of OA is low: 34% in animal laboratory workers43,44 and 7% in psyllium workers.45 Moreover, over 40% of young adults have positive skin-test reactions to common allergens. These findings do not justify routine screening for atopy in high-risk workplaces. The effect of smoking is dependent on the type of occupational agent. An interaction between smoking and atopy has been found in OA in animal laboratory handlers44 and in workers exposed to tetrachlorophthalic anhydride;46 atopic smokers had the highest prevalence of sensitization and nonatopic nonsmokers, the lowest. Among platinum workers, smoking, not atopy, is the most important risk factor for sensitization.39 When agents cause OA by IgE-independent mechanisms, as in the cases of isocyanate-induced asthma and western red cedar asthma, both atopy and smoking are unimportant.10 An association has been reported between HLA class II genes and several types of OA such as isocyanate-,47 trimellitic anhydride-,48 western red cedar-,49 and platinuminduced asthma.50 However, such findings should be considered as preliminary and this type of testing cannot be used for screening of susceptible subjects. Little is known about the determinants of IIA. For IIA with a more gradual onset, atopy has been found to be a predisposing factor in one study.51 Exposure factors Improved industrial hygiene techniques have resulted in the ability to measure several low molecular weight compounds such as isocyanates, formaldehyde, and amines.52 Immunochemical techniques for quantitating aeroallergens have been developed and used in a number of workforce-based studies.53 Several studies have shown that there is a dose–response relationship between the level of exposure to occupational agents and the prevalence of sensitization and/or nonallergic bronchial hyperresponsiveness and/or asthma.These include exposure to high molecular weight allergens such as alphaamylase,54 animal laboratory allergen,55 and low molecular weight compounds such as western red cedar,56 acid anhydride,40 and colophony.57 As a result, a “permissible exposure limit” has been proposed for one high molecular weight allergen, flour, 0.5 mg/m3 of dust.The minimum concentration of occupational allergen that causes sensitization may be one to two orders of magnitude greater than the concentration for eliciting symptoms. Once an individual is sensitized to an agent, a minute dose can trigger an attack of asthma. Concomitant environmental exposures such as low levels of irritants and cigarette smoke may enhance sensitization to some occupational agents. Further studies are required in this area.
Diagnosis All asthmatic subjects should be questioned regarding possible exposure to causal agents in their current or previous workplaces. It has been estimated that approximately 5% of all asthmatics seen in a specialized asthma clinic may suffer from OA. Also, it has to be remembered that because affected subjects could be left with permanent asthma after removal from the workplace, their current asthma symptoms could result from previous exposure to occupational causal agents. Physicians should be aware that certain workplaces have a high risk of exposing subjects to asthma-causing agents. Information on workplaces at risk and on all agents causing OA is available on the Web site ASMANET.COM as prepared and reviewed by Henriette Dhivert-Donnadieu. Safety data sheets (SDS) on all products used in the workplace can be obtained from employers and/or from safety agencies. However, these SDS do not necessarily report all products present in the workplace. Although flour and isocyanates are still the most frequent causes of OA, recently latex and acrylates have emerged as agents that often cause OA. Clinical questionnaires should be sensitive although, in general, they are not very specific tools.58 Exposure to a known causal agent at work and the presence of asthma should be sufficient to alert the physician to the possibility of OA even though the temporal relationship between exposure and symptoms may seem discordant. The possibility of the presence of nasal or conjunctival symptoms should be addressed. Ocular and nasal symptoms often accompany or even precede, in the case of high molecular weight agents, the occurrence of OA.59 Skin-prick tests can be done with extracts derived from specific high molecular weight agents although these extracts are not generally standardized. The presence of immediate skin sensitivity only indicates the presence of sensitization and does not confirm the diagnosis of OA. The target organ, in this case the bronchial, should be shown to be hyperresponsive. This can be done through the assessment of nonallergic airway responsiveness.The combination of positive skin-test reaction to a relevant occupational allergen and nonallergic airway hyperresponsiveness in a subject means that there is a ~80% likelihood that he/she has OA.45 Nonallergic airway hyperresponsiveness can be shown either by assessing the response to bronchodilators if there is airway obstruction, or by estimating the degree of bronchoconstrictive response to a pharmacological agent. If the worker is still employed, nonallergic airway responsiveness should be evaluated on a working day after a minimum period of 2 weeks at work.The absence of nonallergic airway hyperresponsiveness in a subject when still working and exposed to the agent(s) suspected of causing OA virtually excludes OA. Serial measurement of peak expiratory flow rates (PEF) in the diagnosis and management of asthma60,61 has been used since the late 1970s in the investigation of OA.62 Workers are asked to measure and register their PEF at least four times a day and to record their medication, symptoms
Occupational Agents
and whether they are at work or away from work. Although monitoring of PEF has been found to be a useful tool in the investigation of OA,63 there are several pitfalls including generally unsatisfactory compliance64 and tracing, analysis and interpretation of results,for which computerized methods have been suggested.65 In our hands, while positive tracings are most likely associated with confirmed diagnosis, negative graphs cannot exclude OA.66 Exposing individuals to the potential causal agent(s) in a hospital laboratory, or at the workplace under careful supervision, is a good method to confirm OA. This method was first proposed in the 1970s by Professor Jack Pepys at the Brompton Hospital in London, UK.67 However, such tests require the expertise of highly trained personnel and can only
be done in specialized centers. They should be performed in a dose–response manner, exposing subjects to increasing concentrations but nonirritant levels of the agent with serial monitoring of FEV1 following exposure for at least 8 hours.68 The investigation of OA is a step-wise procedure, as illustrated in Fig. 38.1. Management and compensation Physicians may be asked to screen for OA in subjects exposed to known causal agents or in a workplace where cases of OA have been identified.69 These screening programs may include pre-employment testing and periodic assessment. A cost-effectiveness examination of such programs needs to be done. Pre-employment testing to document the
Compatible clinical history and exposure to possible causal agents
Skin and RAST tests (if possible)
Assessment of bronchial responsiveness to pharmacological agents
Normal
Subject still at work
Increased
Subjects no longer at work
Subject still at work
Laboratory challenges with the suspected occupational agent
positive
negative
Consider return to work
Workplace or laboratory challenges with the suspected occupational agent and/or PEF monitoring positive
No asthma
Occupational asthma
Fig. 38.1. Flow chart for the investigation of occupational asthma.
399
negative
Non-occupational asthma
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Asthma and Chronic Obstructive Pulmonary Disease
baseline status may include a questionnaire, spirometry with assessment of nonallergic airway responsiveness and skin testing to work-related allergens in the case of exposure to high molecular weight allergens. Workers with preexisting asthma should not be excluded as there is no reason to believe that asthmatic subjects are more likely to develop OA than anyone else. It is difficult to recommend the frequency for screening assessments. It has been estimated that 40% of subjects with OA due to low molecular weight agents develop their symptoms during the first year of exposure, while the corresponding figure for high molecular weight agents is 20%.70 After that, there is a progressive reduction in the rate of development of OA. Prevention is relevant in high-risk workplaces where inhalational accidents leading to IIA can occur. Assessment of airway responsiveness should also be considered as a preemployment test so that if an accident occurs comparisons are possible.71 Once the diagnosis of OA is confirmed, subjects should be advised to avoid exposure to the causal agent. Whereas wearing cartridge masks does not apparently reduce symptomatology or functional abnormalities,72 more recently introduced helmet masks may eliminate exposure completely and may be considered in some instances. Treatment with inhaled steroids while keeping the subject at work improves the asthma but not to the extent of removal from exposure complemented by inhaled steroids,73 especially when steroids are given early after removal.74 Subjects with OA whose symptoms persist after removal from exposure should be treated in the same way as patients with non-OA. As for OA with a latency period, there might be functional recovery in the 2 years following the inhalation accident leading to IIA.75 Steroids may be beneficial.76 Patients with OA should be offered suitable help in finding another job where there is no further exposure to the causal agent, either with the same employer or another one. Subjects aged 55 or over should be offered early retirement, and young subjects should be retrained for a new job, all with financial compensation. Compensation boards or similar medicolegal agencies should offer these programs to workers and assess their cost-effectiveness. The time needed to make a diagnosis of OA and to implement a program is generally too long, causing hardship to the subjects.77,78 It has been estimated that during the 1990s, a single case of OA in Québec cost approximately C$50,000.77 Because OA can lead to permanent impairment/disability, subjects should be reassessed periodically. The first assessment should take place 2 years after removal from exposure, when a plateau of improvement can occur, as in the case of a high molecular weight agent such as snow-crab,79 although a more recent and longer follow-up study has shown that improvement can also occur at a later stage.80 The three main criteria for assessing impairment/disability for asthma are: (1) airway caliber; (2) airway responsiveness to a bronchodilator if airway obstruction is present or to a bronchoconstrictor if it is not the case; (3) the need for medication, which is a reflection of the clinical severity of asthma.81
Conclusion Asthma is a common respiratory occupational ailment. Whereas improvement in diagnostic tools and pathophysiological mechanisms still need to be considered, emphasis should be put on prevention programs through identification and application of permissible respirable levels and of affected subjects at an early stage of sensitization or disease to prevent long-term sequelae of permanent asthma.
COPD In most patients, COPD is caused by chronic inhalation of polluted air, specifically, air contaminated by proinflammatory agents. The air can be polluted by personal choice (e.g. cigarette smoking), or by exposure sources in the ambient or work environment. Many patients may have been exposed to multiple sources, and the relative contributions of each may be impossible to disentangle. COPD is the symptomatic and functional consequence of chronic exposure to these polluted air sources.Therefore, it seems appropriate to pose a definition for occupational COPD that allows it to co-exist with “smoking-induced COPD” or “urban air pollution-induced COPD”. For the purpose of this section, we will define occupational COPD as “the existence of COPD in a patient with a history of chronic exposure to pro-inflammatory agents in workplace air.”This definition is useful for clinical management and public health prevention as it points to the potential for eliminating or modifying occupational risk factors for the disease. Additional challenges with defining occupational COPD for legal or compensation purposes will be discussed below. Epidemiology: frequency and determinants Occupational COPD is associated with chronic exposure to mineral and/or metal particulate matter and fumes, organic particulate matter, combustion products, irritant gases, and various combinations of these exposures. Evidence for this has emerged primarily from epidemiological studies, some of which are listed in Fig. 38.2. Mineral particulate Prevalence rates for COPD with airflow obstruction among miners range from 6% to 20% among nonsmokers, and up to 60% among smokers.82–85 Exposure–response relationships are also seen. Airflow obstruction was seen among 10.5% of nonsmoking British coal miners exposed to low dust levels and 20.6% of those exposed to medium and high dust levels.84 Similarly, among nonsmoking US underground coal miners the corresponding rates were 7.4% in the lower dust exposure category and 14.3% in the high dust exposure category.86,87 Mine dust with greater crystalline silica content appears to produce even higher COPD rates. Among South African gold miners the estimated effect of dust exposure on airflow obstruction was approximately ten times greater than that seen among coal miners.85,88 COPD has also been clearly
Occupational Agents
401
25
20
%
15
10
5
0 “Expected” rate
Blue collar controls
Wood workers
Grain handlers Industry
Aluminum smelter
Asbestos insulators
Fig. 38.2. Prevalence rates for airflow obstruction (defined as FEV1/FVC % below the lower 95% confidence limit, based on age) among nonsmokers, aged 50 and over, exposed to mixed dusts and fumes and organic dusts, compared with a blue-collar control population143 and to “expected rates”;144 from studies conducted by the UBC Occupational Lung Diseases Research Unit.125,145,146
demonstrated in association with asbestos exposure.89–93 From the evidence to date, airflow obstruction appears more pronounced among workers installing or handling asbestos products than among miners;91 however, only a few studies have looked specifically for airflow obstruction in these populations. Among miners and millers of wollastonite (another fibrous dust) significant dose–response relationships for cumulative dust and airflow obstruction were seen in both nonsmokers and smokers.94 COPD is also linked to particulate exposure (with and without crystalline silica) in other industries, such as quarrying and carbon black manufacturing.95–97 Metal fumes, irritant gases, combustion products Exposure to metal fumes, irritant gases, and combustion products appears to augment the effect of exposure to dust alone on COPD. This has been seen in mining and smelter workers,98,99 workers in rubber manufacturing,100,101 welders,102–105 in tunnel workers,106 and fire fighters.107–110 There is some evidence that the risk of airflow obstruction in welders and smelter workers may be higher among atopic workers, raising the possibility that at least some of the excess airflow obstruction seen in these groups may be related to asthma.104 Indeed, as discussed above in the section on OA, several metal fumes and irritant gases are recognized risk factors for OA. Organic dusts Although organic dust exposure is also associated with asthma and hypersensitivity pneumonitis, there is increasing evidence that chronic respiratory symptoms and nonasthmatic airflow obstruction are caused in part by exposure
to both “allergenic” and “nonallergenic” organic dusts. For example, a recent study of nonasthmatic cedar sawmill workers found that the annual decline in FVC was significantly related to cumulative dust exposure, even when the average dust exposure was well below the accepted limit.111 Studies of sawmill and furniture workers exposed to wood dusts from species not currently known to cause asthma also show exposure-related airflow obstruction.112–117 Generally, in these studies, the excess airflow obstruction linked to dust exposure is similar among nonsmokers and smokers. There is also considerable evidence confirming a link between grain dust and COPD in both smokers and nonsmokers, with consistent dose–response relationships found.118–123 Among retired grain workers, moderate to severe airflow obstruction was found in 40% of nonsmokers and 50% of smokers.124 Mixed exposure to grains, other animal feeds, and animal by-products are found in animal confinement buildings, but the evidence is somewhat mixed about whether or not these environments lead to COPD. There is clear evidence of excess chronic bronchitis among farmers and workers in poultry and swine confinement buildings, with prevalence rates remarkably consistent across studies at about 25–35%.125–131 However, evidence for nonasthmatic chronic airflow obstruction in this industry is less consistent. Some studies indicate no relationship;125,131 others report reductions in airflow associated with duration of exposure.129,132,133 Relationship between cigarette smoking and occupational exposures The research indicates that occupational exposure plays a clinically important role in the development of COPD in
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exposed workers. Among aluminum smelter workers, the impact of a 30-year working career with particulate exposure at the permitted level was about the same as smoking, 75 g/week.134 Among tunnel workers exposed to dust and diesel exhaust, the decline in FEV1 associated with each year of tunnel work was twice that associated with each pack year of cigarette smoking.106 Among fire fighters, the cumulative impact of “being a fire fighter” on longitudinal decline in FEV1 was about half as strong as the impact of cigarette smoking.135 Cigarette smoking and dust exposure appear to exert their effect on airways in a roughly additive fashion regardless of the dust type,84,88,111 although there is a suggestion that the effect is more than additive in patients with marked airflow obstruction, and in the presence of high crystalline silica.136 Natural history Most research suggests that the natural history of COPD is similar regardless of the source of the polluted air. However, there is growing evidence that there may be a link between early rapid decline in airflow rates due to occupational exposures and later airflow obstruction. This has been seen in British,84 US,86 and Italian137 coal miners, among workers exposed to asbestos,138,139 and grain.124,132 Assessment of exposure The relevant exposure for COPD is that to which the patient was exposed in the past. Therefore, the best clinical tool for assessing this is a detailed occupational history, augmented by specific enquiry about exposures to dusts, gases, and fumes. In fact, research has shown that a positive response to the simple question “have you been exposed to dusts, gases, or fumes at work?” is linked to a more rapid decline in FEV1 and increased prevalence of chronic bronchitis in population studies.140,141 Ideally, the occupational history should be reviewed by a professional with knowledge of the typical occupational exposures in the region. However, evidence has shown that the patient is also a reliable source of information about exposure duration and intensity. For each main job, the patient should be asked what year the job began and ended (to estimate duration of exposure); whether or not there was noticeable dust, fumes, or gas exposure; and if so, how often (to estimate intensity of exposure). Although it is not possible to provide a clear answer to the question, “How much exposure is necessary before one should suspect an occupational contribution to COPD?” most research indicates that the relevant exposure duration is measured in years (or even decades), not months or days. Many patients will have held more than one job, and exposure duration should be summed over all jobs with relevant exposures. Time spent in irregular work environments should also be considered (e.g. in the armed forces, in prison, during extended periods of casual or temporary employment) as hazardous exposures are common in these situations. Dust and fume exposures are seldom present every day, all day, so patients should be asked whether
exposure occurred most days, only a few times a month, or only seldom (i.e. a few days a year). Exposure that occurred at least a few times a month should be considered relevant. Clinicians should be cautious about assuming that workplace exposures within “safe” limits were not high enough to produce disease. Many of the studies discussed above found significant airflow obstruction among workers exposed at or below regulated allowable limits. It is useful to consider the example of grain dust, which in many countries (including Canada and much of the United States) is still regulated with reference to the ‘nuisance dust’ standard, despite overwhelming evidence that this standard is unacceptable. The American Conference of Governmental and Industrial Hygienists has adopted the term “particulate not otherwise classified” rather than nuisance dust, to indicate “that all materials are potentially toxic and to avoid the implication that these materials are harmless” and to emphasize that “although these materials may not cause fibrosis and systemic effects, they are not biologically inert.”142 Management and compensation When the clinician sees a patient with chronic nonspecific airflow limitation (regardless of whether or not that patient is a smoker), it is useful to consider the possibility that occupational exposures may have contributed to the disease. This is important as continued occupational exposure may contribute to a worsening of the disease (in the patient, or in others in that workplace), if no preventive action is taken. For the patient still exposed to particulate or irritant gases or fumes, a recommendation should be made to reduce or eliminate the potential for the exposure. For the patient no longer exposed (or no longer working), it is important to record and report the disease as “potentially occupational” in order that public health officials can assess the role of the occupational exposure and use this information to direct prevention activities in the workplace. Whether or not a patient with occupational COPD is entitled to compensation or disability benefits will depend on the specific requirements of the compensation or insurance carrier. These requirements vary broadly. Disability evaluation should be carried out without reference to the question of etiology, as the level of disability or impairment is unaffected by the cause. The decision to attach the label “possibly occupational” to the diagnosis should also be based on the occupational history. Although requirements vary among jurisdictions, it should be the attending physician’s role to raise the possibility of occupational etiology, not to make the final determination in law. General guidance can be found in the following statement from the BC Workers’ Compensation Board policy manual: “Since workers’ compensation . . . operates on an enquiry basis rather than on an adversarial basis, there is no onus on the worker to prove his or her case. All that is needed is for the worker to describe his or her experience of the disease and the reasons why they suspect the disease has an occupational basis. Then it is the responsibility of the Board to research the available scientific literature and carry out any
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other investigations into the origin of the worker’s condition which may be necessary.” That said, unfortunately, physicians do find themselves called upon by legal tribunals, to quantify the relative contribution of occupational exposure to COPD. This can be extremely difficult, if not impossible, in the absence of detailed exposure information and the expertise to interpret it. A useful benchmark may be the research among smelter workers, discussed earlier in this section, that found the effect of working for 30 years at today’s “accepted” exposure concentration had an impact on airflow of about the same magnitude as a similar duration of cigarette smoking. Prevention Some evidence suggests that a rapid decline in FEV1 (but still in the “normal” range) in young exposed workers may be associated with a worse prognosis. Therefore, although these workers are unlikely to seek treatment, if such a patient is encountered (eg. as a result of routine screening or for other reasons) the index of concern should rise. The evidence is not strong enough to suggest that such a worker should be removed from exposure, but the patient should be made aware of his or her excess decline in lung function and the potential role of occupational exposure should be explored. Global prevention of occupational COPD will require increased recognition of the disease (by physicians, by regulators, and by employers), and a willingness by regulators and employers to act to reduce exposure to particulates and irritant gases and fumes in the work environment. Primary care and pulmonary physicians can play a major role in prevention by increasing the recognition of the disease, by reporting it, even if just as “suspect” or “possible” occupational COPD, to the local agency responsible for occupational disease prevention.
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108. Minty BD, Royston D, Jones JG, Smith DJ , Searing CSM, Beeley M. Changes in permeability of the alveolar–capillary barrier in firefighters. Br. J. Ind. Med. 1985; 42:631–4. 109. Rosen G, Lundstrom S. Concurrent video filming and measuring for visualization of exposure. Am. Indust. Hyg. Assoc. J. 1987; 48:688–92. 110. Horsfield K, Guyatt AR, Cooper FM, Buckman M, Cumming G. Lung function in West Sussex firemen: a four year study. Br. J. Ind. Med. 1988; 45:116–21. 111. Noertjojo HK, Dimich-Ward H, Peelen S, Dittrick M, Kennedy SM, Chan-Yeung M. Western red cedar dust exposure and lung function: a dose–response relationship (see comments). Am. J. Respir. Crit. Care Med. 1996; 154:968–73. 112. Chan-Yeung M, Wong R, MacLean L et al. Respiratory survey of workers in a pulp and paper mill in Powell River, British Columbia. Am. Rev. Respir. Dis. 1980; 122:249–57. 113. Brooks SM, Edwards JJ, Apol A, Edwards FH. An epidemiologic study of workers exposed to western red cedar and other wood dusts. Chest 1981; 81(Suppl 79):81S–5S. 114. Hessel PA, Herbert FA, Melenka LS,Yoshida K, Michaelchuk D, Nakaza M. Lung health in sawmill workers exposed to pine and spruce. Chest 1995; 108:642–6. 115. Whitehead LW, Ashkaga T, Vacek P. Pulmonary function status of workers exposed to hardwood or pine dust. Am. Ind. Hyg. Assoc. J. 1981; 41:178–86. 116. Whitehead LW. Health effects of wood dust – relevance for an occupational standard. Am. Indust. Hyg. Assoc. J. 1982; 43:674–8. 117. Goldsmith DF, Shy CM. Respiratory health effects from occupational exposure to wood dusts. Scand. J. Work Environ. Health 1988; 14:1–15. 118. Corey P, Hutcheon M, Broder I, Mintz S. Grain elevator workers show work-related pulmonary function changes and dose–effect relationships with dust exposure. Br. J. Ind. Med. 1982; 39:330–7. 119. Enarson DA, Vedal S, Chan-Yeung M. Rapid decline in FEV1 in grain handlers. Relation to level of dust exposure. Am. Rev. Respir. Dis. 1985; 132:814–17. 120. Huy T, De Schipper K, Chan-Yeung M, Kennedy SM. Grain dust and lung function. Dose–response relationships. Am. Rev. Respir. Dis. 1991; 144:1314–21. 121. Smid T, Heederik D, Houba R, Quanjer PH. Dust- and endotoxinrelated respiratory effects in the animal feed industry. Am. Rev. Respir. Dis. 1992; 146:1474–9. 122. Jorna THJM, Borm PJA, Valds J, Houba R, Wouters EFM. Respiratory symptoms and lung function in animal feed workers. Chest 1994; 106:1050–5. 123. Peelen SJ, Heederik D, Dimich-Ward HD, Chan-Yeung M, Kennedy SM. Comparison of dust related respiratory effects in Dutch and Canadian grain handling industries: a pooled analysis. Occup. Environ. Med. 1996; 53:559–66. 124. Kennedy SM, Dimich-Ward H, Desjardins A, Kassam A, Vedal S, Chan-Yeung M. Respiratory health among retired grain elevator workers. Am. J. Respir. Crit. Care Med. 1994; 150:59–65. 125. Holness DL, O’Blenis EL, Sass-Kortsak AM, Pilger CW, Nethercott JR. Respiratory effects and dust exposures in hog confinement farming. Am. J. Ind. Med. 1987; 11:571–80. 126. Iversen M, Dahl R, Korsgaard J, Hallas T, Jensen EJ. Respiratory symptoms in Danish farmers: an epidemiological study of risk factors. Thorax 1988; 43:872–7. 127. Leistikow B, Pettit W, Donham K, Merchant J, Popendorf W. Respiratory risks in poultry farmers. In: Dosman J, Cockcroft D (eds), Principles of Health and Safety in Agriculture, pp. 62–5. New York: Academic Press, 1989.
128. Donham KJ. Health effects from work in swine confinement buildings. Am. J. Ind. Med. 1990; 17:17–25. 129. Morris PD, Lenhart SW, Service WS. Respiratory symptoms and pulmonary function in chicken catchers in poultry confinement units. Am. J. Ind. Med. 1991; 19:195–204. 130. Zejda JE, Hurst TS, Rhodes CS, Barber EM, McDuffie HH, Dosman JA. Respiratory health of swine producers. Focus on young workers. Chest 1993; 103:702–9. 131. Choudat D, Goehen M, Korobaeff M, Boulet A, Dewitte JD, Martin MH. Respiratory symptoms and bronchial reactivity among pig and dairy farmers. Scand. J. Work. Environ. Health 1994; 20:48–54. 132. Zejda JE, Pahwa P, Dosman JA. Decline in spirometric variables in grain workers from start of employment: differential effect of duration of follow up. Br. J. Ind. Med. 1992; 49:576–80. 133. Schwartz DA, Donham KJ, Olenchock SA et al. Determinants of longitudinal changes in spirometric function among swine confinement operators and farmers. Am. J. Respir. Crit. Care Med. 1995; 151:47–53. 134. Soyseth V, Boe J, Kongerud J. Relation between decline in FEV1 and exposure to dust and tobacco smoke in aluminium potroom workers. Occup. Environ. Med. 1997; 54:27–31. 135. Sparrow D, Bosse R, Rosner B, Weiss ST. The effect of occupational exposure on pulmonary function. Am. Rev. Respir. Dis. 1982; 125:319–22. 136. Holman CD, Psaila-Savona P, Roberts M, McNulty JC. Determinants of chronic bronchitis and lung dysfunction in Western Australian gold miners. Br. J. Ind. Med. 1987; 44:810–18. 137. Carta P, Aru G, Barbieri MT, Avataneo G, Casula D. Dust exposure, respiratory symptoms, and longitudinal decline of lung function in young coal miners. Occup. Environ. Med. 1996; 53:312–19. 138. Hall SK, Cissik JH. Effects of cigarette smoking on pulmonary function in asymptomatic asbestos workers with normal chest radiographs. Am. Indust. Hyg. Assoc. J. 1982; 43:381–6. 139. Copes R, Thomas D, Becklake MR. Temporal patterns of exposure and non-malignant pulmonary abnormality in Quebec chrysotile workers. Arch. Environ. Health 1985; 40:80–7. 140. Kauffmann F, Drouet D, Lellouch J, Brille D. Occupational exposure and 12-year spirometric changes among Paris area workers. Br. J. Ind. Med. 1982; 39:221–32. 141. Le Moual N, Bakke P, Orlowski E et al. Performance of population specific job exposure matrices (JEMs): European collaborative analyses on occupational risk factors for chronic obstructive pulmonary disease with job exposure matrices (ECOJEM). Occup. Environ. Med. 2000; 157:126–32. 142. American Conference of Governmental and Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati: ACGIH, 1998. 143. Kennedy SM, Chan-Yeung M, Marion S, Lea J, Teschke K. Maintenance of stellite and tungsten carbide saw tips: respiratory health and exposure–response evaluations. Occup. Environ. Med. 1995; 52:185–91. 144. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am. Rev. Respir. Dis. 1981; 123:659–64. 145. Chan-Yeung M, Enarson DA, MacLean L, Irving D. Longitudinal study of workers in an aluminum smelter. Arch. Environ. Health 1989; 44:134–9. 146. Kennedy SM, Vedal S, Muller N, Kassam A, Chan-Yeung M. Lung function and chest radiograph abnormalities among construction insulators. Am. J. Ind. Med. 1991; 20:673–84.
Chapter
Infections
39
Simon D. Message and Sebastian L. Johnston National Heart and Lung Institute at St. Mary’s Imperial College School of Science, Technology and Medicine, London UK
A common feature of asthma and COPD is the important role of infection in triggering exacerbations. Infections have also been implicated in the etiology of the two diseases. This chapter reviews the epidemiological evidence implicating infectious pathogens as triggers and will discuss the mechanisms of interaction between the host–pathogen response and preexisting airway pathology that result in an exacerbation.
ASTHMA Asthma affects 20–33% of children in the UK.1 It is a multifaceted syndrome involving atopy, bronchial hyperreactivity and IgE and non-IgE mediated acute and chronic immune responses. The asthmatic airway is characterized by an infiltrate of eosinophils and of T lymphocytes expressing the type 2 cytokines IL-4, IL-5 and IL-13. Trigger factors associated with acute exacerbations of asthma include exposure to environmental allergens, especially animals, molds, pollens and mites, cold, exercise and drugs.The link between respiratory infection and asthma exacerbations is well established, although incompletely understood. In the 1950s this association was attributed to bacterial allergy,2 but it is now clear that the majority of exacerbations are due to viral rather than bacterial infection. Epidemiology Viral respiratory tract infections are a major cause of wheezing in infants and in adult patients with asthma. Their role may have been underestimated in early epidemiological studies because of difficulties in isolation and identification.3 The introduction of PCR to such studies has implicated viral infection in the majority of asthma exacerbations. Indirect evidence from population studies has established a significant correlation between the seasonal variation in wheezing episodes in young children and peaks of virus identification.4 Seasonal patterns of identification of respiratory viruses are associated with peaks in hospital admissions for both children and adults with asthma indicating a role for such infections in severe asthma attacks.5 Direct evidence implicating viral infection in asthma exacerbations has been
provided by studies showing an increased rate of virus detection in individuals suffering asthma attacks. Viruses have been detected in 10–85% of asthma exacerbations in children4,6–8 and in 10–44% in adults.9,10 The highest rates of identification are in those studies where subjects were followed prospectively allowing collection of clinical specimens early in the course of the illness, where PCR-based methods of diagnosis were used in addition to serology and culture, and where the methodology used allowed for detection of rhinoviruses. The rate of detection of viruses between exacerbations when individuals are asymptomatic is only of the order of 3–12%. In contrast a study of transtracheal aspirates in adult asthmatics during exacerbations11 yielded sparse bacterial cultures with no correlation to clinical illness and no difference from those of normal subjects. In almost all studies of asthmatics the predominant viruses are rhinoviruses (RV), RSV and parainfluenza viruses. RV alone are detected in around 50% of virusinduced asthma attacks. Adenoviruses, enteroviruses and coronaviruses are also detected but less frequently. Influenza is only found during annual epidemics. Experimental virus infection The effects of respiratory virus infection in the nasal mucosa and upper respiratory tract have been extensively investigated. More recently the effects of such viruses in the lower respiratory tract have been studied, but detailed knowledge of the pathogenetic mechanisms involved remains limited. Experimental respiratory virus infection in human volunteers is limited by concerns of safety.12 Most studies have therefore focused on the experimental innoculation of rhinovirus in allergic rhinitic or mild asthmatic individuals or normal control subjects.13–25 Such studies provide a useful model of natural virus infection in asthma and offer the advantages of patient selection and monitoring, under controlled conditions before, during and after infection, of RV-induced effects including asthma symptomatology, changes in the use of medication, lung function and airway pathology/immunology. In general, the clinical, physiological and cellular responses to experimental RV infection in asthma are
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relatively mild and do not necessarily mimic exactly the events after a natural common cold. It has been suggested that this requires a more complex model including both virus infection and preexisting increase in allergic airway inflammation. Indeed, recent epidemiological evidence confirms a synergistic interaction between virus infection and allergen exposure in precipitating hospital admissions for asthma. Other trigger factors that may interact with infection include air pollution. A study of asthmatic children demonstrated an increased risk of developing an asthmatic episode within 7 days of an upper respiratory tract infection if the nitrogen dioxide level was greater than 28 lg/m3.26 Most studies of experimental virus infection in allergic subjects are performed outside the relevant season for allergen exposure. One recent attempt to provide a model combining allergen exposure and virus infection utilized RV infection in subjects with allergic rhinitis. Individuals received three high-dose allergen challenges in the week prior to innoculation to try to mimic combined allergen exposure and virus infection.27 Interestingly, prior allergen challenge in this model, somewhat unexpectedly, appeared to protect against a RV cold with delayed nasal leukocytosis, delayed rise of the pro-inflammatory cytokines IL-6 and IL-8 and a delayed, less severe clinical course. There was an inverse correlation between nasal lavage eosinophilia and the severity of cold symptoms. The explanation proposed by the authors of this study is that limited high-dose allergen challenge may not reproduce the effects of chronic low-dose allergen exposure and may stimulate the production of antiinflammatory mediators such as IL-10, or antiviral cytokines such as IFN-c or TNF-a. Further development of models of combined allergen exposure and virus infection is clearly required. Mechanisms of virus-induced asthma exacerbations The interaction of respiratory virus infection and chronic asthmatic airway inflammation results in respiratory symptoms that are more severe than those suffered by nonasthmatic individuals. The detailed immunological mechanisms underlying this interaction are currently unclear. Current hypotheses for the pathogenesis of virus-induced asthma exacerbations are summarized in Table 39.1. The disease syndrome following infection by virus is a consequence both of direct harmful effects of the virus itself and of immunopathology resulting from the host–immune response. In an asthmatic individual, exacerbation may occur because of functional interaction between viral pathology and asthmatic pathology, i.e. through different mechanisms with the same end effect on function, or by sharing the same pathogenetic mechanism in an additive or even in a synergistic fashion. Preexisting asthmatic inflammation might interfere with an effective anti-viral response and thus allow the virus itself to cause increased airway damage. Alternatively, virus infection might increase the sensitivity of the asthmatic airway to trigger factors, such as allergen exposure. In fact, it is likely that virus-induced asthma exacerbations occur because of a combination of
these types of interaction. The increased severity of symptoms, including lower respiratory symptoms, seen in subjects with allergic rhinitis, but without asthma, during viral infection suggests that the atopic phenotype itself is important in determining the clinical syndrome following infection by respiratory viruses. Alternatively, it is possible that virus infection in some way amplifies subclinical allergic lower airway inflammation already present prior to infection. Table 39.1 summarizes some of the current hypotheses proposed to explain the mechanisms of exacerbation of asthma following respiratory virus infection. The evidence supporting these hypotheses is reviewed in detail below. Rhinovirus infection of the lower airway Whereas other respiratory viruses such as influenza, parinfluenza, RSV and adenovirus are well recognized causes of lower airway syndromes, such as pneumonia and bronchiolitis and are capable of replication in the lower airway, until recently there was uncertainty as to whether RV infection occurred in the lower airway, as well as in the upper respiratory tract. Although the possibility of nasopharyngeal contamination cannot be ruled out, RV has been detected in lower airway clinical specimens such as sputum,28 tracheal brushings22 and BAL29 by both RT-PCR and culture. RV has Table 39.1. Current hypotheses for the pathogenesis of virus-induced asthma exacerbations
Epithelial disruption
Reduced ciliary clearance Increased permeability Loss of protective functions
Mediator production
Kinins Complement Arachidonic acid metabolites Nitric oxide Reactive oxygen products
Induction of inflammation
Cytokines Chemokines Immune cell activation Adhesion molecule induction
IgE dysregulation
Increased total IgE Antiviral IgE production
Airway remodeling
Airway smooth muscle Fibroblasts Myofibroblasts Growth factors
Alterations of neural responses
Increased cholinergic sensitivity Neuropeptide metabolism modulation b-Adrenergic receptor dysfunction
Infections
been cultured in cell lines of bronchial epithelial cell origin30 and replication has been demonstrated in primary cultures of bronchial epithelial cells.31,32 The preference of RV for culture at 33C rather than 37C has been used as an argument against lower airway infection, but there is now evidence that replication does occur at lower airway temperatures.33 Finally the use of in situ hybridization has demonstrated RV in bronchial biopsies of subjects following experimental infection.31 These data confirm that RV infection of the lower airway does occur and directly implicate lower airway infection in the pathogenesis of asthma exacerbations. Physiological effects of experimental rhinovirus infection Subjects with asthma and/or allergic rhinitis exhibit increased pathophysiological effects as a result of RV infection as compared with nonatopic nonasthmatic controls. With detailed monitoring, it is possible to detect reductions in both peak flow34 and home recordings of FEV1 in atopic asthmatic patients in the acute phase of experimental RV16 infection.20 There is an enhanced sensitivity to histamine and allergen challenge after RV16 innoculation in nonasthmatic atopic rhinitic subjects.15,25 RV16 increases asthma symptoms, coinciding with an increase in the maximal bronchoconstrictive response to methacholine up to 15 days after infection.16 There is a significant increase in sensitivity to histamine in asthmatic subjects after RV16 infection, most pronounced in those with severe cold symptoms.21 Effects of viruses on airway epithelial cells Respiratory viruses enter into and replicate within epithelial cells lining the lower airway. Entry is dependent on
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interaction with specific receptors, for example the adhesion molecule ICAM-1 in the case of the major group rhinoviruses and the LDL receptor in the case of the minor group rhinoviruses. Influenza viruses bind sialic acid residues via hemaglutinin. The extent of epithelial cell destruction observed in the airway varies according to virus type. Influenza typically causes extensive necrosis,35 whereas RV causes little or only patchy damage. Destruction of epithelial cells results in an increase in epithelial permeability, increased penetration of irritants and allergens, and exposure of the extensive network of afferent nerve fibers.These effects may contribute to the increased bronchial hyperresponsiveness induced by virus infection.16 There is increasing evidence that the epithelium does not simply act as a physical barrier but has important regulatory roles. Epithelial cells contribute to the immune response following virus infection through the production of cytokines and chemokines (Fig. 39.1). They may also act as antigen presenting cells particularly during secondary respiratory viral infections. Epithelial cells express MHC class I and the costimulatory molecules B7-1 and B7-2 and this expression is upregulated in vitro by RV16.36 Inflammation is a central event both in asthma and in viral infections. The processes involved include interacting cascades from the complement, coagulation, fibrinolytic and kinin systems of the plasma, as well as cell-derived cytokines, chemokines and arachidonic acid metabolites. Our understanding of the interaction of viruses with these cascades in asthma is incomplete and it is likely that different viruses interact with each system to different extents. However, it is reasonable to believe that in all cases the
Il-8, Gro-α GM-CSF, Eotaxin, RANTES, MIP-1α
Neutrophils activation, chemotaxis
Eosinophils survival, chemotaxis
IL-1β, MIP-1α, MCP-1, TNF-α Macrophages
Virus IFN-α/β, MIP-1α
RANTES, IL-6
NK cells activation
T lymphocytes activation, chemotaxis
MHC I, ICAM-1, VCAM-1 IFN-α/β Fig. 39.1. Airway epithelial cells participate in the immune response to respiratory virus, producing a variety of cytokines and chemokines with actions on other cells. In addition, the migration of inflammatory cells is aided by the up-regulation of adhesion molecules and interferons help to establish an antiviral state in neighboring epithelial cells. Up-regulation of MHC class I may facilitate presentation of viral antigens.
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initial trigger of the inflammatory reactions is epithelial cell–virus interaction. A multitude of inflammatory mediators are generated or act on the epithelial surface. Bradykinin, a 9 amino acid peptide generated from plasma precursors as part of the inflammatory process has been shown to be present in nasal secretions of RV-infected individuals.37 Bradykinin given intranasally is able to reproduce some of the symptoms of the common cold, such as sore throat and rhinitis.38 Although the presence of kinins in the lungs of virusinfected individuals has not been reported they are present in both the upper and lower airways in allergic reactions.39–41 Some viruses may also cause complement-mediated damage. Complement components bind to epithelial cells both in vitro and in vivo during RSV infections. C3a and C5a are increased in human volunteers infected with influenza A virus.42 NO is produced by diverse sources including epithelial, endothelial and smooth muscle cells. In human airways, NO appears to be important in relaxation of the human airway smooth muscle.43 In experimental animals, parainfluenza virus-induced hyperreactivity correlates with a deficiency in constitutive NO production.44 On the other hand, in inflamed tissues NO reacts with superoxide anion generating peroxynitrite, a highly toxic compound suggesting a dual role for this mediator. Increased levels of exhaled NO are found in nonasthmatic volunteers following natural colds,45 as well as in asthmatic patients after experimental RV infection.46 In the latter study an inverse association between NO increase and worsening of airway hyperresponsiveness was demonstrated arguing in favor of a protective role for this substance. This is further supported by the observation that NO reduces cytokine production and viral replication in an in vitro model of RV infection.47 The up-regulation of ICAM-1 in the asthmatic airway is one explanation for the increased severity of RV infection. RV has itself been shown to further up-regulate ICAM-1 in bronchial biopsies following experimental RV infection.48 In nasal epithelial cells obtained by brushings from atopic subjects, basal levels of ICAM-1 were increased relative to nonatopic subjects and were elevated in the relevant season for peak allergen exposure. Nasal epithelial cells from atopic subjects showed further up-regulation after in vitro culture with allergen. The highest basal level of expression of ICAM-1 was found on nasal polyp epithelial cells and this was increased further after infection with RV14. Viral titers recovered after RV14 infection were significantly higher for polyp epithelial cells than for nonatopic and atopic nonpolyp epithelial cells.49 In vitro RV increases expression of both ICAM-1 and VCAM-1 in cultures of primary bronchial epithelial cells and in the A549 respiratory epithelial cell line via a mechanism involving the transcription factor NF-jB.50,51 Inhibition of the up-regulation of ICAM-1 might be expected to modify favorably the course of RV infection. One effect of corticosteroids is to inhibit NF-jB.52 In both A549 cells and in primary bronchial epithelial cells pretreatment with three
different corticosteroids, hydrocortisone, dexamethasone and mometasone furoate, inhibits RV16-induced increases in ICAM-1 surface expression, mRNA and promoter activation without alteration of virus infectivity or replication.53 Disappointingly, a study of inhaled corticosteroids in asthmatics prior to experimental RV infection failed to show a reduction of virus-induced ICAM-1 expression in bronchial biopsies,48 but it is possible that a longer course and/or a higher dose of inhaled steroid or administration of oral steroids might have demonstrated a significant effect. Viral infection of the respiratory tract results in significant changes in the pattern of cytokine expression by a number of cell types, both by cells of the immune system, which may be increased in number and activation status, and by cells often considered to be structural, but which in fact contribute significantly to the immune response, such as epithelial cells. Efficient orchestration of the immune response by cytokines is essential for eradication of virus. Modification of cytokine expression in the airway may contribute to the increased severity of virus infection in asthma. In vitro studies of bronchial epithelial cell lines have demonstrated the production of a wide range of proinflammatory cytokines such as IL-1, IL-6, IL-11, IFN-a, IFN-c, TNF-a and GM-CSF and the chemokines IL-8, RANTES and MIP-1a in response to RV and RSV.30,54,55 In vivo these cytokines can be found in nasal lavage in association with RV infection.56 The specific roles of individual cytokines in the human lower airway during viral infection are not well understood, but increasing information is becoming available. IL-1, TNF-a and IL-6 share pro-inflammatory properties, such as the induction of the acute phase response and the activation of both T and B lymphocytes. IL-1 enhances the adhesion of inflammatory cells to endothelium, facilitating chemotaxis.57 TNF-a is a potent antiviral cytokine, but in vitro increases the susceptibility of cultured epithelial cells to infection by the major group rhinovirus RV14 through upregulation of ICAM-1.30 IL-6 has been shown to stimulate IgA-mediated immune responses. IL-11 may also be important in virus-induced asthma.58 It appears to cause bronchoconstriction by a direct effect on bronchial smooth muscle.55 In vivo IL-11 is elevated in nasal aspirates from children with colds, levels correlating with the presence of wheezing. Similarly the chemokine MIP-1a is increased in nasal secretions during natural viral exacerbations of asthma.59 Viral up-regulation of cytokines may be mediated through certain key transcription factors. Increases in IL-6 and IL-8 production by cultured epithelial cells due to RV is dependent on NF-jB60,61 as is the induction of IL-1, -6, -8, -11 and TNF-a by RSV.62,63 Effects of viruses on airway smooth muscle cells Studies utilizing isolated rabbit tissues and human cultured airway smooth muscle cells suggest that, for RV16, exposure to the virus may have a direct effect on smooth muscle cells, resulting in increased contractility to acetylcholine and impaired relaxation to isoproterenol.This effect is dependent
Infections
on ICAM-1 and appears to involve an autocrine signaling mechanism, including up-regulation of production of IL-5 and IL-1b by the airway smooth muscle itself.64 Whether rhinovirus reaches airway smooth muscle cells in sufficient quantity to produce a significant effect by this mechanism in vivo is as yet unknown. The effects of other respiratory viruses on smooth muscle require further investigation. The cellular immune response to virus infection in the lower airway A variety of leucocytes show changes in number, site of accumulation and activation state in response to virus infection. Since these cells are also implicated in asthmatic inflammation of the lower airway they provide potential sites of interaction between the immunopathologies of virus infection and asthma. Monocytes/macrophages Alveolar macrophages are present in large numbers in the lower airway. They make up around 90% of the cells seen in BAL from normal volunteers.24 They are ideally placed for early phagocytosis of virus particles and are likely to play an important role in the immune response through antigen presentation to T cells and through the production of cytokines and other mediators. RV has been shown to enter human monocytes and macrophages which express high levels of the major RV receptor ICAM-1. It has not been possible to demonstrate RV replication within alveolar macrophages, although low grade productive infection has been shown in the monocyte cell line THP-1,65 but entry into monocytes does result in activation and the production of both IL-865 and TNF-a.66 Similarly infection of human monocytes in vitro with influenza A causes alterations in structure and activation status and the production of IL-1b, IL-6,TNF-a, IFN-a and IFN-b,67 effects dramatically potentiated by subsequent exposure to bacterial LPS. Dendritic cells Dendritic cells are key cells in antigen presentation both of allergens and pathogens with a capacity to induce primary immune responses. They may also play a role in the regulation of the type of T cell-mediated immune response.68 There is increasing knowledge of the immunobiology of these cells, but they are not well studied in the context of viral exacerbations of asthma. Lymphocytes Bronchial biopsies demonstrate increases in cells positive for CD3, CD4 and CD8 within the epithelium and submucosa of both normal and asthmatic subjects following experimental RV infection.17 Such increases coincide with peripheral lymphopenia suggesting increased recruitment of T cells to the airway, although alternative mechanisms such as reduced apoptosis might also contribute. Since T cells are believed to be key cells in the pathogenesis of asthma the effects of viruses on T cells are of particular importance.
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The normal CD4 T cell response to virus infection is thought in general to be of the T helper 1 (Th1) type. The major type 1 cytokine is IFN-c which, in addition to IFN-a and IFN-b from monocytes and macrophages, plays a role in establishing an “antiviral state” in neighboring cells. IFN-c has varied effects on the pathogenesis of asthma. It appears to increase basophil and mast cell histamine release,69 but on the other hand inhibits the expression of type 2 cytokines. Production of IFN-c is increased in PBMC70 and in nasal secretions56 during RV colds and in human and animal models of influenza, parainfluenza and RSV infection.71,72 Asthma is believed to be characterized by Th2-type inflammation. Many studies have demonstrated mutual inhibition of Th1 and Th2 cells.73,74 It is therefore possible within an airway with a preexisting Th2-type allergic asthmatic microenvironment that there may be inhibition of the normal effective Th1-type antiviral immune responses or that responses may be skewed towards inappropriate and potentially harmful Th2 types (Fig. 39.2). In a recent study of experimental RV16 infection in subjects with allergic rhinitis or asthma, the balance of airway type 1 and type 2 cytokines in sputum induced by viral infection was found to be related to clinical symptoms and viral clearance. Although protein could not be detected in sputum due to the presence of inhibitors of the ELISA assay used, there were increases in mRNA, as determined by semi-quantitative RT-PCR, for both IL-5 and IFN-c. An inverse correlation was demonstrated between the ratio of IFN-c mRNA to IL-5 mRNA and peak cold symptoms. In addition subjects with RV16 still detectable 14 days after inoculation had lower IFN-c/IL-5 ratios during the acute phase of the cold than those subjects who had cleared the virus.75 CD8 T cells are important effector cells in specific cellmediated antiviral immunity. These cells also demonstrate polarization of cytokine production, the major cytokine produced by Tc1 cells being IFN-c and they are believed to play a role in the regulation of CD4 Th1/Th2 balance.76 In a murine model of asthma the induction of bystander CD4 Th2 immune responses to ovalbumin resulted in a switch of virus-peptide-specific CD8 T cells in the lung to the production of Tc2 cytokines including IL-5 with, after challenge with virus peptide, the induction of airway eosinophilia.77 If such a mechanism occurs in man it would suggest a means whereby CD8 antiviral function could be inhibited at the same time as CD8 amplification of allergic inflammation through IL-5 induction of airway eosinophilia. Recruitment of T cells from the blood into the airway is at least in part under the influence of chemokines, including those whose production by epithelial cells is up-regulated following virus infection. Th1 and Th2 cells appear to show differential expression of chemokine receptors. Studies of T cell clones demonstrate increased expression of CXCR3 (receptor for IP-10, I-TAC and Mig) and CCR5 (MIP-1b) in human Th1 cells and increased expression of CCR4 (TARC and MDC) and to a lesser extent CCR3 (eotaxin
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Asthma and Chronic Obstructive Pulmonary Disease
Virus
Macrophage Dendritic cell
IgE IL-12, 18
Th0
ⴚ
IL-2 IFN-γ cytotoxicity
IL-4
IL-4, 13
IL-4
IFN-γ
Eosinophilia
ⴚ
IL-5
Th1
Th1
Th2
Effective early viral clearance
Failure to clear virus
Effective termination of immune response
Persistent eosinophilia
Th2
Th1
Th2
Prolonged inappropriate immune response with immunopathology and tissue damage Amplification of allergic inflammation
Fig. 39.2. Preexisting asthmatic airway inflammation may modify a predominantly Th1 antiviral immune response, favoring a Th2 or mixed response, which may provide less efficient viral clearance and result in prolonged virus-induced inflammation, increased associated immunopathology and increased tissue damage.
and MCP-3) in Th2 cells, with selective migration of cells in response to the appropriate chemokines. CCR1 (RANTES, MIP-1a, MCP-3) and CCR2 (MCP-1,2,3,4) were found on both Th1 and Th2 cells.78 Bronchial biopsies from asthmatics show high levels of expression of CCR4 and significant levels of CCR8 by T cells.79 Increased recruitment of T cells to the airway as a result of virusinduced chemokine production by epithelial cells could amplify preexisting allergic inflammation. If the asthmatic airway microenvironment influences the pattern of chemokine expression following virus infection then this could alter the Th1/Th2 balance of the antiviral immune response. Mast cells/basophils These cells are important sources of inflammatory mediators characteristic of allergic inflammation in asthma. Mast cell basal and stimulated histamine release increases after virus infection.72 Airway mast cell numbers are up-regulated in a rat model of parainfluenza infection. Several viruses can enhance basophil IgE-mediated histamine release, but the role of this cell in human asthma is controversial. Mast cells are also important sources of inflammatory mediators. Their function and localization suggest an early
interaction with viruses. LTC4 is among the major mediators responsible for the late phase of bronchospasm in asthma. During RSV infection increased levels of LTC4 were found in the nasopharyngeal secretions of infants.80 Levels correlated well with the symptoms of the disease with concentrations in infants presenting with bronchiolitis being 5-fold higher than in those with only upper respiratory tract symptomatology. Eosinophils Eosinophils are increased in bronchial epithelium in biopsies taken from both normal and asthmatic human volunteers following experimental RV infection; in a small study, eosinophilic inflammation persisted for up to 6 weeks in asthmatic subjects.17 In allergic rhinitic subjects, experimental RV infection increases BAL eosinophils following segmental allergen challenge, an effect similarly persisting for 6 weeks,24 and increased levels of eosinophil cationic protein are found in the sputum of RV-infected subjects.19 Eosinophils accumulate in the airway under the influence of IL-5, GM-CSF, IL-8, RANTES and eotaxin.81 Expression of the potent eosinophil chemoattractant RANTES is increased in nasal secretions of children with natural virusinduced asthma exacerbations.59 RANTES is up-regulated
Infections
in primary nasal epithelial cell cultures by RSV82 and RV.32 GM-CSF is believed to be important in eosinophil production in the bone marrow and in prolonging eosinophil survival.81 However, levels do not appear to be increased during viral upper respiratory tract infections.59,83 Levels of eotaxin in nasal lavage rise after experimental RV16 infection.84 These data suggest a pathogenic role for eosinophils in virus-induced asthma. However, a protective role is also possible. In allergic rhinitic subjects infected with RV after high-dose allergen challenge the severity and duration of cold symptoms were inversely related to the nasal lavage eosinophil count prior to infection.27 Eosinophils may contribute to antigen presentation during virus infection. Eosinophils purified from PBMC and pretreated with GMCSF bind RV16 via ICAM-1 and present viral antigen to RV16-specific T cells, inducing proliferation and secretion of IFN-c. Eosinophils have antiviral actions in parainfluenza-infected guinea pigs.85 Eosinophil-derived neurotoxin and cationic protein have ribonuclease activity and reduce RSV infectivity.86 The role of the eosinophil in the antiviral immune response thus requires further evaluation. Neutrophils Neutrophils are recruited early in viral infection in response to the production of the chemokine IL-8 by epithelial cells and by activated neutrophils, and are a prominent feature of severe asthma. Induced sputum studies in asthmatic and nonasthmatic volunteers demonstrate a significant increase in sputum neutrophils at day 4 of a natural cold, correlating with sputum IL-8.87 Similar results were obtained in induced sputum taken 2 and 9 days after experimental RV16 infection in asthmatic subjects. Intracellular staining demonstrated that the increase in cells positive for IL-8 at day 2 could be attributed to the increase in IL-8-positive neutrophils.19 The chemokine IL-8 is a potent chemoattractant for neutrophils, but also acts on lymphocytes, basophils and primed eosinophils. An increase in IL-8 has been found in nasal lavage from children with natural colds.56 Experimental infection of atopic asthmatics with RV16 resulted in elevated IL-8 in nasal lavage and this correlated with cold and asthma symptom scores and a fall in histamine PC20.21 Sputum from asthmatics with asthma exacerbations has both elevated IL-8 and neutrophilia.88 A study of experimental virus-induced asthma in children also demonstrated elevated IL-8 and neutrophilia in nasal aspirates during the acute phase of infection and levels of neutrophil myeloperoxidase correlated with symptom severity.89 Such studies suggest a prominent role for the neutrophil in tissues damaged during virus-induced asthma. Natural killer cells NK cells are an important part of the innate immune response, their function being the elimination of a variety of target cells including virus-infected cells and the modulation of adaptive immunity towards viruses.90 Cell killing by NK cells may occur through natural killing, antibody-dependent cellular cytotoxicity (ADCC) or apoptotic killing of
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Fas-positive target cells via membrane bound FasL. The ability to directly kill virus-infected cells is regulated by a balance between inhibitory and activating receptors.91 Killer inhibitory receptors (KIRs), Ig-like receptors that recognize HLA-A, B or C molecules, and the lectin-like CD94/NKG2A receptor that interacts with HLA-E allow NK cells to recognize cells expressing normal self MHC class I.92 Loss of inhibition occurs if potential target cells have lost class I expression following virus infection or if they display abnormal class I/peptide complexes. NK cells are rapid and efficient producers of cytokines such as IFN-c, important both in early viral infection in the antigen-independent activation of antigen-presenting cells such as macrophages, dendritic cells and epithelial cells, and for biasing the development of CD4 Th1 and CD8 Tc1 cells. The function of NK cells in the asthmatic airway is as yet unexplored. It may be that in an airway environment rich in type 2 cytokines that NK type 1 function and effective antiviral activity are inhibited. If this is the case, then a key component of the early immune response would be deficient and viral clearance would be impaired. B lymphocytes and interaction of viruses with IgE dependent mechanisms An elevated serum total and allergen-specific IgE are features of “extrinsic” or atopic asthma. IgE-mediated mechanisms are certainly important in the pathophysiology of extrinsic asthma. Recent studies suggest a similar airway pathology in both extrinsic and “intrinsic” nonatopic asthma,93 where there is an absence of specific serum IgE and negative skin prick tests to aeroallergens. It has been suggested that there may be the production of local IgE to as yet unknown environmental allergens in intrinsic asthma. Up-regulation of total IgE or virus/allergen-specific IgE locally or systemically during respiratory virus infection would be expected to contribute to the duration and severity of symptoms of an asthma exacerbation. Intranasal challenge with RV39 results in an increase in total serum IgE in allergic rhinitic subjects, but no increase in preexisting allergen-specific IgE.94 In children with asthma, during infection with influenza A there was no change in total IgE, but increases were observed in specific serum IgE to house dust mite and in ex-vivo proliferative and IL-2 responses of lymphocytes challenged with house dust mite allergen.95 In a study of RSV infection in infants the development of serum RSV-specific IgE occurred more frequently in atopics and correlated with clinical wheezing, histamine levels in nasal secretions and hypoxia.96 There is no information as yet on the presence of local virus-specific IgE in the airway during asthma exacerbations.
COPD Increasing interest in the clinical features and pathogenesis of COPD reflects the worldwide importance of the disease.
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More than 14 million patients are affected in the United States alone. It is predicted to become the third leading cause of death worldwide by 2020.97 National and global initiatives have been launched and management guidelines have been published.98,99 The frequency of exacerbations is a major factor in the quality of life of patients with COPD.100 Problems exist in defining an acute exacerbation. One definition is an acute tracheobronchitis, generally infectious in etiology, that occurs in a patient with established COPD. An important element of this definition is that other causes of respiratory deterioration frequently encountered in this patient group, such as congestive cardiac failure, cardiac arrhythmias, pneumothorax, pneumonia and pulmonary thromboembolism must be excluded.101 The typical clinical features of an exacerbation include increased dyspnea, wheezing, cough, sputum production and worsened gas exchange. Although noninfectious causes of exacerbations such as allergy, air pollution or inhaled irritants including cigarette smoke may be important, acute airway infections are the major precipitants.102 The infection and consequent host inflammatory response result in increased airway obstruction. Epidemiology At least a third of exacerbations may be caused by viral infections. In a study of 186 patients rhinoviruses, influenza virus, parainfluenza virus and coronavirus were significantly associated with COPD exacerbations. Patients did not seem to have increased susceptibility to these viruses but viral infection had more serious consequences if it occurred.103 The role of bacteria in precipitating exacerbations is controversial. Bacteria may have a primary role in the development of an exacerbation or represent a secondary superinfection of an initial viral process. Various bacterial species are present in the airways of 25–50% of patients, even when the COPD is stable but increased frequency of recovery of bacteria during exacerbations suggests that they play a role.104,105 Significant bacterial infection has been suggested when there is an abundance of neutrophils in the sputum106 and when the sputum is purulent and green (due to neutrophil myeloperoxidase).107 The major bacterial organisms associated with COPD exacerbations are nontypable Haemophilis influenzae, Streptococcus pneumoniae and Moraxella (Branhamella) catarrhalis.108,109 Mycoplasma pneumoniae and Chlamydia pneumoniae may play a part.110 Evidence also suggests that in more severe patients with a baseline FEV1 of 35% predicted or less, Gram-negative bacteria especially Enterobacteriaceae and Pseudomonas play an important part in acute exacerbations.111 Although the results of placebo-controlled trials show conflicting results, overall the effects of antibiotic treatment also suggest an etiological role for bacteria in exacerbations in some patients. A meta-analysis of nine studies showed a small overall benefit when antibiotics were used for COPD exacerbations.112 The largest study included 362 exacerbations in 173 outpatients.106 Compared with placebo, the
rate of symptom resolution and improvement of peak expiratory flow during exacerbations was slightly but significantly faster when patients were treated with cotrimoxazole, amoxicillin or doxycycline. More importantly, treatment failures as defined by respiratory deterioration were nearly twice as likely in the placebo group. Benefit from antibiotics was most evident for patients with most symptoms (dyspnea, increased sputum volume and sputum purulence). Guidelines for the use of antibiotics in acute exacerbations of COPD are unclear because of the difficulties in defining the role of bacterial infection in an individual case. The American Thoracic Society statement on COPD99 suggests using antibiotics if there is evidence of infection (fever, leukocytosis, CXR changes), but not all patients with bacterial bronchial infection have fever (this is more common in viral infection or pneumonia) and few have CXR changes. The European Respiratory Society recommends antibiotics if the sputum is purulent, using standard antibiotics as first line, and sputum culture if these fail.113 The major bacterial pathogens isolated during bronchial infections all form part of the commensal flora in the nasopharynx. Bronchial infections occur in patients with abnormal airways with reduced host defenses. Persistence of bacteria within the bronchial tree may come about through toxins that impair mucociliary clearance, enzymes that break down local immunoglobulin, products that alter immune effector cell function, adherence to mucous and damaged epithelium or other mechanisms of avoiding immune surveillance.114 Bronchial infections usually remain confined to the mucosa. Many will resolve spontaneously without antibiotic treatment. Persistent bacterial infection usually reflects the severity of the impairment of the lung defenses, rather than the virulence of the micro-organism. The damage to lung tissue caused by the host inflammatory response to chronic bacterial infection may be more important than the damage caused directly by the bacteria themselves.102 Evidence for a role for bacterial infection in pathogenesis/progression of COPD – the vicious cycle hypothesis Bacterial infection has a definite role in the pathogenesis of other chronic lung diseases, such as cystic fibrosis and bronchiectasis where bacterial infection is chronic, causing not only acute exacerbations but also influencing long-term prognosis.102 In these diseases chronic bacterial infection sets up a vicious cycle in which the host inflammatory response is unable to clear the bacteria and instead promotes continued infection and tissue damage.114 Neutrophils produce proteinases and reactive oxygen species, and lung antiproteinase defenses are overwhelmed. Both proteinase enzymes and reactive oxygen species cause damage to the epithelium, stimulating mucous production and impairing mucociliary clearance. Neutrophil elastase stimulates epithelial cell production of the chemokine IL-8 which
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attracts further neutrophils and in addition impairs phagocytosis by destroying antibody and cleaving complement receptors from neutrophils and complement components from bacteria. Similar cellular mechanisms operate in COPD. Neutrophils are also stimulated by cigarette smoke. COPD patients may be chronically colonized by bacteria between exacerbations, bacterial numbers then increasing during exacerbations. In a study using bronchoscopic protected brush specimens,104 ten of 40 COPD patients were colonized with bacteria when stable. During exacerbations 50% had bacteria present and when present, bacterial numbers were greater.When protected brush specimens were taken during severe acute exacerbations of COPD requiring ventilation,115 bacteria were detected in 50%, but it was not possible to distinguish patients more likely to have bacteria on the basis of clinical features or other investigations. Bacterial colonization in the stable state represents an equilibrium in which the number of bacteria present in the bronchial tree is contained by the host defenses, but not eliminated. During an exacerbation this equilibrium is upset and bacterial numbers increase, inciting an inflammatory response. Change will usually occur because of a change in the host rather than altered virulence of the bacteria, for example as a result of viral infection. Evidence for a role for viruses in exacerbations of COPD Many exacerbations of COPD occur without the hallmarks of bacterial infection – increased volume or purulence of sputum. Between 33 and 70% of exacerbations are associated with symptoms of the common cold. The frequency of exacerbations requiring hospitalization is higher in the winter. One explanation for this could be the increased frequency of respiratory viruses at this time of the year. A recent study of 321 exacerbations in 83 patients with moderate to severe COPD using new diagnostic methods including RT-PCR shows a high incidence of viral infection.116 Viruses were detected in nasal aspirates at exacerbation in almost 40% of cases. Rhinovirus was the most common, occurring in 58% of cases where a virus was present. The presence of virus was associated with increased dyspnea, cold symptoms and sore throat and with prolonged recovery from exacerbation. Earlier studies relying on serology and virus culture quote lower virus detection rates of 15–20%.103,117–119 It has been suggested that persistent virus infection contributes to the progression of COPD. In particular, adenovirus appears to persist in a latent form in which viral proteins are produced without replication of complete virus. Such latent infection may amplify lung inflammation due to cigarette smoke.120 Adenoviral E1A DNA persists in human lungs from patients with COPD compared with patients of similar age, sex and smoking history who do not have COPD.121 The E1A protein has been demonstrated in airway epithelial cells from smokers.122 It is able to amplify many host genes through attachment to the DNA-binding sites of transcription factors.123 Airway epithelial cells
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transfected with E1A produce excess inflammatory cytokines such as IL-8,124 and surface adhesion molecules such as ICAM-1125 after in-vitro challenge by an NF-jBdependent mechanism.126 RSV has been identified in induced sputum from patients with stable COPD. These individuals have a higher plasma fibrinogen and serum IL-6, a higher pCO2 and increased frequency of exacerbations.116 This suggests either that low grade persistent RSV infection contributes to COPD severity or that patients with more severe COPD are less able to clear RSV from the airway. The immunology of virus infection in COPD is not well understood. Fewer data are available than for virus infection in asthma, since this has not been the subject of human experimental infection studies. Such studies are clearly needed in view of the increasing evidence for a major role for viruses in causing COPD exacerbations.
THERAPY Currently much of the treatment of infective exacerbations of both asthma and COPD is symptomatic, consisting of increased bronchodilators, or supportive in the form of oxygen and in severe cases noninvasive or invasive ventilatory measures. Corticosteroids are widely used in inhaled or oral form for their anti-inflammatory actions and have a major role in asthma. They are also effective in many infective exacerbations of COPD even if the patient, when stable, shows little evidence of steroid responsiveness.The effects of corticosteroids are the result of actions at many points in various inflammatory cascades. Whilst this undoubtedly contributes to their beneficial effects it also results in significant side-effects, in particular if systemic steroid treatment is prolonged or frequent. In addition systemic steroids may interfere with the antiviral immune response resulting in reduced viral clearance.127 Specific antibiotic therapy is available for bacterial infections and is indicated where there is good evidence of such infection or when the exacerbation is severe and bacterial involvement is a possibility. However, as discussed above, the majority of infective asthma exacerbations are of viral rather than bacterial origin and viruses are also common in exacerbations of COPD. Vaccination The success of vaccination to prevent respiratory virus infections has been limited by significant variation within the major virus types causing disease. There are 102 serotypes of rhinovirus and no effective vaccine has been introduced. The influenza viruses display antigenic shift and drift. New vaccines must be developed every 2–3 years to cover the strains prevalent at the time. When a new pandemic strain arises there is a delay before sufficient quantities of vaccine can be made available. In spite of such problems combined influenza vaccination is of value in individuals with chronic respiratory diseases, especially in the
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elderly. Vaccination against RSV experienced a major setback when the use of formalin-inactivated virus in young babies resulted in increased disease severity following subsequent virus infection. Antivirus approaches There are two main approaches to therapy for a viral exacerbation. The first is to use antiviral agents with direct actions against the virus itself. Because of the large number of viruses producing similar clinical syndromes the use of specific antiviral drugs requires rapid accurate diagnostic methods such as PCR. The second approach is to identify key components of the antiviral immune response and design drugs that will either enhance beneficial antiviral aspects of the immune response or inhibit components that lead to immunopathology. Understanding the complexities of the antiviral immune response, in particular how it may be altered in the context of preexisting chronic airway diseases such as asthma or COPD, is an essential first step. Simple nonspecific treatments for the common cold do exist although their efficacy is debated. Vitamin C and zinc gluconate128 both may shorten the duration of a cold by 1–2 days. The inhalation of humidified hot air provides symptomatic relief.129 Nasal IFN-a is an effective treatment for the common cold,130 but must be given either prior to or shortly after exposure to the virus. It is also expensive and is associated with significant local side-effects such as bleeding and discharge. These problems have limited its clinical use. Amantadine and rimantadine are effective against influenza A. They inhibit the viral M2 ion channel, important for uncoating and release of the virus genome into the host cell. The use of amantadine has been limited by CNS side-effects, such as dizziness and insomnia; fewer such sideeffects are seen with rimantadine. Both drugs are indicated for use during epidemics of influenza A both for treatment and for prophylaxis in high-risk groups including patients with asthma or COPD. Neither is active against influenza B. Two new neuraminidase inhibitors, zanamivir and oseltamivir, are active against both influenza A and B.131–133 These agents are 67–82% effective in preventing infection when used as prophylaxis during the influenza season and, as treatment, they reduce the duration of illness by 1–1.5 days if started within 36–48 hours of the onset of illness. Zanamivir must be given by inhalation, whereas oseltamivir can be given orally. Ribavarin is a nucleoside analogue, active against RSV in vivo and also against influenza in vitro. Oral preparations have limited benefit in influenza due to rapid metabolism, but inhaled ribavirin may be effective in reducing symptoms and viral shedding. Because of its toxicity, it is not appropriate for asthma or COPD. Its use is restricted to infants and children in the first 3 days of RSV bronchiolitis. RSV-enriched immunoglobulin is effective as prophylaxis for infants at high risk of RSV bronchiolitis and trials with RSV neutralizing monoclonal antibodies are in progress, but
these therapies are not indicated for patients with asthma or COPD. Rhinoviruses are a major target for drug treatment. It has been estimated that rhinoviruses result in between six and ten colds per year in young children and between two and five per year in adults. As yet no effective agent is available for clinical use. Capsid binding/canyon inhibitors block the binding of rhinoviruses to their host cell receptor (ICAM-1 in the case of the major group). These drugs can be extremely potent but their clinical usefulness is limited by serotype specificity and the rapid development of resistance. Alternative targets include soluble ICAM-1 which inhibits major rhinovirus infection in vitro and conserved viral enzymes such as protein 3D, the RNA-dependent RNA transcriptase, protein 2C, the associated ATP-helicase, and the cysteine protease 3C.
S U M M A RY Infection, in particular by respiratory viruses, is a common trigger of exacerbations of asthma and COPD. Our knowledge of the mechanisms of virus-induced exacerbations remains incomplete. In the case of asthma, investigation of the interactions between preexisting asthmatic airway inflammation and the antiviral immune response, and between virus infection and allergen exposure have been furthered by the use of the model of experimental rhinovirus infection in human volunteers. Similar studies are required in COPD exacerbations for which fewer data are currently available. Current therapy for virus-induced exacerbations of asthma and COPD relies on increased treatment of preexisting disease. Corticosteroids form the major antiinflammatory component of such therapy, but their use can be associated with significant side-effects, especially if used systemically and in high doses. Antibiotics are indicated for bacterial infection. Antiviral agents do exist, in particular for influenza viruses, but the effective use of such drugs in asthma and COPD requires viral diagnosis and commencement of treatment early in the course of an exacerbation or the targeting of high-risk groups for prophylaxis. Clinically effective broad spectrum agents are not yet available for the rhinoviruses which are the most common cause of exacerbations. Alternative strategies for drug development may involve the identification of key factors common to exacerbations induced by a range of different viruses. Increased knowledge of the host–virus interaction is required to design treatments that will increase virus clearance and minimize immunopathology.
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61. Zhu Z, Tang W, Ray A et al. Rhinovirus stimulation of interleukin6 in vivo and in vitro. Evidence for nuclear factor kappa Bdependent transcriptional activation. J. Clin. Invest. 1996; 97:421–30. 62. Mastronarde JG, He B, Monick MM, Mukaida N, Matsushima K, Hunninghake GW. Induction of interleukin (IL)-8 gene expression by respiratory syncytial virus involves activation of nuclear factor (NF)-kappa B and NF-IL-6. J. Infect. Dis. 1996; 174:262–7. 63. Bitko V, Velazquez A, Yang L, Yang YC, Barik S. Transcriptional induction of multiple cytokines by human respiratory syncytial virus requires activation of NF-kappa B and is inhibited by sodium salicylate and aspirin. Virology 1997; 232:369–78. 64. Grunstein MM, Hakonarson H, Maskeri N, Chuang S. Autocrine cytokine signaling mediates effects of rhinovirus on airway responsiveness. Am. J. Physiol. Lung Cell. Molec. Physiol. 2000; 278:L1146–53. 65. Johnston SL, Papi A, Monick MM, Hunninghake GW. Rhinoviruses induce interleukin-8 mRNA and protein production in human monocytes. J. Infect. Dis. 1997; 175:323–9. 66. Gern JE, Dick EC, Lee WM et al. Rhinovirus enters but does not replicate inside monocytes and airway macrophages. J. Immunol. 1996; 156:621–7. 67. Peschke T, Bender A, Nain M, Gemsa D. Role of macrophage cytokines in influenza A virus infections. Immunobiology 1993; 189:340–55. 68. Banchereau J, Briere F, Caux C et al. Immunobiology of dendritic cells. Ann. Rev. Immunol. 2000; 18:767–811. 69. Huftel MA, Swensen CA, Borcherding WR et al.The effect of T-cell depletion on enhanced basophil histamine release after in vitro incubation with live influenza A virus. Am. J. Respir. Cell Mol. Biol. 1992; 7:434–40. 70. Hsia J, Goldstein AL, Simon GL, Sztein M, Hayden FG. Peripheral blood mononuclear cell interleukin-2 and interferon-gamma production, cytotoxicity, and antigen-stimulated blastogenesis during experimental rhinovirus infection. J. Infect. Dis. 1990; 162:591–7. 71. Corne JM, Holgate ST. Mechanisms of virus induced exacerbations of asthma. Thorax 1997; 52:380–9. 72. Folkerts G, Nijkamp FP. Virus-induced airway hyperresponsiveness. Role of inflammatory cells and mediators. Am. J. Resp. Crit. Care Med. 1995; 151:1666–73. 73. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol.Today 1996; 17:138–46. 74. Romagnani S. The Th1/Th2 paradigm. Immunol. Today 1997; 18:263–6. 75. Gern JE,Vrtis R, Grindle KA, Swenson C, Busse WW. Relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection. Am. J. Resp. Crit. Care Med. 2000; 162:2226–31. 76. Hussell T, Spender LC, Georgiou A, O’Garra A, Openshaw PJ.Th1 and Th2 cytokine induction in pulmonary T cells during infection with respiratory syncytial virus. J. Gen. Virol. 1996; 77:2447–55. 77. Coyle AJ, Erard F, Bertrand C, Walti S, Pircher H, Le Gros G. Virus-specific CD8 cells can switch to interleukin 5 production and induce airway eosinophilia. J. Exp. Med. 1995; 181:1229–33. 78. Bonecchi R, Bianchi G, Bordignon PP et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J. Exp. Med. 1998; 187:129–34. 79. Panina-Bordignon P, Papi A, Mariani A et al. The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergenchallenged atopic asthmatics. J. Clin. Invest. 2001; 107:1357–64. 80. Volovitz B, Faden H, Ogra PL. Release of leukotriene C4 in respiratory tract during acute viral infection. J. Pediatrics 1988; 112:218–22.
Infections
81. Gleich GJ. Mechanisms of eosinophil-associated inflammation. J. Allergy Clin. Immunol. 2000; 105:651–63. 82. Saito T, Deskin RW, Casola A et al. Respiratory syncytial virus induces selective production of the chemokine RANTES by upper airway epithelial cells. J. Infect. Dis. 1997; 175:497–504. 83. Noah TL, Henderson FW, Henry MM, Peden DB, Devlin RB. Nasal lavage cytokines in normal, allergic, and asthmatic schoolage children. Am. J. Resp. Crit. Care Med. 1995; 152:1290–6. 84. Greiff L, Andersson M, Andersson E et al. Experimental common cold increases mucosal output of eotaxin in atopic individuals. Allergy 1999; 54:1204–8. 85. Adamko DJ, Yost BL, Gleich GJ, Fryer AD, Jacoby DB. Ovalbumin sensitization changes the inflammatory response to subsequent parainfluenza infection. Eosinophils mediate airway hyperresponsiveness, m(2) muscarinic receptor dysfunction, and antiviral effects. J. Exp. Med. 1999; 190:1465–78. 86. Domachowske JB, Dyer KD, Adams AG, Leto TL, Rosenberg HF. Eosinophil cationic protein/RNase 3 is another RNase A-family ribonuclease with direct antiviral activity. Nucleic Acids Res. 1998; 26:3358–63. 87. Pizzichini MM, Pizzichini E, Efthimiadis A et al. Asthma and natural colds. Inflammatory indices in induced sputum: a feasibility study. Am. J. Resp. Crit. Care Med. 1998; 158:1178–84. 88. Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J. Allergy Clin. Immunol. 1995; 95:843–52. 89. Teran LM, Johnston SL, Schroder JM, Church MK, Holgate ST. Role of nasal interleukin-8 in neutrophil recruitment and activation in children with virus-induced asthma. Am. J. Resp. Crit. Care Med. 1997; 155:1362–6. 90. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Ann. Rev. Immunol. 1999; 17:189–220. 91. Moretta L, Biassoni R, Bottino C, Mingari MC, Moretta A. Human NK-cell receptors. Immunol.Today 2000; 21:420–2. 92. Mingari MC, Ponte M, Bertone S et al. HLA class I-specific inhibitory receptors in human T lymphocytes: interleukin 15induced expression of CD94/NKG2A in superantigen- or alloantigen-activated CD8 T cells. Proc. Natl Acad. Sci. U.S.A. 1998; 95:1172–7. 93. Humbert M, Menz G, Ying S et al. The immunopathology of extrinsic (atopic) and intrinsic (non-atopic) asthma: more similarities than differences. Immunol.Today 1999; 20:528–33. 94. Skoner DP, Doyle WJ, Tanner EP, Kiss J, Fireman P. Effect of rhinovirus 39 (RV-39) infection on immune and inflammatory parameters in allergic and non-allergic subjects. Clin. Exp. Allergy 1995; 25:561–7. 95. Lin CY, Kuo YC, Liu WT, Lin CC. Immunomodulation of influenza virus infection in the precipitating asthma attack. Chest 1988; 93:1234–8. 96. Welliver RC, Wong DT, Sun M, Middleton EJ, Vaughan RS, Ogra PL. The development of respiratory syncytial virus-specific IgE and the release of histamine in nasopharyngeal secretions after infection. N. Engl. J. Med. 1981; 305:841–6. 97. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997; 349:1498–504. 98. Anonymous. BTS guidelines for the management of chronic obstructive pulmonary disease. The COPD Guidelines Group of the Standards of Care Committee of the BTS. Thorax 1997; 52 (Suppl 5):S1–28. 99. Anonymous. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am. J. Resp. Crit. Care Med. 1995; 152:S77–121. 100. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am. J. Resp. Crit. Care Med. 1998; 157:1418–22.
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101. Madison JM, Irwin RS. Chronic obstructive pulmonary disease. Lancet 1998; 352:467–73. 102. Wilson R. The role of infection in COPD. Chest 1998; 113(4 Suppl):242S–8S. 103. Smith CB, Golden CA, Kanner RE, Renzetti AD Jr. Association of viral and Mycoplasma pneumoniae infections with acute respiratory illness in patients with chronic obstructive pulmonary diseases. Am. Rev. Resp. Dis. 1980; 121:225–32. 104. Monso E, Ruiz J, Rosell A et al. Bacterial infection in chronic obstructive pulmonary disease. A study of stable and exacerbated outpatients using the protected specimen brush. Am. J. Resp. Crit. Care Med. 1995; 152:1316–20. 105. Irwin RS, Erickson AD, Pratter MR et al. Prediction of tracheobronchial colonization in current cigarette smokers with chronic obstructive bronchitis. J. Infect. Dis. 1982; 145:234–41. 106. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern. Med. 1987; 106:196–204. 107. Stockley RA, O’Brien C, Pye A, Hill SL. Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest 2000; 117:1638–45. 108. Murphy TF, Sethi S. Bacterial infection in chronic obstructive pulmonary disease. Am. Rev. Resp. Dis. 1992; 146:1067–83. 109. Ball P, Tillotson G, Wilson R. Chemotherapy for chronic bronchitis. Controversies. Presse Medicale 1995; 24:189–94. 110. Blasi F, Legnani D, Lombardo VM et al. Chlamydia pneumoniae infection in acute exacerbations of COPD. Eur. Respir. J. 1993; 6:19–22. 111. Eller J, Ede A, Schaberg T, Niederman MS, Mauch H, Lode H. Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function. Chest 1998; 113:1542–8. 112. Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations. A meta-analysis. JAMA 1995; 273:957–60. 113. Siafakas NM,Vermeire P, Pride NB et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur. Resp. J. 1995; 8:1398–420. 114. Wilson R, Dowling RB, Jackson AD. The biology of bacterial colonization and invasion of the respiratory mucosa. Eur. Resp. J. 1996; 9:1523–30. 115. Fagon JY, Chastre J, Trouillet JL et al. Characterization of distal bronchial microflora during acute exacerbation of chronic bronchitis. Use of the protected specimen brush technique in 54 mechanically ventilated patients. Am. Rev. Resp. Dis. 1990; 142:1004–8. 116. Seemungal TA, Harper-Owen R, Bhowmik A et al. Respiratory viruses, symptoms and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am. J. Resp. Crit. Care Med. 2001; 164:1618–23. 117. Gump DW, Phillips CA, Forsyth BR, McIntosh K, Lamborn KR, Stouch WH. Role of infection in chronic bronchitis. Am. Rev. Resp. Dis. 1976; 113:465–74. 118. Tager I, Speizer FE. Role of infection in chronic bronchitis. N. Engl. J. Med. 1975; 292:563–71. 119. Greenberg SB,Allen M,Wilson J,Atmar RL. Respiratory viral infections in adults with and without chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 162:167–73. 120. Hogg JC. Childhood viral infection and the pathogenesis of asthma and chronic obstructive lung disease. Am. J. Respir. Crit. Care Med. 1999; 160:S26–8. 121. Matsuse T, Hayashi S, Kuwano K, Keunecke H, Jefferies WA, Hogg JC. Latent adenoviral infection in the pathogenesis of chronic airways obstruction. Am. Rev. of Respir. Dis. 1992; 146:177–84. 122. Elliott WM, Hayashi S, Hogg JC. Immunodetection of adenoviral E1A proteins in human lung tissue. Am. J. Respir. Cell Mol. Biol. 1995; 12:642–8.
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123. Liu F, Green MR. Promoter targeting by adenovirus E1a through interaction with different cellular DNA-binding domains. Nature 1994; 368:520–5. 124. Keicho N, Elliott WM, Hogg JC, Hayashi S. Adenovirus E1A upregulates interleukin-8 expression induced by endotoxin in pulmonary epithelial cells. Am. J. Physiol. 1997; 272:L1046–52. 125. Keicho N, Elliott WM, Hogg JC, Hayashi S. Adenovirus E1A gene dysregulates ICAM-1 expression in transformed pulmonary epithelial cells. Am. J. Respir. Cell Mol. Biol. 1997; 16:23–30. 126. Keicho N, Higashimoto Y, Bondy GP, Elliott WM, Hogg JC, Hayashi S. Endotoxin-specific NF-kappaB activation in pulmonary epithelial cells harboring adenovirus E1A. Am. J. Physiol. 1999; 277:L523–32. 127. Gustafson LM, Proud D, Hendley JO, Hayden FG, Gwaltney JM, Jr. Oral prednisone therapy in experimental rhinovirus infections. J. Allergy Clin. Immunol. 1996; 97:1009–14.
128. Marshall S. Zinc gluconate and the common cold. Review of randomized controlled trials. Can. Fam. Phys. 1998; 44:1037–42. 129. Singh M. Heated, humidified air for the common cold. Cochrane Database Syst. Rev. 2000; (2):CD001728. 130. Hayden FG, Gwaltney JM Jr. Intranasal interferon-alpha 2 treatment of experimental rhinoviral colds. J. Infect. Dis. 1984; 150:174–80. 131. Khare MD, Sharland M. Influenza. Exp. Opin. Pharmacother. 2000; 1:367–75. 132. Lalezari J, Campion K, Keene O, Silagy C. Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials. Arch. Intern. Med. 2001; 161:212–17. 133. Monto AS, Robinson DP, Herlocher ML, Hinson JMJ, Elliott MJ, Crisp A. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA 1999; 282:31–5.
Chapter
Exercise as a Trigger
40
S. Godfrey Institute of Pulmonology, Hadassah University Hospital, Jerusalem, Israel
Asthma and chronic obstructive pulmonary disease (COPD) are different entities although some patients with COPD have an asthmatic element to their disability and some chronic severe asthmatics ultimately develop irreversible airflow obstruction akin to that found in COPD. Asthma, at least in young people, has many of the elements suggesting a genetically determined disorder in which the patient inherits genes which enable the disease to become manifest. This involves developing the type of immunologically determined eosinophilic bronchitis which leads to bronchial hyperreactivity to a variety of stimuli, and the clinical pattern of recurrent episodes of airway obstruction which reverse spontaneously or in response to treatment. COPD is chiefly a disease caused by cigarette smoking which leads to distortion of the smaller airways and increasingly severe chronic airflow obstruction. Both the poorly controlled asthmatic and the patient with significant COPD are limited in the amount of physical exercise which they can perform, but in most cases this is for entirely different reasons. In the case of the asthmatic, physical exercise acts as a trigger to increased airway obstruction – exercise-induced asthma (EIA), while in the patient with COPD limitation in maximum pulmonary function and secondary changes in the muscles of ambulation limit exercise performance. Most asthmatics if they exercise hard enough under the appropriate conditions will develop EIA which may well prevent them from continuing to exercise if it is severe enough.1 However, asthmatic children who are treated adequately and allowed to take part in normal physical activities do not show any reduction in maximum exercise performance compared with their peers.2 Patients with COPD are limited in their exercise performance in a manner which is roughly proportional to the severity of their airway obstruction and only partially improved by treatment.3 Bronchial hyperreactivity is not entirely unimportant in COPD, since increased responsiveness of the airways to irritant stimuli such as methacholine4,5 and increased bronchodilatation during exercise6 have been documented in these patients but differ markedly from the responsiveness found in asthmatics.7,8
E X E R C I S E I N T H E PAT I E N T W I T H ASTHMA EIA has been recognized for at least 300 years since Sir John Floyer, himself an asthmatic, clearly described the adverse effects of physical exercise on his asthma.9 He wrote that “all Violent Exercise makes the Asthmatic to breathe short”.The changes in lung function which occur in response to about 6 minutes of reasonably hard exercise are quite characteristic and are illustrated in Table 40.1 and Fig. 40.1 taken from the results of an exercise challenge in an 11-year-old asthmatic girl. From studies in which lung function has also been measured during exercise there is little change in lung function or even some improvement at first. Towards the end of the exercise period lung function may begin to deteriorate and in some patients this fall can be quite marked. The major fall in lung function normally occurs 5 to 10 minutes after stopping the exercise, after which lung function returns spontaneously to baseline over 30 to 45 minutes. It is customary to express the severity of the EIA as the fall in FEV1 as a percentage of the baseline measurement, since there is no advantage in using other more sensitive indices of lung function. There are considerable similarities in the time course of the changes in lung function in EIA when compared with the early response to allergen inhalation. Both are rapid in onset, pass off over some 30 minutes, are largely prevented by prior administration of sodium cromoglycate and are easily prevented or reversed by the inhalation of a b2-agonist. However, the late phase response often seen some 6–8 hours after an antigen challenge is apparently quite uncommon after exercise.10,11 There are a number of important factors which influence the magnitude of the response. The type of exercise Asthmatics are often aware that some types of exercise are likely to provoke an attack while other types have little or no effect, even when of similar intensity and duration. Thus EIA is far less marked with swimming compared with running under normal conditions.12,13 Most of the difference between swimming and running depends on the fact that
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Table 40.1. Lung function and results of a bronchial provocation challenge consisting of 6 minutes of running at a constant speed and slope on a treadmill in an 11-year-old girl with asthma
Baseline resting lung function before exercise
Percent predicted
Maximum change in lung function after exercise (% baseline)
1.74 1.30 1.18
88 70 43
16 38 62
Forced vital capacity (FVC) (l) Forced expired volume in 1 second (FEV1) (l) Maximum mid-expiratory flow (MEF50) (l/min)
100
FEV1 (% predicted)
Bronchodilator 75
Baseline
50
25 Exercise 0 0
5
10
15
20
25
Time (min) Fig. 40.1. Typical pattern of exercise-induced asthma in the asthmatic patient whose data are shown in Table 40.1. In this instance lung function was not measured during exercise which comprised 6 minutes of treadmill running at a speed of 5 kph and a gradient of 10%. The greatest fall in FEV1 occurred 3 minutes after stopping.
the air breathed during swimming is humid and this reduces the severity of EIA although there is still a small difference when subjects breath dry air while swimming.14 Severity and duration of the stimulus The severity of the asthma which follows a period of exercise has been shown by Silverman and Anderson15 to depend upon the severity of the exercise and its duration. The level of exercise producing the maximal severity of EIA is approximately two-thirds of the maximum working capacity of the patient which corresponds to a heart rate of about 170–180/min in children and somewhat less in adults. With a given severity of exercise, the post-exertional EIA increases with the duration of the exercise up to about 6–8 minutes after which it reaches a plateau or even becomes less severe. Exercise of greater severity or duration does not usually produce a greater response, probably because there is a plateau effect. The pattern of exercise and refractoriness It has been known for a long time that prior exercise reduces the response to a subsequent challenge and that asthmatics can become refractory to exercise challenges repeated over a
short period.16,17 This prior exercise may take the form of brief warming-up periods18 or a single, more prolonged, exercise period.19,20 The refractoriness in the second of the pair of tests depends upon the time between the challenges and the half-life of the effect is about 45 minutes so that after about 2–3 hours the asthmatic is again fully responsive to an exercise challenge.19 This helps explain why not all exercise encountered in everyday life is prone to cause EIA even if the exercise is apparently intense, especially if it is intermittent as in many team games. Originally it was thought that refractoriness to exercise was due to the liberation of chemical mediators in the first attack which were used up and took time to be resynthesized, but the studies of O’Byrne and others21–23 strongly suggest that it is due to the release of inhibitory prostaglandins by the first exercise period. Climatic conditions during the challenge In a number of important studies it has been noted that the severity of EIA is greatly influenced by the climate of the air breathed.24–26 Breathing warm, humid air virtually abolishes EIA while breathing cold, dry air increases its intensity. The hyperventilation associated with exercise leads to drying and cooling of the airway mucosa as the water evaporates from the surface and this cooling is accentuated if the dry air is also cold. The cooling was first demonstrated by recording temperature change in the esophagus and later by direct recording within the airways.27,28 Cooling, or more probably drying of the airways explains the differences in the severity of EIA induced by swimming, in which the subject breathes relatively humid air and running, in which under normal laboratory conditions, the air is relatively dry. Realizing the fundamental importance of this phenomenon in the pathogenesis of EIA, Anderson and colleagues29 developed the hypothesis that it was changes in the osmolarity of the fluid lining the airways which was the triggering event in EIA. They had previously shown that asthma closely resembling EIA could be provoked by inhaling fogs of hypotonic or hypertonic salt solutions.30 Allergenic environment and air pollution The prevalence of allergens in the environment has long been known to influence nonspecific bronchial reactivity in asthmatics.31,32 Benckhuijsen et al.33 have also shown that asthmatic children who spent a month in the relatively
Exercise as a Trigger
allergen-free alpine town of Davos, Switzerland showed a modest but significant decrease in the severity of their EIA. We undertook exercise challenges in asthmatic children on the day before and during the week after specific allergen bronchial provocation tests34 and found that there was a clear-cut increase in the response to the same level of exercise with the fall in FEV1 almost doubling. Air pollution, simulated in the laboratory by adding small amounts of sulfur dioxide to the air, has also been shown to considerably enhance EIA,35 further complicating the prediction of the severity of EIA under conditions of natural exposure. The clinical severity of the asthma It would be expected that the clinical severity of asthma would influence the severity of EIA obtained with a standard challenge, but hard data to support this idea are difficult to find. In a recent study of the severity of EIA in 272 mild, moderate and severe young asthmatics defined according to accepted management guidelines we found that the mean fall in FEV1 was 15.8%, 22.8% and 21.1%, respectively, and the only significant difference was between the mild group and the other asthmatic groups.36 Other data on the relationship between the severity of asthma and EIA are notable by their absence and it seems likely that exercise is a poor tool for distinguishing between asthmatics of different clinical severity.
PAT H O P H Y S I O L O G Y O F E I A Physical exercise appears to exert its effect on the asthmatic through five main actions: • It causes hyperventilation with consequent cooling and drying of the bronchial mucosa, which liberates bronchoconstricting mediators such as LTD4. • It may have a direct (intrinsic) effect, which would explain residual differences between different types of exercise or different exercise protocols. • It increases sympathetic drive or reduces bronchial tone which generally prevents much change in lung function during the exercise. • Towards the end or after the exercise, the bronchoconstricting mediators cause the attack of EIA by constricting the bronchial smooth muscle. An alternative suggestion37 has been that the cooling of the airways and subsequent rewarming at the end of exercise causes airway narrowing as a type of reactive hyperemia. This appears to be less likely since EIA often begins during exercise while the airways are still cool. • It releases an inhibitory prostaglandin possibly mediated by the rise in LTD4 which results in refractoriness to a subsequent exercise challenge. The cooling and drying of the airways is dependent upon the climatic conditions of the inspired air. During exercise the subject is relatively (though not always com-
423
pletely) protected either by an increased sympathetic drive or alternatively by a reduction in bronchial tone. This shortterm protection stops as soon as the exercise ends allowing the bronchospasm to become manifest. Another type of protection is built up more slowly by the release of an inhibitory prostaglandin which probably accounts for the refractory period after EIA. The effect of the released mediator on the airways also depends upon the basic level of bronchial reactivity which, in turn, depends upon such factors as the level of allergenic stimulation, recent viral infections and air pollution. Thus it is characteristic of EIA that: • It is inherently variable because of the many factors which interact to produce the bronchoconstriction. • The severity of the response on any one occasion is largely unpredictable since not all the variables can be quantified.
E X E R C I S E I N T H E PAT I E N T W I T H C O P D COPD due to cigarette smoking in adults causes damage to the small- and medium-sized airways and often to the alveolar structure with resultant airways obstruction which is largely irreversible. There are other causes of COPD in adults and children, but the ultimate effect is similar with airflow obstruction which limits pulmonary function. Exercise tolerance in COPD is not limited just by the reduction in pulmonary function as recently reviewed succinctly by Patessio.38 Physiological abnormalities during exercise in COPD The main physiological defects in pulmonary function due to COPD are: • Increased resistance to airflow which limits maximum ventilatory capacity and increases the work of breathing. • Uneven distribution of ventilation and blood flow to the lungs, which results in ventilation/perfusion imbalance and limits the ability of the lungs to transfer gases efficiently, especially during exercise. • Pulmonary vascular disease which reduces the number of pulmonary capillaries that can be recruited when blood flow increases during exercise. • Slow adaptation of ventilation, gas exchange and blood flow at the start of exercise so that a larger than normal oxygen debt is built up.39 The limitation of exercise performance in COPD is only poorly correlated with tests of lung function. Thus Haggerty et al.40 found that the pre-rehabilitation 6-minute walking distance of their patients correlated well with a symptombased scale, but the correlation with FEV1, although significant, was poor (r 0.33, P 0.001). Other factors besides the reduced airway caliber must contribute to exercise limitation in these patients. An early onset of anaerobic
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metabolism and its rapid increase during exercise, resulting in excessive lactic acidosis is typical of the patient with COPD even with the mild exercise needed for simple everyday activities. There are probably a number of factors which contribute to this including less efficient oxygen transport from the lungs to the muscles, poor delivery of oxygen from the capillaries to the muscle fibers, and inefficient metabolism within the muscle fibers. The lactate is buffered in the blood by bicarbonate which results in the generation of excess CO2 that has to be blown off in the lungs so the demand for ventilation is further increased. It is quite typical of the COPD patient that the ventilatory exchange ratio (CO2 output/O2 uptake) at the mouth and the ventilatory equivalents for O2 and CO2 (minute ventilation/O2 or CO2 output) are increased well above normal during exercise. In progressive exercise tests the rate of output of CO2 becomes disproportionately high in relation to the rate of oxygen uptake. The results of a progressive exercise test in a typical patient with COPD are summarized in Table 40.2 and Fig. 40.2. This woman had moderately severe irreversible obstructive lung disease at rest. On exercise she reached her anaerobic threshold early after which CO2 production and minute ventilation increased disproportionately fast. She was ventilatory limited as shown by the fact that her maximum minute ventilation at the end of exercise was equal to her maximum voluntary ventilation which was itself less than her predicted normal. Because of this limitation her maximum O2 uptake was also reduced below predicted. Her O2 pulse, which reflects cardiac function, although less than her predicted maximum, was normal for the level of O2 consumption achieved suggesting that there was no cardiac impairment.
Given the poor correlation between exercise performance and lung function in COPD, other factors have been sought that might contribute to the limitation. Many patients with COPD are underweight and even if not there is often a relative decrease in muscle mass. It has been shown that fatfree weight, which reflects muscle mass, is significantly correlated with maximum and submaximum parameters of exercise performance independently of the severity of the airways obstruction.41,42 This reduction in muscle mass is probably due to a combination of factors. COPD subjects become progressively more sedentary and unfit as their dyspnea progresses so that they enter a vicious cycle of decreasing exercise capability. This may be exaggerated in those treated with large doses of corticosteroids which can cause myopathy.43 With severe COPD, malnutrition may contribute to muscle weakness as patients are too breathless to eat adequately. At all levels of disease fear of the breathlessness they develop on exertion is another limiting factor. Bronchial hyperreactivity in COPD Although in COPD the airways obstruction is, by definition, very largely irreversible in many subjects, it is possible to increase the obstruction even further by an appropriate stimulus,44,45 in other words many subjects with COPD have bronchial hyperreactivity (BHR). However, careful studies of BHR using various stimuli have shown interesting differences between patients with COPD and those with asthma. Thus Ramsdale et al.5,46 found that 19 out of 27 COPD patients responded abnormally to a methacholine challenge, but only three responded to hyperventilation with cold air, while 26 out of 27 asthmatics responded to cold air hyperventilation as well as to methacholine.
Table 40.2. Lung function and results of progressive exercise test in a woman aged 49 with COPD
Resting lung function Forced vital capacity (FVC) (l) Forced expired volume in 1 second (FEV1) (l) Maximum voluntary ventilation (MVV) (l/min)
Observed
Percent predicteda
After bronchodilator
2.97 2.53 56
82 66 64
81 68
Observed Progressive exercise test Anaerobic threshold (AT) (ml/min) Maximum oxygen uptake (V˙ O2max) (ml/min) Maximum heart rate (HRmax) min Maximum ventilation (V˙ Emax) (l/min) Maximum O2 pulse (V˙ O2max/HRmax) (ml/beat) a b
469 974 130 43.8 7
Predicted normal values based on age, sex and size as appropriate. Predicted at observed V˙ O2max.
Percent predicted a
b
56 46 86 71 58
113 125 93
Exercise as a Trigger
50
1200 40
30 800
20
600
Ventilation (L/min)
CO2 production (mL/min)
1000
425
while the healthy smoking group were equally sensitive to both (ratio = 1.1). Thus, although the asthmatics were far more responsive to AMP than the COPD subjects, the latter were more sensitive than the normal subjects and smoking increased this sensitivity. Rutgers et al.47 were able to compare airway inflammation on bronchial biopsies in groups of COPD patients with and without increased reactivity to AMP. They found hyperresponsiveness to AMP in COPD was associated with airway inflammation characterized by increased numbers of mucosal CD8 cells and percentages of sputum eosinophils. This might indicate that a subset of patients with COPD have an asthma-like element to their disease but this requires further study.
MANAGEMENT OF THE EXERCISE L I M I TAT I O N I N A S T H M A A N D C O P D 400
10
200 200
400 600 800 1000 O2 consumption (mL/min)
1200
Fig. 40.2. Results from the progressive exercise test of the patient with COPD whose data are presented in Table 40.2. The thin solid line is drawn through simultaneous measurements of O2 consumption and CO2 production during the test (individual points not shown). The thin dashed line shows the projection of this relationship after the point at which CO2 production increases at a faster rate than O2 consumption (the anaerobic threshold) indicated by the vertical arrow. The thick dashed line shows that minute ventilation tracks the CO2 production, rather than the O2 consumption.
Oosterhoff et al.4 showed that both asthmatics and COPD patients were responsive to methacholine when compared with controls, but the asthmatics were also far more responsive to adenosine 5-monophosphate (AMP) inhalation, especially when compared with nonsmoking COPD patients. In this study, the healthy smoking control subjects were not responsive to either methacholine (provoking concentration causing a 20% fall in FEV1, PC20 = 180 mg/ml) or AMP (PC20 = 375 mg/ml), the nonsmoking COPD, smoking COPD and nonsmoking asthmatics were all similarly hyperreactive to methacholine (PC20 = 0.50, 0.35, 0.56 mg/ml, respectively) but differed in their reactivity to AMP (PC20 = 58.5, 7.2, 3.8 mg/ml, respectively). The difference in reactivity to AMP between nonsmoking asthmatics and nonsmoking COPD subjects was significant, as was the difference between smoking and nonsmoking COPD subjects. On a molar basis their results showed asthmatics to be 3.8 times less sensitive to AMP compared with methacholine, smoking COPD subjects to be 11.5 times less sensitive, and nonsmoking COPD subjects to be 65 times less sensitive,
Medications As far as the very large majority of asthmatics is concerned, there is no reason why they should be limited in their capacity to exercise since EIA can be prevented or substantially reduced by appropriate medication. Indeed, in a study of asthma in United States Olympic athletes who participated in the 1996 summer games the incidence of current asthma (currently taking anti-asthma medication) was 10.4%, and 16.7% reported having had a diagnosis of asthma or having used asthma medications. Of the 73 athletes with active asthma, an amazing 32.9% won medals compared with 28.7% of the 582 athletes without asthma.48 It has been known for a long time that the most effective method of preventing or reversing EIA is the simple administration of a selective b2-agonist. The newer long-acting inhaled b2-agonists inhibit EIA for substantially longer than the older drugs.49,50 This means that if the patient has used a short-acting b2-agonist within about 4 hours or a longacting b2-agonist within about 12 hours of exercise the severity of the resultant EIA is likely to be reduced considerably. Other drugs that have been shown to prevent or reduce EIA if given before exercise include the specific antihistamine drug terfenadine51,52 and the cromones, sodium cromoglycate and nedocromil sodium.53 Sodium cromoglycate is not a bronchodilator and its exact mechanism of action is disputed but it is interesting that it only inhibits EIA if given before exercise, but not if given at the end of the exercise and before the onset of the EIA.54 Drugs which inhibit the release or binding of potential mediators of EIA have also been shown to reduce EIA, in particular the leukotriene antagonists.55,56 For many years it was generally believed that corticosteroids did not affect EIA but more recent studies show that inhaled corticosteroids can reduce the response to both exercise and pharmacological agents.57,58 It may be that the efficacy of inhaled steroids depends on both the dose and duration of treatment. A single (1000 lg) dose of budesonide was unable to inhibit EIA in the study of Venge et al.59
426
Asthma and Chronic Obstructive Pulmonary Disease
while 4 weeks of the same daily dose produced a significant reduction. Pedersen and Hansen60 carried out a dose–response study of the effect of inhaled budesonide on asthmatic children with moderate and severe asthma, each dose being given for 4 weeks. They found that 100 lg/day was effective in controlling symptoms and no further clinical benefit was seen with higher doses. However, they found a considerable dose– response effect on the inhibition of EIA with 100 lg/day reducing the fall in FEV1 to 26% compared with 55% before treatment and 400 lg/day reducing it to 10%. There is now little doubt that EIA is likely to be reduced significantly if the patient is taking a moderate or high dose of an inhaled corticosteroid on a regular basis. Thus for the asthmatic, EIA can be largely prevented by the use of appropriate medication to control the overall severity of the asthma with an additional short-acting b2-agonist bronchodilator taken shortly before exercise in those not totally free from EIA. It is rarely justified to commence preventive corticosteroid therapy in an asthmatic who is only troubled by exercise and otherwise virtually symptom-free. The value of medication in improving the exercise performance of patients with COPD is far less impressive than that for the asthmatic. There have been a number of studies of the effect of various bronchodilators on exercise performance in COPD. On the whole, the improvement with medication is small and there is little difference between the drugs in terms of efficacy. Guyatt et al.3 found what they believed to be clinically significant improvement in symptoms and function with 2 weeks of treatment with either the b2-agonist salbutamol or a theophylline type of drug, although the 6-minute walking distance only improved by about 10%. Patakas et al.61 compared the immediate effects of salmeterol with the anticholinergic ipratropium bromide on exercise performance in patients with COPD. They found small but significant improvements in airflow limitation and increase in the walking distance in a progressive type of stress test from 270 to 355 meters. Interestingly, the time for arterial O2 saturation to recover after exercise was shortened from about just under 2 minutes with placebo to just over 1 minute with either drug. The immediate effects of ipratropium bromide were also investigated by O’Donnell et al.62 in patients with severe COPD who found a 7% increase in resting FEV1 and a 32% increase in exercise endurance time compared with placebo, but they noted that changes in the spirometric parameters of lung function were poor predictors of the change in exercise endurance. These and similar studies suggest that patients with COPD might obtain a modest benefit from bronchodilator therapy as far as their exercise ability is concerned. Oxygen is another drug that ought to benefit exercise performance in patients with COPD since arterial oxygen saturation falls during exercise in patients with significant disease. However, objective evidence of the benefits of ambulatory oxygen therapy during exercise in such patients
is quite hard to find. Roberts et al.63 compared different oxygen delivery systems during a 6-minute walk in patients with severe COPD and found that continuous oxygen administration was better than intermittent administration and improved the walking distance, but only from 271 to 295 meters. Despite the use of oxygen, quite marked desaturation occurred during exercise. Killen et al.64 found that the dyspnea of a short stair climb was reduced by giving the patient oxygen, but it did not matter if this was given before or after the exercise. Using additional oxygen during exercise training sessions in a pulmonary rehabilitation program did not affect the exercise tolerance although patients were a little less dyspneic.65 On the whole it seems that giving the patient oxygen while exercising may reduce the sense of breathlessness, but is unlikely to significantly improve performance. Rehabilitation In the past asthma was often thought of, at least in part, as a ‘weakness of the chest’ which could be improved by ‘breathing exercises’. Sedentary asthmatics are generally unfit and a number of investigators have explored the value of rehabilitation by means of physical training for asthmatics. Properly controlled studies have demonstrated that asthmatics who undergo physical training can improve their fitness, as measured by maximum oxygen uptake, to a similar degree as nonasthmatics who undergo similar training.66,67 Whether this improved fitness can reduce the likelihood of developing EIA is not a simple issue because improved physical fitness results in decreased minute ventilation for a given level of oxygen consumption and since the trigger for EIA is probably related to the level of ventilation, one might expect less EIA after training for a similar exercise stress. A small reduction in EIA of this type at a given level of exercise has been obtained by training in some studies.68,69 Others have found improvements in lung function and asthma control after general fitness training, but it is difficult to ensure adequate controls in such studies and to separate the effects, if any, of training from those of better supervision of the asthma. On the other hand several investigators have failed to find any change in bronchial reactivity after physical training,66,70,71 which casts some doubt on the ability of general exercise training to improve the asthma. The overall conclusion is that physical training can restore normal levels of physical fitness to the asthmatic although it is unlikely to make a significant reduction in the severity of the bronchial hyperreactivity or affect the need for pharmacological treatment.72 Training undoubtedly improves the sense of well-being of the patient and provides important psychological support. Given the relative inability of medication to affect the severity of exercise limitation in COPD, other modalities assume greater importance, especially rehabilitation involving physical exercise. Many studies have been undertaken over the years, often with rather poor control, but Lacasse et al.73 were able to include 14 studies in a meta-analysis of effects of training programs on exercise capacity and a
Exercise as a Trigger
health-related quality-of-life questionnaire. They found an overall treatment effect larger than the minimally clinically important difference for dyspnea and ability to master tasks. The improvement in exercise performance amounted on average to about 56 meters in the 6-minute walk test and 8.3 watts in ergometer exercise tests. Carrieri-Kohlman et al.74 undertook a study of 51 patients with COPD designed to see if coaching was more beneficial than uncoached training. The patients exercised under supervision at the clinic for 12 weeks and then continued at home for another 8 weeks. Dyspnea and the associated distress and anxiety improved significantly with no difference between the groups. The 6-minute walk distance increased by about 13%. Casaburi et al.75 studied the effect on exercise tolerance of 6 weeks of vigorous exercise training. Rehabilitation yielded an average increase in peak work rate of 36% in a progressive exercise test, an increase of about 16% in maximum oxygen consumption, and an increase of 77% in duration in a constant workload test. They concluded that a rigorous exercise training for patients with severe COPD resulted in a more efficient exercise breathing pattern and lower minute ventilation which was associated with improved exercise tolerance. In 1999 an official statement on pulmonary rehabilitation was published by the American Thoracic Society which reviewed many aspects of rehabilitation with supporting evidence for various components using data from controlled trials.76 This statement concluded “In truth most of the improvements are small and do not affect survival but there is a substantial body of evidence supporting improvement in exercise performance and various aspects of quality of life. . . . The benefits achieved extend beyond increases in exercise ability and include decreases in dyspnea and improvements in health status”.
S U M M A RY In asthma, the dyspnea of physical exercise is a manifestation of bronchial hyperreactivity triggered by the cooling and drying of the intrathoracic airways which results in a short attack of reversible airways obstruction. In COPD the dyspnea is due to the disturbances in airway function and gas exchange compounded by the de-training of the muscles of locomotion. The management of exercise-induced asthma is basically the management of the other clinical manifestations supplemented, if necessary, by a short-acting bronchodilator taken a few minutes before exercise. With proper treatment the very large majority of asthmatics should not be limited in their capacity for exercise. Pharmacological treatment is much less effective in COPD and only small benefits are seen from the use of bronchodilators. Small improvement in COPD patients can be obtained by a vigorous and sustained program of physical exercise rehabilitation. Nevertheless, this may make a very considerable difference to the quality of life in severely handicapped COPD patients.
427
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Exercise as a Trigger
64. Killen JW, Corris PA. A pragmatic assessment of the placement of oxygen when given for exercise induced dyspnoea. Thorax 2000; 55:544–6. 65. Garrod R, Paul EA,Wedzicha JA. Supplemental oxygen during pulmonary rehabilitation in patients with COPD with exercise hypoxaemia. Thorax 2000; 55:539–43. 66. Cochrane LM, Clark CJ. Benefits and problems of a physical training programme for asthmatic patients. Thorax 1990; 45:345–51. 67. Rupp NT, Guill MF, Brudno S. Unrecognized exercise-induced bronchospasm in adolescent athletes. Am. J. Dis. Child 1992; 146:941–4. 68. Svenonius E, Kautto R, Arborelius M. Improvement after training of children with exercise-induced asthma. Acta Paediatr. Scand. 1983; 72:23–30. 69. Haas F, Pasierski S, Levine N et al. Effect of aerobic training on forced expiratory airflow in exercising asthmatic humans. J. Appl. Physiol. 1987; 63:1230–5. 70. Robinson DM, Egglestone DM, Hill PM, Rea HH, Richards GN, Robinson SM. Effects of a physical conditioning programme on asthmatic patients. N. Z. Med. J. 1992; 105:253–6.
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Atmospheric Pollutants
Chapter
41
Jon Ayres Department of Respiratory Medicine, Birmingham Heartlands Hospital, Birmingham, UK
In the 1940s and 1950s, air pollution was a fact of life in industrialized cities, but the true extent of its health risks was not appreciated until the London Fog Incident of 1952,1 which caused 4000 excess deaths largely from cardiac disease, bronchitis or pneumonia. At the time, it was believed that the combination of particles and SO2 was the cause of such effects, but latterly reanalysis of these historical data has suggested that the acidity of the aerosol may have been the major contributor to mortality.2 As the Clean Air Act of 1956 began to reduce black smoke levels, day to day changes in pollution had progressively less impact on symptoms in chronic bronchitis3 and the advice given to Government was that air pollution would never again represent a risk to human health, even though studies of urban compared with rural areas showed a higher prevalence of productive cough in urban areas.4 However, by the late 1970s such reassurance was being questioned as vehicle-generated air pollution was being shown to impact on human health.
C U R R E N T P O L L U TA N T E X P O S U R E S The air pollutants relevant to asthma and COPD are: • • • •
sulfur dioxide (SO2) nitrogen dioxide (NO2) ozone particles
Levels of these pollutants vary worldwide and health-based air quality standards have been produced by many individual countries or agencies (Table 41.1). These give an indication of the levels to which populations are currently exposed, although levels exceeding these are commonplace in large cities. The time-frame for these standards varies between pollutants. For example, the UK air quality standard for SO2 is 100 ppb over a 15-minute sampling time-frame, because of its ability to cause acute bronchoconstriction in asthma, whereas the standard for ozone is based on 8 hours, being the time-scale in which ozone is formed during sunlight.
Sources of gaseous pollutants The main source of SO2 is the burning of fossil fuel in coalfired power stations, domestic fires or industrial processes with a variable contribution from sulfur-containing engine fuels. NO2 is largely derived from vehicle emissions, although the highest individual exposures are from gas appliances indoors. Ozone is a secondary pollutant formed by the action of ultraviolet light on components of vehicle exhaust. Sources of particulate pollutants The main sources of particles are vehicle emissions. Particles are often measured by a reflectance method, black smoke (BS) which, while simple and cheap has been superceded by a mass measure of particles either using a high volume filter system or a TEOM (tapered element oscillating microbalance). This produces measures such as PM10 (particles broadly 10 lm in diameter) or PM2.5 (2.5 lm in diameter), depending on the size of the air inlet.There is some evidence that at least part of the toxic fraction of particles resides in the ultrafine fraction (100 nm). The relevance of the surface chemistry of particles in terms of health effects is now recognized and the need for a measure of particle surface area has arisen. This is difficult, but particle numbers can be used as a surrogate measure, and there is some evidence that this metric relates to health effects. Exposures Exposure of an individual to pollutants is only very crudely estimated by levels obtained from sentinel monitoring sites, which do not take into account indoor levels of pollutants and factors such as personal activity and preexisting lung disease, which will affect the amount of a given pollutant inhaled. Particles, once emitted, agglomerate to produce secondary particles of varying size and shape and undergo chemical reactions depending on the emission source and the atmosphere into which they are emitted. There are marked differences in the deposition of particles by size both regionally in the lung and with respect to the airway level at which deposition occurs. Larger particles (10 lm in diameter) mostly impact in the upper airways with those in the
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Table 41.1. Air quality standards
WHO
EC
UK
Sulfur dioxide 10 minutes 15 minutes 24 hours Annual
175 ppb (500 lg/m3)a — 45 ppb (128.7 lg/m3)a 17 ppb (47 lg/m3)a
Nitrogen dioxide 1 hour Annual
110 ppb (207 lg/m3) 21 ppb (40 lg/m3)
70.6 ppb (133 lg/m3)b 26.2 ppb (49 lg/m3)c
150 ppb (282 lg/m3)
Ozone 8 hour moving avge
60 ppb (120 lg/m3)
55 ppb (110 lg/m3)
50 ppb (100 lg/m3)
Particles 24-hour mean
—d
80 lg/m3
50 lg/m3
100 ppb (286 lg/m3) 48.8 ppb if smoke 60 lg/m3 67.5 ppb if smoke 60 lg/m3
WHO, World Health Organization; EC, European Community; UK, United Kingdom. a No longer linked to smoke levels. b 98% centile. c 50th centile. d Table of a range of health effect sizes provided.
respirable range (7.2 lm) penetrating deeper (Fig. 41.1). The belief that ultrafine particles (1 lm) do not remain in the lung and are simply breathed out again leaving none in the lung is now not held. Once penetrating to the distal lung, some particles will deposit and will either be taken up by alveolar macrophages or become interstitialized. Deposition of gases will depend on, amongst other things, gas solubility, minute ventilation and the presence of airflow obstruction. The endogenous anti-oxidant systems (largely urate in the nose and glutathione in the lower respiratory tract) will, up to certain concentrations, counteract the proinflammatory effects of oxidant gases (ozone and NO2) thus also altering the exposure of the epithelium to the inhaled gas.
A S S E S S I N G T H E H E A LT H E F F E C T S O F A I R P O L L U TA N T S Health effects of air pollution Exposure to air pollutants can result in: • Acute, or day-to-day effects; • Chronic effects; • Latent effects. Acute effects occur in patients with preexisting disease, while chronic effects may impact on patients who are apparently disease-free prior to exposure. The major at-risk groups for acute effects are patients with asthma or COPD,
although both deaths and hospital admissions for patients with cardiac disease increase on days of higher particulate levels.5 While the cardiac effects will not be covered here, the frequent coincidence of coronary heart disease and COPD means that patients with COPD may be affected by air pollution more through their cardiac than their pulmonary disease. Methods of assessment of health effects • Epidemiological studies provided the first evidence of and quantified, to an extent, the adverse health effects of air pollution. Time series studies of routinely collected data (mortality, hospital admissions) and panel studies of putative susceptible groups (asthma, COPD) have provided information across a range of severities. • Experimental studies in man have relied on controlled laboratory exposure of volunteers (almost exclusively normal subjects or patients with mild asthma) to specific pollutants, on in vitro work on cells obtained from nasal or bronchoalveolar lavage and studies of cultured cell monolayers. • Animal studies can be used for the study of more prolonged exposures than is possible with man. Experimental and animal studies both have the benefit of being able to study specific, controlled exposures of single or combined pollutant exposures. • Computer modeling can predict outcomes providing the specific exposure characteristics of the pollutant(s) and recognized co-exposures (e.g. meteorological variables) and host factors (e.g. exercise) are known.
433
Atmospheric Pollutants
Macrophage overload Interstitialization Inflammation
COPD
Heart disease
Thrombogenesis
IgE-mediated responses Upper airway stimulation 100
Autonomic disturbance
% deposition
Eosinophil/Neutrophil recruitment Inflammation
Asthma and COPD
Asthma Heart disease
Extrathoracic
50
Bronchial Alveolar 0 0.01
0.1
1.0
10.0
Particle diameter (µm) Fig. 41.1. Deposition of particles at various levels of the respiratory tract by particle size and likely mechanisms of health effect.
Most health effects of air pollutants are respiratory although in COPD these are limited to mortality and hospital admissions as there are no contemporary panel studies of well-characterized patients with COPD and no human challenge evidence. In asthma, in contrast, there is a substantial body of evidence ranging from hospital admissions to challenge studies. Responses to an air pollutant Individual response to an air pollutant is affected by many things (Table 41.2). Where possible these need to be allowed for when assessing the effects of a specific pollutant, usually by complex statistical manipulation of the data.6 The observation of an effect will depend on whether there is a threshold for an effect which will always be present at an individual level but which may be more difficult to determine for populations.
CHRONIC EFFECTS OF AIR POLLUTION The importance of a possible chronic effect of exposure to air pollution is that it brings more members of the population into the subpopulation susceptible to triggering by air pollutant exposure. At present, the evidence for air pollution contributing to the prevalence of both COPD and asthma is not compelling. However, it is generally believed that the chronic effects of air pollution may prove to be, at least in public health terms, more important than the acute effects.
Table 41.2. Factors affecting response to air pollutants
Pollutant Co-exposure
Host factors
Degree of exposure (concentration) Duration of exposure Other pollutants (both indoor and outdoor) Allergens Viral infections Meteorological conditions (e.g. cold air) Degree of physical activity Cigarette smoke (both active and passive) Atopy Age (infants, perhaps the elderly) The fetus Preexisting disease state Use of treatment (e.g. bronchodilators) Airflow obstruction Bronchial hyperresponsiveness
A chronic effect can best be identified either from prospective, longitudinal studies such as the US Six Cities Study7 and the American Cancer Society Study,8 from crosssectional studies comparing prevalence between areas of differing pollutant exposure or from life table analysis.9 All types of study are open to the criticism that early life
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pollutant exposures could have contributed to later life symptoms and morbidity, but are the best currently available methods for assessing chronic effects. Asthma In some cases, serial cross-sectional studies have provided important insights into changes in respiratory disease in the face of alterations in pollutant exposures. The German preand post-reunification studies10,11 have demonstrated that, with marked reductions in black smoke and SO2 levels (although no change in NO2 levels) in what was previously East Germany, the prevalence of episodes of bronchitis in children has fallen. Asthma prevalence has, however, remained unchanged at a lower level than in the old West Germany, although both hayfever and eczema have begun to increase. The implications of these findings are still unclear. It is likely that the higher levels of SO2 and black smoke experienced in East Germany before reunification contributed to sputum production and episodes of bronchitis, in parallel with the pattern of symptoms seen in industrialized cities in the Western world up to the 1960s. Whether these exposures protected the airway against asthmagenic stimuli is debatable. Any such effect may take longer to be expressed than we have had time to observe to date, but the change in hayfever rates does suggest that allergic conditions may be emerging as a result of this differing exposure, although indoor exposures and possible changes in diet may also be playing a part. The studies of Seventh Day Adventists12 (a nonsmoking population) suggest that chronic exposure to different components of the pollutant mix may result in an increased incidence of new cases of diagnosed asthma over time, but these are isolated findings in an unusual population and it is difficult to extrapolate these findings more widely. COPD The evidence for pollution contributing to the prevalence of COPD is limited to studies from the early 1960s in the UK.4 The overwhelming effect of cigarette smoking as the main cause of this condition means that contributions from other environmental exposures to initiation of COPD are difficult to quantify. The recent findings that coal dust exposure may contribute to chronic productive bronchitis and airflow obstruction independent of cigarette smoke13 adds some supportive evidence to the possibility that current air pollutant exposure may contribute to the prevalence of COPD, although the character of the particulate exposures is clearly greatly different both in amount and type.
associated with effects being NO2, ozone and particles. On average, inhaler use and symptoms increase by around 3% for every 10 lg/m3 rise in PM10 with a 1% fall in peak flow for the same change.14 However, not all studies show such effects and the PEACE study from Europe was essentially negative.15,16 Where they occur, effects are most marked in children either with more preexisting symptoms or who are atopic or both. It is not clear whether greater disease severity predicts greater effects.17 There is some evidence to suggest that personal exposure to NO2 (most of which is likely to be from indoor sources) may predispose asthmatic subjects to exacerbations in association with respiratory tract infections.18 Hospital admissions Hospital admissions for asthma have been shown to be related to air pollutant levels on a day to day basis in both adults and children,19,20 although not consistently. This may appear to conflict with the small effects seen in the panel studies, although it can be argued that some individuals may be more likely to be admitted on days when other asthmagenic factors combine to produce an attack if they are concurrently exposed to higher levels of pollution. Mortality No relationship has been shown between death from asthma and day to day changes in air pollution although the numbers of asthma deaths occurring in a city on a given day are so few that a small effect might yet exist. Episodes Episodes of air pollution might in theory result in asthma deaths or hospitalization. The London smog of 19521 resulted in many deaths from bronchitis, but no clear evidence of an effect in asthma. The more recent 199121 episode in the same city (where the sources of pollutants were quite different) showed no effect on any index of asthma, suggesting that any effect that might have occurred would have been in terms of small changes in symptoms rather than severe attacks. COPD Panel studies There is limited information on day to day changes in clinical state in patients with COPD. There is some evidence for changes in symptoms in relation to particles and treatment use in relation to NO2 and for changes in lung function.22 These changes were modest (the lung function change amounted to a 0.2% fall in FEV1 for a 10 lg/m3 rise in PM10) and changes were either same day effects or lagged by 24 hours.
ACUTE EFFECTS OF AIR POLLUTION Asthma Panel studies Panel studies of children with asthma, mostly from North America, have shown small day to day changes in peak flow and symptoms,14 the most frequently reported pollutants
Hospital admissions There is a consistent effect of air pollutant exposure and hospital admissions for COPD from studies across a wide range of countries. In the United States, hospital admissions increase by between 1 and 3% for a 10 lg/m3 rise in PM10,14 while in Europe, the APHEA studies have shown smaller
Atmospheric Pollutants
overall effects of around 1%.23,24 In most instances particles seem to be the most important pollutant, although the London study25 showed no effect of particles, but an effect of ozone in the warmer months only. There is a range of effects however, across countries, with effects being less marked in eastern Europe and more marked in western countries (Fig. 41.2). Mortality Deaths from COPD are similarly associated with pollution and the effects are usually most strongly seen at lags of around 3 days14 mediated largely through particles, although SO2 also appears to contribute in Europe. On average the increase in respiratory mortality for a 10 lg/m3 rise in PM10 is 3.4% on a day to day basis,14 although in those parts of Europe where particle exposures are generally higher, this effect is less marked suggesting a tolerance effect.26,27
MECHANISMS OF THE EFFECTS OF AIR P O L L U TA N T S Mechanisms of damage by particles Particles are likely to exert health effects via a number of mechanisms. One hypothesis is that macrophages become overloaded allowing particles to penetrate through the
β-coefficient 0.1 London (13)
0
0.1
Barcelona (40) Paris (26) Athens (73) Cracow (73) Lodz (57) Wroclaw (54) Poznan (34) Pooled relative risk Pooled relative risk (western cities) Pooled relative risk (eastern cities) 0.9
1 Relative risk
1.1
Fig. 41.2. Relative risks for death by city from respiratory disease for a 50 lg/m3 rise in black smoke for a range of European cities (the APHEA project27).
435
alveolar/bronchiolar wall and become interstitialized.28 This initiates an inflammatory response which could both affect gas exchange in COPD and also release pro-thrombogenic cytokines, which, in an individual with a compromised coronary circulation, could lead to an acute cardiac event.29 The inflammation may be caused through release of free radicals, perhaps because of transition metals on the particles30,31 although just the very small size of the particles themselves may be responsible.32 Patients with COPD have a condition which is almost exclusively caused by cigarette smoking and many will thus have co-existent atheromatous coronary disease. It is possible, therefore, that increase in hospital admissions and deaths seen in patients with COPD associated with days of higher air pollution might not simply be due to enhancement of airway inflammation or facilitation of microbial pathogenicity, but due to cardiac decompensation. There have been few studies of particulate challenge in asthma and none in COPD. One series of freshly generated diesel challenges in healthy normal subjects33 has revealed infiltration of inflammatory cells and increases in some proinflammatory cytokines, notably IL-8, albeit at high pollutant concentrations which may be of relevance in both the asthmatic and COPD settings. For asthma, there is also evidence that diesel exhaust can potentiate the local production of specific IgE in the nose with an associated shift in T cell patterns compatible with this.34,35 Mechanisms of damage by gases Sulfur dioxide SO2 is a highly soluble, irritant gas quickly absorbed by the respiratory tract. It is a potent bronchoconstrictor in asthma particularly with exercise, but there is marked variability in the response between individuals, individuals responding to between 200 ppb and over 1500 ppb.36 An airway effect is only seen in normal subjects at exposures of 4 to 5 ppm. In asthma SO2 is thought to activate rapidly adapting receptors (RAR),37 thus leading directly to bronchoconstriction. Lower doses inhaled at rest (200 ppb) can alter autonomic balance in asthma invoking the possibility that the gas initially activates neurogenic inflammation through a RAR initiated, vagally mediated reflex which subsequently results in an autonomic modulating response which differs from that seen in normal subjects.38 Nitrogen dioxide Nitrogen dioxide is an oxidant gas which at high concentrations can cause acute pulmonary edema (e.g. silo filler’s disease). At levels usually experienced in ambient air (15–30 ppb as urban background levels) effects are difficult to find. At high concentrations (1000–3000 ppb usually with exercise) some changes in spirometric indices and BHR have been recorded in asthmatic subjects, but these are of modest degree.39 At these high concentrations some inflammatory markers are raised in broncho-alveolar lavage fluid after challenge in normal subjects, although there is considerable inconsistency between studies.40,41
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Asthma and Chronic Obstructive Pulmonary Disease
At lower exposures (400 ppb) NO2 has been shown to enhance the acute bronchoconstrictor effect of house dust mite allergen exposure, both at high dose42 or as repeated smaller doses of allergen.43 This suggests that exposure to gaseous air pollutants may exert more subtle effects than can be identified by epidemiological studies and which consequently may prove very difficult to quantify at a population level. There is no evidence that any such potentiating effects are seen in COPD, for instance with respect to viral infections. Ozone Ozone is a highly reactive, oxidant gas and can cause inflammatory changes in the bronchial mucosa (largely in the terminal bronchioles) in animals at concentrations similar to those which can be experienced in ambient air (80–120 ppb).41,44 With exercise, it can produce similar degrees of bronchoconstriction in both normal and asthmatic subjects although there are large interindividual variations in response.45 Ozone can also increase nonspecific airway responsiveness in both normal and asthmatic subjects in a dose-related manner.46 Repeated daily exposures of asthmatic subjects to ozone leads to progressive loss of the response suggesting tolerance to its effects.47 Ozone also potentiates the bronchoconstrictor effect of allergen in asthma either alone48 or in combination with NO2.49 The inflammatory response to ozone is very variable. Although most studies have shown an increase in neutrophils in BAL some, but not all, have shown increases in certain adhesion molecules and cytokines (notably IL-8).41,50,51 There are, however, marked interindividual differences and any changes in airflow so induced do not necessarily match changes in inflammatory markers which are often present at elevated levels some hours after exposure even though the cellular response has settled. There is suggestive evidence that patients with mild COPD exposed to ozone (along with exercise) at 200–300 ppb may show small decrements in both lung function and oxygen saturations although this needs confirmation with adequately powered studies.52,53
S U M M A RY Air pollution can affect some patients with asthma, in terms of symptoms and hospital admissions although the picture varies between countries and perhaps according to severity. There is evidence for all components of the pollutant mix to be capable of playing a role, although the mechanisms are only just being unravelled. For patients with COPD, air pollution increases the risks of hospital admission and death, particles being the most important pollutant. Particles may exacerbate inflammation by generation of free radicals, perhaps through transition metals. Interstitialization of particles at bronchiolo-alveolar level may exacerbate COPD itself or induce cardiac events by release of prothrombotic cytokines. Fig. 41.1 summarizes the possible mechanisms of the health effects of particles in both COPD and asthma.
At present there is no specific approach for dealing with any air pollution-induced changes in clinical state in either asthma or COPD, although increasing inhaled antiinflammatory treatment makes intuitive sense, while avoiding exertion and other known triggers during periods of higher air pollution may also be sensible. The overall impact on public health of these triggering events of air pollution on patients with airway diseases is significant although may prove to be swamped by the size of the chronic effects once these are adequately quantified.54,55
REFERENCES 1. Ministry of Health. Mortality and morbidity during the London fog of December 1952, London: HMSO, 1954. 2. Lippmann M, Ito K. Separating the effects of temperature and season on daily mortality from those of air pollution in London: 1965–1972. Inhal.Toxicol. 1995; 7:85–97. 3. Lawther PJ, Waller RE, Henderson M. Air pollution and exacerbations of bronchitis. Thorax 1970; 25:525–39. 4. Holland WW, Reid D. The urban factor in chronic bronchitis. Lancet 1965; i:445–8. 5. Poloniecki JD, Atkinson RW, Ponce de Leon A, Anderson HR. Daily time series for cardiovascular hospital admissions and previous day’s air pollution in London. Occup. Environ. Med. 1997; 54: 534–40. 6. Schwartz J. Air pollution and hospital admissions for respiratory disease. Epidemiology 1996; 7:20–8. 7. Dockery DW, Pope CA III, Xu X et al. An association between air pollution and mortality in six US cities. New Engl. J. Med. 1993; 329: 1753–9. 8. Pope CA, Thun MJ, Namboodiri MM et al. Particulate air pollution as a predictor of mortality in a prospective study of US adults. Am. J. Respir. Crit. Care Med. 1995; 151:669–74. 9. Hurley JF, Holland MR, Markandya A et al. Towards assessing the health impacts of ambient particulate air pollution in the UK. Final report for UK Department of Health, 2000. 10. von Mutius E, Fritzsch C, Weiland SK, Roll G, Magnussen H. Prevalence of asthma and allergic disorders among children in united Germany. Br. Med. J. 1992; 305:1395–9. 11. Weiland SK, von Mutius E, Hirsch T et al. Prevalence of respiratory and atopic disorders among children in the East and West of Germany five years after unification. Eur. Respir. J. 1999; 14:862–70. 12. Abbey DE, Nishino N, McDonnell WF et al. Long-term inhalable particles and other air pollutants related to mortality in nonsmokers. Am. J. Respir. Crit. Care Med. 1999; 159:373–82. 13. Henneberger PK, Attfield MD. Respiratory symptoms and spirometry in experienced coal miners: effects of both distant and recent coal mine dust exposures. Am. J. Indust. Med. 1997; 32:268–74. 14. Dockery DW, Pope CA. Acute respiratory effects of particulate air pollution. Ann. Rev. Public Health 1994; 15:107–32. 15. Roemer W, Hoek G, Brunekreef B, Haluszka J, Kalandidi A, Pekkanen J. Daily variations in air pollution and respiratory health in a multicentre study: the PEACE project. Eur. Respir. J. 1998; 12:1354–61. 16. Roemer W, Hoek G, Brunekreef B et al. The PEACE project: general discussion. Eur. Respir. Rev. 1998; 8:125–30. 17. Brunekreef B, Kinney PL, Ware JH et al Sensitive subgroups and normal variation in pulmonary function response to air pollution episodes. Env. Health Perspect. 1991; 90:189–93. 18. Linaker CH, Coggon D, Holgate ST et al. Personal exposure to nitrogen dioxide and risk of airflow obstruction in asthmatic children with upper respiratory infection. Thorax 2000; 55:930–3.
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19. Walters S, Griffiths RK, Ayres JG. Temporal association between hospital admissions for asthma in Birmingham and ambient levels of sulphur dioxide and smoke. Thorax 1994; 49:133–40. 20. Sunyer J, Spix C, Quenel P et al. Urban air pollution and emergency admissions for asthma in four European cities: The APHEA project. Thorax 1997; 52:760–5. 21. Anderson HR, Limb ES, Bland JM, Ponce de Leon A, Strachan DP, Bower JS. Health effects of an air pollution episode in London, December 1991. Thorax 1995; 50:1188–93. 22. Harre ESM, Price PD, Ayrey RB, Toop LJ, Martin IR, Town GI. Respiratory effects of air pollution in chronic obstructive pulmonary disease: a three month prospective study. Thorax 1997; 52:1040–4. 23. Spix C, Anderson HR, Schwartz J et al. Short-term effects of air pollution on hospital admissions of respiratory diseases in Europe: a quantitative summary of APHEA study results. Air Pollution and Health: a European Approach. Arch. Environ. Health 1998; 53:54–64. 24. Anderson HR, Spix C, Medina S et al. Air pollution and daily admissions for chronic obstructive pulmonary disease in 6 European cities: results from the APHEA project. Eur. Resp. J. 1997; 10:1064–71. 25. Ponce de Leon A, Anderson HR, Bland JM, Strachan DP, Bower J. Effects of air pollution on daily hospital admissions for respiratory disease in London between 1987–88 and 1991–92. J. Epidemiol. Comm. Health 1996; 50 (Suppl. 1):S63–S70. 26. Sunyer J, Castellsagué J, Sáez M, Tobias A, Antó JM. Air pollution and mortality in Barcelona J. Epidemiol. Comm. Health 1996; 50 (Suppl 1):S76–S80. 27. Katsouyanni K, Touloumi G, Spix C et al. Short term effects of ambient sulphur dioxide and particulate matter on mortality in 12 European cities: results from time series data from the APHEA project. Br. Med. J. 1997; 314:1658–63. 28. Oberdörster G, Ferin J, Lehnert BE. Correlation between particle size, in vivo particle persistence and lung injury. Environ. Health Perspect. 1994; 102 (Suppl 5):173–9. 29. Seaton A, MacNee W, Donaldson K, Godden D. Particulate air pollution and acute health effects. Lancet 1995; 345: 176–8. 30. Carter JD, Ghio AJ, Samet JM, Devlin RB. Cytokine production by human airway epithelial cells after exposure to an air pollution particle is metal dependant. Toxicol. Appl. Pharmacol. 1997; 146:180–8. 31. Costa DL, Dreher K-L. Bioavailable transition metals in particulate matter mediate cardiopulmonary injury in health and compromised animal models. Environ. Health Perspect. 1997; 105(S5):1053–60. 32. Donaldson K, Li XY, MacNee W. Ultrafine (nanometer) particlemediated lung injury. J. Aerosol. Sci. 1998; 29:553–60. 33. Salvi SS, Nordenhall C, Blomberg A et al. Acute exposure to diesel exhaust increases IL-8 and GRO-alpha production in healthy human airways. Am. J. Respir. Crit. Care Med. 2000; 161:550–7. 34. Diaz-Sanchez D, Dotson AR, Takenaka H, Saxon A. Diesel exhaust particles induce local IgE production in vivo and alter the pattern of IgE messenger RNA isoform. J. Clin. Invest. 1994; 94:1417–25. 35. Diaz-Sanchez D, Tsien A, Fleming J, Saxon A. Combined diesel exhaust particulate and ragweed allergen challenge markedly enhances human in vivo nasal ragweed specific IgE and skews cytokine production to a Th2 type phenotype. J. Immunol. 1997; 158: 2406–13. 36. Sheppard D, Saisho A, Nadel JA, Boushey HA. Exercise increases sulfur dioxide-induced bronchoconstriction in asthmatic subjects. Am. Rev. Respir. Dis. 1981; 123:486–91.
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37. Atzori L, Bannenberg G, Corriga AM et al. Sulfur dioxide-induced bronchoconstriction via ruthenium red-sensitive activation of sensory nerves. Respiration 1992; 59:272–8. 38. Tunnicliffe WS, Mark D, Harrison RM, Ayres JG. Effect of particle and sulphur dioxide challenge on heart rate variability in normal and asthmatic subjects. Eur. Resp. J. 2001; 17:604–8. 39. Folinsbee L. Does nitrogen dioxide exposure increase airways responsiveness? Toxicol. Ind. Health 1992; 8:273–83. 40. Blomberg A, Krishna MT, Bocchino V et al. The inflammatory effects of 2 ppm NO2 on the airways of healthy subjects. Am. J. Respir. Crit. Care Med. 1997; 156:418–24. 41. Blomberg A. Airway inflammatory and antioxidant responses to oxidative and particulate air pollutants – experimental exposure studies in humans. Clin. Exp. Allergy 2000; 30:310–17. 42. Tunnicliffe WS, Burge PS, Ayres JG. Effect of domestic concentrations in nitrogen dioxide on airway responses to inhaled allergen in asthmatic patients. Lancet 1994; 344:1733–6. 43. Strand V, Svartengren M, Rak S, Barck C, Bylin G. Repeated exposures to an ambient level of NO2 enhances asthmatic response to a non-symptomatic allergen dose. Eur. Respir. J. 1998; 12:6–12. 44. Aris RM, Christian D, Hearne PQ, Kerr K, Finkbeiner WE, Balmes JR. Ozone-induced airway inflammation in human subjects as determined by airway lavage and biopsy. Am. Rev. Respir. Dis. 1993; 148:1363–72. 45. Hazucha MJ. Relationship between ozone exposure and pulmonary function changes. J. Appl. Physiol. 1987; 62:1671–80. 46. Horstman DH, Folinsbee LJ, Ives PJ, Abdul-Saleem S, McDonnell WF. Ozone concentration and pulmonary response relationships for 6.6 hour exposures with five hours of moderate exercise to 0.08, 0.10 and 0.12 ppm. Am. Rev. Respir. Dis. 1990; 142:1158–63. 47. Horvath SM, Gliner JA, Folinsbee LJ. Adaptation to ozone: duration of effect. Am. Rev. Respir. Dis. 1981; 123:496–9. 48. Jörres R, Nowak D, Magnussen H. The effect of ozone exposure on allergen responsiveness in subjects with asthma or rhinitis. Am. J. Respir. Crit. Care Med. 1996; 153:56–64. 49. Jenkins HS, Devalia JL, Mister RL, Bevan AM, Rusznak C, Davies RJ. The effect of exposure to ozone and nitrogen dioxide on the airway response of atopic asthmatics to inhaled allergen. Am. J. Respir. Crit. Care Med. 1999; 160:33–9. 50 Holz O, Jörres R, Timm P et al. Ozone-induced airway inflammatory changes differ between individuals and are reproducible. Am. J. Respir. Crit. Care Med. 1999; 159:776–84. 51. Jörres RA, Holz O, Zachgo W et al. The effect of repeated ozone exposures on inflammatory markers in bronchoalveolar lavage fluid and mucosal biopsies. Am. J. Respir. Crit. Care Med. 2000; 161:1855–61. 52. Solic JJ, Hazucha MJ, Bromberg PA. The acute effects of 0.2 ppm ozone in patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1982; 125:664–9. 53. Kehrl HR, Hazucha MJ, Solic JJ, Bromberg PA. Responses of subjects with chronic obstructive pulmonary disease after exposure to 0.3 ppm ozone. Am. Rev. Respir. Dis. 1985; 131:719–24. 54. Committee on the Medical Effects of Air Pollution. Quantification of the health effects of air pollution in the UK. Department of Health: The Stationery Office, 1997. 55. Künzli N, Kaiser R, Medina S et al. Public health impact of outdoor and traffic-related air pollution: a European assessment. Lancet 2000; 356:795–801.
Drugs
Chapter
42
G.J. Gibson Freeman Hospital, Newcastle upon Tyne, UK
COPD Therapeutic drugs in normal clinical doses are of little relevance to either the etiology or exacerbations of COPD. There is no evidence that the therapeutic drugs discussed below in relation to asthma have adverse effects in patients with nonasthmatic COPD. The only point of clinical relevance is the predictably reduced efficacy of bronchodilators, particularly b-sympathomimetic agonists, following treatment with the relevant antagonists. Although b-adrenergic antagonists (beta blockers) are commonly regarded as contra-indicated in all patients with airway obstruction, there is no evidence that they provoke exacerbations in nonasthmatic COPD. Caution is, however, justified in patients with chronic airway obstruction as it is not uncommon for the underlying asthmatic nature of the airway narrowing to go unrecognized until “uncovered” by treatment with a beta blocker. An unusual form of premature emphysema is sometimes seen in abusers of intravenous illicit drugs, in particular opiates1 and methylphenidate (Ritalin).2–4 The characteristic lower lobe emphysema which occurs is associated with evidence of talcosis and is probably due to particle embolization rather than to the drugs themselves.
ASTHMA Repeated inhalation of certain drugs during their manufacture can sensitize the airways of a previously nonasthmatic individual and cause occupational asthma. This has been an occasional problem with some antibiotics.5 Otherwise, asthma induced by drugs usually occurs as an exacerbation of preexisting disease, although occasionally, asthma is first recognized after starting treatment, for example, as mentioned above, with a beta blocker. Usually in this situation, a detailed history will reveal preexisting features of the condition. Exacerbations of asthma may result either from a predictable consequence of the pharmacological properties of the drug or as an idiosyncratic effect. The most important agents in the former category are the beta blockers and in
the latter, the nonsteroidal anti-inflammatory agents (NSAIDs). In addition, with inhalational drugs, a nonspecific effect related to the carrier agent or mode of delivery is sometimes seen. In particular, exacerbation of asthma by chlorofluorocarbons (CFCs) is well-recognized in some individuals using metered-dose inhalers. Such an adverse effect may be obscured by the therapeutic effect of the bronchodilator which the aerosol carries. This effect became more obvious following the introduction of longacting b-agonists such as salmeterol, the therapeutic effect of which has a relatively slow onset compared to that of short-acting b stimulants, allowing a bronchoconstrictor effect of the carrier agent to become evident.6 With the phasing out of CFCs, this is likely to become less of a problem, although it is not yet clear whether the newer alternative carriers have a similar potential. Nebulized bronchodilator solutions have occasionally provoked bronchoconstriction, related either to the tonicity of the solution7 or to preservatives added to the solution,8 as also may nebulized antibiotics or pentamidine.9 Pharmacological effects Cholinergic agents produce bronchoconstriction by a direct action on smooth muscle; both systemic agents such as carbachol and ophthalmic preparations of pilocarpine10 have been implicated. The increased cholinergic effect associated with the cholinesterase inhibitor pyridostigmine used to treat myasthenia gravis has similarly been reported to exacerbate asthmatic symptoms.11 The bronchoconstrictor prostaglandin, PGF2a, used to induce abortion is also recognized as potentially hazardous in patients with asthma. Cough is a well-known side-effect of treatment with nonspecific inhibitors of angiotensin-converting enzyme (ACE). The effects have been attributed to inhibition of the breakdown of bradykinin and substance P,12 and this effect is much less common with the newer specific angiotensin II receptor antagonists such as losartan which do not affect the catabolism of kinins. Most individuals affected by ACE inhibitors have no features to suggest asthma, but occasionally deterioration of preexisting asthma has been reported,13 although other data suggest that the association may be coincidental.14
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Beta blockers Exacerbation of asthma by b-adrenergic antagonists has been recognized for many years and is relatively common due to their widespread use in the treatment of both hypertension and ischemic heart disease. The more selective b1antagonists such as metoprolol and atenolol are less dangerous than nonselective drugs such as propranolol, but the degree of selectivity is relative and none can be regarded as completely safe in patients with asthma.15The adverse effect is presumed to be due to antagonism of b2-adrenoceptors, but the precise mechanism is not clear as human bronchial smooth muscle has no significant direct sympathetic innervation. It is usually assumed that circulating catecholamines have a tonic bronchodilator effect in asthmatic subjects and that this is blocked by b-antagonists, but, in view of the very low concentrations of circulating catecholamines in resting subjects and the wide range of agents which are capable of antagonizing propranolol-induced bronchoconstriction, other mechanisms may be involved. In particular, there is evidence of interaction between beta blockers and the parasympathetic nervous system, leading to the suggestion that propranolol may cause bronchoconstriction by blockade of inhibitory presynaptic b2-adrenoceptors on cholinergic nerves.16 Even a single therapeutic dose of a nonselective beta blocker can result in life-threatening asthma.17 Furthermore, previously mild asthma may become more difficult to control after a period of treatment with a beta blocker.18 The most important factors determining the occurrence and severity of an adverse reaction are the selectivity of the drug concerned and its plasma concentration. Possibly, also, the response may vary with genetically determined b-receptor polymorphisms, but to date no evidence is available to evaluate this hypothesis. In relation to plasma levels, it has been shown that the bronchoconstrictor effect can be minimized by use of an osmotic release drug delivery system which gives a stable concentration.19 However, unless use of a beta blocker is essential, they are best avoided in asthma. Luckily, at least for the treatment of hypertension, several other classes of effective drugs are available, but recent evidence of the beneficial effect of beta blockers after myocardial infarction has reopened debate on whether, in subjects with mild asthma, the benefits of selective agents may outweigh the acknowledged risks.15 Beta blockers are widely used in ophthalmological practice as eyedrops for the treatment of glaucoma. One of the most popular is the relatively nonselective agent, timolol, which has been associated with exacerbations of asthma in many patients.20 In part, this is because use of such preparations is more easily overlooked than with oral or systemic beta blockers. Also, intraocular administration gives rapid access to the systemic circulation via the nasolacrimal duct and nasal mucosa; even one drop of a 0.5% solution gives measurable plasma levels of the drug.21 Furthermore, glaucoma is largely a disease of the elderly, in whom asthma is relatively underdiagnosed22 and awareness of bronchoconstriction may be impaired.23 In
one study of 80 patients with glaucoma and no clear antecedent history of asthma, as many as one-quarter were shown to have reversible airway obstruction on objective testing.24 Betaxolol is a selective b1-antagonist which can be used as eye drops in preference to timolol or alternatively, a sympathomimetic such as the adrenalin precursor, dipivefrin, is effective in glaucoma without the risk of bronchoconstriction.20 Idisyncratic effects Acute anaphylaxis or a similar, but nonimmunologically mediated anaphylactoid reaction may occur following parenteral injection of certain drugs. Often, but not always, this occurs in patients with preexisting asthma. Such reactions are characterized by life-threatening bronchoconstriction associated with angioneurotic edema and hypotension. Antibiotics, especially penicillin25 and intravenous dextran preparations26 are among the most frequently recognized causes. Anaphylactoid reactions during anesthesia have been associated with certain volatile agents such as althesin and with muscle relaxants such as suxamethonium and D-tubocurarine.27 Intravenous N-acetylcysteine given in the treatment of paracetamol poisoning can occasionally provoke an asthmatic exacerbation, the mechanism of which is unknown.28 NSAID-induced asthma The prevalence of sensitivity to aspirin and other NSAIDs in patients with asthma varies considerably in different series, and estimates depend importantly on how sensitivity is defined. When based on history alone, the estimated rates are between 2 and 5% of asthmatic individuals, but when challenge tests are performed, the prevalence is significantly higher, with estimates ranging from 8 to 22%.29 It has been apparent for many years that the pathogenesis of aspirin-induced asthma is in some way related to prostaglandin metabolism30 as the agents which can provoke asthma share the property of inhibition of cyclo-oxygenase (COX), the enzyme responsible for prostaglandin synthesis. Although the precise mechanism remains uncertain, the picture has been clarified in recent years by better understanding of the interactions between prostaglandins and leukotrienes and by the discovery that there are two isoforms of COX. The constitutive enzyme, COX-1 produces prostacyclin and is cyto-protective, at least for the gastric mucosa and kidney, while the inducible COX-2 is stimulated by pro-inflammatory cytokines and increases markedly in various inflammatory conditions. It is now recognized that the anti-inflammatory effects of NSAIDs are dependent on inhibition of COX-2, while many of the side-effects result from inhibition of COX-1.31 One hypothesis to explain the mechanism of NSAIDinduced asthma was that inhibition of COX would “shunt” the metabolism of arachidonic acid towards the 5lipoxygenase pathway, thereby increasing the generation of
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leukotrienes and resulting in bronchoconstriction, but this alone does not explain why only a proportion of asthmatic subjects react adversely to NSAIDs. The cysteinyl leukotrienes, and in particular leukotriene C4 (LTC4) are probably the most important bronchoconstrictors in aspirin-induced asthma.32 Cowburn et al.33 showed that expression of the enzyme LTC4 synthase in cells in bronchial biopsies from asthmatic subjects with aspirin sensitivity correlated with bronchial responsiveness to inhaled lysine aspirin, whereas no such correlations were seen between aspirin responsiveness and expression of other relevant enzymes such as 5-lipoxygenase, COX-1 or COX-2. Patients with aspirin sensitivity had many more cells (mainly eosinophils) expressing this enzyme in the airway than either nonsensitive asthmatic or normal subjects.33 Furthermore, it has been recognized for some years that the stable leukotriene, LTE4 (to which LTC4 is rapidly metabolized) is excreted in greater amounts in subjects with aspirin sensitivity than in nonsensitive asthmatics. The excretion of LTE4 increases further after aspirin challenge.34,35 Recently, polymorphisms of the LTC4 synthase gene promoter have been identified and one polymorphism associated with greater expression of LTC4 synthase is more frequent in aspirin-sensitive than nonsensitive asthmatic subjects.36 Aspirin-sensitive individuals respond to local bronchial challenge with lysine aspirin by marked suppression of synthesis of the bronchodilator prostaglandin PGE2 without inhibition of other prostanoids, unlike the situation in aspirin-tolerant asthma, where synthesis of other prostaglandins is also reduced.37 It has therefore been proposed that PGE2 normally acts as a “brake” on the effects of the bronchoconstrictor leukotrienes and when this “brake” is removed by NSAIDs, greater amounts of leukotrienes are produced.34,38 Consequently, in sensitive individuals, inhibition of PGE2 synthesis by NSAIDs may be a “trigger” allowing unopposed action of bronchoconstrictor leukotrienes which are present in greater amounts in such individuals,33 possibly due to a particular polymorphism of the LTC4 synthase gene.36 However, this hypothesis does not completely explain aspirin-sensitive asthma as a proportion of patients do not possess the predisposing variant of the LTC4 synthase gene.39 Expression of the COX-1 isoform in bronchial mucosa is similar in aspirin-sensitive, aspirin-tolerant and normal subjects, whereas COX-2 expression is greater in the two asthmatic groups.33,40 It has been shown that, in practice, greater adverse effects are likely with NSAIDs with relatively greater capacity to inhibit COX-1.39 The recently introduced, more specific COX-2 inhibitors such as celecoxib and rofecoxib may be less likely to provoke asthma than nonselective inhibitors. Results of studies in small numbers of patients are promising41 but caution is necessary as early reports of adverse events of rofecoxib to the UK Committee on Safety of Medicines include exacerbation of asthma.42 One less specific COX-2 inhibitor, nimesulide, has been available in several countries (but not
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the UK) for some years and therapeutic doses appear to be well-tolerated by asthmatic subjects with NSAID sensitivity.43 The drug does, however, also have other properties and its apparent lack of adverse effects in asthma might be attributable to these.44 Clinical features The typical patient with aspirin-sensitive asthma develops asthma in adult life, although sensitivity is also seen occasionally in childhood.45 Aspirin-sensitive asthma is more common in women than men in a ratio of approximately two to one, and about 50% of patients have associated nasal polyps. Viewed from the other direction, about one-fifth of subjects with nasal polyps have overt aspirin sensitivity.46 In the absence of a suggestive clinical history, only a small minority of patients with polyps is likely to be sensitive to aspirin.47 Contrary to early reports, the prevalence of positive skin tests to common allergens is similar in subjects with and without aspirin sensitivity.48 Clinical experience shows that patients with aspirin sensitivity often have “difficult to manage” asthma and up to half require continuous, or almost continuous, treatment with oral steroids. Of note also, these individuals comprise an important proportion of patients subject to life-threatening attacks – in one series, 25% of patients requiring assisted ventilation for acute asthma were sensitive to aspirin.49 In its most dramatic form, the acute response to ingestion of aspirin or other NSAID may be anaphylactoid, with lifethreatening bronchoconstriction associated with nasal symptoms and edema of the upper airway, leading to a choking sensation and rapid loss of consciousness. Less sensitive individuals show gradual deterioration over a couple of hours which may be less readily attributable to the provoking drug. In many patients, the history is sufficiently clear for further investigation to be unnecessary, other than that required to assess the severity of the asthma. In less clear-cut cases or when treatment with an NSAID is desirable, carefully controlled challenge tests may be justified. Bronchial challenge using inhaled lysine aspirin has been shown to be safe and more rapid than oral challenge, but is a little less sensitive.50 An even simpler alternative is nasal challenge, but this is rather less reliable for confident exclusion of sensitivity.51 Treatment The evidence on pathogenesis discussed above suggests that drugs which inhibit the synthesis of cysteinyl leukotrienes or antagonize their effects are likely to be useful in patients with aspirin-sensitive asthma. Several studies have reported attenuation of the response by such agents in single exposure challenges.52,53 In a recent double-blind placebocontrolled cross-over study of 6 weeks’ treatment of 40 patients with aspirin-sensitive asthma, the beneficial effects of the 5-lipoxygenase inhibitor, zileuton, were clearly shown.54 However, it is not yet clear whether subjects with aspirin sensitivity derive greater benefits from leukotriene inhibitors than those with nonsensitive asthma.
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In general, patients with a clear history of intolerance should be advised to avoid all aspirin-containing products and other NSAIDs. Although the selective COX-2 antagonists may prove to be safer, this cannot yet be stated with certainty. Paracetamol (acetominophin) is a very weak COX inhibitor which is safe in normal therapeutic doses in most patients with NSAID sensitivity, although large doses produce reactions in a sizeable minority.55 Desensitization to aspirin has been practised for several years with well-documented good results in selected patients. A single NSAID challenge results in a refractory period which can last for up to 5 days.56,57 This observation led to desensitization schedules using gradually increasing doses followed by regular treatment which is necessary to maintain the refractory state.58 After desensitization to aspirin, there is loss of sensitivity to other NSAIDs.58 Occasional patients with aspirin sensitivity have been reported to react adversely to intravenous hydrocortisone sodium succinate.59–61 The adverse effect usually appears to be related to the succinate ester and may be avoided by using hydrocortisone sodium phosphate or a different corticosteroid.62 Illicit drugs Ironically, certain illicit or “street” drugs now recognized as potentially provoking asthma, were previously included in preparations to treat asthma. For example, amphetamine was used in early inhalers for asthma,63 and cocaine was a constituent of “Dr Tucker’s asthma specific” a nasally applied therapy, which was available over the counter in the USA in the early twentieth century. Exacerbation of asthma is well-recognized as an occasional consequence of smoking “crack” cocaine.64,65 Recently, it has become apparent that cocaine use may be a much more significant risk factor than hitherto appreciated, at least in some communities. In one recent study66 of an inner-city emergency department in the USA, cocaine was found in the urine of 13% of those subjects with acute asthma who agreed to be tested and the asthma was more severe in these individuals than in those with negative screening. Furthermore, a sizeable number of patients declined the urine test so that the prevalence of cocaine use may have been a significant underestimate. In another North American study of patients attending an emergency department,67 as many as 36% of those with apparently new-onset asthma showed positive results for cocaine metabolites. Finally, at least one death due to asthma has been associated with use of the “designer” amphetaminelike drug, methylenedioxymethamphetamine (MDMA or “ecstasy”).68
REFERENCES 1. Paré JP, Cote G, Fraser RS. The long term follow-up of drug abusers with intravenous talcosis. Am. Rev. Respir. Dis. 1989; 139:233–41.
2. Sherman CB, Hudson LD, Pierson DJ. Severe precocious emphysema in intravenous methylphenidate (Ritalin) abusers. Chest 1987; 92:1085–7. 3. Schmidt RA, Glenny RW, Godwin JD, Hampson NB, Cantino ME, Reichenbach DD. Panlobular emphysema in young intravenous Ritalin abusers. Am. Rev. Respir. Dis. 1991; 143:649–56. 4. Ward S, Heyneman LE, Reittner P, Kazerooni EA, Godwin JD, Muller NL. Talcosis associated with i.v. abuse of oral medications: CT findings. Am. J. Roentgenol. 2000; 174:789–93. 5. Coutts II, Dally MB, Newman Taylor AJ, Pickering CAC, Horsfield N. Asthma in workers manufacturing cephalosporins. Br. Med. J. 1981; 283:950. 6. Wilkinson JRW, Roberts JA, Bradding P, Holgate ST, Howarth PH. Paradoxical bronchoconstriction in asthmatic patients after salmeterol by metered dose inhaler. Br. Med. J. 1992; 305:931–2. 7. Mann JS, Howarth PH, Holgate ST. Bronchoconstrictor induced by ipratropium bromide in asthma: Relation to hypotonicity. Br. Med. J. 1984; 289:469. 8. Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor properties of preservatives in ipratropium bromide (Atrovent) nebuliser solution. Br. Med. J. 1987; 294:1197–8. 9. Shelton MJ, Minor JR. Aeosolized pentamidine in AIDS patients with asthma. Am. J. Hosp. Pharm. 1991; 48:556–7. 10. Bruchhausen D, Haschem J, Dardenne MU. Veranderungen des Bronchialwiderstandes bei Asthmatikern nach Applikaton von Pilocarpin in den Konjunktivalsack. Dtsch. Med. Wochenschr. 1969; 94:1651–4. 11. Shale DJ, Lane DJ, Davis CJF. Air-flow limitation in myasthenia gravis. Am. Rev. Respir. Dis. 1983; 128:618–21. 12. Skidgel RA, Engelbrecht S, Johnson AR, Erdos EG. Hydrolysis of substance P and neurotensin by converting enzyme and neutral endopeptidase. Peptides 1984; 5:769–76. 13. Lunde H, Hedner T, Samuelsson O et al. Dyspnoea, asthma and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors. Br. Med. J. 1994; 308:18–21. 14. Inman WHW, Pearce G, Wilton L, Mann RD. Angiotensin converting enzyme inhibitors and asthma. Br. Med. J. 1994; 308:593–4. 15. Chafin CC, Soberman JE, Demirkan K, Self T. Beta-blockers after myocardial infarction: do benefits ever outweigh risks in asthma? Cardiology 1999; 92:99–105. 16. Myers JD, Higham MA, Shakur BH, Wickremasignhe PW. Attenuation of propranolol-induced bronchoconstriction by frusemide. Thorax 1997; 52:861–5. 17. Williams IP, Millard FJC. Severe asthma after inadvertent ingestion of oxprenolol. Thorax 1980; 35:160. 18. Anderson EG, Calcraft B, Jariwalla AG, Al-Zaibak M. Persistent asthma after treatment with beta-blocking drugs. Br. J. Dis. Chest 1979; 73:407–8. 19. Bauer K, Kaik G, Kaik B. Osmotic release oral drug delivery system of metoprolol in hypertensive asthmatic pateints. Pharmacodynamic effects on b2-adrenergic receptors. Hypertension 1994; 24:339–46. 20. Diggory P, Franks WA. Glaucoma therapy may take your breath away. Age Ageing 1997; 26:63–7. 21. Passo MS, Palmer EA, Van Buskirk EM. Plasma timolol in glaucoma patients. Ophthalmology 1984; 91:1361–3. 22. Bannerjee DK, Lee GS, Malik SK, Daly S. Underdiagnosis of asthma in the elderly. Br. J. Dis. Chest 1987; 81:23–9. 23. Connolly MJ, Crowley JJ, Neilson CP,Vestal RE. Reduced subjective awareness of bronchoconstriction provoked by methacholine in elderly asthmatic and normal subjects as measured on the simple awareness scale. Thorax 1992; 47:410–13. 24. Diggory P, Cassels-Brown A, Vail A, Abbey LM, Hillman JS. Avoiding unsuspected respiratory side-effects of topical timolol with cardioselective or sympathomimetic agents. Lancet 1995; 345:1604–6.
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25. Idsoe O, Guthe T, Willcox RR, Weck AL. Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull. World Health Org. 1968; 38: 159–88. 26. Ljungstrom KG, Renck H, Strandberg K, Hedin H, Richter W, Widerlov E. Adverse reactions to dextran in Sweden 1970–1979. Acta Chirurg. Scand. 1983; 149:253–62. 27. Stoelting RK. Allergic reactions during anesthesia. Anesth. Analg. 1983; 62:341–56. 28. Mant TG, Tempowski JH, Volans GN, Talbot JC. Adverse reactions to acetylcysteine and effects of overdose. Br. Med. J. 1984; 289:217–19. 29. Dor PJ, Vervloet D, Baldocchi G, Charpin J. Aspirin intolerance and asthma: induction of a tolerance and long-term monitoring. Clin. Allergy 1985; 15:37–42. 30. British Medical Journal. Analgesics and asthma (editorial). Br. Med. J. 1973; ii:419–20. 31. Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc. Natl Acad. Sci. USA 1991; 88:2692–6. 32. Israel E, Fischer AR, Rosenberg MA et al. The pivotal role of 5lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am. Rev. Respir. Dis. 1993; 148: 1447–51. 33. Cowburn AS, Sladek K, Soya J et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirinintolerant asthma. J. Clin. Invest. 1998; 101:834–46. 34. Christie PE, Tagari P, Ford-Hutchinson AW et al. Urinary leukotriene E4 after lysine-aspirin inhalation in asthmatic subjects. Am. Rev. Respir. Dis. 1992; 146:1531–4. 35. Daffern PJ, Muilenburg D, Hugh TE, Stevenson DD. Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses. J. Allergy Clin. Immunol. 1999; 104:559–64. 36. Sanak M, Simon H-U, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 1997; 350:1599–600. 37. Szczeklik A, Sladek K, Dworski R et al. Bronchial aspirin challenge causes specific eicosanoid response in aspirin-sensitive asthmatics. Am. J. Respir. Crit. Care Med. 1996; 154:1608–14. 38. Sestini P, Armetti L, Gambaro G et al. Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTE4 excretion in aspirin-sensitive asthma. Am. J. Respir. Crit. Care Med. 1996, 153:572–5. 39. Szczeklik A, Stevenson DD. Aspirin-induced asthma: Advances in pathogenesis and management. J. Allergy Clin. Immunol. 1999; 104:5–13. 40. Sousa AR, Pfister R, Christie PE et al. Enhanced expression of cyclo-oxygenase isoenzyme 2 (COX-2) in asthmatic airways and its cellular distribution in aspirin-sensitive asthma. Thorax 1997; 52:940–5. 41. Kosnik M, Music E, Matjaz F, Suskovic S. Relative safety of meloxicam in NSAID-intolerant patients. Allergy 1998; 53:1231–3. 42. Committee on Safety of Medicines. In focus: rofecoxib (Vioxx). Curr. Probl. Pharmacovigilance 2000; 26:13. 43. Baybeck S, Celik G, Ediger D, Mungan D, Demiral YS, Misirligil Z. The use of nimesulide in patients with acetylsalicyclic acid and nonsteroidal anti-inflammatory drug intolerance. J. Asthma 1999; 36:657–63. 44. Bennett A. The importance of COX-2 inhibition for aspirin induced asthma. Thorax 2000; 55 (Suppl.2):S54–6. 45. Fischer TJ, Guilfoile TD, Kesarwala HH et al. Adverse pulmonary responses to aspirin and acetaminophen in chronic childhood asthma. Pediatrics 1983; 71:313–18. 46. Larsen K. The clinical relationship of nasal polyps to asthma. Allergy Asthma Proc. 1996; 17:243–9.
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47. Killen JWW, Wilson JA, Gibson GJ. Objective assessment of aspirin sensitivity in patients with nasal polyposis. Thorax 1998; 53(Suppl.4):A41. 48. Kalyoncu AF, Karacaya G, Sahin AA et al. Occurrence of allergic conditions in asthmatics with analgesic intolerance. Allergy 1999, 54:428–35. 49. Marquette CH, Saulnier F, Leroy O et al. Long-term prognosis of near-fatal asthma. Am. Rev. Respir. Dis. 1992; 146:76–81. 50. Nizankowska E, Bestynska-Krypel A, Cmiel A, Szczeklik A. Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma. Eur. Respir. J. 2000; 15:863–9. 51. Milewski M, Mastalerz L, Nizankowska E, Szczeklik A. Nasal provocation test with lysine-aspirin for diagnosis of aspirinsensitive asthma. J. Allergy Clin. Immunol. 1998, 101:581–6. 52. Christie PE, Smith CM, Lee TH. The potent and selective sulphidopeptide leukotriene antagonist, SK & F 104353, inhibits aspirin-induced asthma. Am. Rev. Respir. Dis. 1991; 144:957–8. 53. Yamamoto H, Nagata M, Kuramitsu K et al. Inhibition of analgesic-induced asthma by the leukotriene receptor antagonist ONO-1078. Am. J. Respir. Crit. Care Med. 1994; 150:254–7. 54. Dahlén B, Nizankowska E, Szczeklik A et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am. J. Respir. Crit. Care Med. 1998; 157:1187–94. 55. Settipane RA, Shrank PJ, Simon RA, Mathison DA, Christensen SC, Stevenson DD. Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatics. J. Allergy Clin. Immunol. 1995; 96:480–5. 56. Zeiss CR, Lockey RF. Refractory period to aspirin in a patient with aspirin-induced asthma. J. Allergy Clin. Immunol. 1976; 57:440–8. 57. Van Arsdel PP. Aspirin idiosyncracy and tolerance. J. Allergy Clin. Immunol. 1984; 73:431–4. 58. Pleskow WW, Stevenson DD, Mathison DA, Simon RA, Schatz M, Zeiger RS. Aspirin desensitisation in aspirin-sensitive asthmatic patients: Clinical manifestations and characterisation of the refractory period. J. Allergy Clin. Immunol. 1982; 69:11–19. 59. Partridge MR, Gibson GJ. Adverse bronchial reactions to intravenous hydrocortisone in two aspirin-sensitive asthmatic patients. Br. Med. J. 1978; i:1521–2. 60. Dajani BM, Sliman NA, Shubair KS, Hamzeh YS. Bronchospasm caused by intravenous hydrocortisone sodium succinate (SoluCortef) in aspirin-sensitive asthmatics. J. Allergy Clin. Immunol. 1981; 68:201–4. 61. Szczeklik A, Nizankowska E, Czerniawska-Mysik G, Sek S. Hydrocortisone and airflow impairment in aspirin-induced asthma. J. Allergy Clin. Immunol. 1985; 76:530–6. 62. Taniguchi M, Sato A, Hayakawa H et al. Aspirin-induced asthmatics show cross-sensitivity to steroid succinate esters. Am. Rev. Respir. Dis. 1991: 143(Suppl. 4):A30. 63. Albertson TE, Walby W, Derlet RW. Stimulant-induced pulmonary toxicity. Chest 1995; 108:1140–9. 64. Rebhun J. Association of asthma and freebase smoking. Ann.Allergy 1988; 60:339–42. 65. Rao AN, Polos PG, Walther FA. Crack abuse and asthma: A fatal combination. NY State J. Med. 1990; 90:511–12. 66. Rome LA, Lippmann ML, Dalsey WC, Taggart P, Pomerantz S. Prevalence of cocaine use and its impact on asthma exacerbation in an urban population. Chest 2000; 117:1324–9. 67. Osborn HH, Tang M, Bradley K, Duncan BR. New onset bronchospasm or recrudescence of asthma associated with cocaine abuse. Acad. Emerg. Med. 1997, 4:689–92. 68. Dowling G, McDonough E, Bost R. “Eve” and “Ecstacy” – A report of five deaths associated with the use of MDEA and MDMA. JAMA 1987; 257:1615–17.
Chapter
Diagnosis
43
M. Romagnoli, L. Richeldi and L.M. Fabbri University of Modena and Reggio Emilia, Modena, Italy
INTRODUCTION Asthma and COPD are two different inflammatory disorders sharing one common functional feature, i.e. airflow limitation.1–3 Airflow limitation in asthma is at least partly reversible, either spontaneously or with treatment,1,2 whereas in COPD airflow limitation is poorly reversible and is usually progressive.3–6 In the pathogenesis of both asthma and COPD, individual genetic susceptibility and environmental exposures are relevant for disease expression. Cigarette smoking is the major cause of COPD; the causes of asthma remain largely uncertain. The differential diagnosis between asthma and COPD is quite simple when considering the typical clinical and functional features of these two diseases. In this context, it is easy to recognize asthma in a young, atopic, nonsmoking subject with recurrent dyspnea, wheezing or chest tightness and variable reversible airflow limitation. It is also easy to diagnose COPD in a subject older than 40, with a history of cigarette smoking and presenting with dyspnea, chronic cough, sputum and fixed airflow limitation. The difficulty comes when trying to make a diagnosis of asthma and/or COPD in a middle-aged patient who smokes, and is atopic with a history of asthma, complaining of dyspnea but not chronic cough and sputum and presenting with poorly reversible airflow limitation. In these “borderline” patients, differential diagnosis might become important from a clinical and therapeutic point of view. Steroids are the first choice of medication in controlling asthma but not in COPD, and thus before prescribing long-term treatment with steroids to a single patient, particularly if old with an increased risk of osteoporosis, one would want to be certain about the diagnosis.
DEFINITION OF ASTHMA AND COPD Asthma is a syndrome characterized by recurrent respiratory symptoms, i.e. dyspnea, wheezing, chest tightness or cough associated with reversible airflow limitation.1,2 Other important features of asthma are an exaggerated responsiveness of the airways to various stimuli, and a rather specific
chronic inflammation of the airways characterized by an increased number of CD4, Th2 lymphocytes, and eosinophils in the airway mucosa, and by sub-epithelial fibrosis. Familiar predisposition, atopy, and exposure to allergen and sensitizing agents are important risk factors for asthma, even if the causes of asthma, meaning that the factors responsible for new cases of asthma instead of exacerbations of asthma, remain largely undetermined.1,2 COPD is characterized by poorly reversible airflow limitation, usually progressive, often associated with chronic respiratory symptoms such as dyspnea and/or chronic cough and sputum.3–6 Airflow limitation and respiratory symptoms are associated with chronic inflammation of the airways, remarkably different from asthmatic inflammation, and characterized by increased numbers of CD8, Th1/Tc1 lymphocytes in the airway mucosa and neutrophils in the lumen, without sub-epithelial fibrosis.7,8 Even if genetic and familiar predisposition as well as occupational exposure were to be considered, cigarette smoking is by far the most important risk factor for COPD.
MINIMUM REQUIREMENTS FOR THE DIAGNOSIS OF ASTHMA AND COPD The diagnosis of asthma and COPD is based on clinical history and lung function test, particularly peak expiratory flow (PEF) and spirometry with assessment of spontaneous or post-bronchodilator reversibility of airflow limitation. Symptoms and medical history of asthma and COPD Symptoms of asthma may be triggered or worsened by several factors such as exercise, exposure to allergens, viral infections, and emotions. A typical feature of asthma symptoms is their variability. The triad of wheezing, chest tightness, and shortness of breath is typical of asthma, and one or more of these symptoms are reported by more than 90% of patients.9 However, the simple presence of these symptoms is not diagnostic, as identical symptoms may be triggered in nonasthmatic subjects by acute viral infections, particularly in children. In some subjects wheezing and chest tightness are absent, and the only symptom the patient complains of is chronic unproductive cough.10
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Asthma clusters in families, and its genetic determinants appear to be linked to those of other allergic IgE-mediated diseases.11,12 Thus, a personal or family history of asthma and/or allergic rhinitis, atopic dermatitis, and eczema increases the likelihood of a diagnosis of asthma.The important aspects of a patient’s history include exposures to agents known to worsen asthma in the home (e.g. heating systems, cooking systems, house dust mites) or workplace, use of air conditioning, the presence of pets, cockroaches, and environmental tobacco smoke.13–17 The conditio sine qua non for the diagnosis of asthma is the presence of reversible airflow limitation and/or airway hyperresponsiveness in the absence of airflow limitation. Since respiratory symptoms of asthma are nonspecific, the differential diagnosis is quite extensive and the main goal for the physician is to consider and exclude other possible diagnoses (Table 43.1). This is even more important if the response to a therapy trial (i.e. bronchodilators) has been negative. The conditio sine qua non for the diagnosis of COPD is the presence of airflow limitation. As spirometry is rarely performed in asymptomatic patients, COPD goes largely undiagnosed. Having said that, most patients who are diagnosed with COPD seek medical attention because of dyspnea, particularly when caused by effort.18 Other symptoms present in the early stages of COPD are chronic cough and sputum production, which in smokers may even be present without airflow limitation. Cough and sputum may precede by many years the development of airflow limitation. Dyspnea usually appears later. Regular production of sputum for 3 or more months in 2 consecutive years is defined as chronic bronchitis.19 In some subjects chronic cough may be unproductive20–22 and airflow limitation may develop in the absence of cough. In COPD, dyspnea is characteristically persistent, differing
Table 43.1. Differential diagnosis of asthma
Localized diseases
Inhaled foreign body Endobronchial tumor Vocal cord dysfunction
Diffuse airway diseases
COPD Post-infectious airway hyperresponsiveness Cystic fibrosis Bronchiectasis Left ventricular failure
Other diseases
Gastroesophageal reflux Pulmonary embolism Pulmonary eosinophilia Drug-induced airway hyperresponsiveness
from asthma, and is progressive. During the first stages of the disease, dyspnea is only noted on effort, but as lung function decreases, it becomes more serious and is present during everyday activities or at rest. Dyspnea is not closely correlated with arterial blood gases, as the typical “blue bloater” with peripheral edema, hypoxemia, and hypercapnia generally has less dyspnea, in contrast to the “pink puffer,” who generally does not have these blood gas abnormalities, but is much more dyspneic. Wheezing and chest tightness are nonspecific symptoms of COPD, and may be variable between days and over the course of a single day. A detailed medical history of a patient with or suspected as having COPD might assess the exposure to risk factors (e.g. smoking and occupational or environmental exposures), family history of COPD or other chronic respiratory disease, pattern of symptom development, history of exacerbations, with or without hospitalizations, presence of comorbidities, medical treatment and quality of life. The differential diagnosis of COPD is presented in Table 43.2. Physical examination Physical examination is usually not very useful in establishing the diagnosis of asthma or COPD. Physical examination of patients with asthma or COPD may often be normal, especially during stable conditions. However, it may be useful to diagnose the presence and/or evaluate the severity of acute exacerbations (ronchi and wheezing, cyanosis, ankle edema). Lung function tests Spirometry In asthma and COPD, lung function tests play a crucial role in the diagnosis and follow-up of the diseases (Chapter 5). The standard test for assessing airflow limitation is spirometry. FEV1 (volume of air expired in the first second of a forced expiration from total lung capacity) is the beststandardized, most widely used test for airflow limitation. The standard reported values also include the exhaled slow (VC) or forced vital capacity (FVC). Airflow obstruction is indicated by reduced FEV1 and/or FEV1/VC or FEV1/FVC relative to predicted values. Spirometry is recommended at the time of diagnosis and for assessment of the severity of both asthma and COPD. It should be repeated in order to monitor the diseases and when there is a need for reassessment, e.g. during exacerbations.2
Table 43.2. Differential diagnosis of COPD
Other inflammatory airway diseases
Asthma Bronchiectasis Diffuse panbronchiolitis
Infectious airway diseases
Tuberculosis
Cardiac diseases
Congestive heart failure
Diagnosis
The presence of a post-bronchodilator FEV1 80% of the predicted value in combination with an FEV1/FVC ratio 70% of predicted implicates the presence of airflow limitation that is not fully reversible.3 Measurements of residual volume and total lung capacity are useful to determine the degree of hyperinflation and/or enlargement of airspaces due to emphysema. In asthma, the airflow limitation is usually spontaneously reversible or reversible after treatment, except for more severe asthma with fixed airway obstruction.1,2 In COPD, airflow limitation is not reversible, even if up to one-third of COPD patients shows a significant increase in FEV1 (15%) after inhaled b-adrenergic agonists,23 FEV1/FVC ratio remains 70% of predicted. Peak expiratory flow An important tool for the diagnosis and subsequent treatment of asthma is the use of the peak expiratory flow meter to measure peak expiratory flow (PEF). PEF is the highest flow obtained during a forced expiration starting immediately after a deep inspiration from total lung capacity. PEF is a simple, reproducible index and can be measured with inexpensive and portable peak flow meters. If spirometry does not reveal airflow limitation, home monitoring of PEF for 2–4 weeks may help to detect an increased variability of airway caliber, and thus to diagnose asthma. For most asthmatic patients, PEF correlates well with FEV1. Daily monitoring of PEF (at least in the morning at awakening and in the evening hours, preferably after bronchodilator use)1,2 is also useful to assess the severity of asthma and its response to treatment, and it can help patients in detecting early signs of asthma deterioration – i.e. of an exacerbation.24 However, PEF measurements have some limitations. PEF is effort dependent and mainly reflects the caliber of large airways and may, therefore, underestimate the degree of airflow limitation present in peripheral airways.25 Diurnal variability is calculated as follows: PEFmax PEFmin 100 PEFmax PEFmin /2 A diurnal variability of PEF of more than 20% is diagnostic of asthma, the magnitude of the variability being broadly proportional to severity of the disease. PEF monitoring may be of use not only in establishing a diagnosis of asthma and assessing its severity but also in uncovering an occupational cause for asthma. When used in this way, PEF should be measured more frequently than twice daily and special attention paid to changes occurring inside and outside the workplace.26 Even if PEF is at least as important in prognosis of moderate to severe COPD as FEV1,27 PEF and PEF monitoring are infrequently used in COPD for two reasons. PEF reflects the patency of central airways, and airflow limitation in COPD starts from peripheral airways. Thus, PEF may underestimate the airflow limitation, particularly if it occurs in peripheral airways. Second, by definition, airflow limita-
449
tion is poorly reversible in COPD, and thus monitoring of PEF is not necessary as usually it does not vary significantly. Reversibility to bronchodilators The demonstration of a reversibility of airflow limitation following bronchodilator therapy is an accepted criterion in support of the diagnosis of asthma.1,2 A return to normal expiratory flows after any treatment is diagnostic of asthma. However, subjects with moderate to severe asthma may develop a poorly reversible airflow limitation, with a response to treatment, but not a return to normal values. Similarly, COPD patients may show significant responses to treatment, even without a return to normal expiratory flows. In subjects with airflow limitation, an improvement in FEV1 of more than 12–15% predicted and more than 200 mL after using a bronchodilator (e.g. 200 lg inhaled salbutamol from a metered dose inhaler) is generally considered a hallmark of asthma.2,28 However, an incomplete response to a single bronchodilator administration does not exclude reversibility to longer treatment, and reversibility to steroids.29,30 Thus, particular attention should be paid to the response to long-term treatment. The bronchodilator reversibility testing should generally be performed at least once in COPD patients. In fact, airflow limitation in COPD is usually not reversible, even if up to one-third of COPD patients show a significant response to bronchodilator agents along with the irreversible airflow limitation (e.g. increase in FEV1 15%).23,31 These patients are the ones most likely to benefit from corticosteroids.32 The absence of a response to a bronchodilator should never be a reason to withhold bronchodilator drug therapy, as the response to bronchodilators in COPD is mainly symptomatic rather than functional.33–36 The reversibility test is also useful in assessing the best lung function of an individual subject, a value extremely useful in adjusting therapy to achieve and maintain lung function at the best possible values which is one of the objectives of asthma and COPD management.
ADDITIONAL TESTS Reversibility to steroids In patients with airflow limitation not relieved by a single dose of a short-acting bronchodilator, the improvement after 2 weeks of treatment with oral or inhaled corticosteroids and bronchodilators should be evaluated. Corticosteroids may be administered orally (e.g. 40 mg daily prednisone), by aerosol (e.g. 2 mg daily beclomethasone, or equivalent) or both,37–39 for at least 14 days.40 Owing to their efficacy and infrequent adverse events, inhaled corticosteroids are increasingly used as first-choice therapy to investigate the reversibility of airflow limitation.32,41,42 In most cases the reversibility to corticosteroids is usually very helpful in distinguishing asthma frofm COPD, even if significant overlap exists.43 In fact, asthma is usually responsive to corticosteroids, whereas COPD usually is not or less
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Asthma and Chronic Obstructive Pulmonary Disease
so. In asthma, a combination of sputum eosinophilia and increased nitric oxide (NO) levels may be useful in predicting the response to a trial of oral steroids.44 Sputum eosinophilia predicts the response to steroids also in COPD.45 However, some COPD patients may show a functional significant improvement after corticosteroid treatment,46 particularly if they present with pathological abnormalities similar to asthma. The simplest and potentially safest way of identifying these COPD patients is a treatment trial with inhaled corticosteroids for 6 weeks to 3 months using the same criteria for reversibility as in the bronchodilator trial (FEV1 increase of 200 mL and 12%).39 The response to corticosteroids should be evaluated with respect to the postbronchodilator FEV1.3 The COPD patients who respond to corticosteroids present some pathological features of asthma, such as a significantly larger number of eosinophils and higher levels of ECP in their BALF, and a thicker reticular basement membrane.46,47 Some recent long-term studies on the effects of inhaled corticosteroid therapy in COPD have demonstrated the absence of any effect on the natural history of COPD, as evaluated by the FEV1.48–52 Therefore, given some documented risks of chronic corticosteroid therapy both in asthma53 and in COPD such as osteoporosis,48,54 the decision to start long-term treatment with steroids is critical. In patients with poorly reversible airflow limitation due to asthma the beneficial effects of steroids are likely to overcome the risks of systemic effects,32 whereas in patients with poorly reversible airflow limitation due to smoking this may not be the case. Diffusion capacity Measurement of the diffusing capacity of the lung for carbon monoxide (DLCO) has been recommended for distinguishing asthma from COPD. In asthma the diffusing capacity for carbon monoxide (DLCO) is usually normal or increased.55 By contrast, the DLCO is usually reduced in COPD, possibly due to emphysema,56 but it may also be reduced in smokers without airflow limitation.57 The DLCO is lower in COPD patients than in asthmatics with incomplete reversible airflow limitation.47,58 However, patients with severe alpha(1)-antitrypsin deficiency may present with normal DLCO, despite having a significant component of fixed airway obstruction and prominent panacinar emphysema on high-resolution CT scan (HRCT), suggesting the limitations of DLCO in this setting.59 Airway hyperresponsiveness In patients with symptoms consistent with asthma, but normal lung function, measurements of methacholine or histamine airway hyperresponsiveness support the diagnosis of asthma.60 These measurements are sensitive for a diagnosis of asthma, but have low specificity. This means that a negative test can be useful to exclude a diagnosis of current persistant asthma, but a positive test does not always mean that a patient has asthma. In fact, airway hyperresponsiveness has been described in patients with allergic
rhinitis61,62 and with other diseases with airflow limitation such as cystic fibrosis63 and COPD.64 Thus, COPD is often accompanied by airway hyperresponsiveness, especially in current smokers,65,66 that is no different from asthmatics with a similar degree of airflow limitation.47 In conclusion, the measurement of airway hyperresponsiveness is not useful in the differential diagnosis between asthma and COPD, particularly when they are associated with a similar degree of poorly reversible airflow limitation. Allergy tests The presence of allergic disorders in family history should be investigated, especially when asthma is suspected. A history provides important information about lifestyle and occupation (both influencing exposure to allergens), the time and the factors possibly involved in onset and in exacerbations of asthma. In asthmatics, the relationship between exposure to one or more allergens and the occurrence of asthma and/or ocular and nasal symptoms should be established. Also, the relationship with the months of the year (seasonal pollen asthma) and with the presence of pets should be assessed, together with a description of the patient’s home including special attention to carpets, pillows, and other dust collectors. The identification of the presence of an allergic component in asthma adds little to the diagnosis of asthma, but it can help in identifying the risk factors for prevention or immunotherapy.1 Skin tests with all relevant allergens present in the patient’s area represent the first choice of test in the diagnosis of allergy. Deliberate provocation of the airways with a suspected allergen or sensitizing agent may also be helpful in establishing causality, especially in the occupational setting.26 The cost–benefit ratio of performing inhalation tests with allergens or other sensitizing agents should be carefully examined in each patient, taking into account the high cost and the potential risks involved.28 The assessment of atopy is less useful in COPD. In fact, even if atopy is a risk factor in both asthma and COPD,67,68 the demonstration of atopy in COPD patients does not help in the diagnosis or in the identification of potential triggers. Imaging In asthma, a routine chest radiograph may show hyperinflation of the lungs and bronchial wall thickening,69 but it is almost invariably normal70 (Chapter 45). COPD cannot be diagnosed by chest radiograph, but several radiographic signs can suggest the diagnosis, in particular in the presence of emphysema.71 Among radiographic signs, over-inflation, bronchial wall thickness and the presence of prominent lung markings are typical of chronic bronchitis/COPD. The coexistence of over-inflation (usually represented by flattening of the diaphragm with a concavity of its superior surface), oligoemia, and bullae is often associated with emphysema, while a pattern of increased markings is characteristic of chronic bronchitis. High-resolution computerized tomography scan (HRCT scan) may also help in distinguishing asthma from COPD,
451
Diagnosis
as HRCT is more sensitive than radiographs in showing emphysema, large airways abnormalities such as bronchiectasis, and small airways abnormalities such as bronchiolectasis and the tree-in-bud appearance72,73 (Table 43.3). However, recent data have highlighted the fact that at least some patients with chronic stable asthma may develop a reduction in CT lung density similar to that in patients with chronic bronchitis and emphysema, and that there is an approximate correlation between severity of asthma and the degree of this particular abnormality.72 Thus, in some cases, even HRCT scan by itself may not distinguish asthma from COPD. Assessment of airway inflammation Bronchopulmonary inflammation is markedly different in asthma and COPD.8,74–77 While airway biopsies and bronchoalveolar lavage may provide useful information in research protocol, they are considered too invasive for the diagnosis or staging of both asthma and COPD.78 By contrast, noninvasive markers of airway inflammation have been increasingly used, first in research protocols and then in clinical practice to differentiate asthma from COPD (Chapter 44). Sputum Sputum induction has been widely performed for studying airway inflammation in asthma and COPD because it is a safe, reproducible and noninvasive technique that can be used on repeated occasions, even during exacerbations.79,80 Sputum findings mainly represent the bronchial compartment. Induced sputum from asthmatic patients during stable conditions is usually characterized by a higher percentage of eosinophils and metachromatic cells than samples from healthy subjects.81,82 Sputum neutrophilia may be present in severe asthmatics.83,84 In patients with chronic bronchitis, with no airflow limitation, macrophages are the dominant cell type in sputum, with few eosinophils or metachromatic cells.85 It has been widely demonstrated that in stable conditions previous or current smokers with COPD characteristically present an increased total cell number in spontaneous or induced sputum, with a predominant percentage of neutrophils and, to a lesser extent, of eosinophils.86,87 In some smokers with chronic bronchitis, with or without chronic airflow limitation, an excess proportion of eosinophils (3%) in lower respiratory sputum secretions
known as “eosinophilic bronchitis”, can also occur, the reason for this still being controversial.45,80 Sputum analysis of asthmatic and COPD exacerbated patients has provided novel and interesting information. Mild exacerbations of asthma induced by tapering the dose of inhaled steroids are associated with sputum eosinophilia.88,89 By contrast, mild spontaneous asthma exacerbations are associated with eosinophilia in about half of subjects, the other half presenting with an absence of sputum eosinophilia.90 In contrast to mild exacerbations, severe asthma exacerbations are associated with more prominent sputum neutrophilia.91 Bronchial neutrophilia has also been observed in bronchial lavage of asthmatics during status asthmaticus.92 Interestingly, exacerbations of chronic bronchitis/COPD are associated with similar cell count changes in sputum. In fact, mild exacerbations of chronic bronchitis/COPD are associated with eosinophilia in sputum and in biopsies,93 and severe COPD exacerbations are associated with sputum neutrophilia.94 Thus, at least in sputum, the changes in inflammatory cells during exacerbations are no different between asthma and COPD. Once more, this evidence underlines the existing similarities between the two entities and the difficulties in differential diagnosis in the few cases where clinical findings are not helpful. Several biochemical markers have been studied in the induced sputum of both asthma and COPD patients95–99 (Table 43.4). Although some markers are markedly different between asthma and COPD and their study may provide useful information in research protocols, their use in clinical practice has not been shown to be superior to simple cell counts. Exhaled nitric oxide Endogenous nitric oxide (NO) may be involved in the pathophysiology of asthma and COPD100 (Chapter 32). Exhaled NO is increased in atopic asthma,101–104 less so in nonatopic asthma,105,106 and it is reduced by corticosteroids107 but not by bronchodilators.108 Conflicting results have been obtained in COPD.109–114 In patients with stable COPD, a partial bronchodilator response to inhaled salbutamol is associated with increased exhaled NO (Fig. 43.1) and sputum eosinophilia.115 Taken together with previous studies,46 this study suggests that there is a subset of patients with COPD that share some characteristics of asthmatic inflammation, and who may be responsive to steroids.45
Table 43.3. High-resolution computerized tomography scanning in patients with asthma and COPD72,73
Bronchial wall thickening Emphysema Bronchiectasis
Mild-to-persistent asthma
Severe asthma
COPD
Healthy
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Asthma and Chronic Obstructive Pulmonary Disease
DIFFERENTIAL DIAGNOSIS BETWEEN ASTHMA AND COPD In most subjects the clinical presentation of the patient, and particularly their history, provides the strongest diagnostic criteria to distinguish asthma from COPD (Table 43.5). Pulmonary function tests, and particularly spirometry, showing an almost complete reversibility of airflow limitation in asthma and poorly reversible airflow limitation in COPD allow confirmation of the diagnosis (Table 43.5). Differential diagnosis between asthma and COPD becomes more difficult in elderly subjects when some features overlap (either smoking or atopy), and more importantly, when the patient develops a poorly reversible airflow limitation that responds only partially to treatment. In these
cases, symptoms, lung function, airway responsiveness, imaging, and even pathology may overlap, and thus may not provide solid information for differential diagnosis. As the differential diagnosis aims mainly at providing better treatment, it is important in these cases to undertake an individual approach and to perform additional tests. Reversibility to steroids, measurements of lung volume and diffusion capacity, analysis of sputum and exhaled NO, and imaging of the chest may demonstrate whether asthma or COPD is the prevalent cause of airflow limitation (Table 43.6). By
50
Table 43.4. Biochemical markers in induced sputum of stable asthma and COPD patients95–99
Eosinophil cationic protein Myeloperoxidase Human neutrophil lipocalin Interleukin-8 Tumor necrosis factor-a Leukotriene B4
Asthma
COPD
Exhaled NO (ppb)
40 30
**
20 10 0 Control
COPD-REV
COPD-nonREV
Fig. 43.1. Exhaled NO levels in COPD patients with and without a response to bronchodilators. Reproduced with permisison from Reference 15.
Table 43.5. History, symptoms and pulmonary function tests in differential diagnosis between asthma and COPD
Onset Smoking Cough and sputum Dyspnea on effort Nocturnal symptoms Airflow limitation Response to bronchodilator Airway hyperresponsiveness
Asthma
COPD
At any time in life Usually non smokers Less common Variable Relatively common Increased diurnal variability Good In most patients, with or without airflow limitation
In mid- to late-adult life Almost invariably smokers Common (in “bronchitic” type) Predictable and progressive over months/years Uncommon Normal diurnal variability Only in 15–25% of patients In most patients
Table 43.6. Ancillary tests in the differential diagnosis between asthma and COPD
Ancillary test
Asthma
COPD
Reversibility to steroids Lung volumes Diffusion capacity Airway hyperresponsiveness Allergy tests Imaging of the chest Sputum Exhaled NO
Usually present Usually normal Usually normal Usually increased Usually positive Usually normal Eosinophilia Usually increased
Usually absent Usually increased Decreased Usually increased Usually negative Usually abnormal Neutrophilia Usually normal
Diagnosis
contrast, reversibility to bronchodilator and assessment of airway hyperresponsiveness or skin testing may not be useful in these patients.
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39. Weir DC, Burge PS. Effects of high dose inhaled beclomethasone dipropionate, 750 micrograms and 1500 micrograms twice daily, and 40 mg per day oral prednisolone on lung function, symptoms, and bronchial hyperresponsiveness in patients with non-asthmatic chronic airflow obstruction. Thorax 1993; 48:309–16. 40. Weir DC, Robertson AS, Gove RI, Burge PS. Time course of response to oral and inhaled corticosteroids in non-asthmatic chronic airflow obstruction. Thorax 1990; 45:118–21. 41. van Grunsven PM, van Schayck CP, Derenne JP et al. Long term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis (see comments). Thorax 1999; 54:7–14. 42. Pauwels RA, Lofdahl CG, Postma DS et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group (see comments) (published erratum appears in N Engl. J. Med. 1998; 338:139). N. Engl. J. Med. 1997; 337:1405–11. 43. Kesten S, Rebuck AS. Is the short-term response to inhaled betaadrenergic agonist sensitive or specific for distinguishing between asthma and COPD? Chest 1994; 105:1042–5. 44. Little SA, Chalmers GW, MacLeod KJ, McSharry C, Thomson NC. Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma. Thorax 2000; 55:232–4. 45. Brightling CE, Monteiro W, Ward R et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2000; 356:1480–5. 46. Chanez P, Vignola AM, O’Shaugnessy T et al. Corticosteroid reversibility in COPD is related to features of asthma. Am. J. Respir. Crit. Care Med. 1997; 155:1529–34. 47. Papi ARM, Romagnol ML, Bellettato CM et al. Pulmonary function and pathology in asthma and chronic obstructive pulmonary disease (COPD) with similar degree of irreversible airflow limitation. Eur. Respir. J. 2000; 16 (Suppl. 31):551s. 48. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343:1902–9. 49. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Longterm effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999; 353:1819–23. 50. Pauwels RA, Lofdahl CG, Laitinen LA et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N. Engl. J. Med. 1999; 340:1948–53. 51. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br. Med. J. 2000; 320:1297–303. 52. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimiou J. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group. Lancet 1998; 351:773–80. 53. Wong CA, Walsh LJ, Smith CJ et al. Inhaled corticosteroid use and bone-mineral density in patients with asthma. Lancet 2000; 355:1399–403. 54. Mapp CE. Inhaled glucocorticoids in chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343:1960–1. 55. Collard P, Njinou B, Nejadnik B, Keyeux A, Frans A. Single breath diffusing capacity for carbon monoxide in stable asthma. Chest 1994; 105:1426–9. 56. Clausen JL. The diagnosis of emphysema, chronic bronchitis, and asthma. Clin. Chest Med. 91990; 11:405–16.
57. Sansores RH, Pare P, Abboud RT. Effect of smoking cessation on pulmonary carbon monoxide diffusing capacity and capillary blood volume. Am. Rev. Respir. Dis. 1992; 146:959–64. 58. Boulet LP, Turcotte H, Hudon C, Carrier G, Maltais F. Clinical, physiological and radiological features of asthma with incomplete reversibility of airflow obstruction compared with those of COPD. Can. Respir. J. 1998; 5:270–7. 59. Wilson JS, Galvin JR. Normal diffusing capacity in patients with PiZ alpha(1)-antitrypsin deficiency, severe airflow obstruction, and significant radiographic emphysema. Chest 2000; 118:867–71. 60. Cockcroft DW, Hargreave FE. Airway hyperresponsiveness. Relevance of random population dataa to clinical usefulness. Am. Rev. Respir. Dis. 1990; 142:497–500. 61. World Health Organization Initiative. Allergic Rhinitis and its Impact on Asthma (ARIA). Geneva: WHO, 2000. 62. Ramsdale EH, Morris MM, Roberts RS, Hargreave FE. Asymptomatic bronchial hyperresponsiveness in rhinitis. J. Allergy Clin. Immunol. 1985; 75:573–7. 63. van Haren EH, Lammers JW, Festen J, van Herwaarden CL. Bronchial vagal tone and responsiveness to histamine, exercise and bronchodilators in adult patients with cystic fibrosis. Eur. Respir. J. 1992; 5:1083–8. 64. Rutgers SR, Timens W, Tzanakis N et al. Airway inflammation and hyperresponsiveness to adenosine 5-monophosphate in chronic obstructive pulmonary disease. Clin. Exp. Allergy 2000; 30:657–62. 65. Tashkin DP, Altose MD, Bleecker ER et al. The lung health study: airway responsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation. The Lung Health Study Research Group. Am. Rev. Respir. Dis. 1992; 145:301–10. 66. Kanner RE, Connett JE, Altose MD et al. Gender difference in airway hyperresponsiveness in smokers with mild COPD. The Lung Health Study. Am. J. Respir. Crit. Care Med. 1994; 150:956–61. 67. Pearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax 1999; 54:268–72. 68. Weiss ST. Atopy as a risk factor for chronic obstructive pulmonary disease: epidemiological evidence. Am. J. Respir. Crit. Care Med. 2000; 162:S134–6. 69. Lynch DA. Imaging of asthma and allergic bronchopulmonary mycosis. Radiol. Clin. North Am. 1998; 36:129–42. 70. O’Connor GT, Weiss ST. Clinical and symptom measures. Am. J. Respir. Crit. Care Med. 1994; 149:S21–8; discussion S29–30. 71. Sanders C. The radiographic diagnosis of emphysema. Radiol. Clin. North Am. 1991; 29:1019–30. 72. McLean AN, Sproule MW, Cowan MD, Thomson NC. High resolution computed tomography in asthma. Thorax 1998; 53:308–14. 73. Webb WR. Radiology of obstructive pulmonary disease. Am. J. Roentgenol. 1997; 169:637–47. 74. Saetta M. Airway pathology of COPD compared with asthma. Eur. Respir. Rev. 1997; 7:29–33. 75. Saetta M. Airway inflammation in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:S17–20. 76. Saetta MTW, Jeffrey P. Pathology. In: Postma DS, Siafakas NM (Eds), Management of Chronic Obstructive Pulmonary Disease, pp. 92–101. Sheffield: European Respiratory Society, 1998. 77. Fabbri L, Beghe B, Caramori G, Papi A, Saetta M. Similarities and discrepancies between exacerbations of asthma and chronic obstructive pulmonary disease. Thorax 1998; 53:803–8. 78. Fabbri LM, Durham S, Holgate ST, O’Byrne PM, Postma DS. Assessment of airway inflammation: an overview. Eur. Respir. J. Suppl. 1998; 26:65–85. 79. Pizzichini MM, Pizzichine E, Clelland L et al. Sputum in severe exacerbations of asthma: kinetics of inflammatory indices after prednisone treatement. Am. J. Respir. Crit. Care Med. 1997; 155:1501–8.
Diagnosis
80. Hargreave FE, Leigh R. Induced sputum, eosinophilic bronchitis, and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:S53–7. 81. Pin I, Gibson PG, Kolendowicz R et al. Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax 1992; 47:25–9. 82. Kips JC, Peleman RA, Pauwels RA. Methods for sputum induction and analysis of induced sputum: a method for assessing airway inflammation in asthma. Eur. Respir. J. 1998; 11 (Suppl. 26):9S–12S. 83. Louis R, Lau LC, Bron AO, Roldaan AC, Radermecker M, Djukanovic R. The relationship between airways inflammation and asthma severity. Am. J. Respir. Crit. Care Med. 2000; 161:9–16. 84. Kips JC. Cellular composition of induced sputum and peripheral blood in severe persistent asthma. Eur. Respir. J. 1999; 14 (Suppl. 30):333s. 85. Gibson PG, Girgis-Gabardo A, Morris MM et al. Cellular characteristics of sputum from patients with asthma and chronic bronchitis. Thorax 1989; 44:693–9. 86. Rutgers SR, Postma DS, ten Hacken NH et al. Ongoing airway inflammation in patients with COPD who do not currently smoke. Thorax 2000; 55:12–18. 87. Pizzichini E, Pizzichini MM, Gibson P et al. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am. J. Respir. Crit. Care Med. 1998; 158:1511–17. 88. Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am. J. Respir. Crit. Care Med. 2000; 161:64–72. 89. in’t Veen JC, Smits HH, Hiemstra PS, Zwinderman AE, Sterk PJ, Bel EH. Lung function and sputum characteristics of patients with severe asthma during an induced exacerbation by doubleblind steroid withdrawal. Am. J. Respir. Crit. Care Med. 1999; 160:93–9. 90. Turner MO, Hussack P, Sears MR, Dolovich J, Hargreave FE. Exacerbations of asthma without sputum eosinophila. Thorax 1995; 50:1057–61. 91. Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J. Allergy Clin. Immunol. 1995; 95:843–52. 92. Lamblin C, Gosset P, Tillie-Leblond I et al. Bronchial neutrophilia in patients with noninfectious status asthmaticus. Am. J. Respir. Crit. Care Med. 1998; 157:394–402. 93. Saetta M, Di Stefano A, Maestrelli P et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am. J. Respir. Crit. Care Med. 1994; 150:1646–52. 94. Piattella M, Maestrelli P, Saetta M et al. Sputum eosinophilia during mild exacerbations and sputum neutrophilia during severe exacerbations of COPD. Am. J. Respir. Crit. Care Med. 1996; 153 (Suppl.):A822. 95. Hill AT, Bayley D, Stockley RA. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am. J. Respir. Crit. Care Med. 1999; 160:893–8. 96. Keatings VM, Barnes PJ. Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am. J. Respir. Crit. Care Med. 1997; 155:449–53. 97. Keatings VM. Comparison of inflammatory cytokines in chronic obstructive pulmonary disease, asthma and controls. Eur. Respir. Rev. 1994; 7:146–50.
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98. Pizzichini E, Pizzichini MM, Efthimiadis A et al. Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am. J. Respir. Crit. Care Med. 1996; 154:308–17. 99. O’Driscoll BR, Cromwell O, Kay AB. Sputum leukotrienes in obstructive airways diseases. Clin. Exp. Immunol. 1984; 55:397–404. 100. Barnes PJ. Nitric oxide and airway disease. Ann. Med. 1995; 27:389–93. 101. Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur. Respir. J. 1993; 6:1368–70. 102. Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343:133–5. 103. Persson MG, Zetterstrom O, Agrenius V, Ihre E, Gustafsson LE. Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 1994; 343:146–7. 104. Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM. Expired nitric oxide levels during treatment of acute asthma. Am. J. Respir. Crit. Care Med. 1995; 152:800–3. 105. Henriksen AH, Lingaas-Holmen T, Sue-Chu M, Bjermer L. Combined use of exhaled nitric oxide and airway hyperresponsiveness in characterizing asthma in a large population survey. Eur. Respir. J. 2000; 15:849–55. 106. Gratziou C, Lignos M, Dassiou M, Roussos C. Influence of atopy on exhaled nitric oxide in patients with stable asthma and rhinitis. Eur. Respir. J. 1999; 14:897–901. 107. van Rensen EL, Straathof KC, Veselic-Charvat MA, Zwinderman AH, Bel EH, Sterk PJ. Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Thorax 1999; 54:403–8. 108. Yates DH, Kharitonov SA, Barnes PJ. Effect of short- and longacting inhaled beta2-agonists on exhaled nitric oxide in asthmatic patients. Eur. Respir. J. 1997; 10:1483–8. 109. Maziak W, Loukides S, Culpitt S, Sullivan P, Kharitonov SA, Barnes PJ. Exhaled nitric oxide in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 157:998–1002. 110. Corradi M, Majori M, Cacciani GC, Consigli GF, de’Munari E, Pesci A. Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease. Thorax 1999; 54:572–5. 111. Robbins RA, Floreani AA, Von Essen SG et al. Measurement of exhaled nitric oxide by three different techniques. Am. J. Respir. Crit. Care Med. 1996; 153:1631–5. 112. Rutgers SR, Meijer RJ, Kerstjens HA, van der Mark TW, Koeter GH, Postma DS. Nitric oxide measured with single-breath and tidal-breathing methods in asthma and COPD. Eur. Respir. J. 1998; 12:816–19. 113. Rutgers SR, van der Mark TW, Coers W et al. Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease. Thorax 1999; 54:576–80. 114. Kanazawa H, Shoji S, Yoshikawa T, Hirata K, Yoshikawa J. Increased production of endogenous nitric oside in patients with bronchial asthma and chronic obstructive pulmonary disease. Clin. Exp. Allergy 1998; 28:1244–50. 115. Papi A, Romagnoli M, Baraldo S et al. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 162:1773–7.
Noninvasive Assessment of Airway Inflammation
Chapter
44
Sergei A. Kharitonov National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
The need to monitor inflammation in the lungs has led to the exploration of exhaled gases and condensates. Noninvasive monitoring may assist in differential diagnosis of pulmonary diseases, assessment of disease severity and response to treatment including patients with severe disease and children. Breath analysis is currently a research procedure, but there is increasing evidence that it may have an important place in the diagnosis and management of lung diseases in the future. This will drive the development of cheaper and more convenient analyzers, which can be used in a hospital and later in a family practice setting, then eventually to the development of personal monitoring devices for use by patients.
a surrogate marker of inflammation, but interpretation is confounded by the use of bronchodilator therapy. Furthermore, it is difficult to perform this measurement in children and in patients with severe disease. • Induced sputum technique is relatively reproducible and allows the quantification of inflammatory cells and mediators. However, this technique is somewhat invasive as it involves inhalation of hypertonic saline, that may induce coughing and bronchoconstriction, and it is difficult to use in small children. Furthermore, the technique itself induces an inflammatory response so that it is not possible to repeat measurements in less than 24 hours.1
THE NEED FOR NEW MARKERS
E X H A L E D B R E AT H C O N D E N S AT E
This chapter discusses the use of exhaled breath analysis in the diagnosis and monitoring of asthma and COPD. Although most studies have focused on exhaled nitric oxide (NO) (Chapter 32), several endogenous substances (inflammatory mediators, cytokines, oxidants) have been detected in expired breath condensates, opening up new perspectives for exhaled breath analysis. In addition, various other volatile gases (carbon monoxide, ethane, pentane) have also been used. Asthma and COPD involve chronic inflammation and oxidative stress.Yet there are several problems with existing measurements.
Exhaled breath condensate is collected by cooling or freezing exhaled air and uses a totally noninvasive collection technique. The collection procedure has no influence on airway function or inflammation, and there is accumulating evidence that abnormalities in condensate composition may reflect biochemical changes of airway lining fluid. Several nonvolatile chemicals, including proteins, have now been detected in breath condensates. The first studies identifying surfaceactive properties, including pulmonary surfactant, of exhaled condensate were published in the USSR in the 1980s2,3 and since then several inflammatory mediators, oxidants and ions have been identified in exhaled breath condensates.
• In asthma fiberoptic bronchial biopsies have become the “gold standard” for measuring inflammation in the airway wall, but this is an invasive procedure that is not suitable for routine clinical practice and cannot be repeated often. It is also unsuitable for use in children and patients with severe disease. • Symptoms may not accurately reflect the extent of underlying inflammation due to differences in perception and masking by bronchodilators in airway disease. • In asthma, measurement of airway hyperresponsiveness by histamine or methacholine challenge has been used as
Origin Potentially, condensate measurements reflect different markers and molecules derived from the mouth (oral cavity and oropharynx), tracheobronchial system and alveoli, and their proportional contribution has not yet been sufficiently studied. It is assumed that airway surface liquid becomes aerosolized during turbulent airflow, so that the content of the condensate reflects the composition of airway surface liquid, although large molecules may not aerosolize as well as small soluble molecules.
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Asthma and Chronic Obstructive Pulmonary Disease
Factors affecting measurements Several methods of condensate collection have been described. The most common approach is to ask the subject to breathe tidally via a mouthpiece through a nonrebreathing valve in which inspiratory and expiratory air is separated (Fig. 44.1). During expiration the exhaled air flows through a condenser, which is cooled to 0C by melting ice, or to 20C by a refrigerated circuit, and breath condensate is then collected into a cooled collection vessel. A low temperature may be important for preserving labile markers as lipid mediators during the collection period, which usually takes between 10 and 15 minutes to obtain 1–3 mL of condensate. Exhaled condensate can be stored at 70C and is subsequently analyzed by gas chromatography and/or extraction spectrophotometry, or by immunoassays (ELISA). Potentially, salivary contamination may influence the levels of thromboxane B2, LTB-4, PGF2a, but low levels of PGE2 and prostacyclin have been found in saliva of children with acute asthma.4 It is therefore important to minimize and monitor salivary contamination. Subjects should rinse their mouth before collection and keep the mouth dry by periodically swallowing their saliva. Hydrogen peroxide Activation of inflammatory cells, including neutrophils, macrophages, and eosinophils, results in an increased production of O2 which by undergoing spontaneous or enzyme-catalyzed dismutation leads to formation of hydrogen peroxide (H2O2). As H2O2 is less reactive than other reactive oxygen species, it has the propensity to cross biological membranes and enter other compartments. Because it is volatile, increased H2O2 in the airway equilibrates with air. Compared with the cellular antioxidant scavenging systems, the extracellular space and airways have significantly less ability to scavenge reactive oxygen species. Thus exhaled H2O2 may be a good marker of oxidative stress in the lungs.
Asthma H2O2 has been detected in exhaled condensate in healthy adults and children with increased concentrations in asthma.5,6 It is related to the number of sputum eosinophils and airway hyperresponsiveness, is elevated in severe unstable asthmatics, and is reduced by corticosteroids. COPD Cigarette smoking causes an influx of neutrophils and other inflammatory cells into the lower airways and five-fold higher levels of H2O2 have been found in exhaled breath condensate of smokers than in nonsmokers.7 Levels of exhaled H2O2 are increased compared with normal subjects in patients with stable COPD and are further increased during exacerbations.5 However, no significant differences have been found between H2O2 levels in current smokers with COPD and COPD subjects who have never smoked, indicating that oxidative stress cannot be explained entirely by the oxidants present in tobacco smoke. Eicosanoids Eicosanoids are potent mediators of inflammation responsible for vasodilatation/vasoconstriction, plasma exudation, mucus secretion, bronchoconstriction/bronchodilatation, cough and inflammatory cell recruitment. Noninvasive exhaled condensate analysis may be a better predictor of clinical efficacy of leukotriene antagonists, or thromboxane inhibitors in lung disease than urine, serum, or invasive BAL. Prostanoids There is an increased expression of COX-2, which forms prostaglandins and thromboxane in asthma and COPD.8 Most prostaglandins and thromboxane have proinflammatory properties, but others, for example PGE2 and PGI2, are anti-inflammatory. For example, PGE2 inhibits induction of NOS2 in cell lines and when inhaled reduces exhaled NO in asthma.9 Exhaled prostanoids are detectable
Tidal breathing
Sampling chamber (20 C)
Room air
2–4 ml condensate/5–10 min Fig. 44.1. Exhaled breath condensate: diagram of the apparatus.
Noninvasive Assessment of Airway Inflammation
in exhaled breath condensate. PGE2 and PGF2a are markedly increased in patients with COPD, whereas these prostaglandins are not significantly elevated in asthma. Leukotrienes Leukotrienes (LTs) are potent constrictor and proinflammatory mediators that contribute to the pathophysiology of asthma. The cysteinyl-leukotrienes (cys-LTs) LTC4, LTD4 and LTE4 are generated predominantly by mast cells and eosinophils. By contrast, LTB4 has potent chemotactic activity towards neutrophils.10 In mild asthmatic patients, levels of LTE4, LTC4, and LTD4 in exhaled condensate are increased during the late asthmatic response to allergen challenge, and steroid withdrawal in moderate asthma leads to worsening of asthma and is associated with a significant increase in the concentration of LTB4, LTE4, LTC4, and LTD4 in exhaled condensate.11 We have demonstrated that exhaled leukotriene levels are increased in patients with more severe asthma12 (Fig. 44.2). Isoprostanes Isoprostanes are a novel class of prostanoids formed by free radical-catalyzed lipid peroxidation of arachidonic acid. They are stable compounds, detectable in all normal
Exhaled LTC4/D4/E4 (pg/ml)
30
P < 0.01
20
10
0 Control Mild
Asthma Moderate
Severe
300
Exhaled LTB4 (pg/ml)
P < 0.01
200
100
0 Control Mild
Asthma Moderate
Severe
Fig. 44. 2. Exhaled leukotrienes in asthma. Reproduced from reference 12 with permission.
459
biological fluids and tissues, and their formation is increased by systemic oxidative stress.13 Asthma 8-isoprostane levels are approximately doubled in mild asthma compared with normal subjects, and increased by about three-fold in those with severe asthma, irrespective of their treatment with corticosteroids.14 The relative lack of effect of corticosteroids on exhaled 8-isoprostane has been confirmed in a placebo-controlled study with two different doses of inhaled steroids.15 This provides evidence that inhaled corticosteroids may not be effective in reducing oxidative stress. Exhaled isoprostanes may be a better means of reflecting disease activity than exhaled NO. COPD Urinary levels of isoprostanes, in particular 8-isoprostane, are increased in COPD, and decline in patients with acute exacerbation as their clinical condition improves.16 The concentration of 8-isoprostane in exhaled condensate is also increased in normal cigarette smokers, but to a much greater extent in COPD patients.17 Interestingly, exhaled 8-isoprostane is increased to a similar extent in COPD patients who are ex-smokers as they are in smoking COPD patients, indicating that the exhaled isoprostanes in COPD are largely derived from oxidative stress from airway inflammation, rather than from cigarette smoking. NO-related products NO reacts with superoxide to yield peroxynitrite, can be trapped by thiol-containing biomolecules, such as cysteine and glutathione to form S-nitrosothiols, or can be oxidized to nitrate and nitrite. Nitrogen intermediates, for example peroxynitrite, can induce a number of covalent modifications in various biomolecules, such as nitroso- and nitroadducts. One such modification yields 3-nitrotyrosine, and detection of this adduct in proteins is now commonly used as a diagnostic tool to identify involvement of NO-derived oxidants in many disease states. The balance between nitrite/nitrate, S-nitrosothiols, and nitrotyrosine in lung epithelial lining fluids, as reflected by exhaled breath condensate, gives an insight into NO synthesis and short- and long-term changes in NO production. Asthma High levels of nitrite have been found in exhaled breath condensate of asthmatic patients, especially during acute exacerbations.18 A deficiency in S-nitrosothiols has been demonstrated in the tracheal lining fluid in asthmatic children with respiratory failure,19 suggesting that the levels of S-nitrosothiols, which are endogenous bronchodilators, may normally counteract increased airway tone in asthma. Increased levels of nitrotyrosine in exhaled breath condensate are associated with worsening of asthma symptoms and deterioration of lung function during inhaled steroid withdrawal in moderate asthma,12 suggesting that nitrotyrosine may be a predictor of asthma deterioration.
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Asthma and Chronic Obstructive Pulmonary Disease
COPD Habitual smokers have unusually high antioxidant concentrations in the epithelial lining fluid and higher resistance to oxidative pulmonary damage. Chronic oxidative stress presented to the lung by cigarette smoke may decrease the availability of thiol compounds and may increase decomposition of nitrosothiols, explaining elevated levels of S-nitrosothiols in exhaled condensate in healthy smokers, which are related to smoking history. A significant negative correlation between FEV1 and the amount of nitrotyrosine formation has been demonstrated in patients with COPD, but not in those with asthma and normal subjects,20 suggesting that NO produced in the airways is consumed by its reaction with superoxide anion and/or peroxidase-dependent mechanisms, and that reactive nitrogen species play an important role in the pathobiology of the airway inflammatory and obstructive process in COPD. Hydrogen ions An acidic microenvironment up-regulates NOS2 in macrophages through the activation of NF-jB, making NO release moderately pH dependent.21 Elevated levels of lactic acid have been found in exhaled condensate in patients with acute bronchitis,22 and a low pH of exhaled condensate was seen in patients with acute asthma.23 Proteins and cytokines Measurement and identification of proteins in exhaled condensate is controversial. It has been reported that the amount of protein in the breath condensate of eight healthy individuals was from 4 lg to 1.4 mg, originating from the nasopharynx, oropharynx, and lower airways.24 The same group has also reported the presence of IL1b, soluble IL-2 receptor protein, IL-6 and TNF-a in exhaled breath condensate of patients with a variety of respiratory conditions.24 Recently, higher concentrations of total protein in exhaled condensate have been found in young smokers compared with nonsmokers, whilst the levels of IL-1b and TNF-a were not different.25 We have found that IL-8 levels in exhaled condensate are mildly elevated in stable CF, but are more than doubled in unstable CF patients compared with normal subjects (unpublished observations).
Origin and measurement In contrast to the predominantly airway source of exhaled NO, hydrocarbons are representative of blood-borne concentrations through gas exchange in the blood/breath interface in the lungs. Exhaled hydrocarbons are measured by gas chromatography. New techniques have also been developed for analyzing small volumes of gas (ethane, pentane) from single-breath samples, in which no pre-concentration is required,26 and exhaled air, collected during a single flow-controlled exhalation into aTeflon reservoir, is injected directly into a gas chromatograph.27,28 The contamination of ambient ethane can be eliminated by discarding the dead space during the first part of exhalation, and potential loss of organic vapors to condensed water is excluded by using silica gel granules in reservoirs. Factors affecting hydrocarbon levels in exhaled air Hydrocarbons are present in ambient air, inhaled and retained in steady-state in the equilibrium between various body compartments (body fat) and ambient air. Although it takes a few minutes to wash out the lungs, it requires no less than 90 minutes to wash out the body stores of hydrocarbons, making this approach impractical.29 To make exhaled breath hydrocarbon tests usable in clinical medicine two approaches to deal with ambient contamination have a considerable advantage:30 • employment of a washout period (4–10 minutes); • to record the local ambient levels of hydrocarbons and subtract them from the levels in exhaled breath.27,28
EXHALED HYDROCARBONS
No statistically significant changes in exhaled hydrocarbons are found relative to the fasting level, suggesting that diet does not alter ethane or pentane excretion in healthy subjects.31 Although different minute volumes have no effect on ethane excretion in children,32 the diffusion rate of lipophilic substances, such as ethane and pentane, may be reduced and will require a longer exhalation, or collection of the last part of exhalation.27,28 Smoking increases exhaled ethane and pentane. This effect is possibly related to oxidative damage caused by smoking and to high concentrations of hydrocarbons in cigarette smoke.28,33,34 Exhaled hydrocarbons may help to estimate the magnitude of in-vivo lipid peroxidation by measuring, for example, pentane and ethane exhaled in breath, and to monitor the effect of novel drugs with anti-oxidant properties in clinical practice.
Hydrocarbons are nonspecific markers of lipid peroxidation, which is one of the consequences of the constant and inevitable formation of oxygen radicals in the body. For volatile organic compounds, sampling and analysis of breath is preferred to direct measurement from blood samples because it is noninvasive, and the measurements are much simpler in a gas phase rather than in a complex biological tissue such as blood.
Asthma Exhaled pentane is elevated during acute asthma exacerbations and reduced to normal levels during recovery.35 Exhaled ethane levels are higher in mild steroid-naive asthmatics compared with steroid-treated patients and normal subjects27 (Fig. 44.3). The measurements of two different exhaled markers, NO and pentane for example, might be helpful in distinguishing
Noninvasive Assessment of Airway Inflammation
3 weeks failed to reduce exhaled ethane, cigarette smokers whose ethane values were found to fall the most tended to have better preserved lung function.39 Increased levels of volatile organic compounds in exhaled breath could be used as biochemical markers of exposure to cigarette smoke and oxidative damage caused by smoking. However, if transient elevation of ethane in exhaled air (returned to baseline within 3 hours) in healthy smokers is due to ethane in cigarette smoke, chronically elevated ethane levels in current and, especially in ex-smokers, are related to oxidative damage.33 In fact, there is a correlation between the ethane levels and the degree of airway obstruction in COPD,28 and current (packs per day) and lifelong (pack-years) tobacco consumption.34
Asthma
P < 0.05 6
P < 0.05
Exhaled ethane (ppb)
5
4
3
2
CARBON MONOXIDE
1
Carbon monoxide (CO) is a gas that may be formed endogenously and is detectable in exhaled air.
0
Normal
Asthma No steroids
Steroids
COPD 6
P < 0.05 5 Exhaled ethane (ppb)
461
4
Source of exhaled CO There are three major sources of CO in exhaled air: enzymatic degradation of heme, non-heme related release (lipid peroxidation, xenobiotics, bacterial) and exogenous CO. The predominant endogenous source of CO (~85%) in the body is from the degradation of hemoglobin by the enzyme heme oxygenase (HO), and approximately 15% arises from degradation of myoglobin, catalase, NO synthase, guanylyl cyclase and cytochromes.40 There are several reasons for considering that alveoli are the predominant site of exhaled CO in normal subjects. • Levels of exhaled CO measured at the end of exhalation are similar to those measured via a bronchoscope at the level of the main bronchus.41 • Exhaled CO levels are less flow- or breath-hold dependent than exhaled NO,42 suggesting less airway contribution. • Maximal CO levels are seen close to the end of exhalation, as for CO2.
3
2
1
0
Normal
Asthma No steroids
Steroids
Fig. 44.3. Exhaled ethane in asthma27 and COPD.28 Reproduced from reference 28 with permission.
severe nocturnal asthma from obstructive sleep apnea. Elevated levels of exhaled and nasal NO but not pentane have been found in patients with sleep apnea,36 suggesting the presence of predominantly upper airway inflammation in these patients. COPD Pentane37 and isoprene38 are increased in smokers,34 and ethane in COPD28 (Fig. 44.3). Although vitamin E given for
There is also a small proportion of CO derived from the airways, which is higher after allergen challenge measured either via bronchoscope,41 or at the mouth.43 The fact that breathing through the nose increases the CO levels obtained in the exhaled air44 suggests that nose and paranasal sinuses may also contribute to the CO production of the human airways. Indeed, HO-like immunoreactivity is seen in the respiratory epithelium, in connection with seromucous glands and in the vascular smooth muscle of the nose.44 Heme oxygenase CO is a by-product of rate-limited oxidative cleavage of hemoglobin by HO, which exists in three isoforms, i.e. HO1, HO-2, and HO-3. Like other stress proteins HO-1 can be induced by a variety of stimuli, such as pro-inflammatory cytokines, bacterial toxins, heme, ozone, hyperoxia, hypoxia, reactive oxygen species, and reactive nitrogen species. Both
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HO-1 and HO-2 are expressed in human airways and are found in most cell types, with particularly strong immunofluorescence in airway epithelial cells. Effect of oxidative stress There is a close link between the reactive oxygen and nitrogen species and CO. Thus, a dose-dependent increase in exhaled CO has been shown following a 1 hour exposure to different concentrations of O2.45 HO-1 activation can be diminished by N-acetylcysteine, a precursor of glutathione with antioxidant properties.46 Both superoxide anions and peroxynitrite can stimulate HO-1 activation and subsequent release of CO is an important negative-feedback regulatory mechanism limiting the release of these cytotoxic substances.47 Measurement Exhaled CO as a marker to assess different diseases (cardiovascular, diabetes and nephritis) was first described in the USSR in 1972.48 Over the last 20 years, exhaled CO has been measured to identify current and passive smokers, to monitor bilirubin production including hyperbilirubinemia in newborns, and in the assessment of lung diffusion capacity. Most of the measurements in humans have been made using electrochemical CO sensors. The sensor is selective, gives reproducible results,49 and is inexpensive. However, these instruments are susceptible to interference from a large number of substances, for example, hydrogen, which is present in exhaled breath and may be increased after glucose ingestion. H2-insensitive CO sensors, which are now available, are therefore recommended. End-tidal exhaled CO measurements can be made during a single exhalation and are routine in cooperative adults. It can also be easily performed in children over 5 years of age.50 A method for measuring CO in nasally sampled exhaled air in uncooperative neonates has been developed which involves the relatively noninvasive placement of a small catheter into the posterior of the nasopharynx, and collection of breath samples either manually or automatically. Factors affecting exhaled CO measurements Regional and local levels of CO in ambient air can vary significantly depending on the time of day and season, on wind velocity, industrialization, traffic, and altitude. While some exposure to CO may occur in normal day-to-day life due to environmental pollution, active or passive smoking is the most likely reason for high levels of exhaled CO. A cut-off level of 6 ppm51 effectively separates nonsmokers from smokers. Other individual factors which can markedly affect the amount of CO that a person may inhale are type and location of home and occupation, cooking/heating appliances, and mode of transportation. Asthma Elevated levels of exhaled CO have been reported in stable asthma52 with normal levels in patients treated with inhaled corticosteroids. The increased levels in stable asthma are
likely to be due to increased HO-1 expression, which is seen in alveolar macrophages in induced sputum of patients with asthma. There is also an increase in the concentration of bilirubin in induced sputum, indicating increased HO-1 activity. Further evidence that exhaled CO increases may reflect HO activity is the demonstration that inhaled hemin, which is a substrate for HO, results in a significant increase in exhaled CO concentration in normal and asthmatic subjects. Increased levels of exhaled CO are seen in acute exacerbations of asthma, and are reduced after treatment with oral corticosteroids.53 Significantly elevated CO levels are found in patients with severe asthma,54 including patients treated with 30 mg of prednisolone for 2 weeks.55 In view of the simplicity of CO measurements and the portability of CO analyzers, exhaled CO may be useful in noninvasive monitoring of pediatric asthma. For example, children with persistent asthma despite treatment with steroids, which reduce their NO levels, have significantly higher exhaled CO compared with those with infrequent episodic asthma.50 COPD A major limitation of exhaled CO in COPD is the marked effect of cigarette smoking, which masks any increase that may occur due to the disease process. There is no difference in exhaled CO in patients with chronic bronchitis (without airflow obstruction) when compared with normal subjects.56 However, exhaled CO levels are elevated in ex-smoking COPD patients,57 suggesting ongoing oxidative stress or inflammation. HO is induced in fibroblasts exposed to cigarette smoke.58 There is an increase in exhaled CO during acute exacerbations of COPD, with a decline after recovery.59
S U M M A RY Accurate assessment of airway inflammation and oxidative stress is important to the clinical management of a variety of pulmonary conditions, including asthma and COPD. It may allow the clinician to monitor the progression of the disease and to assess the efficacy of anti-inflammatory or antioxidant treatment.
REFERENCES 1. Nightingale JA, Rogers DF, Barnes PJ. Effect of repeated sputum induction on cell counts in normal volunteers. Thorax 1998; 53:87–90. 2. Sidorenko GI, Zborovskii EI, Levina DI. Surface-active properties of the exhaled air condensate (a new method of studying lung function). Ter. Arkh. 1980; 52:65–8. 3. Kurik MV, Rolik LV, Parkhomenko NV, Tarakhan LI, Savitskaia NV. Physical properties of a condensate of exhaled air in chronic bronchitis patients. Vrach. Delo. 1987; 37–9. 4. Mozalevskii AF, Travianko TD, Iakovlev AA, Smirnova EA, Novikova NP, Sapa II. Content of arachidonic acid metabolites in blood and saliva of children with bronchial asthma. Ukr. Biokhim. Zh. 1997; 69:162–8.
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5. Dekhuijzen PN, Aben KK, Dekker I et al. Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1996; 154: 813–16. 6. Jöbsis Q, Raatgeep HC, Schellekens SL, Hop WCJ, Hermans PWM, de Jongste JC. Hydrogen peroxide in exhaled air of healthy children: reference values. Eur. Respir. J. 1998; 12:483–5. 7. Guatura SB, Martinez JA, Santos BP, Santos ML. Increased exhalation of hydrogen peroxide in healthy subjects following cigarette consumption. Sao Paulo Med. J. 2000; 118:93–8. 8. Taha R, Olivenstein R, Utsumi T et al. Prostaglandin H synthase 2 expression in airway cells from patients with asthma and COPD. Am. J. Respir. Crit. Care. Med. 2000; 161:636–40. 9. Kharitonov SA, Sapienza MA, Barnes PJ, Chung KF. Prostaglandins E2 and F2a reduce exhaled nitric oxide in normal and asthmatic subjects irrespective of airway calibre changes. Am. J. Respir. Crit. Care Med. 1998; 158:1374–8. 10. Larfars G, Lantoine F, Devynck MA, Palmblad J, Gyllenhammar H. Activation of nitric oxide release and oxidative metabolism by leukotrienes B4, C4, and D4 in human polymorphonuclear leukocytes. Blood 1999; 93:1399–405. 11. Hanazawa T, Kharitonov SA, Oldfield W, Kay AB, Barnes PJ. Nitrotyrosine and cystenyl leukotrienes in breath condensates are increased after withdrawal of steroid treatment in patients with asthma. Am. J. Respir. Crit. Care Med. 2000; 161:A919. 12. Hanazawa T, Kharitonov SA, Barnes PJ. Increased nitrotyrosine in exhaled breath condensate of patients with asthma. Am. J. Respir. Crit. Care Med. 2000; 162:1273–6. 13. Mori TA, Dunstan DW, Burke V et al. Effect of dietary fish and exercise training on urinary F2-isoprostane excretion in noninsulin-dependent diabetic patients. Metabolism 1999; 48:1402–8. 14. Montuschi P, Corradi M, Ciabattoni G, Nightingale J, Kharitonov SA, Barnes PJ. Increased 8-isoprostane, a marker of oxidative stress, in exhaled condensate of asthma patients. Am. J. Respir. Crit. Care Med. 1999; 160:216–20. 15. Kharitonov SA, Donnelly LE, Corradi M, Montuschi P, Barnes PJ. Dose-dependent onset and duration of action of 100/400 mcg budesonide on exhaled nitric oxide and related changes in other potential markers of airway inflammation in mild asthma. Am. J. Respir. Crit. Care Med. 2000; 161:A186. 16. Pratico D, Basili S, Vieri M, Cordova C, Violi F, Fitzgerald GA. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress. Am. J. Respir. Crit. Care Med. 1998; 158:1709–14. 17. Montuschi P, Collins JV, Ciabattoni G et al. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am. J. Respir. Crit. Care Med. 2000; 162:1175–7. 18. Hunt J, Byrns RE, Ignarro LJ, Gaston B. Condensed expirate nitrite as a home marker for acute asthma. Lancet 1995; 346:1235–6. 19. Gaston B, Sears S, Woods J et al. Bronchodilator S-nitrosothiol deficiency in asthmatic respiratory failure. Lancet 1998; 351:1317–19. 20. Ichinose M, Sugiura H,Yamagata S, Koarai A, Shirato K. Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways. Am. J. Respir. Crit. Care Med. 2000; 162:701–6. 21. Sheu FS, Zhu W, Fung PC. Direct observation of trapping and release of NO by glutathione and cysteine with electron paramagnetic resonance spectroscopy. Biophys. J. 2000; 78:1216–26. 22. Goncharova VA, Borisenko LV, Dotsenko EK, Pokhaznikova MA. Kallikrein-kinin indices and biological composition of exhaled condensate in acute bronchitis patients with varying disease course. Klin. Med. 1996; 74:46–8.
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23. Hunt JF, Fang K, Malik R et al. Endogenous airway acidification. Implications for asthma pathophysiology. Am. J. Respir. Crit. Care Med. 2000; 161:694–9. 24. Scheideler L, Manke HG, Schwulera U, Inacker O, Hammerle H. Detection of nonvolatile macromolecules in breath. A possible diagnostic tool? Am. Rev. Respir. Dis. 1993; 148:778–84. 25. Garey KW, Neuhauser MM, Rafice AL, Robbins RA, Danziger LH, Rubinstein I. Protein, nitrite/nitrate, and cytokine concentration in exhaled breath condensate of young smokers. Am. J. Respir. Crit. Care Med. 2000; 161:A175. 26. Zarling EJ, Clapper M. Technique for gas-chromatographic measurement of volatile alkanes from single-breath samples. Clin. Chem. 1987; 33:140–1. 27. Paredi P, Kharitonov SA, Barnes PJ. Elevation of exhaled ethane concentration in asthma. Am. J. Respir. Crit. Care Med. 2000; 162:1450–4. 28. Paredi P, Kharitonov SA, Leak D, Ward S, Cramer D, Barnes PJ. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 162:369–73. 29. Morita S, Snider MT, Inada Y. Increased N-pentane excretion in humans: a consequence of pulmonary oxygen exposure. Anesthesiology 1986; 64:730–3. 30. Kneepkens CM, Lepage G, Roy CC. The potential of the hydrocarbon breath test as a measure of lipid peroxidation. Free Radic. Biol. Med. 1994; 17: 127–60. 31. Zarling EJ, Mobarhan S, Bowen P, Sugerman S. Oral diet does not alter pulmonary pentane or ethane excretion in healthy subjects. J. Am. Coll. Nutr. 1992; 11:349–52. 32. Refat M, Moore TJ, Kazui M, Risby TH, Perman JA, Schwarz KB. Utility of breath ethane as a noninvasive biomarker of vitamin E status in children. Pediatr. Res. 1991; 30:396–403. 33. Habib MP, Clements NC, Garewal HS. Cigarette smoking and ethane exhalation in humans. Am. J. Respir. Crit. Care Med. 1995; 151:1368–72. 34. Do BK, Garewal HS, Clements NCJ, Peng YM, Habib MP. Exhaled ethane and antioxidant vitamin supplements in active smokers. Chest 1996; 110:159–64. 35. Olopade CO, Zakkar M, Swedler WI, Rubinstein I. Exhaled pentane levels in acute asthma. Chest 1997; 111:862–5. 36. Olopade CO, Christon JA, Zakkar M et al. Exhaled pentane and nitric oxide levels in patients with obstructive sleep apnea. Chest 1997; 111:1500–4. 37. Jeejeebhoy KN. In vivo breath alkane as an index of lipid peroxidation. Free Radic. Biol. Med. 1991; 10:191–3. 38. Foster WM, Jiang L, Stetkiewicz PT, Risby TH. Breath isoprene: temporal changes in respiratory output after exposure to ozone. J. Appl. Physiol. 1996; 80:706–10. 39. Habib MP, Tank LJ, Lane LC, Garewal HS. Effect of vitamin E on exhaled ethane in cigarette smokers. Chest. 1999; 115:684–90. 40. Berk PD, Rodkey FL, Blaschke TF, Collison HA, Waggoner JG. Comparison of plasma bilirubin turnover and carbon monoxide production in man. J. Lab. Clin. Med. 1974; 83:29–37. 41. Kharitonov SA, Lim S, Hanazawa T, Chung FK, Barnes PJ. Exhaled carbon monoxide derives predominantly from alveoli in healthy non-smokers, smokers and mild stable asthmatics, but also from asthmatic airways after allergen challenge. Am. J. Respir. Crit. Care Med. 2000; 161:A584. 42. Kharitonov SA, Paredi P, Barnes PJ. Methodological aspects of exhaled carbon monoxide measurements as a possible noninvasive marker of oxidative stress: influence of exhalation flow, breathholding and ambient air. Eur. Respir. J. 1998; 12:128S. 43. Paredi P, Leckie MJ, Horvath I, Allegra L, Kharitonov SA, Barnes PJ. Exhaled carbon monoxide is elevated following allergen challenge in patients with asthma. Eur. Respir. J. 1999; 13:48–52. 44. Andersson JA, Uddman R, Cardell LO. Carbon monoxide is endogenously produced in the human nose and paranasal sinuses. J. Allergy. Clin. Immunol. 2000; 105:269–73.
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45. Skrupskii VA, Stepanov VE, Shulagin IUA. Monitoring of endogenous carbon monoxide elimination in exhaled air of rats in hyperoxia. Aviakosm. Ekolog. Med. 1995; 29:49–52. 46. Motterlini R, Kerger H, Green CJ, Winslow RM, Intaglietta M. Depression of endothelial and smooth muscle cell oxygen consumption by endotoxin. Am. J. Physiol. 1998; 275:H776–82. 47. Foresti R, Sarathchandra P, Clark JE, Green CJ, Motterlini R. Peroxynitrite induces haem oxygenase-1 in vascular endothelial cells: a link to apoptosis. Biochem. J. 1999; 339:729–36. 48. Nikberg II, Murashko VA, Leonenko IN. Carbon monoxide concentration in the air exhaled by the healthy and the ill. Vrach. Delo. 1972; 12:112–14. 49. Kharitonov SA, Paredi P, Barnes PJ. Reproducibility of exhaled carbon monoxide measurements and its circadian variation in normal subjects. Am. J. Respir. Crit. Care Med. 1998; 157:A613. 50. Uasuf CG, Jatakanon A, James A, Kharitonov SA, Wilson NM, Barnes PJ. Exhaled carbon monoxide in childhood asthma. J. Pediatr. 1999; 135:569–74. 51. Middleton ET, Morice AH. Breath carbon monoxide as an indication of smoking habit. Chest 2000; 117:758–63. 52. Zayasu K, Sekizawa K, Okinaga S,Yamaya M, Sasaki H. Increased carbon monoxide in exhaled air of asthmatic patients. Am. J. Respir. Crit. Care Med. 1997; 156:1140–3.
53. Yamara M, Sekizawa K, Ishizuka M, Monma M, Sasaki H. Exhaled carbon monoxide levels during treatment of acute asthma. Eur. Respir. J. 1999; 13:757–60. 54. Stirling RG, Lim S, Kharitonov SA, Chung FK, Barnes PJ. Exhaled breath carbon monoxide is minimally elevated in severe but not mild atopic asthma. Am.J.Respir.Crit.Care Med. 2000; 161:A922. 55. Biernacki W, Kharitonov SA, Barnes PJ. Exhaled carbon monoxide measurements can be used in general practice to predict the response to oral steroid treatment in patients with asthma. Am. J. Respir. Crit. Care Med. 1999; 159:A631. 56. Delen FM, Sippel JM, Osborne ML, Law S, Thukkani N, Holden WE. Increased exhaled nitric oxide in chronic bronchitis. Comparison with asthma and COPD. Chest 2000; 117:695–701. 57. Culpitt SV, Paredi P, Kharitonov SA, Barnes PJ. Exhaled carbon monoxide is increased in COPD patients regardless of their smoking habit. Am. J. Respir. Crit. Care Med. 1998; 157:A787. 58. Muller T, Gebel S. The cellular stress response induced by aqueous extracts of cigarette smoke is critically dependent on the intracellular glutathione concentration. Carcinogenesis 1998; 19:797–801. 59. Biernacki W, Kharitonov SA, Barnes PJ. Carbon monoxide in exhaled air in patients with lower respiratory tract infection. Eur. Respir. J. 1998; 12:345S.
Chapter
Imaging
45
Sujal R. Desai King’s College Hospital, London, UK
David M. Hansell Imperial College School of Medicine, London and Royal Brompton Hospital, London, UK
The limitations of the plain chest radiograph for the evaluation of obstructive lung disease have been recognized for some time. In this regard, computed tomography (CT) has had an important effect on clinical practice. Since the mid-1980s the technique of high resolution CT (HRCT) has added a further dimension to the noninvasive investigation of lung disease; subtle parenchymal abnormalities, imperceptible on plain radiographs, are readily depicted on HRCT. In specific circumstances, other techniques for imaging the lungs may be used including nuclear medicine scanning, single positron emission tomography and magnetic resonance imaging (including the novel maneuver of scanning after inhalation of a hyperpolarized gas). However, the utility of some of these more sophisticated tests, outside of specialized research centers, remains to be confirmed. The present chapter outlines the benefits and limitations of currently available imaging techniques. This is followed by a more detailed review of the value and limitations of radiology (specifically plain radiography and CT) in patients with asthma and COPD.
IMAGING TECHNIQUES IN OBSTRUCTIVE LUNG DISEASE Plain chest radiography Plain chest radiography has endured since the early years following the discovery of the X-ray and changed little over 100 years.1,2 As an imaging tool, there is much in favor of chest radiography; an important attribute is the low radiation compared with other radiological investigations. The additional benefits of plain radiography are relatively low cost and speed. Despite these advantages, it is acknowledged that conventional radiography is an imperfect method for lung imaging. Inevitably, because of its two-dimensional nature there is anatomical superimposition. Consequently, the chest radiograph only demonstrates relatively gross
morphological abnormalities. Moreover, because there are different densities in the thorax (namely air, soft tissues, and bone), it is often difficult to achieve an optimal exposure throughout the image. These problems are further compounded by known differences in observer experience and film quality.3,4 Digitized radiography An important advance in radiographic technology was the development of digital systems. Although a detailed discussion of digital radiography is beyond the scope of the present chapter, a brief review is pertinent. In the earliest (so-called phosphor plate) systems, transmitted X-ray energy was trapped by a thermoluminescent phosphor, a material which releases its energy in the form of light.5 The X-ray plate is “read” by a laser light source so that light photons (with an energy proportional to the absorbed X-ray energy) are emitted. This light signal is amplified electronically and digitized. The principal advantage of digital radiography is that diagnostic images can be produced over a wider range of X-ray exposures and the need for re-take films is reduced. Computed tomography The reconstruction of a transaxial image from multiple (Xray) projections of a region is the essence of CT imaging.6–9 There are two attributes of CT which set it apart from plain chest radiography: first, the exquisite sensitivity to subtle differences in lung parenchymal density and secondly, the absence of anatomical superimposition.10,11 It is important to appreciate the differences between “volumetric” CT data acquisition (spiral and multidetector CT) and narrow section or high resolution imaging. Spiral CT/multidetector CT Because of misregistration of data, respiratory motion frequently degrades the CT image. However, with the increasing capacity for faster (nowadays subsecond) acquisition
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and reconstruction, the problem of movement artefact can be minimized. In this regard, the development of socalled “spiral” CT technology is considered a major advance.12,13 The image acquisition time is reduced principally because scanning occurs while the patient is moved through the CT gantry. This contrasts with older generations of CT scanners in which movement of the patient only alternated with periods of scanning. In the thorax, the main benefit of spiral CT scanning is that images can now be acquired during a single breath-hold maneuver. By using a bank of detectors, instead of a single row, multidetector CT machines are capable of reducing image acquisition time further. High resolution CT The spatial resolution on CT can be increased by narrowing slice thickness (or collimation) and is a key feature of the HRCT technique. Curiously, the realization that narrow collimation improves resolution came as a result of investigations in patients with solitary pulmonary nodules;14–16 narrowing of beam collimation increases the likelihood that a small lesion will have dimensions comparable to the size of a voxel. Despite more than a decade of experience, there is no strict definition of optimal slice thickness for HRCT. Technically, a beam of 3-mm thickness is suitable since the differences in image quality between 1 and 3 mm are almost imperceptible.17 In practice, for imaging the lung parenchyma, the X-ray beam is collimated to between 1 and 1.5 mm.18–20 Thereoretically, narrower collimation would further improve resolution. However, any improvement would certainly be offset by an increase in image “noise” because of the reduction in number of X-ray photons reaching the detectors. Radiation considerations There are justifiable concerns about radiation exposure to patients undergoing CT.21–23 It is known, for example, that “man-made” radiation (97% attributable to medical exposure) contributes significantly to the annual radiation burden of the UK population.24 The most obvious way of reducing exposure is to restrict the total number of images per examination. In this regard, HRCT has an inherent advantage since, in the typical study of patients with diffuse lung disease, there is no need to image the whole thorax. Instead the lungs are “sampled” by interspaced images and there may be a gap of 10 to 30 mm between each CT slice. Consequently, there is a significant fall in the mean skin radiation dose compared with an examination with contiguous images.25 The radiation dose can be further reduced by decreasing milliamperage (mA). In one early (non-HRCT) study, normal anatomical landmarks were well seen and pathological abnormalities adequately demonstrated despite a reduction from 280 mA to 20 mA.26 The trade-off is in increased image “noise” with the lower exposure setting. Moreover, ground-glass opacification and emphysema become less
conspicuous on lower dose protocols.27 Although these differences are usually insignificant, such variations may be crucial in the detection of early or subtle parenchymal disease. Magnetic resonance imaging Since its introduction, MRI has been exploited widely and its clinical repertoire continues to grow. However, the role of MRI in the imaging of the lungs is, at best, embryonic. There are three fundamental problems: • The density of protons or hydrogen atoms (on which MR imaging is crucially dependent) in lung is low. Thus, the signal-to-noise ratio is poor and images of the lung are suboptimal. • Unlike other solid organs, the lungs are difficult to magnetize uniformly: the large number of air–tissue interfaces result in heterogeneous lung magnetization. Consequently, the MR signal decays too rapidly. • Respiratory and cardiac motion both conspire to degrade the MR image. Many novel techniques have been devised to circumvent some of the problems of MR imaging of the lungs.28–32 The role of MRI in the clinical evaluation of patients with pulmonary disease remains limited.
ASTHMA Plain chest radiography The radiographic abnormalities in asthma have been widely studied. In uncomplicated disease, the chest radiograph is frequently unremarkable.33,34 In one of the earliest series, the majority (95/117 (81%)) of radiographs were entirely normal.35 However, in a variable proportion of patients there are discernible changes and, in these patients, hyperinflation and abnormalities of the airways are the most common radiographic manifestations. In the following sections, the plain chest radiographic features of uncomplicated asthma are reviewed. Hyperinflation Of the reported radiographic signs, hyperinflation is perhaps the most common. Given the pathophysiology of asthma, it is not difficult to understand that overinflation of the lung can be seen during an acute episode: lung function tests typically demonstrate airflow obstruction, a depression of expiratory flow rate, elevation of residual volume and an increase in both functional residual and total lung capacity.36,37 However, it is important to appreciate that lung function abnormalities can persist during remission.37–39 Consequently, hyperinflation is not uncommon on radiographs taken between acute episodes.35,40 On the frontal radiograph, hyperinflation is seen as an increase in lung “length” (an imaginary line from the lung apex to the dome of the right hemidiaphragm), depression of the diaphragm
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and a decrease in the transverse cardiac diameter35,41 (Fig. 45.1). A useful practical rule of thumb is to count the number of anterior ribs on the frontal radiograph: in healthy subjects it is normal to see only the first six ribs projected over the lungs. The tell-tale sign on the lateral view is an increase in the depth of (normal) retrosternal transradiancy. The prevalence of hyperinflation on conventional radiographs varies between 19%35 and 72%.41 Such a wide range almost certainly reflects the known influences of the age of the patient, the age at onset of asthma and, crucially, the timing of the examination in relation to an acute exacerbation.35,41–43
• Bronchial wall thickening was more common in children (seen in all asthmatic patients aged below 10). • Airway abnormalities were more frequent in patients with a presumed infective etiology than in those with “allergic” asthma. • The prevalence of wall thickening was related to the severity of asthma: one-third of patients with grade 1 severity (characterized by short episodes and prolonged remission) had bronchial wall thickening as compared with 90% of patients with grade 3 disease (i.e. continuous wheezing with superimposed acute exacerbations),48 a finding substantiated in subsequent studies.34
Bronchial wall thickening Abnormalities of the large airways are not uncommon in asthma. This is not surprising since airway inflammation and thickening are regarded as key features in the pathophysiology of asthma.44–47 On a frontal radiograph it is often possible to see normal segmental bronchi: because of the “end-on” orientation, the anterior segmental bronchi of the upper lobes (seen as a thin circular line around an area of lucency) are particularly conspicuous. In one of the larger studies of plain film changes, thickwalled bronchi were seen in two-thirds of patients with asthma.48 There were a number of other important ancillary findings:
The reported prevalence of bronchial wall thickening in other studies has not been as high: in one study from the early 1980s there were definite or possible signs of bronchial wall thickening in 42% of cases40 and Paganin and colleagues noted this sign in only one-third of their 57 patients.34 As with hyperinflation, persistent bronchial wall thickening is seen in a proportion of patients between acute episodes.34,40 It is important to appreciate that the identification of bronchial wall thickening on plain radiography in patients with asthma is prone to error; this sign is subjective and observer disagreement for determining its presence or absence is likely to be high. Computed tomography The parenchymal and airway changes of asthma on CT have been studied in recent years. Not surprisingly, because of its superior contrast resolution, morphological abnormalities are more frequently seen on HRCT than plain radiography.34,49
Fig. 45.1. Chest radiograph in a patient with longstanding asthma. Both hemidiaphragms are depressed and flat; the anterior ends of nine ribs can clearly be counted over the lungs. Note the thickening of the anterior segmental bronchus in the right upper lobe.
Bronchial dilatation/Bronchiectasis In one of the earlier series, the HRCT features of 57 patients with asthma were analyzed.34 Airway abnormalities (mainly cylindrical bronchiectasis) were noted in just over half of the 57 patients studied and persisted on follow-up CT in ten patients. Bronchial wall thickening was seen less frequently and there were a number of minor features (considered reversible, at least in the short term) notably mucous plugging, acinar filling, and atelectasis. The demonstration of bronchiectasis in these patients was surprising, since the authors had attempted to exclude patients with allergic bronchopulmonary aspergillosis.34 Bronchiectasis has been reported in many CT studies of asthma.49–51 However, the clinical significance of airways dilatation, in asthmatic patients is unclear: plainly, the majority of patients with asthma in whom “bronchiectasis” is demonstrated do not have symptoms associated with classical bronchiectasis. Using more stringent criteria (to exclude patients with known bronchiectasis) Lynch and colleagues compared the HRCT features of 48 asthmatic subjects with 27 healthy volunteers.49 Bronchial dilatation was more common in patients with asthma than in controls (77% versus 59%, respectively). When individual bronchi were reviewed, the authors showed that 36% of bronchi in
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the asthmatic group appeared dilated compared with 26% in volunteers (P < 0.05). Although the differences were statistically significant, in no case was the diameter of a dilated bronchus greater than 1.5 times that of the accompanying artery. Accordingly, the authors were cautious about using the diagnostic label of bronchiectasis (advocating the less emotive phrase, bronchial dilatation) in the absence of unequivocal signs of nontapering airways on sequential CT images.49 The exercise of determining bronchial dilitation on CT, using the yardstick of the accompanying artery, is not entirely straightforward. In one study, bronchial dilatation on CT was more common in patients with asthma than in controls, when the evaluation was based solely on visual assessment.51 However, when more objective measurements were made, in which the ratio of the internal diameter of the lumen of the airway over the external diameter of the accompanying artery (termed the broncho-arterial ratio) was quantified, there were no differences between mild/moderate asthmatics and controls. If anything, there was a tendency towards a reduction of the broncho-arterial ratio (presumably due to wall thickening) in patients with more severe disease: in asthmatics with a forced 1 second expiratory volume (FEV1) of less than 60% predicted, the mean broncho-arterial ratio was lower than in healthy volunteers (0.48 ± 0.11 versus 0.65 ± 0.16, respectively; P < 0.01).51 Bronchial wall thickening Bronchial wall thickening is a frequent CT finding in patients with asthma34,49,51,52 (Fig. 45.2). The quoted prevalence of this CT sign varies widely, ranging from the 15% reported by Paganin et al.34 to 92% seen in the series of Lynch et al.49 This variation is due partly to technical factors (peculiar to CT) which can influence apparent wall thickening:53
Fig. 45.2. Bronchial wall thickening in asthma. HRCT through the lower lobes demonstrates thick-walled subsegmental bronchi bilaterally. Note that there is no evidence of bronchiectasis, by strict CT criteria.
• Differences in image display parameters (i.e. window level and width) can affect the perception of size on CT.54–58 • In the specific context of bronchial wall thickening, one study has indicated that window width may be more important than the center.58 Using insufflated cadaveric lungs, the authors quantified bronchial wall thickening at different window settings and compared these readings with planimetric measurements. Images were reviewed at 12 window widths (ranging from 400 HU to 1500 HU, in steps of 100 HU) and 15 window centers (range = 200 HU to 900 HU, in steps of 50 HU); all possible combinations of window width and center were evaluated. In this study, window width but not the center had the greatest influence on the measurement of bronchial wall thickening. Within the broad range of 250 to 700 HU, the window center had little bearing on the CT assessment of wall thickening.58 The ideal range of window widths for determining bronchial wall thickening was determined to be between 1000 and 1500 HU; below this range, wall thickness could be exaggerated, whereas above it, there was underestimation. Factors other than window setting can also confound the perception of wall thickness. In practice, the interpretation of thickening should be restricted to airways which are roughly perpendicular to the imaging plane: effectively, the distal airways in the upper or lower lobes. The measurements of wall thickening in bronchi passing obliquely across an image slice are often erroneous.56 Finally, the type of asthma will also affect whether or not abnormalities are seen on CT:permanent bronchial changes,such as wall thickening, are reportedly more extensive in patients with nonallergic asthma.50 The identification of bronchial wall thickening in patients with asthma may have some clinical significance. In an early study, it emerged that there was a relationship between the presence of wall thickening on plain radiography and asthma severity.34 Similar inferences have been drawn based on observations using CT.34,50 In their original study, for example, Paganin and colleagues found that the prevalence of wall thickening on CT increased with the severity of asthma: none of the patients with mild asthma had signs of wall thickening compared with a quarter of those with the most severe disease.34 In a more sophisticated analysis, wall thickening was measured and expressed as the ratio of wall thickness (T) to the outer diameter (D) of the airway in asthmatic patients (with either irreversible airflow obstruction or stable disease) and controls.59 The only notable finding was that in the group with fixed obstruction, an increased T/D ratio was correlated with enhanced airway hyperresponsiveness, a relationship not seen in stable asthma or in the controls. There were no group differences in the T/D ratio and no relationship between the T/D ratio and physiological indices of airflow obstruction. However, an important methodological constraint of this study was that the determination of wall thickening was limited to
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analysis of a single central airway (the bronchus intermedius) rather than the more distal bronchi.59 Using the same T/D ratio, but this time in the segmental and subsegmental airways, Awadh and colleagues evaluated wall thickness in patients with and without asthma.60 There were statistically significant differences both in absolute values of wall thickening and the T/D ratio between patients with near fatal or moderate asthma and those with mild asthma or control subjects. There was also a small but significant difference in the T/D ratio between the group with mild asthma and controls. Another approach to the quantification of wall thickening is the calculation of wall area (i.e. the difference between the cross-sectional area of the whole airway and the luminal area).61,62 In a recent study, the clinical features, lung function indices and severity of wall thickening in 81 asthmatic patients were compared with 28 healthy controls.62 Patients with asthma were divided according to whether the disease was intermittent or persistent (the latter further subdivided into mild, moderate or severe). There were no differences between the groups for the total duration of asthma. However, there was a clear trend towards increased bronchial wall thickening, expressed as the wall area, in patients with increasingly severe asthma. Although there was no difference in wall area between controls and patients with intermittent episodes, all patients with persistent asthma had significantly greater wall thickening than controls; patients with severe persistent asthma had significantly thicker bronchial walls than all other groups of asthma severity.62 Dynamic studies Experiments on animals using HRCT have shown the acute airway response to histamine and a deep inspiratory effort.63,64 These studies confirmed that accurate measurements of airways with a luminal diameter of down to 1 mm (but probably no less) were possible on HRCT.63,64 More importantly, it was seen that the bronchoconstrictor response of individual airways is strikingly nonuniform, both between animals and in the same animal which may, in part, be due to differences in local neural control.63–66 CT has been used more recently to study the dynamic airway changes in human lungs.61,67 Okazawa and colleagues compared bronchial wall thickening (using the measurement of wall area (see above)) and the response to methacholine in asthmatic patients and healthy volunteers.61 Not surprisingly, wall thickening was more pronounced in patients with asthma. For the dynamic studies, methacholine was administered to both groups at concentrations sufficient to induce a 20% depression of the FEV1. By doing this, it was shown that the bronchoconstrictor effect of methacholine (manifest as a decrease in luminal area), was most evident in airways with a diameter of 2–4 mm, in both study groups. There was no difference in the luminal area between asthmatics and volunteers after methacholine challenge. However, there was a decrease in wall area in the normal subjects following bronchial provocation, which was not seen in asthmatics. Based on these results, the postulate
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was that the inflammatory thickening of the airway wall somehow “uncoupled” the airway smooth muscle from the normal elastic recoil provided by the lung parenchyma, thereby contributing to the hyperresponsiveness of asthmatic airways.61 Goldin and colleagues have also confirmed that, in patients with asthma, the smallest airways (i.e. crosssectional area = 2–5 mm2) show the greatest bronchoconstrictor response to methacholine.67 Moreover, these authors were able to demonstrate the reversible nature of the airway changes by administering a b2-agonist following bronchial provocation. Ancillary CT abnormalities Emphysema: CT demonstrates features suggestive of emphysema in a proportion of patients with asthma.39,68,69 Furthermore, it is generally accepted that some patients with asthma develop a component of irreversible airflow obstruction. However, the concept that longstanding asthma predisposes to emphysema or that these entities lie along the same disease spectrum, is contentious.70–72 In one series, CT signs of emphysema were recorded in ten of 57 (17%) patients with asthma; all subjects were lifelong nonsmokers.34 In quantifying emphysema, the authors produced a cumulative total of the number of lobes showing areas of decreased attenuation (in a subset of ten patients) but no objective quantification of the extent of emphysema on CT. Moreover, it was suggested that the emphysema in their patients may indeed have been secondary to parenchymal destruction in regions with peribronchiolar fibrosis, sometimes called “paracicatricial” or “irregular” emphysema.73,74 Many authors have argued that, in the absence of a history of cigarette smoking, asthma per se, does not predispose to emphysema.39,68,69 In a study of asthmatic patients with irreversible airflow obstruction there was a statistically significant difference in the extent of emphysema on CT between smokers and nonsmokers (10%, (range = 1–60%) versus 0% (range = 0–4%), respectively; P < 0.001).39 Furthermore, in the subset in whom total lung capacity exceeded 120% predicted, all the smokers, but none of the nonsmokers, had CT evidence of emphysema. These findings are supported by another study in which 14 of 62 patients with asthma had CT evidence of emphysema.69 Once again, all the patients with emphysema were smokers and there was no evidence of emphysema in nonsmokers regardless of the severity or duration of asthma. The view that chronic asthma leads to emphysema has also been voiced. Biernacki and colleagues demonstrated changes in lung parenchymal density on CT in patients with chronic asthma.75 Quantitatively similar changes of density were noted in patients with smoking-related chronic obstructive lung disease. These observations were used to suggest that emphysema may develop in a proportion of (nonsmoking) asthmatic patients. However, such a conclusion warrants scrutiny. The measurement of global lung density (incidentally on thick (10 mm collimation) sections) is, at best, a “blunt” marker for parenchymal disease, not accounting for the fact that reduced lung attenuation on CT
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is not a specific sign of emphysema.51,76–78 More importantly, small airways disease (considered important in the pathogenesis of asthma79,80) also causes areas of decreased attenuation on CT.81–83 Furthermore, the authors claimed that the depression of corrected gas transfer (Kco, perhaps the best single physiological marker of emphysema84,85), in patients with asthma, supports the hypothesis that emphysema was responsible for the reduction in parenchymal density on CT. However, a low Kco was seen in only seven of 17 asthmatics in this study.75 Moreover, in the group of asthmatics, as a whole, the mean Kco more closely matched that of normal subjects than those with smoking-induced chronic airflow obstruction. Small airways disease: A mosaic attenuation pattern on CT (i.e. patchy regions of decreased lung attenuation within which there is reduction in the number and caliber of pulmonary vessels86) is a recognized finding on inspiratory HRCT images in patients with asthma.49,52 Occasionally, the sign of mosaic attenuation will not be appreciated on inspiratory images and in such cases, scans taken at endexpiration (see section on “Small Airways Disease”) may be the only clue to the associated small airways obstruction87,88 (Fig. 45.3).
(a)
(b)
EMPHYSEMA The diagnosis of emphysema (defined as “abnormal, permanent enlargement of the airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, but without obvious fibrosis”), is made on findings at histopathological examination.74 The definition is necessarily cumbersome but emphasizes the importance of identifying destruction (i.e. “nonuniformity in the pattern of respiratory airspace enlargement so that the orderly appearance of the acinus and its components is lost”) in the pathological diagnosis of emphysema.74 The requirement that “obvious fibrosis” needs to be excluded is potentially problematic: there is evidence that fibrosis may be an integral component in some patients with emphysema.89,90 Indeed, there are intriguing parallels in the pathogenesis of pulmonary fibrosis and emphysema, with tobacco smoke being the most obvious etiological link.91–94 The histopathological types of emphysema are categorized conveniently according to the anatomical distribution of disease within the acinus (i.e. the unit of lung distal to the terminal bronchiole).73 Three morphological patterns are described: • Centrilobular (centriacinar) emphysema: There is abnormal dilatation of respiratory bronchioles with sparing of the more distal structures of the acinus.73,95 The disease shows striking heterogeneity so that adjacent lobules are affected to different extents. • Paraseptal emphysema: The characteristic histopathological feature is enlargement of alveoli juxtaposed with connective tissue septa or the pleura and is typically
Fig. 45.3. HRCT in a patient with asthma. (a) Inspiratory CT with imperceptible changes in the lower lobes. (b) Expiratory scan (at a more caudal level) accentuates patchy areas of decreased attenuation due to air-trapping.
located at the periphery of the secondary lobule. This type of emphysema may be thought of as a “peripheral” manifestation of centrilobular disease. • Panlobular (panacinar) emphysema: In the early stages, there may be more selective involvement of the alveolar ducts compared to other regions of the acinus. However, as the term suggests, the pathological hallmark of this form of emphysema is uniform involvement of the entire acinus. Lung destruction is randomly distributed throughout the lungs but is manifestly most marked in this form of emphysema. Thus, not surprisingly, panlobular emphysema is most often associated with clinically significant disease. Panlobular emphysema is typically most pronounced in the lower zones.73,96,97 Chest radiography Because the diagnosis is based on histopathological features, the detection of emphysema in life, necessarily depends on indirect evidence from clinical, physiological and radiological investigation. As with asthma, the plain radiograph is often the first radiological test to be requested. It needs to be
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understood that only emphysema of moderate-to-marked severity is (although not invariably) detectable on plain radiographs.96 The plain radiographic signs of emphysema reflect the morphological changes (due to parenchymal destruction) and the characteristic physiological abnormality (airflow obstruction) (Table 45.1). The basic radiographic changes of emphysema were identified by Kerley in 1936:98 hyperinflation and abnormalities of peripheral small vessels (a diminution in the number and caliber) were the key features. However, Laws and Heard were the first to evaluate radiographic features in patients with histopathologically proven disease.99 Not surprisingly, the plain radiograph was normal in patients with limited centrilobular emphysema. However, there was broad correlation between the extent of emphysema and the likelihood of there being abnormalities on the plain radiograph, a relationship validated in subsequent publications.96,100 With extensive disease (i.e. >60% of a lung slice), and particularly when there was panacinar emphysema, the radiograph was frequently abnormal. The earliest studies emphasized the importance of pulmonary vascular abnormalities in the radiological diagnosis of emphysema.99,101 A reduction in the number and caliber of peripheral lung vessels has been consistently reported in the published series100,102–105 (Fig. 45.4). However, the predictive value of vascular attenuation on plain radiographs is questionable.104–106 Moreover, observer disagreement for the recognition of this radiographic sign is high.103,106 Unlike vascular attenuation, hyperinflation is a more robust indicator of emphysema on plain radiographs.104,106 The radiographic signs of hyperinflation in emphysema are no different to those seen in asthma.107,108 Flattening of the diaphragm is typical and is better appreciated on the lateral view.104,106 A consequence of diaphragmatic flattening is the change in the configuration of the cardiac silhouette, the so-called “narrow” heart.107 Bullae (i.e. air spaces >1 cm diameter when distended95) are common in emphysema. However, the demonstration of bullae is not synonymous with disease, since bullae occur in the absence of emphysema. An avascular region demarcated by a thin curvilinear wall is the characteristic radiographic sign. Large bullae, which encroach on the contralateral lung, can have a physiological impact.109 In some patients (commonly those with more severe (centrilobular) emphysema) there are increased markings in the peripheral lung.73 The pathological significance of these increased markings is not clear.
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Fig. 45.4. Chest radiography in a patient with severe air flow obstruction and emphysema. (a) Pulmonary vessels in the upper zones, particularly the right, are attenuated in comparison to the lower zones. (b) Magnified view of the right upper zone in the same patient shows the paucity and distortion of vascular markings.
Table 45.1. Indications for CT in emphysema
• • • •
Evaluation of patients with complex obstructive and restrictive lung function indices Monitoring of “baseline” disease extent (particularly in clinical drug trials) Evaluation of disease distribution to identify “target” areas in patients being considered for lung volume reduction surgery Pre-surgical assessment of bullous disease
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Computed tomography The ability of CT to detect emphysema has been recognized for nearly two decades,110,111 and some of the commoner indications for HRCT in emphysema are given in Table 45.2. The earliest observations (albeit with thick collimation) demonstrated a reduction in global lung density.111 However, the more specific morphological features of centrilobular emphysema were described subsequently: foci of decreased attenuation, usually without visible walls and of nonuniform distribution, are the expected signs on CT.86,112 There is “permeative” parenchymal destruction with distortion of pulmonary vessels, giving a “moth eaten” appearance (Fig. 45.5). It is often possible to identify a focus of high density (the lobular arteriole) in the center of a region of low attenuation with surrounding normal lung. However, with more extensive disease it is sometimes impossible to see the normal lung and, in such cases, foci of low density may appear to have well-defined walls (Fig. 45.6). Centrilobular emphysema is generally most marked in the upper lobes, particular in early disease. With progression the lesions become confluent and the distinction between centrilobular and panacinar emphysema on CT is often blurred.78 The lung destruction, mostly in the lower zones, is more uniform in pure (a-1-antitrypsin-related) panacinar emphysema and there are generalized areas of low density and vascular
attenuation; it is notable that there is no architectural disturbance as shown by the normal disposition of attenuated vessels (Fig. 45.7). The changes of paraseptal emphysema are easily recognized: there are areas of low attenuation, in (a)
(b)
Table 45.2. Recognized radiological signs of centrilobular emphysema on conventional radiography and CT
Chest radiography Hyperinflation Diaphragmatic flattening Diaphragmatic depression Increased retrosternal transradiancy Blunted costophrenic recesses Narrow cardiac silhouette Vascular pruning (diminution in number and caliber of peripheral vessels) Bullae Increased lung markings
(c)
Computed tomography Focal areas of low attenuation (“permeative” parenchymal destruction) No definable wall High density central “dot” (the lobular arteriole) in centrilobular emphysema Upper zone predominance No obvious fibrosis (usually) Vascular pruning Vascular distortion Bullae
Fig. 45.5. Centrilobular emphysema on HRCT in three patients with (a) minimal, (b) extensive, and (c) markedly asymmetric disease. In all cases, there are foci of low density without obvious walls in the upper lobes. Distortion of pulmonary vasculature is most obvious in (b) and (c). The permeative parenchymal destruction results in a characteristic “moth-eaten” appearance.
Imaging
Fig. 45.6. HRCT through the upper lobes. The parenchymal destruction is widespread and many of the areas of decreased attenuation appear to have well-defined walls.
Fig. 45.7. Panacinar emphysema in a-1-antiitrypsin deficiency. HRCT through the lower lobes shows asymmetric low density on the right. Pulmonary vessels are attenuated (compared with similar vessels in the left lung) but there is no achitectural distortion. Note that the subsegmental bronchi in the right lower lobe are probably bronchiectatic but comparison of the airway diameter with the accompanying pulmonary artery is invalid because of the generalized attenuation of the pulmonary vasculature in this case.
the peripheral (subpleural) lung, usually with distinct walls (Fig. 45.8). Utility in the diagnosis of emphysema The validity of a CT diagnosis has been established in studies comparing CT signs with pathologically proven emphysema: nonperipheral areas of decreased attenuation predict the presence of emphysema on histopathological examination.112,113 However, with increasing reliance on a CT diagnosis, the question of whether early or mild emphysema is detectable, has been raised. One study concluded that CT was unreliable for the detection of emphysematous lesions less than 0.5 cm diameter.114 In this study, the extent
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Fig. 45.8. Paraseptal emphysema. There are peripheral areas of low parenchymal attenuation, best seen on the left. The regions of low density have well-defined walls. There is more generalized centrilobular emphysema in the remainder of the lungs.
and severity of emphysema on CT was compared with pathological scores. While there was broad correlation between CT and pathology, it was clear that CT frequently underperformed: there were concordant results between CT and pathology scores in only two patients. The extent of (mild or moderate) emphysema was underestimated in 26 of 29 patients.114 In a separate study, there was a relationship between pathological scores and CT; the conclusion was that CT could distinguish reliably between moderately severe and no (or limited) emphysema.115 However, even in this study the extent of emphysema was often underscored on CT (and consistently so using 5-mm slice thickness). Notably, quantification of extent was more accurate on thin (1 mm) collimation images. Regardless of the arguments, there is no denying the utility of HRCT in the clinical detection of emphysema.116 Moreover, the value of studies in which CT is evaluated against a pathological “gold standard” has perhaps been overstated. The determination of the extent of emphysema by pathologists is not straightforward and the evolution of different histopathological methods for quantification (none of which are entirely satisfactory) is testimony to this.117 Quantifying the extent of emphysema The advent of novel treatments for emphysema, notably lung volume reduction surgery and gene replacement therapy, will inevitably increase the demand for means of accurately staging disease extent and monitoring progress. Unlike plain radiography, objective quantification is possible on CT. Accepted methods for determining the extent of emphysema range from simple visual assessment,113,115 through “density masking”118 and other thresholding techniques119,120 to the most sophisticated computer-aided analyses.121–123 Of the many methods, visual grading has the attraction of expediency, simplicity and low cost. Agreement between experienced readers for quantifying the extent of
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emphysema is acceptable: observer variation between radiologists is less than for nonradiologists.113,115 In one recent study, visual scoring compared favorably with more complex (automated) image analysis.122 There was close correlation between visual and computer-generated estimates of the extent of emphysema. Moreover, the relationships between visual grading and lung function indices were similar or better than those seen with more sophisticated analyses. In one of the earliest tests of objective quantification, a “density mask” program (in which voxels with densities below a specified range are highlighted) was evaluated.118 The correlation between the density mask score of emphysema (with a threshold density of 910 HU) and the pathological scoring was good. However, there were comparable results to visual scoring. Emphysema detected by pathological examination (of between 5 and 20% extent) was missed by both visual grading and density masking in a small proportion of cases.118 Many technical factors can influence the quantification of emphysema on CT.124–126 Owing to the exquisite sensitivity to subtle changes in parenchymal attenuation, variations in the degree of inspiratory effort in the same patient will also affect density measurements.10,127 In this regard, a method for gating of CT scanning to the respiratory cycle may prove useful.128 For computer-aided quantification the density threshold (for detecting areas of decreased attenuation) may be crucial: the area of lung occupied by voxels with density lower than 950 HU, for example, accurately predicts the extent of macroscopic and microscopic emphysema.119,120 Relationships between CT abnormalities and lung function tests The relationships between morphological changes (on CT) and physiological impairment in emphysema are of increasing interest. In other diseases the comparison of CT patterns with functional tests has been helpful in the interpretation of complex functional abnormalities.129–131 Previous studies have compared CT abnormalities with pulmonary function tests in patients with emphysema. In one study, the correlation between CT features (taken to denote “obstructive lung disease”) and functional impairment was poor132 but the data contrasted with the results of another study.133 Using a density mask, Kinsella and colleagues showed that there were strong correlations between CT extent and indices of airflow obstruction and gas transfer.134 Indeed, a recurring message from subsequent studies (with some caveats) is the relationship between the CT extent of emphysema and indices of gas transfer, particularly gas transfer corrected for alveolar volume (Kco).115,120,122,135–138 The relationship between emphysema on CT and Kco is consistent with the view that the latter is a reliable physiological marker of emphysema.37 The mechanisms and site of airflow obstruction in patients with COPD has been widely debated.85,139–141 Theoretically, expiratory obstruction is either because of loss of elastic recoil (due to emphysema per se) or obliteration of small airways. CT has been used in an attempt to address the question. In 56 patients with “fixed” COPD, the correlation
between the CT extent of emphysema and functional indices was poor.136 In 35 patients with severe obstruction (FEV1 50% predicted), only ten had significant emphysema on CT, contrasting with seven patients with mild obstruction (FEV1 70% predicted) of whom two had “significant” CT emphysema. There was strong correlation between gas transfer indices and CT emphysema but only in those patients with an FEV1 1 L.Thus, the conclusion that the functional contribution of emphysema in patients with fixed COPD was insignificant compared with that from intrinsic small airways disease seems valid.136 Second, the concept that indices of gas transfer (specifically Kco) consistently differentiates between emphysema and obliterative small airways diseases142 has been challenged.136 Ancillary imaging techniques Magnetic resonance imaging There has been a renaissance of interest in lung MR imaging.143–145 By supplying a source of protons, the breathing of a hyperpolarized noble gas (typically helium-3 or xenon-3) can increase the MR signal significantly. In normal volunteers, the gas distributes homogeneously to provide a “map” of pulmonary ventilation.146,147 The corollary is that in diseases which alter pulmonary ventilation, such as emphysema, the signal is nonuniform.146 Helium-3 has the advantage over xenon-129 in that it is insoluble in blood and therefore unlikely to cause adverse systemic effects.144 However, against this, is the relative scarcity and expense of helium-3 compared with the relative abundance of xenon129. Clearly, further evaluation of hyperpolarized gas MRI imaging in pulmonary disease is required. Until then, the utility of this sophisticated (and costly) technique remains undefined.
S M A L L A I R WAY S D I S E A S E Abnormalities of the small airways (namely the terminal and respiratory bronchioles) are common95 (Table 45.3). The renaissance of interest in small airways diseases started with the observation that peripheral bronchi contributed little to normal airflow resistance.139 The implication was that significant but physiologically “silent” damage could occur to the small airways.148 The reliable diagnosis of small airways disease has always been problematic: standard physiological tests and plain radiography lack sensitivity and specificity. Part of the problem is the differences in the pathological, physiological and clinical definition of the apparently simple term “small airways disease”.149 Various classifications of small airways disease have been proposed.82,150–152 However, the recent division into constrictive and exudative forms (exemplified by diffuse panbronchiolitis), is simple and has the practical attraction that it accounts for the majority of patients.153 In constrictive obliterative bronchiolitis (the subject of the remainder of the present discussion), the cardinal histopathological feature is submucosal and peribronchiolar
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Table 45.3. Causes and associations of small airways diseases87,153
• Infection (viral, Mycoplasma pneumoniae) • Toxic fume inhalation • Connective tissue disorders (rheumatoid arthritis, Sjögren’s syndrome) • Allogeneic transplantation (heart–lung, lung, bone marrow) • Drugs (penicillamine, Sauropus androgynous) • Bronchiectasis • Extrinsic allergic alveolitis • Sarcoidosis • Follicular bronchiolitis • Inflammatory bowel disease • Asthma • Micro-carcinoid tumorlets
fibrosis, with narrowing and obliteration of the bronchiolar lumen. The causes of constrictive obliterative bronchiolitis are given in Table 45.3. Chest radiography in constrictive obliterative bronchiolitis There is a limited role for plain chest radiography in the diagnosis of obliterative bronchiolitis (OB).154 At best, the plain radiographic features of OB are indirect.155,156 A reduction in the size and number of peripheral vessels is the typical plain chest radiographic manifestations of OB and there may be signs of overinflation.157 Clearly, the plain film signs are nonspecific and, not surprisingly, inconsistently identified.157–159 HRCT in constrictive bronchiolitis In the earliest description of CT in patients with constrictive OB, there were abnormalities in 13 of 15 cases: there were “patchy irregular areas of high and low attenuation in variable proportions, accentuated in expiration”.158 Indeed, the common CT feature in subsequent descriptions has been the heterogeneity of lung parenchymal density (the so-called “mosaic attenuation pattern”)76,81,160 (Fig. 45.9). Areas of decreased attenuation either have poorly defined margins or a well-demarcated geographical outline;161 the higher attenuation regions represent shunting of blood to normally ventilated lung. Vessels within low attenuation areas are typically reduced in caliber and number, but not distorted, as is the case in centrilobular emphysema.76,160,161 The density differences that make up the mosaic pattern may be very subtle on inspiratory CT.88 In such cases, postprocessing of a “slab” of contiguous thin sections may help: in a “minimum intensity projection” image, the lowest attenuation value of adjacent pixels is projected on to the final image.162,163 This technique enhances the detection of subtle areas of low attenuation, encountered in small airways disease and emphysema.163 In the future, more sophisticated
Fig. 45.9. Mosaic attenuation pattern on inspiratory HRCT in constrictive obliterative bronchiolitis. There is herterogeneity of lung parenchymal density; in regions of low attenuation there is a reduction in the number and caliber of pulmonary vessels reflecting vasoconstriction. In contrast, vessels in regions of increased attenuation are of increased dimensions denoting blood redistribution to better ventilated regions of lung.
image processing methods may improve further detection of subtle areas of decreased attenuation.164,165 The practice of performing HRCT at end-expiration has been advocated in patients with suspected OB.87 Normally, as air is expelled, parenchymal density increases homogeneously and there is a decrease in lung cross-sectional area.127,166,167 The implication of a focal or more generalized lack of change in density and cross-section, is that there is air trapping (Fig. 45.10). Clearly, because of dyspnea, some patients will find it difficult to maintain the expiratory effort for the duration of scanning. In this situation, a useful technique is to perform expiratory CT with the patient in the lateral decubitus position.168 In patients with OB, areas of decreased attenuation on inspiratory scans are accentuated on expiratory HRCT images.88,169,170 Although air-trapping can be seen in normal subjects, it is generally of limited extent.166,171 The benefits of expiratory CT, as an adjunct to conventional inspiratory images, have recently been highlighted: expiratory images may detect air-trapping in patients with physiological airflow obstruction but a normal inspiratory study.88 Moreover, observer confidence in the detection of areas of decreased attenuation is improved on expiratory scans.172
FUTURE PROSPECTS FOR THE IMAGING O F O B S T R U C T I V E P U L M O N A RY DISEASES With advances in CT and computer technology in general, it is likely that sophisticated automated quantification of emphysema will become accurate and feasible. The wider
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(a)
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Fig. 45.10. HRCT at the level of the carina in a patient with suspected bronchiectasis. (a) Inspiratory image demonstrates imperceptible differences in parenchymal density which are accentuated on (b) the inspiratory image.
availability of spiral (and multidetector) CT machines will allow the rapid acquisition of “volumetric” images; such data are likely to provide valuable insights into the pathophysiology of obstructive lung disease.173 More detailed analyses of subtle density differences on CT may, in future, not only facilitate more accurate diagnosis, but also stratification of patients presently categorized under the generic term COPD.174–176
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172. Ng CS, Desai SR, Rubens MB, Padley SPG, Wells AU, Hansell DM. Visual quantification and observer variation of signs of small airways disease at inspiratory and expiratory CT. J.Thorac. Imaging. 1999; 14:279–85. 173. Mergo PJ,WilliamsWF, Gonzalez-Rothi R et al.Three-dimensional volumetric assessment of abnormally low attenuation of the lung from routine helical CT: inspiratory and expiratory quantification. Am. J. Roentgenol. 1998; 170:1355–60. 174. Yang GZ, Chabat F, Hansell DM. Enhancement of subtle density differences of the lung parenchma on CT. Br. J. Radiol. 1998; 71:686–90. 175. FotheringhamT, Chabat F, Hansell DM et al. A method for enhancing the detection of areas of decreased attenuation on CT caused by airways disease. J. Comput.Assist.Tomogr. 1999; 23:385–9. 176. O’Brien C, Guest PJ, Hill SL, Stockley RA. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax 2000; 55:635–42.
Assessment of Disability
Chapter
46
Paul W. Jones St George’s Hospital Medical School, London, UK
Asthma and COPD both cause disability. Indeed it may be argued that COPD is characterized as much by disability as by airflow limitation, since patients with this disease rarely present to a physician until they have significant disturbance of their daily activities. Even those patients with COPD who are first identified following an acute exacerbation, almost invariably provide a retrospective account of progressively increasing dyspnea and exercise limitation over a number of years. The reasons for this apparent initial tolerance of disability are not understood.There has not yet been a study of the level of disability in newly diagnosed patients with COPD, but surveys of patients with diagnosed COPD reveal high levels of disturbance to normal daily activities, as shown in Table 46.1.1 While there may have been responder bias in this survey, the impact of the disease is still striking. Patients with asthma have much less physical disability than patients with COPD, although as discussed below, many asthma patients now meet the latest WHO definition for disability.
DEFINITIONS The concept of disability has changed over time and in some respects has become quite complex. The current WHO definition uses the word as an umbrella term to include impairment, activity limitation and participation restriction:
Table 46.1. Disturbances of daily activities reported by 2500 patients with COPD
Activity
% of respondents
Washing/bathing Making the bed Housework Walking outside the house Gardening Climbing stairs
55 59 65 68 75 79
• Impairments include problems in body function (for example lung function or exercise capacity). • Activity limitations are difficulties an individual may have in executing activities (such as mobility or self-care). • Participation restrictions are problems an individual may experience in involvement in life (what an individual does in his or her current environment). It may also be useful to think of the consequences of chronic disease in terms of primary effects in the principal organ affected (the lungs), secondary effects in other organs (e.g. cardiovascular, musculo-skeletal systems) and tertiary effects (disability). Activity limitation and participation restriction are both influenced by the environment in which the patients find themselves. While there is a clear and coherent logic behind the WHO classification, it is not always helpful to combine physical impairment such as exercise limitation that is objectively measureable in the laboratory with activity limitation and participation restriction that occurs in the home or more widely in society. In this chapter, the term disability will be restricted to cover activity limitation and participation restriction and refers specifically to exercise limitation where appropriate. In this respect, the word disability will be used closer to its every day usage rather than with the specific meaning now attached to it by the WHO. It will be noted that the older term “handicap” is no longer used in the WHO classification. The new use of the term disability removes a problem that arose in distinguishing between disability in its previous usage (largely equivalent to the current term activity limitation) and handicap – which involved interaction with the external environment (and is now included under participation restriction). For example, was difficulty washing and dressing a disability or a handicap? The list of activities shown in Table 46.1 illustrates how blurred this distinction could become. It is much better now to think of them all as disabilities. Strictly speaking, the items in Table 46.1 form only one type of disability – activity limitation. Social restrictions are more complex because they depend upon the patient’s specific environment which has physical, social and economic components. They are, therefore, more difficult to specify then many daily activities,
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so they are often described more generically, e.g. restrictions on work, visiting, social functioning, taking recreation etc.
Muscle wasting
MECHANISMS OF DISABILITY It is commonly thought that disability in COPD is due to breathlessness, but there are other factors. Development work for one of the main disease-specific questionnaires designed to measure health status in COPD, the Chronic Respiratory Questionnaire (CRQ), identified fatigue as being an important factor, but not one that patients volunteer unless specifically asked.2 This observation is supported by the finding that patients stop exercising during a symptomlimited ergometer test as much because of leg fatigue as because of breathlessness.3 Until recently it was thought that leg weakness was mainly due to disuse atrophy, but it is becoming clear that loss of lean body mass (cachexia) is an important factor. Acute exacerbations of COPD may be an important contributor to this process through cytokine release triggered by the acute inflammation.4 The mechanism of breathlessness in COPD has been clarified with the recognition that breathlessness is an inspiratory event5,6 related to the work of breathing. The functional residual capacity begins to rise sharply as the FEV1 falls below 50%7 and this has a major effect on the work of breathing. At the onset of exercise this effect is worsened through the development of dynamic hyperinflation.8,9 Recently, it has been shown that parameters of inspiratory lung function may be better correlates of dyspnea than the FEV1.10 While there are well-recognized structural and functional causes of breathlessness, there may be other factors such as impaired mood and reduced expectations of exercise tolerance that will add to patients’ functional disability (and lead to further disuse atrophy of the legs). These potential mechanisms are less well-documented than the physiological pathways, but there is evidence that expectations of exercise performance are more powerful predictors of 6minute walking distance than the FEV1.11 When summarized graphically, it becomes clear that the pathways between disease in the lungs and disability are quite complex even when summarized in a simple model (Fig. 46.1) so it will be difficult to predict disability from measures of expiratory airflow limitation such as the FEV1. In asthma there may be physiological limitations to exercise capacity similar to those in COPD, but impacts on disability may be more through the effect of asthma symptoms on participation – and the effect of triggers of bronchoconstriction such as exercise and environmental factors such as pollen and pollutants.
MEASURING DISABILITY There are no specific respiratory disability questionnaires, but a number of existing questionnaires do assess disability, as now defined, albeit under other names.
Fatigue
Lung disease
Airflow limitation Over-inflation Dynamic hyperinflation V/Q mismatch
Breathlessness
Exercise limitation
Disability
Fig. 46.1. Model of some of the pathways between lung disease and its resulting disability.
Dyspnea scales The simplest disability measure is the MRC Dyspnea Scale (Fig. 46.2). Although described as a dyspnea scale, this is really a scale of activity limitation due to breathlessness. It is the most widely used respiratory disability measure and can be translated into different languages with little ambiguity. It is simple to use and score. A recent validation in COPD patients has shown that it does discriminate between different levels of disability, at least in the three most severe grades.12 It has only three minor weaknesses. • Its simplicity is achieved at the cost of precision. The scale is quite coarse, with only five grades. This is not a weakness when making cross-sectional comparisons between patients or populations of patients, but it is a problem when used to assess change following therapy, since large changes in disability are required to move the patient from one grade to the next. • It combines two activity limitations within one grade, e.g. grade 5: difficulty dressing and leaving the house. Using factor analysis of acitivites limited by breathlessness during the development of the St George’s Respiratory Questionnaire (SGRQ), we found that such limitations were highly correlated (Jones, unpublished observations), but no formal analysis has ever been published of the validity of combining these aspects of disability. • There are two methods of scoring: 0–4 (widely used in the USA) and 1–5 (USA, UK, and elsewhere). Whenever the MRC grade is reported the scale must be reported as
Assessment of Disability
Grade 1
Breathless with strenuous exercise
Grade 2
Short of breath when hurrying on the level or walking up a slight hill
Grade 3
Walk slower than people of the same age on the level or stop for breath while walking at own pace on the level
Grade 4
Stop for breath after walking about 100 yards or after a few minutes on the level
Grade 5
Too breathless to leave the house or breathless when dressing or undressing
Fig. 46.2. MRC Dyspnea Scale.
well. Despite these minor deficiencies, this questionnaire provides a most valuable method of making standardized estimates of disability in chronic lung disease. A more sophisticated measure of disability due to breathlessness is the Baseline Dyspnea Index (BDI).13 This clinician-administered instrument provides an index of functional impairment by addressing the magnitude of the task and the magnitude of effort associated with it. There is an associated scale, the Transition Dyspnea Index (TDI) which quantifies the change in breathlessness. This is largely a research tool, but unlike the MRC scale the TDI has been shown to be responsive to therapy.14 Another comprehensive dyspnea questionnaire is the UCSD Shortness of Breath Questionnaire.15 This is a 24item questionnaire, that can be completed by the patient themselves. It has good reliability and validity, although like the BDI and TDI it is largely a research instrument that has found extensive use in pulmonary rehabilitation. Functional limitation questionnaires As their name implies, these questionnaires record limitations of function, but not necessarily just those that require physical activity. The most comprehensive questionnaire of this type is the Sickness Impact Profile (SIP).16 It has 136 items and is also often classified as a general health measure since it covers a wide range of functions, both physical and psycho-social. It was widely used in COPD studies 10–20 years ago17 but has largely been abandoned because of its size and the relatively low level of content relevant to COPD – which results in low severity scores even in patients with severe disease. Two comprehensive function limitation questionnaires have been developed specifically for COPD, the modified Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ-M)18 and the Pulmonary Functional Status Scale (PFSS).19 Both largely cover physical functions and have found application most widely in the context of pulmonary rehabilitation, especially in the USA.
483
Activity of daily living scales Disability also includes limitations of activities of daily living (ADL). Use of this term is usually restricted to basic selfcare and mobility around the home, so questionnaires of this type tend to be more suitable for patients at the severe end of the spectrum. The Nottingham Extended Activity of Daily Living Scale, developed for patients with stroke, has been shown to have validity in COPD,20 and recently a new ADL questionnaire specifically for COPD has also been described.21 Disability as a component of health status questionnaires Disability forms an important, but not the sole, component of impaired health status (“health-related quality of life”). General health status questionnaires such as the SF-36 address disability, and the physical function component of that questionnaire provides a general measure of disability that has been shown to improve following pulmonary rehabilitation.22 The two most widely used disease-specific health status measures for COPD, the CRQ23 and SGRQ,24,25 both have components that reflect disability in terms of activity limitation and participation restrictions. The CRQ Dyspnea component has the strength that it allows the patient to identify activities restricted by breathlessness that are important to them. The disadvantage with this approach is that it is not standardized, so does not allow direct comparisons between patients. Two components of the SGRQ reflect disability, the Activity score and the Impacts score. These are both standardized. The Activity component is largely concerned with activity limitation.The Impacts score examines participation, but it also addresses other aspects of mood and impaired well-being. This is reflected in the partial correlations between these scores and other measures of disease activity. The Activity score correlates only with the MRC Dyspnea grade and 6-minute walking distance, whereas the Impacts score correlates with these but also with mood state and respiratory symptom level.25 Asthma may induce disability, both through dyspneainduced exercise limitation and through the effect of the disease or the impact of the environment on the patients’ ability to participate in activities of their choice or play a full role in their family and society at large. Two different disease-specific questionnaires, both termed Asthma Quality Of Life Questionnaire (AQLQ),26,27 address activity limitation through their Breathlessness and Dyspnea components. Participation restriction is not addressed specifically, but elements of it are reflected in the Social subscale of the AQLQ by Marks et al.26 and the Environment component of the AQLQ by Juniper et al.27 The SGRQ is also validated for use in asthma. It is noteworthy that in all of the disease-specific questionnaires for asthma and COPD, activity limitation is contained within clearly identified components but participation restriction is addressed only partially under a number of headings.
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Asthma and Chronic Obstructive Pulmonary Disease
WHY MEASURE DISABILITY? COPD is characterized by disability that results, not only from breathlessness, but also through secondary effects on other organs such as musculo-skeletal function. It is not surprising, therefore, that the association between FEV1 and activity limitation is too weak to permit a reliable estimate of disability from a measure of airways function (Fig. 46.3). There is a much better association between exercise tolerance (physical impairment) and activity limitation. For example, the correlation between 6-minute walking distance and SGRQ Activity score is rather higher.25 This supports the WHO approach of combining physical impairment and activity limitation under the umbrella term of disability. Another important feature of the relationship between activity limitation and disability shown in Fig. 46.3 is the fact that many patients with mild airways obstruction have marked levels of disability. As pointed out earlier, this is due to the complex etiology of disability in COPD. Measurements of disability have an important role in assessing the response to therapy, since this is an important treatment outcome, especially for pulmonary rehabilitation. There is strong evidence that rehabilitation can reduce disability by a clinically significant amount.28 Disability is also a prognostic factor in COPD. Two studies in patients who had received pulmonary rehabilitation have shown that 6and 12-minute walking distances and PFSS score were all predictors of mortality.29,30 In those studies, the FEV1 was only a weak predictor of mortality compared with the measures of disability. It is perhaps worth noting that the CRQ Dyspnea score was also measured in one of the studies.29 It proved to be only a weak predictor of mortality and this is almost certainly due to its unstandardized nature. In this component of the CRQ, the patients are allowed to choose and scale seven activities that are important to them. This approach was adopted by the questionnaire’s authors to increase its sensitivity to change (i.e. its evaluative
SGRQ activity score
(Severe disability) 100
(No disability)
80 60 40 20 0 10
20
30
40 50 60 70 FEV1 (% predicted)
80
90
100
Fig. 46.3. Relationship between post-bronchodilator FEV1 and disability measured using the SGRQ Activity score in COPD.
properties). This may have been at the expense of its ability to distinguish different levels of disease between patients (discriminative property).
LONG-TERM PROGRESSION OF DISABILITY COPD and to a much lesser degree, asthma, are recognized as progressive diseases in terms of their airways function. More recently, it has been recognized that disability worsens with COPD31 and that high-dose inhaled corticosteroid (fluticasone proprionate 500 lg twice a day) may reduce the rate of decline by 38%.32 The mechanism of action is not clear, but may be related to a reduction in exacerbation rate since the exacerbation rate is reduced by fluticasone, but not the rate of decline of FEV1. One postulated mechanism is that exacerbations reduce exercise level for a period leading to further disuse atrophy of the muscles. They may also break a pattern of routine exercise established following a pulmonary rehabiliation. In addition, there is evidence for cytokine release during an acute infection that may cause loss of lean body mass.4 Finally, proximal muscle more severe exacerbations are treated with courses of oral steroids that may cause further loss of strength.33 Thus, each exacerbation may reduce exercise performance through a number of mechanisms and the cumulative effect of repeated exacerbations may be a faster progression of disability.
MEASUREMENTS OF DISABILITY IN ROUTINE PRACTICE Assessment of disability clearly has an important role in COPD that complements spirometry. Reliance on the FEV1 would fail to identify the true impact of the disease in many patients with COPD, as shown in Fig. 46.3. Most of the available questionnaires are too complex to use in everyday practice. Field exercise tests such as the timed walking tests measure physiological impairment and are quite closely correlated with respiratory-induced activity limitation,34 but still require time and technical support. The MRC dyspnea scale does meet criteria for ease of use and standardization and can be used in any clinical setting whether primary care or specialist clinic. It is even simpler to obtain valid measurements of breathlessness-induced activity restriction using this measure than it is to obtain good quality postbronchodilator spirometric measurements. The data in Fig. 46.4 show that the relationship between FEV1 and MRC Dyspnea grade is weak. The important implication of this is that the FEV1 may not reflect the level of the patient’s disability. Eighteen percent of patients with MRC grades 4 and 5 had a post-bronchodilator FEV1>50% (i.e. mild COPD using the ATS criteria). By contrast, the association between MRC grade and 6-minute walking distance is rather stronger. It appears that the FEV1 and MRC dyspnea grade provide different but complementary pieces of information
FEV1 (% predicted)
Assessment of Disability
75 70 65 60 55 50 45 40 35 30 25
6-minute walking distance (m)
500 450 400 350 300 250 200 150 1
2
3 Grade
4
5
Fig. 46.4. Postbronchodilator FEV1 and 6-minute walking distance at different MRC dyspnea grades.
about the severity of COPD. In view of the prognostic value of disability measurements, their importance in terms of reflecting a broader impact of the disease and the potential that pulmonary rehabilitation offers patients with COPD, a clear case can be made for routine recording of MRC dyspnea grades in patients with COPD. This may not be so important in asthma since that disease causes less disability, but the absence of major disability in asthma can be readily confirmed using this simple measure.
REFERENCES 1. British Lung Foundation. Living with Chronic Obstructive Pulmonary Disease. London: British Lung Foundation, 2000. 2. Guyatt GH, Berman LB, Pugsley SO et al. Development of a responsive measure of quality of life for patients with chronic cardiorespiratory disease. Clin. Res. 1984; 32:222. 3. Killian KJ, Summers E, Jones NL, Campbell E. Dyspnea and leg effort during incremental cycle ergometry. Am. Rev. Respir. Dis. 1992; 145:1339–45. 4. Schols AMWJ, Buurman WA, Staal-van den Brekel AJ, Dentener MA, Wouters EFM. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 1996; 51:819–24. 5. Burns BH, Howell JBL. Disproportionately severe breathlessness in chronic bronchitis. Quart. J. Med. 1969; 38:277–94.
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6. Chapman KR, Rebuck AS. Inspiratory and expiratory loading as a model of dyspnea in asthma. Respiration 1983; 44:425–32. 7. Begin R, Bureau M, Lupien L, Bernier JP, Lemiuex B. Pathogenesis of respiratory insufficiency in myotonic dystrophy. Am. Rev. Respir. Dis. 1982; 125:312–18. 8. O’Donnell DE, Webb KA. Breathlessness in patients with severe chronic airflow limitation: physiological correlates. Chest 1992; 102:824–31. 9. O’Donnell DE, Webb KA. Exertional breathlessness in patients with chronic airflow limitation: the role of hyperinflation. Am. Rev. Respir. Dis. 1993; 148:1351–7. 10. Taube C, Lehnigk B, Paasch K, Kirsten DK, Jörres RA. Factor analysis of changes in dyspnea and lung function parameters after bronchodilation in chronic obstructive pulmonary disease. Am. Rev. Respir. Crit. Care Med. 2000; 162:216–20. 11. McGavin CR, Artvinli M, Naoe H, McHardy GJR. Dyspnoea, disability and distance walked: comparison of estimates of exercise performance in respiratory disease. Br. Med. J. 1978; 2:241–3. 12. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999; 54:581–6. 13. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. Measurements of dyspnea. Contents, interobserver correlates of two new clinical indices. Chest 1984; 85:751–8. 14. Mahler DA, Donohue JF, Barbee RA et al. Efficacy of salmeterol xinofoate in the treatment of COPD. Chest 1999; 115:957–65. 15. Eakin EG, Resnikoff PM, Prewitt LM, Ries AL, Kaplan RM. Validation of a new dyspnea measure. Chest 1998; 113:619–24. 16. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The Sickness Impact Profile: development and final revision of a health status measure. Med. Care 1981; 19:787–805. 17. Jones PW. Quality of life measurement for patients with diseases of the airways. Thorax 1991; 46:676–82. 18. Lareau SC, Breslin EH, Meek PM. Functional status instruments: outcome measure in the evaluation of patients with chronic obstructive pulmonary disease. Heart Lung 1996; 25:212–24. 19. Weaver TE, Narsavage GL, Guilfoyle MJ. The development and psychometric evaluation of the Pulmonary Functional Status Scale: an instrument to assess functional status in pulmonary disease. J. Cardpulm. Rehabil. 1998; 18:105–11. 20. Okubadejo AA, O’Shea L, Jones PW, Wedzicha JA. Home assessment of activities of daily living in patients with severe chronic obstructive pulmonary disease on long-term oxygen therapy. Eur. Respir. J. 1997; 10:1572–5. 21. Garrod R, Bestall JC, Paul EA, Wedzicha JA, Jones PW. Development and validation of a standardized measure of activity of daily living in patients with severe COPD: the London Chest Activity of Daily Living scale (LCADL). Respir. Med. 2000; 94:589–96. 22. Griffiths TL, Burr ML, Campbell IA et al. Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial. Lancet 2000; 355:362–8. 23. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax 1987; 42:773–8. 24. Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir. Med. 1991; 85:25–31. 25. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A selfcomplete measure for chronic airflow limitation – the St George’s Respiratory Questionnaire. Am. Rev. Respir. Dis. 1992; 145:1321–7. 26. Marks GB, Dunn SM, Woolcock AJ. A scale for the measurement of asthma quality of life questionnaire in adults with asthma. J. Clin. Epidemiol. 1992; 45:461–72. 27. Juniper EJ, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax 1992; 47:76–83.
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28. Lacasse Y, Wong E, Guyatt GH, King D, Cook DJ, Goldstien RS. Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. Lancet 1996; 348:1115–19. 29. Geradi DA, Lovett L, Benoit-Connors ML, Reardon JZ, Zu Wallack RL. Variables related to increased mortality following out-patient pulmonary rehabilitation. Eur. Respir. J. 1996; 9:431–5. 30. Bowen JB, Votto JJ, Thrall RS et al. Functional status and survival following pulmonary rehabilitation. Chest 2000; 118:697–703. 31. Spencer S, Calverley PMA, Burge PS, Jones PW. Health status deterioration in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 163:122–8.
32. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br. Med. J. 2000; 320:1297–303. 33. Miravitlles M, Murio C, Guerro T, on behalf of the DAFNE Study Group. Factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. Eur. Respir. J. 2001; 17:928–33. 34. Guyatt GH,Thompson PJ, Berman LB, Sullivan MJ,Townsend M, Jones NL, Pugsley SO. How should we measure function in patients with chronic lung disease? J. Chron. Dis. 1985; 38:517–24.
Allergen Avoidance Adnan Custovic and Ashley Woodcock North West Lung Centre, Wythenshawe Hospital, Manchester, UK
Allergen avoidance in the treatment of allergic disorders dates from the sixteenth century. The Italian physician, Gerolamo Cardano (1501-1576), was invited to Scotland by the Archbishop of St. Andrews to give advice on the treatment of his asthma.' Cardano recommended that the Archbishop should get rid of his feather bedding, which was followed by a "miraculous" remission. T h e first controlled attempts to treat asthma by environmental manipulation began in the early twentieth century.^'^ In 1925 the Leopold brothers treated patients with asthma and other allergic disorders by moving them into a dust-free room.^ Storm van Leeuwen created a "climate" chamber in Holland in 1927 and demonstrated that asthmatic patients improved when moved from their homes into the chamber.^ The effectiveness of allergen reduction in the treatment of asthma was suggested by studies in the low-allergen environment of high-altitude sanatoria.''"* However, the real challenge has been to create a low-allergen environment in patients' homes. Although not easy, it is possible to achieve sub-
stantial reductions in allergen exposure. Effective control strategies should be tailored to individual allergens, flexible to suit individual needs, and cost-effective.
DISTRIBUTION AND AERODYNAMIC PROPERTIES OF I N D O O R ALLERGENS RELEVANCE T O A V O I D A N C E Allergens from mites, cats, dogs, and cockroaches have different aerodynamic properties.'"' Mite and cockroach allergens can be detected in the air in significant amounts only after vigorous disturbance, and are predominantly contained within relatively large particles ( > 1 0 |im diameter).' In contrast, air-borne cat and dog allergens are readily measured in houses with pets (and in a quarter of the homes without pets; Fig. 47.1), and ~25% of air-borne Fel d 1 and Can f 1 is associated with small particles ( < 5 |im diameter); Fig. 47.2.8'''
Homes with dogs
10,000
O Homes without dogs
1000
"D J3)
a
o
100
10
•••••• •••••••
••'ift
o
• •
Or
§8 of
0.1
000006860000 000 Mattress
GOOOOo •o~
Bedroom carpet
Living room carpet
Upholstered furniture
Fig. 4 7 . 1 . Dog allergen levels in homes with and without dogs. Reproduced from Reference 9, with permission.
490
Asthma and Chronic Obstructive Pulmonary Disease
80
Der p 2
Can f 1
70 60
%
50 40 30 20 10 0 >4.7
3.3–4.7
2.1–3.3 µm
1.1–2.1
0.65–1.1
Fig. 47.2. The particle size distribution of air-borne Der p 2 and Can f 1 after artificial disturbance. Reproduced from Reference 7, with permission.
These differences in the aerodynamic characteristics of allergens underlie the difference in the clinical presentation of the disease. Mite- and cockroach-sensitive asthmatics are usually unaware of the relationship between allergen exposure at home and asthma symptoms (exposure is low-grade and chronic), whereas cat or dog allergic patients often develop symptoms within minutes of entering a home with a pet. Furthermore, this implies that air filtration may be useful in removing cat and dog allergen from the air, but has no place in mite or cockroach avoidance. The bed is the most important source of mite allergens and lowering exposure in the bedroom is the primary target of avoidance, while the majority of exposure to pet allergens may occur in the living room area.
CONTROL OF HOUSE DUST MITES AND MITE ALLERGENS Bed and bedding The most effective and probably the most important avoidance measure is to cover the mattress, pillows and duvet with covers that are impermeable to mite allergens. Allergen levels are dramatically reduced after the introduction of covers,10 which should be robust, easily fitted and easily cleaned, as their effectiveness is reduced if they are damaged. Several randomized controlled trials have suggested benefits of such an intervention on symptoms, airway responsiveness and medication use (reviewed in Reference 11). All exposed bedding should be washed at 55°C (the temperature that kills mites).12 Additives for detergents providing a concentration of 0.03% benzyl benzoate, or dilute solutions of essential oils in normal- and low-temperature washing provide alternative methods of mite control.13
Carpets and upholstered furniture Carpets are an important microhabitat for mite colonization and a possible source from which beds can be reinfested. Fitted carpets should ideally be replaced with polished wood or vinyl flooring. Exposure of carpets to direct strong sunlight may be used in loosely fitted carpets in certain climatic areas.14 Alternatively, high-pressure steam cleaning may be utilized as a method of killing mites and reducing allergen levels in carpets.15 A number of different chemicals that kill mites (acaricides) have been identified, and shown to be effective under laboratory conditions.16 However, data on whether these chemicals can be successfully applied in homes to control the mite population in carpets and upholstered furniture are conflicting.17 The main problems of chemical treatment are how to get the chemicals to penetrate deep into carpets and soft furnishings, the persistence of mite allergen until recolonization occurs, and the nuisance of frequent reapplications. Freezing with liquid nitrogen can kill mites.18 However, the technique can only be carried out by a trained operator, which limits its use, especially since treatment needs to be repeated regularly. Both acaricides and liquid nitrogen need to be combined with intensive vacuum cleaning following administration. Due to its protein-denaturing properties, tannic acid has been recommended for the reduction of allergen levels in house dust. However, high levels of proteins in dust (e.g. home with a cat) block its effect.19 Intensive vacuum cleaning may remove large amounts of dust from carpets, reducing the size of the allergen reservoir. However, vacuum cleaners with inadequate exhaust filtration may increase air-borne allergen levels during use.20 Thus, atopic asthmatic patients should use high-effeciency particulate arrest (HEPA)-filter vacuum cleaners with double thickness vacuum cleaner bags. High levels of humidity are essential for mite population growth and reducing humidity may be an effective control
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Allergen Avoidance
method, but only in areas with appropriate climatic and housing conditions.21–23 Reducing humidity by mechanical ventilation should be used in those regions where the outdoor humidity is low for at least part of the year.24 Owing to the aerodynamic characteristics of mite allergens, it makes little sense to use air filtration units and ionizers as a way of reducing personal exposure. Since mites live in different sites throughout the house, it is unlikely that a single measure can solve the problem of exposure, and an integrated approach including barrier methods, dust removal and removal of mite microhabitats is needed (Table 47.1). One such regimen was recently used and shown to be highly effective in achieving and maintaining a very low-allergen environment in homes of children at high risk of allergic disease.25 Although many of these interventions can reduce mite allergen levels in the environment, the effects on symptoms are not always clear. Indeed, a meta-analysis of house mite avoidance trials suggested that this approach should not be used in the treatment of asthma,26 suggesting that a single intervention may be insufficient. However, this metaanalysis was justifiably subjected to criticism27,28 and much more data are needed before definitive recommendations can be made.
P E T A L L E R G E N AV O I D A N C E Complete avoidance of pet allergens is all but impossible, as sensitized patients can be exposed to pet allergens not only in homes with pets, but also in homes without pets and in public buildings and on public transport (Fig. 47.3).29–32 The best way to reduce high-level exposure to cat or dog allergen is to remove the animal from the home. Even after permanent removal of the animal, it can take many months before reservoir allergen levels decrease.33 Unfortunately, despite continued symptoms, many pet allergic patients refuse to get rid of their pet. Thus there have been attempts to develop strategies for reducing personal exposure, while allowing these patients to keep their pets. Control of air-borne allergen levels with a pet in the home Air-borne pet allergen levels immediately increase by approximately five-fold when the pet is in the room, indicating that the presence of a pet contributes to current airborne allergen levels.9 The pet should be kept out of the bedroom, and preferably outdoors. Several studies on allergen levels have investigated the effects of washing cats.34–37 Washing dogs in a bath, using a hand-held shower unit and
Table 47.1. Measures for reducing house dust mite allergen exposure
Measure
Evidence level for effectiveness in reducing allergen
Evidence level for clinical effectiveness
Encase mattress, pillow and quilt in impermeable covers
Ib
Ib
Wash all bedding in the hot cycle (55–60°C) weekly
IIb
IV
Replace carpets with linoleum or wood flooring
Ib
IV
Treat carpets with acaricides and/or tannic acid
IV
IV
Minimize upholstered furniture/replace with leather furniture
IV
IV
Keep dust-accumulating objects in closed cupboards
IV
IV
Use a vacuum cleaner with integral HEPA filter and double thickness bags
IIb
IV
Replace curtains with blinds or easily washable (hot cycle) curtains
IV
IV
Hot wash/Freeze soft toys
IV
IV
Evidence level was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) recommendations as follows: Ia Evidence obtained from meta-analysis of randomized controlled trials Ib Evidence obtained from at least one randomized controlled trial IIa Evidence obtained from at least one well-designed controlled study without randomization IIb Evidence obtained from at least one other type of well-designed quasi-experimental study III Evidence obtained from well-designed nonexperimental descriptive studies, such as comparative studies, correlation studies and case studies IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
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Asthma and Chronic Obstructive Pulmonary Disease
100
o o 10
8o
oo ••
o
go o
o o«o oo
Oo
o
0.1 Carpets
Public houses
Seats
Carpets
'
Cinema
Seats
Carpets
Seats
Mattress
Hotel -
'
Carpets
Seats
School
Public transport
Fig. 47.3. Dog allergern \n public buiidirngs arid orn public trarnsport. Based orn data from Reference 30, with permissiorn.
shampoo and rinsing thoroughly, produced substantial but short-lived falls in recovered Can f 1 (Fig. 47.4).^*The main benefit of washing pets regularly (twice weekly) may be the reduction in the build-up of allergen in dust reservoirs, but this too is unproven. Air-borne pet allergens in homes with pets can be reduced by the use of HEPA air cleaner.^' In patients who are allergic to cats or dogs and persist in keeping their pet we propose the set of measures listed in Table 47.2. However, the clinical effectiveness of these measures remains unproven.
50 o
40 o
30 E
o
D) C T—
A V O I D A N C E OF C O C K R O A C H ALLERGENS In areas where housing conditions sustain large cockroach populations, both physical and chemical control measures have been tried (reviewed in Reference 11). Reducing access to food and water is critical, thus waste food should be removed and surface water should be contained by reducing leakage through faulty taps and pipework, and reducing condensation by improved ventilation. Cockroach access can be restricted by caulking and sealing cracks and holes in the plasterwork and flooring. Several chemicals are marketed for controlling cockroach infestation, including diazinon, chlorpyrifos, and boric acid. The most useful for patients with allergic disease are bait stations, where the chemical (hydramethylnon, avermectin) is retained within a plastic housing. A paste formulation of hydramethylonon may be used on cockroach runways and underneath counters, etc. Bait stations are generally effective at reducing cockroach numbers for 2-3 months. Attempts to reduce cockroach allergen exposure rely on improving patient education and concerted attempts by pest control companies and public
•
M -
o
o
20
•
0
10
A
g • 8 1
Baseline
•
A
T
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s
B
1
2
•
8 ^
O
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8
V A
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8 4^
X
V
2
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6
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Fig. 47.4. Major dog allergern Carn f 1 recovered from the samples of dog hair irn 1 5 dogs before, arid orn 7 days after washirig the dogs. Washirngthe dog reduces dog al lergern levels (but the dog rneeds to be washed twice a week). Reproduced from Referernce 38, with permissiorn.
health departments to reduce cockroach infestation. To date, they have not produced prolonged falls in allergen exposure or measurable benefits for patients.
493
Allergen Avoidance
Table 47.2. Measures for reducing pet allergen exposure
Measure
Evidence level for effectiveness in reducing allergen
Evidence level for clinical effectiveness
IIb
IV
Keep the pet out of the main living areas and bedrooms
IIb
IV
Install HEPA air cleaners in the main living areas and bedrooms
IIb
IV
Have the pet washed twice a week
IIb
IV
Thoroughly clean upholstered furniture/Replace with leather furniture
IV
IV
Replace carpets with linoleum or wood flooring
IV
IV
Use a vacuum cleaner with integral HEPA filter and double thickness bags
IV
IV
Remove cat/dog from the home If the pet cannot be removed:
Evidence level was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) recommendations as follows: Ia Evidence obtained from meta-analysis of randomized controlled trials Ib Evidence obtained from at least one randomized controlled trial IIa Evidence obtained from at least one well-designed controlled study without randomization IIb Evidence obtained from at least one other type of well-designed quasi-experimental study III Evidence obtained from well-designed nonexperimental descriptive studies, such as comparative studies, correlation studies and case studies IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
MOLDS Mold exposure may have an allergen-specific effect on sensitization, but also a nonspecific effect on the immune system facilitating sensitization to other allergens (perhaps via mycotoxins and b-glucans). Removing or cleaning moldladen objects may reduce the number of fungal spores. Maintaining a low humidity (less than 50%) could be important, but may be difficult to achieve in areas with a humid climate. Care should be taken to make sure that if dehumidifiers or air conditioners are used, they do not become contaminated with molds and thus form a new source of allergens or nonspecific irritants. In tropical and subtropical climates, fungi may grow on house walls because of water leakage and humidity. To avoid this, walls can be tiled or should be cleaned as necessary.
AV O I D A N C E O F O U T D O O R A L L E R G E N S The outdoor allergens that most often produce symptoms in susceptible people are pollens and mold spores, but the thresholds required for clinical impact remain to be determined. Although outdoor pollen and molds are impossible to avoid completely, exposure may be reduced by
closing windows and doors, remaining indoors when pollen and mold counts are highest, and using air conditioning with HEPA filters. Knowledge of a patient’s sensitivity to specific allergens may be useful for giving advice about the timing and location of that patient’s travel. In patients who are allergic to pollen we propose the set of measures listed in Table 47.3.
A L L E R G E N AV O I D A N C E I N T H E T R E AT M E N T O F A S T H M A The rationale for the use of allergen avoidance in the treatment of asthma is based on the suggestion that allergen exposure increases asthma severity in sensitized individuals. Allergen exposure and asthma severity Allergen exposure has been related to disease severity.40–43 Following a controlled or seasonal exposure to allergens, sensitized subjects experience an increase in airway reactivity.44 Exposure to Alternaria allergen has been shown to be a risk factor for sudden respiratory arrest in asthmatics.45 Sensitization to mites, cat, and cockroach was found to be a significant risk factor for acute asthma in patients admitted to the hospital Emergency Department in Charlottesville,
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Asthma and Chronic Obstructive Pulmonary Disease
Table 47.3. Measures for reducing grass pollen exposure
Keep car doors and windows tightly shut Avoid open grassy spaces, particularly late afternoons and evenings Consider fitting a car pollen filter Consider taking your holiday during June-July by the sea or abroad (for example Southern Europe)
VA, USA.46 A case-controlled study on patients presenting to an emergency room in Wilmington, DE, USA confirmed a very strong relationship between sensitization to indoor allergens and acute asthma.47 Further data, however, did not establish, or refute, a quantitative relationship between current exposure and the risk of acute asthma among sensitized individuals admitted to hospital.48,49 Showing a direct relationship between allergen exposure and disease severity has always been difficult due to the number of possible confounding factors. Asthmatic patients are often sensitized and exposed to more than one allergen, and relative contribution of each one is sometimes difficult to elucidate. Furthermore, viral infections are known to be important triggers of asthma symptoms.
EVIDENCE FROM EPIDEMIOLOGICAL STUDIES In a comparison of the relationship between mite allergen exposure and asthma, Peat et al.50 investigated two population samples of Australian children living in Lismore (a hot, humid, coastal region) and Moree/Narrabri (a hot, dry, inland region). Mite allergen levels were seven-fold higher by the coast, and airway reactivity (assessed by histamine challenge test) in children sensitized to mites was more severe in coastal children. In a further population-based epidemiological study, Peat et al.51 found that mite-allergic children with asthma had more reactive airways when living in the areas where mite allergen levels are high compared to areas where exposure to mites is low. There is further indirect epidemiological evidence that a high level of exposure to allergens may be associated with asthma symptoms in the UK. Strachan and Carey52 showed that the most powerful risk factors for severe asthma in 11to 16-year-old children were pet ownership and nonfeather bedding. The authors estimated that if the association between nonfeather pillows and severe asthma was causal, it could account for 53% of the severe asthma in the studied population. It has recently been demonstrated that polyester pillows contain five to eight times more mite, cat, and dog allergen than do feather pillows.53–55
ALLERGEN EXPOSURE INCREASES ASTHMA SEVERITY IN SENSITIZED PAT I E N T S A significant correlation has been observed between objective measures of asthma severity and mite allergen levels in the beds of subjects with positive skin tests to mites, but no relationship was seen in those who had negative skin test.56 A study on exposure to mite allergen and pediatric hospital admissions in the UK has shown that the majority of children admitted to hospital with exacerbation of asthma were both sensitized and exposed to mite allergen.57 It also suggested that continued exposure to higher concentrations of mite allergen might be associated with the risk of readmission. There is probably a considerable variability between individuals in the magnitude of response to the same levels of allergen exposure. In a group of individuals with similar levels of IgE antibodies, some will develop symptoms only if they are exposed to high levels of allergens, while others require very low exposure to maintain symptoms – i.e. the level of exposure necessary to induce and maintain airway inflammation, airway reactivity and symptoms varies over a wide range. However, a pattern emerges in which sensitized patients will have more severe disease if their exposure to offending allergen is high, than when it is low. A recent case–control study in Birmingham, UK, has shown that patients with brittle asthma (with frequent physician contacts and high medication requirements), are significantly more often both sensitized and exposed to high levels of allergens (especially to pets) to which they are allergic, compared with patients with mild disease.58 A further study has demonstrated that exhaled NO, a marker of airway inflammation, is much higher in asthmatics who are both sensitized and exposed to the relevant allergen compared with those that are sensitized, but not exposed.59 In the recent National Co-operative Inner-City Asthma Study in the USA, children from eight major inner city areas were assessed for atopy and exposure to allergens in their home.60 Almost 37% of children were allergic to cockroach allergen. Those children who were both allergic to cockroaches and exposed to high levels of cockroach allergens in the dust had 3.5-fold higher hospitalization rates, more unscheduled medical visits for asthma per year, more missed school days, more days of wheezing and nights with disturbed sleep compared with all other children. Neither increased exposure to cockroach allergen alone, nor allergy to cockroaches by itself, was associated with greater morbidity.
ALLERGEN EXPOSURE AND RESPONSE T O T R E AT M E N T A recent study by Nimmagadda et al.61 provides evidence that allergen exposure may confound the pharmacological management of the disease. The effect of allergen exposure
Allergen Avoidance
on glucocorticosteroid receptor (GCR)-binding affinity and GC responsiveness of peripheral blood mononuclear cells (PBMCs) was investigated in atopic asthmatics both in vivo and in vitro. The effect of in-vivo exposure was tested in ragweed-allergic asthmatics, before, during and after the ragweed pollen season. A significant reduction in GCRbinding affinity was observed during the pollen season as compared with pre- and post-season measurements. The effect of in-vitro allergen exposure was also determined by incubating PBMC of atopic asthmatics with either the relevant allergen to which they were sensitized or Candida albicans (as a control). PBMC of ragweed allergic asthmatics obtained outside the pollen season and of cat allergic patients not exposed to cats, had significantly reduced GCR-binding activity after incubation with ragweed and cat allergen, respectively, compared with both baseline and Candida albicans stimulation. The observed effect appears to be allergen specific, and is restricted to atopic asthmatic patients (i.e. no similar effect was found in atopic nonasthmatic individuals or nonatopic subjects). Furthermore, the allergen-induced reduction in GCR-binding activity of PBMCs from atopic asthmatics made the lymphocytes significantly less responsive to the inhibitory effect of hydrocortisone. The finding that allergen exposure can reduce GCR binding activity in atopic asthmatics both in vivo and in vitro, with the resulting functional alteration in cellular response to glucocorticoids, could suggest that high allergen exposure in sensitized individuals may contribute to poor asthma control and maintenance of the inflammatory process in the airways by reducing the effectiveness of treatment with inhaled steroids.
CLINICAL TRIALS Having explored various methods of allergen avoidance and the relationship between allergen exposure and asthma severity, the important question is whether allergen avoidance in homes by these techniques improves asthma control in sensitized patients. This is an area of controversy, mainly because of the inadequacies of the clinical studies on allergen avoidance. Lessons from occupational asthma Occupational asthma is a useful model for the study of asthma. The essential first step in assessing patients with suspected occupational asthma is to identify the causal agent. Early diagnosis and removal from exposure were found to be associated with recovery,62 and this is true both for occupational asthma caused by low molecular weight and high molecular weight agents.63 Determinants of the unfavorable prognosis are long duration of exposure before the onset of symptoms, long duration of symptoms before diagnosis and dual response after specific challenge test.64 Further occupational exposure in sensitized subjects leads to persistence and sometimes progressive deterioration of
495
asthma.65 Thus, early detection of the offending agent and immediate cessation of exposure are important factors for favorable prognosis.65 The studies in occupational asthma clearly indicate that: • it is crucially important to identify the sensitizing agent as early as possible • early cessation of exposure to sensitizing agent is associated with good prognosis in terms of objective measures of disease severity, medication requirements and quality of life. This model indicates that early allergy diagnosis and avoidance of domestic allergens in newly diagnosed asthmatics may be important. Lessons from high-altitude studies In Europe, mite allergen levels are very low at high altitude where the ambient humidity is insufficient to support mite populations. There are several sanatoria built in the Alps (e.g. Davos, Switzerland, and Misurina, Italy), in which long-term residence can be beneficial for asthmatic children. Dust mite-sensitive asthmatic children had a progressive reduction in nonspecific airway reactivity after a 1year period spent in Davos.66,67 Several studies from Misurina reported a reduction in asthma symptoms and significant decreases in mite allergen-induced basophil histamine release, mite-specific serum IgE level and methacholine and allergen-induced airway reactivity.4–6 However, further studies also observed reversal of this trend towards improvement after returning to sea level. The results of high-altitude studies suggest that allergen avoidance leads to a decrease of airway inflammation with consequent improvement in specific and nonspecific airway reactivity and symptoms and that re-exposure results in a rapid relapse. These studies were not controlled, and there is a possibility that other domestic factors (e.g. exposure to pets, environmental tobacco smoke etc.) contributed to the improvement observed in asthma control. Nevertheless, allergen avoidance is the most plausible reason for clinical success. High-altitude studies also provide an important proof of principle: a substantial reduction in allergen exposure over a long period of time may result in clinical improvement in allergic asthmatic patients. Mite allergen avoidance in patients’ homes In a recent review,11 31 trials of mite allergen avoidance regimens in asthma in the literature were considered.68–98 Since then, several further studies have been published, but have failed to provide unequivocal evidence as to whether mite allergen avoidance is effective, which patients may benefit, and by how much.99–102 Most of the studies were small, poorly controlled and used measures that failed to reduce mite allergen exposure (Appendix). Of these 35 studies, only 11 showed a significant reduction in mite counts and/or mite allergen levels. In four of these 11, the period of treatment was too short, but none the less three showed some effect. The final seven controlled studies, all of which used bed covers, achieved both
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Asthma and Chronic Obstructive Pulmonary Disease
significant reduction in mite/allergen levels and were of sufficient duration to show an effect on outcomes. Although these seven studies had different endpoints, they all showed some evidence of clinical benefit, but this was usually of questionable clinical significance as a result of the small size of the studies. Certainly, the impact of their widespread use by asthmatics has not been determined in a public health context. Which patients benefit and whether treatment is cost-effective is unknown. Large-scale trials are needed to answer these questions and one such study, which is due to randomize 1800 patients, is underway in the UK. Pet allergen avoidance in patients’ homes A recent study investigated the effectiveness of environmental allergen control using HEPA air cleaners in the management of asthma and rhinitis in cat-allergic patients who were sharing their home with one or more cats.103 Although a small reduction in airborne Fel d 1 was observed in the active (but not in the control) group, there was no difference between the groups in any of the outcome measures during the 3 months of the study. The reduction in cat allergen exposure afforded by the measures used in this trial was modest (~50%). It seems likely that a much more complex series of measures are needed if substantial reduction in exposure to air-borne cat allergen is to be achieved. Very intriguing and interesting data were recently reported, showing that reduction in Fel d 1 concentration by the use of high-efficiency vacuum cleaners can produce a significant improvement in the lung function in patients with cat sensitivity, but who did not possess a cat themselves.104 It is possible that a reduction in passive exposure to pet allergens in pet-sensitized individuals may have a beneficial clinical effect.
lence of wheeze was negatively associated with the use of feather pillows (reduction in the odds of 36% for infrequent wheeze and 61% for frequent wheeze). Furthermore, when changes in potential risk factors over time were investigated, an observed rise in the use of nonfeather pillows from 44% to 67% was estimated to be large enough to explain more than half of the increase in wheeze.105 It is tempting to speculate that the increased use of nonfeather pillows has contributed to increasing allergen exposure, which could be partly responsible for the increase in the prevalence of wheezing. Sensitization and exposure to indoor allergens and asthma Generally, individuals get sensitized to the allergens to which they are exposed. There is overwhelming evidence that sensitization to dust mites is a major independent risk factor for asthma in all areas where the climate is conducive to support the mite population growth.106,107 For allergens other than mites, the relationship depends on the climate, habits and socio-economic features of the local community.108–110 Exposure to allergens may have a profound effect on the development of IgE-mediated sensitization (primary sensitization), progression from sensitization to allergic disease (secondary exposure) and the severity of symptoms in patients with established disease (tertiary exposure) (Fig. 47.5). It has been relatively straightforward to demonstrate a quantitative dose–response relationship between exposure to mite allergens and subsequent sensitization.111,112 Early infancy has been identified as a critical period for primary sensitization. Evidence to support this view comes from studies relating atopy to month of birth,113,114 and the importance of early exposure to mite allergen in primary sensitization has been well-defined in recent studies.115 However, the situation seems to be much more complex with pet allergens.
A L L E R G E N AV O I D A N C E I N T H E P R I M A RY P R E V E N T I O N O F AT O P Y The rising trend in asthma prevalence can be linked to a possible increase in exposure to allergens in indoor environment. While there is no direct evidence to confirm an increase in dust mite allergen exposure, the indirect evidence, that this could be one among several important cofactors, is compelling. For example, over the last few decades, sales of pillows using synthetic fillings have increased enormously based on the concept that they are nonallergenic (as opposed to feather pillows). It has already been outlined that synthetic pillows accumulate mite allergens faster and ultimately contain approximately fivefold more Der p 153,54 and eight to ten times more cat and dog allergen that feather pillows.55 A UK study found a moderate, but significant increase by 20% in the ratio of current childhood wheezers to never wheezers, and an increase of 16% in the 12-month period prevalence of wheezing attacks between 1978 and 1991.105 The preva-
P E T O W N E R S H I P, S E N S I T I Z AT I O N A N D AT O P I C D I S E A S E In recent years, different groups of investigators have published intriguing and often conflicting data on the effect of pet ownership in early life on the subsequent development of sensitization and asthma. Some studies found that exposure to pets in early infancy was associated with specific IgE sensitization and allergic disease later in childhood,116,117 while others reported the opposite finding – an apparent protective effect.118,119 The difficulty in interpretation relates to the retrospective nature of the studies and the possibility of selection bias (e.g. parents at risk have got rid of pets). In the only prospective study with objective measurements of exposure, Wahn et al.112 have demonstrated a strong positive dose–response relationship between cat allergen exposure and specific sensitization during the first 3 years of life.
Allergen Avoidance
Sensitizers (allergens: mite, cat, dog, cockroach, etc.) Genetic predisposition Primary prevention
Enhancers Viruses, endotoxin, air pollution
IgE-mediated hypersensitivity
Sensitizers (allergens: mite, cat, dog, cockroach, etc.)
Genetic predisposition
Secondary prevention Airway inflammation and bronchial hyperreactivity Treatment of established disease
Triggers (inflammatory) Viruses, allergens, air pollution, endotoxin
Asthma symptoms
Triggers (noninflammatory) Exercise, histamine, cold air, methacholine, smoking
Figure 47.5. The potential benefits of allergen avoidance: prevention of allergic sensitization (primary prevention by allergen avoidance); prevention of atopic disease in sensitized individuals (secondary avoidance); and treatment of the established disease.
At present, it is difficult to explain these apparently irreconcilable differences between studies. First, prospective studies indicate that extremely low levels of cat allergen exposure are associated with some risk of sensitization, and that at least in early life, there appears to be a dose–response relationship between exposure and sensitization.112 Cat allergen is ubiquitous, and exposure outside the domestic environment may lead to specific IgE responses. A recent report has indirectly confirmed the potential importance of passive exposure, finding a significant correlation between the community prevalence of cat ownership and community prevalence of sensitization to cats, prevalence of respiratory symptoms, physician-diagnosed asthma and current asthma medication.120 It is possible that later cat allergen exposure is a risk for disease, but early exposure to cats may be protective. Two possible mechanisms for the protective effect of cat own-
497
ership (as opposed to passive exposure in homes without pets and/or public areas) are increased microbial exposure (enhancing Th1 immunity),120,121 or the induction of an allergen-specific IgG4, rather that IgE response. Only the long-term prospective follow-up of well-defined cohorts, avoiding recall biases and with objective measure of exposure, will provide a definitive answer to this important question and inform a decision about appropriate public health strategies for prevention (i.e. having or not having a pet). Primary prevention by environmental control Successful environmental control could be anticipated to have a greater impact on prevalence of asthma than interventions directed at other risk factors such as exposure to environmental tobacco smoke, dietary intervention and breast feeding.122 So far, only one prospective, randomized study has investigated the efficacy of avoidance of indoor allergens (house dust mites) in high-risk infants followed from birth (Isle of Wight study).123–125 This study has produced the first indications that even a modest reduction in mite allergen levels in homes of infants at risk of allergy may reduce the prevalence of sensitization to mites and recurrent wheezing during the first years of life. The trial was unfortunately complicated by the very complex nature of intervention strategy, including dietary advice to mothers during pregnancy, as well as an attempt to reduce mite allergen exposure by the use of benzyl benzoate (ineffective mite allergen avoidance measure). Recently, a prospective study in Manchester has documented that mite avoidance measures can achieve and maintain a very low mite allergen environment during pregnancy and in the first year of life in homes of infants at risk of atopy.25 Several other ongoing studies are addressing this important question (Canada, Australia, The Netherlands, and Southampton, UK). The results of these longitudinal studies are still awaited, as reasonable conclusions can only be drawn once the children are at least 5 years of age.
A L L E R G E N AV O I D A N C E I N S E C O N D A RY PREVENTION OF ASTHMA Secondary prevention strategies could be used to prevent development of symptomatic disease in sensitized, but still asymptomatic, individuals. In this context, environmental control might be beneficial. A recent study from Japan suggested that the use of bedding encasement was effective in preventing atopic infants with eczema and food allergy from being sensitized to house dust mites.126
S U M M A RY Minimizing the impact of identified environmental risk factors is an important consideration to reduce the prevalence and severity of asthma. Although environmental control is
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Asthma and Chronic Obstructive Pulmonary Disease
difficult, it is likely to become an integral part of the overall management of allergen-sensitized patients. Nevertheless, which subgroups of patients benefit, and by how much remains unclear. There are few data on the benefits of primary and secondary prevention by environmental control, and several prospective studies are currently underway. Finally, the mechanisms of the interaction between increased allergen exposure and an apparently increased susceptibility of the population to allergic disease need urgent exploration.
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Appendix Clinical studies of measures aimed at the reduction in house dust mite allergen levels applied in homes of patients with asthma. Reproduced from Reference II, with permission.
Author Ref.
Study design and duration
Avoidance measures
Effect on mites/ Allergen
Clinical outcome
Sarsfield et al68. 1974, UK – Leeds
Ch, As, MS; n = 14; UC; 3–12 months
Mattress encased (plastic covers); synthetic pillows; bedding washed weekly; dusting, vacuuming
Reduction in mite counts (from 80 to 2; P < 0.01)
Improvement in symptom scores (9 to 1.89; P < 0.05)
Burr et al.69 1976, UK – Cardiff
Ad, As, MS; n = 32; crossover PC; 6 weeks
Mattress encased (plastic covers); vacuum-cleaning of bed; laundering of bedding
Not monitored
No improvement in daily PEF reading or drug usage
Burr et al.70 1980, UK – Cardiff
Ch, As, MS; n = 53; PC; 8 weeks
Mattress, carpets and upholstery vacuumed; blankets, sheets laundered; bedding washed; feather pillows, quilts replaced; soft toys removed
No difference in mite counts before and after treatment
Both active and control group improved, no difference between groups
Burr et al.71 1980, UK – Cardiff
Ch, As, MS; n = 21; crossover, C; 1 month + 1 month
New sleeping bags, pillows and blankets; mattress encased (plastic covers); carpets vacuumed
Colonization occurred on new bedding after second study period
PEF variability lower during treated period, but the difference NS; majority with higher PEF during the treated period (P < 0.01)
Mitchell and Elliott72 1980, Auckland – New Zealand
Ch, As, MS; n = 10; C, cross-over; 8 weeks (4+4)
Electrostatic precipitator in child’s bedroom
Not monitored
Control versus active period: PEF NS; medication use: NS
Continued
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Appendix (continued)
Author Ref.
Study design and duration
Avoidance measures
Effect on mites/ Allergen
Clinical outcome
Korsgaard73 1982, Denmark – Aarhus
Ad, As and/or AR, HDS; n = 23; UC; 6 months
Mattress encased (plastic covers) n = 3; synthetic pillows n = 22; bedroom carpet removed n = 7; dusting, vacuuming
Not monitored in the study group over time
Beneficial effect reported by 15 patients, no change by 4
Korsgaard74 1983, Denmark – Aarhus
Ad, Ch, As, MS; n = 46; C; 12 weeks run in +12 weeks intervention
Mattress vacuumed twice; synthetic pillows and quilts; bedding washed; bedroom carpet removed; bedroom aired + no plants
Difference between groups in BC (P < 0.01) but not in LC or M
Improvement active versus control group: PEF NS (both improved) Symptoms: P < 0.05 medication: NS
Murray and Ferguson75 1983, Canada – Vancouver
Ch, As, MS and/or HDS; n = 20; C; 1 month
Mattress, pillows encased (vinyl covers); toys, carpets and upholstery removed (bedroom); washing, dusting, vacuuming
Not monitored
Improvement active versus control group: symptoms (P < 0.01), medication (P < 0.5), PEF (P < 0.05) and BHR (P < 0.001)
Bowler et al.76 1985, Brisbane – Australia
Ad, Ch, As, MS; n = 9; PC, cross-over; 4 weeks (2+2)
Active period: Mattress and pillow covered; washing, dusting, vacuuming; dust retardant and anti-static spray; active electrostatic filter of HEPA filter. Placebo: inactivated air filter
Not monitored
Control versus active period: Symptom scores NS; PEF NS
Walshaw and Evans77 1986, UK – Liverpool
Ad, As; n = 50; C; 1 year
Mattress, pillows encased (plastic covers); synthetic duvets; bedroom carpet, upholstery removed (n = 7); washing, dusting, vacuuming
Significant fall in mite counts in the active (P < 0.001), but not in the control group
Improvement in MS As in active group: FEV1/FVC (P < 0.02), PEFR (P < 0.05), BHR (PC20)(P < 0.01), medication (P < 0.05), total IgE (P < 0.05)
Gillies et al.78 1987, UK – Leeds
Ch, As; n = 26; C; A-12/52 avoidance, B 6/52 observation + 6/52 avoidance
Mattress, pillows encased (plastic covers); synthetic bedding; soft toys and pets excluded from bedroom; vacuuming
Mite counts: A 40 (start), 1.2 (6/52), 0.8 (12/52); B-22 (start), 10 (6/52), 2 (12/52)
Fall in total serum IgE in MS Ch (P < 0.005); BHR, symptoms, medication use and PEF NS
Continued
503
Allergen Avoidance
Appendix (continued)
Author Ref.
Study design and duration
Avoidance measures
Effect on mites/ Allergen
Clinical outcome
Dorward et al.79 1988, UK – Glasgow
Ad, As, MS; n = 21; C; 8 weeks
Mattress and bedroom carpet treated with liquid nitrogen; washing, dusting, vacuuming; soft toys, plants and upholstery excluded from bedroom
Fall in number of intact mites in active group (P < 0.01); no change in control
Active versus control: Fall in the number of hours wheezing (P < 0.05); reduction in BHR (P < 0.02); total and specific IgE NS
Verrall et al.80 1988, Canada – Hamilton
Ad, Ch, As, MS; n = 13: DB, crossover; 4 periods, 3/52 each
Laminar flow air cleaner device in the bedroom
Not monitored
No difference between the groups in the number of symptom-free days, symptom severity and PEFR
Reiser et al.81 1990, UK – London
Ch, As, MS; n = 46; DB PC; 24 weeks
Mattress sprayed once every 2 weeks for 3 months with either Natamycin or placebo; mattress vacuumed
Small, NS trend to a fall in Der p 1 in both groups
No change in BHR, symptoms and LF
Reisman et al.82 1990, USA – Buffalo
Ad, Ch, As, AR, MS; n = 32; DB PC, cross-over; 8 weeks (4+4)
Active period: HEPA air cleaner; Placebo period: placebo filter
Not monitored
Control versus active period: symptom and medication scores NS; Last 2 weeks of each period: nasal congestion, discharge eye irritation P < 0.05; asthma symptoms NS
Morrow Brown and Merrett83 1991, UK – Derby
Ad and Ch, As and/or AR and/or AD, MS; n = 25; UC; 12 months
Acarosan foam on mattress and bedding and moist powder on carpets and soft furniture
Reduction in Der p 1 level
As (n = 12): 7 better, 5 no change; AR (n = 8): 6 improved, 2 no change; AD (n = 5): 2 improved
Antonicelli et al.84 1991, Italy – Ancona
Ad, Ch, As, MS; n = 9; PC, cross-over; 16 weeks (8+8)
Active period: HEPA air cleaner. Placebo period: placebo filter; Routine house cleaning
No difference in reservoir levels of mite allergens between the periods; fall within both groups P < 0.05
Control versus active period: AR symptoms NS; LF NS; PEF NS; BHR (methacholine) NS
Continued
504
Asthma and Chronic Obstructive Pulmonary Disease
Appendix (continued)
Author Ref.
Study design and duration
Avoidance measures
Effect on mites/ Allergen
Clinical outcome
Ehnert et al.85 1992, Germany – Berlin
Ch, As, MS; n = 24; DB PC; 12 months
A: Mattress, pillow and quilt covered, carpets sprayed (3% tannic acid) 4 monthly; B: Mattress and carpet treated with benzyl benzoate; C: Placebo on mattress and carpet
Significant decrease in Der 1 in Group A (P < 0.005); no change in Group B and C
Significant increase in BHR (PC20) in the encasing regimen group (A): within group P < 0.01; no change in Groups B and C: between groups P < 0.05
Huss et al.86 1992, USA – Washington
Ad, As, MS; n = 52; 12 weeks
Investigated the effect of supplementary computer instruction on adherence to mite avoidance measures
Significantly lower Group 1 level in bedroom carpet in computer instructed group
No change in FEV1; Computerinstructed group significantly less symptomatic by study weeks 9 and 10 (P = 0.033)
Dietemann et al.87 1993, France – Strasbourg
Ad, Ch, As, MS; n = 26; DB PC; 12 months
Benzyl benzoate foam or placebo on mattress and upholstery; benzyl benzoate powder or placebo on carpets
No significant difference in Der 1 between the groups
Active versus placebo: Clinical score, drug score, LF, PEF NS
Warner et al.88 1993, UK – London
Ch, As, MS; n = 20; DB PC cross-over; 12 weeks (6+6)
Active period: active ionizers. Placebo period: placebo ionizers
Active versus control period: Airborne Der p1– P < 0.0001
Active versus control period: PEF NS; Symptom scores NS (trend towards increased cough during active period); Medication NS
Warburton et al.89 1994, UK – Manchester
Ad, As, MS; n = 12; cross-over (active + passive period 30+24 days)
Active period: HEPA air cleaner. Passive period: no HEPA air cleaner
Airborne Der p 1 below detection limit in twothirds of samples
Active versus passive period: Symptom scores NS; LF NS; BHR (histamine) NS; PEF NS
Marks et al.90 1994, Australia – Sydney
Ad, Ch, As; PC; 3 months run-in + 6 months treatment
Active: tannic acid/ acaricide to mattress, pillow, duvet, blankets, carpets and upholstery; mattress, pillow and quilt covered. Placebo: inactive spray
At 2 weeks Der p 1 fell to 29% of baseline (P = 0.04 compared to placebo); 3 and 6 months NS
Significant improvement in symptoms in both groups, but active versus placebo NS; LF and BHR: active versus placebo NS
Continued
505
Allergen Avoidance
Appendix (continued)
Author Ref.
Study design and duration
Avoidance measures
Effect on mites/ Allergen
Clinical outcome
Sette et al.91 1994, Italy – Verona
Ch, As, MS; n = 32
All homes: synthetic materials in the bedroom; daily vacuum cleaning and mopping; no feather pillows. Mattress treated with benzyl benzoate or placebo (n = 24)
Assessed by Acarex test: no difference between 3 study groups
No difference in BHR (PC20 ) between 3 study groups; no change in serum IgE concentrations
Huss et al.92 1994, USA – Washington
Ad, As; n = 12; DB PC; 12 months
Benzyl benzoate powder (n = 6) or placebo (n = 6)
No change in mite allergen content in Bc or LC
No difference in LF and PEF between the groups
GellerBernstein et al.93 1995, Israel – Rehovot
Ch, As, AR, MS; n = 32 (As n = 31); C, DB
Acardust or placebo in bedrooms on day 0 and day 90; bedsheet changed every week, damp dusting daily; vacuuming weekly
Active: Fall in Der f 1 from 10.05 to 4.15: Control: Fall in Der f 1 from 6.01 to 3.01
Significant improvement in severity of asthma; No difference in PEFR and wheeze
Carswell et al.94 1996, UK – Bristol
Ch, As, MS; n = 49; DB PC; 6 months
Benzyl benzoate powder or placebo on BC; benzyl benzoate foam or placebo on mattress, pillow and quilt; mattress, pillow and quilt covered (active or placebo); washing, dusting, vacuuming; soft toys excluded
M: 100% reduction in active versus 53% reduction in placebo (P < 0.001); BC: Active versus placebo NS
Active versus placebo: PEF NS; BHR (histamine) NS; LF (FEV1 ) P < 0.05; symptoms P < 0.05; medication use: P < 0.01
Frederick et al.95 1997, UK – Southampton
Ch, As, MS; n = 31; single blind, crossover; run-in 2/52, treatment periods 3/12
Period 1 – Group 1: active covers, Group 2: placebo covers (3/12); wash out 1/12; Period 2 – Group 1: placebo covers, Group 2: active covers (3/12)
Active versus placebo: significant reduction in Der p 1 in mattress, duvet and pillow (P < 0.0001)
Active versus placebo: significantly lower levels of eosinophil peroxidase (P = 0.02); within group: symptoms, FEV1, BHR (PC20 histamine): NS
Continued
506
Asthma and Chronic Obstructive Pulmonary Disease
Appendix (continued)
Author Ref.
Study design and duration
Avoidance measures
Effect on mites/ Allergen
Clinical outcome
Van der Heide et al.96 1997, The Netherlands – Groningen
Ad, As, MS; n = 45; DB, randomized, 3 parallel group; 6 months
Group 1: active air cleaner; Group 2: placebo air cleaner + mattress and pillow covers; Group 3: active air cleaner + mattress and pillow covers
Significant reduction in Der p 1 with covers (Groups 2 and 3) compared to Group 1
Significant improvement in BHR (histamine) in Group 3; trend to improvement in Group 2
Halken et al.97 1997, Denmark – Odense
Ch, As, MS; n = 60; DB PC 12 months
Active group: semipermeable mattress and pillow covers. Control group: cotton mattress and pillow covers
Active versus placebo: significant reduction in Der p 1 in mattress
Significant reduction in the dose of inhaled steroids, allergen specific BHR, morning PEFR and night asthma symptom score
van der Heide et al.98 1997, The Netherlands – Groningen
Ad, As, MS; n = 59; DBPC randomized, 3 parallel group; 12 months
Group 1: Acarosan on mattresses and floors (n = 21); Group 2: placebo (n = 19); Group 3: mattress and pillow covers (n = 19)
Significant reduction in Der p 1 with covers (Group 3) compared to Groups 1 and 2
Significant improvement in BHR (histamine) in Groups 1 and 3
Kroidl et al.99 1998, Germany – multicenter
Ad, Ch, As MS; n = 118; PC, randomized; 12 months
Active group: Benzyl benzoate Control group: placebo
Not monitored
No difference in self assessment, physician assessment, histamine BHR, IgE and SPT
Cloosterman et al.100 1999, The Netherlands – Nijmegen
Ad, mild As, MS, n = 157; PC, randomized; 20 weeks
Active group: Benzyl benzoate and semipermeable mattress and bedding covers Control group: placebo covers + water
Active versus placebo: significant reduction in Der p 1 in mattress
Active versus placebo: LF (FEV1 ) NS; BHR (histamine) NS; PEFR NS; symptom scores NS
Shapiro et al.101 1999, USA – Seattle
CH, AS, MS; n = 36; DB, R; 12 months
Active: mite impermeable covers to bed; clean blanket + bed linen monthly; tannic acid 2-monthly; vacuum cleaner provided; Control: placebo spray
Active versus placebo: significant reduction in Der p 1
Active versus control: doubling PD20 methacholine 47.0% versus 23.5%; P < 0.05
Continued
507
Allergen Avoidance
Appendix (continued)
Author Ref.
Study design and duration
Avoidance measures
Effect on mites/ Allergen
Clinical outcome
Warner et al.102 2000, UK – Southampton
CH (n = 27), AD (n = 13), As, MS; R; 12 months; 4 groups
1. Mechanical ventilation + vacuum cleaner; 2. Mechanical ventilation 3. Vacuum cleaner 4. No intervention
Der p 1: trend for Group 1 < Group 2 < Group 3
Trend for Groups 1 and 2 to have higher PC20 than Groups 3 and 4 (P = 0.085)
Ad = adults; Ch=children; As = asthma; MS = mite sensitive; HDS = house dust sensitive; AD = atopic dermatitis; AR = allergic rhinitis; P = placebo; DB = double blind; C = controlled; UC = uncontrolled; BC = bedroom carpet; LC = living room carpet; M = mattress; NS = not significant; Der 1 = Der p 1 + Der f 1.
Chapter
Smoking Cessation
48
Andrew W.P. Molyneux and John Britton University of Nottingham, Division of Respiratory Medicine, City Hospital, Nottingham, UK
Cigarette smoking is the single most important avoidable cause of death and disability in the developed world1 and is a growing cause for concern in many developing countries.2 In the UK it is estimated that most of the deaths and nearly half of the hospital admissions attributable to smoking will be for respiratory diseases, of which COPD makes up the bulk.3 Despite widespread knowledge of its harmful effects, cigarette smoking remains remarkably common, with over 25% of adults in the UK currently smoking.4 In this chapter we outline:
ation is continuous across the population and the concept of two discrete groups of smokers, who are either “susceptible” or “not susceptible” to COPD,6 is probably not valid. In general, however, the greater the number of cigarettes smoked the greater the risk of COPD7 and those with COPD who continue to smoke will experience a more rapid decline in lung function.6,8 In addition, adults exposed to passive smoke are at greater risk of developing symptoms of chronic bronchitis.9
• the effects of smoking on COPD and asthma; • the benefits of stopping smoking (smoking cessation) on COPD and asthma; • the central role of nicotine addiction in smoking; • that smoking is itself in essence a chronic addictive disease; • the evidence for the effectiveness of smoking cessation interventions; • guidance for putting such evidence into clinical practice.
THE EFFECT OF SMOKING ON ASTHMA There is relatively little information available on the effects of smoking on asthma but one longitudinal study has shown that active smoking exacerbates asthma and that asthmatics who smoke experience a more rapid decline in their FEV1.10 In asthmatic adults passive smoking is associated with more severe disease, lower health status and greater health care usage.11 In children, passive smoking increases the risk of developing wheeze or asthma,12 and is associated with more severe disease in asthmatic children.13
THE EFFECT OF SMOKING ON COPD The evidence for the harmful effect of active smoking on COPD is unequivocal: smoking is the single most important etiological factor in the development of COPD. Most adult smokers start to smoke in adolescence,1 before attaining their maximal lung function. Longitudinal studies of lung function (as measured by forced expiratory volume over 1 second, FEV1) have shown that those adolescents who smoke achieve a lesser maximal lung function than their nonsmoking peers, that lung function begins to decline at an earlier age in young adult smokers, and that this decline is faster in smokers (mean loss of 40 mL per year) than in nonsmokers (mean 25 mL per year).5 It should be noted that while the average rate of decline in FEV1 is faster in smokers than in nonsmokers there is a marked variability in this rate of decline in both smokers and nonsmokers.5 This variation accounts for the apparently marked differences in individual susceptibility to COPD in smokers, but the vari-
T H E B E N E F I T S O F S M O K I N G C E S S AT I O N The benefits of stopping smoking in COPD are unequivocal. Fletcher and Peto6 were the first to report that in smokers with COPD, the rate of decline in FEV1, and subsequent mortality from COPD is reduced in those who give up smoking (Fig. 48.1). Several other studies have since demonstrated that smoking cessation results in a reduction in rate of decline in FEV1 to approximately that of typical nonsmokers (see review in Reference 5). This finding is probably most clearly demonstrated in the US Lung Health Study, a prospective 5-year study of smoking cessation in individuals with early COPD8 (Fig. 48.2). Few studies have looked at the benefit of smoking cessation in asthma, but it is reasonable to infer that the benefits of smoking cessation on decline in FEV1 demonstrated in COPD will also apply to asthma.
Forced expiratory volume in 1 second (% of value at age 25)
510
Asthma and Chronic Obstructive Pulmonary Disease
Never smoked or not susceptible to smoke
100 75 50
Smoked regularly and susceptible to its effects
Stopped at 50
Disability
Stopped at 65
25 Death 0 25
50 Age (in years)
75
Fig. 48.1. The natural history of chronic bronchitis and emphysema. Adapted from Reference 6.
2.9
Postbronchodilator FEV1, L
Sustained quitters 2.8
2.7 Continuing smokers 2.6
2.5
2.4 Screen
1
2
3
4
5
Follow-up, years Fig. 48.2. Decline in post bronchodilators forced expiratory volume in one second (FEV1) over five years in smokers and ex-smokers with mild asymptomatic COPD. Reproduced from Reference 8 with permission.
SMOKING AND NICOTINE ADDICTION Smoking has traditionally been seen as a “social habit” that smokers adopt from choice alone. The last 20 years has seen an enormous increase in our understanding of the nature of smoking, and the emergence of clear neurophysiological and clinical evidence that smoking is an addictive behavior due to addiction to nicotine.14,15 Neurophysiological evidence Cigarette smoke is a complex mixture of gases and particulates, a major component of which is nicotine.16 When cigarette smoke is inhaled it reaches the small airways and alveoli of the lung where nicotine is rapidly absorbed into the pulmonary circulation. Within 10–19 seconds of inhalation, nicotine reaches the brain (at arterial concentrations
two to six times venous levels,17,18 and has a number of effects, in particular causing the release of dopamine in the nucleus accumbens in the mesolimbic system.19,20 Animal model work has shown that this pathway plays a central role in addictive behavior.21 Clinical evidence Nicotine meets many of the standard clinical criteria for an addictive drug,22–24 since users have a strong desire to take the drug,25 difficulty in controlling their use (i.e. stopping smoking),26 continued use despite harmful consequences,4 tolerance to the drug24 and withdrawal symptoms when the drug is stopped.25 Comparisons between nicotine and other drugs of addiction indicate that it is as addictive as cocaine, opiates, and amphetamines.27–30 The symptoms of this addiction can start within weeks of the first cigarette, often before the onset of daily smoking.31 The majority of adolescent daily smokers report symptoms of withdrawal,32,33 and over three-quarters of adolescent smokers who try to quit will fail.34 Most adolescent smokers will continue into young adulthood1 and of these about half are likely to still be smoking at the age of 60.26 The majority of smokers report that they would prefer not to smoke, and approximately one in three adult smokers has tried, unsuccessfully, to give up smoking in the past year.4 Most smokers do not thus continue to smoke out of choice, but because of addiction to nicotine. The nicotine withdrawal syndrome One of the reasons that nicotine is so addictive is the severity of the withdrawal syndrome that smokers experience when they stop smoking. This syndrome is characterized by well-recognized changes in mood, physical symptoms, physiological changes, and urges to smoke (Table 48.1). These signs and symptoms are due specifically to withdrawal from nicotine, as opposed to any other aspect of smoking, as evidenced by the fact that they are reduced by nicotine replacement therapy.25 Most symptoms of nicotine withdrawal resolve within the first 4 weeks of stopping smoking; increased appetite can last for considerably longer and is responsible for the weight gain often seen after smokers become abstinent. Of all the symptoms and signs of withdrawal, urges to smoke and depression are the principal features known to predict relapse, of which urges to smoke are probably the most important predictors.35–39
SMOKING AS A CHRONIC DISEASE In addition to being an addictive behavior, smoking shares many of the features of a chronic disease, in particular being characterized by remissions and relapses. Only a minority of smokers stop permanently at their first attempt; most will start smoking again and go through cycles of stopping and starting. Many smokers who do stop for long periods of time will later relapse and start smoking again.40
511
Smoking Cessation
Table 48.1. Major signs and symptoms of nicotine withdrawal (adapted from Reference 25)
Symptom
Duration (Hughes)91
Reduced by NRT
Predicts relapse (Hughes et al.)35
Incidence Self-quitters (%) Clinic patients (%) (Hughes)91 (Hughes and Hatsukami)36
Irritability/aggression Depression Anxiety Restlessness Poor concentration Increased appetite Urges to smoke Night-time awakenings Decreased heart rate
4 weeks 4 weeks 2 weeks 2 weeks 1 week 10 weeks 2 weeks 1 week 10 weeks
Yes Yes Yes Yes Yes Yes Yes Not known Yes
No Yes No No No No Yes No Not known
38 31 49 46 43 53 37 39 61
80 60 87 71 73 67 62 24 79
NRT, nicotine replacement therapy.
Many clinicians fail to appreciate this, and lose their motivation to help smokers stop smoking because of their patients’ or their own perceived failure. Smoking, like a chronic disease, may need continuing care and support with repeated treatments for current smokers, providing motivation to stop and appropriate support for those willing to stop, and for ex-smokers by preventing relapse, with the aim of long-term permanent abstinence.
intensive counselling with pharmacotherapy.43 Individual smoking cessation interventions can be broken down into several components: • • • •
counselling and behavioral therapies; self-help and other supplementary materials; pharmacotherapy; alternative therapies.
EFFECTIVENESS OF SMOKING C E S S AT I O N
There are also other important issues relating to who should deliver these interventions, the setting of the intervention, and the special case of patients with respiratory disease.
There is clear evidence, summarized in systematic reviews,41 and guidelines from both the UK42,43 and USA44,45 that smoking cessation interventions are both effective and costeffective. There is a wide variety of approaches to smoking cessation, ranging from media campaigns, which aim to raise awareness and motivation to stop at a population level, to individual level interventions, which aim to improve a smoker’s chances of stopping successfully with counseling and pharmacotherapy. In this chapter, we will focus on the evidence for the effectiveness of smoking cessation interventions that can be delivered at the individual level by healthcare professionals, and their effect on long-term success in stopping smoking. Long-term success is usually defined as continuous abstinence for 6 or more months, validated by a biochemical test.42,43 The most commonly used test is to measure carbon monoxide in expired air, which should be less than ten parts per million in an abstinent smoker. Cotinine, a metabolite of nicotine, can also be measured in saliva and urine as a marker of nicotine intake. Depending on the overall intensity of the intervention delivered, the incremental increase in sustained cessation achieved by cessation interventions ranges from about 2% for brief opportunistic advice from a clinical to nearly 20% for
Counseling and behavioral therapies Counseling and behavioral therapies aim to motivate a smoker to stop, improve a smoker’s chance of stopping (by helping an individual to develop specific skills and strategies to cope with withdrawal), and to change their behavior following cessation.The success of these therapies is broadly related to amount of contact a smoker has with a counselor,42,43,45,46 that is, the longer or more intensive an intervention, the greater a smoker’s chance of successfully stopping. Paradoxically, however, it is also the case that the more intensive an intervention the greater the financial cost of providing the service and the greater the demand on a smoker’s time, and hence the smaller the proportion of smokers it can reach.46 Thus, brief interventions may offer a relatively low chance of success at an individual level but can be made available to a larger proportion of smokers than more intensive counseling. At a population level, it may therefore be more effective in terms of maximizing smoking cessation to adopt a strategy of applying a less intensive intervention across the entire population than to invest heavily in low coverage, higher success interventions. Brief and intensive interventions are described in more detail below.
512
Asthma and Chronic Obstructive Pulmonary Disease
Brief interventions Brief interventions can be provided by any clinician or health care professional in any setting, but are of especial relevance to those in primary care (general practice) and out-patient clinics. The main effect of such interventions is to motivate the smoker to stop.43 The evidence suggests that even an intervention lasting only 3 minutes can lead to a significant increase in longterm cessation. Although the success rate is small (an intervention lasting 3 minutes has a long-term success rate of 5% compared with 3% in those receiving no help),42,43 because of their high population reach they are highly cost-effective. Such advice should include the following points: • give a clear, strong message to stop smoking; • stress the benefits of giving up smoking (health, financial etc.). If the smoker is willing to stop now, the clinician should: • encourage the smoker to set a quit date; • emphasize the importance of total abstinence, ‘not even one puff’; • provide written support materials; • give advice on pharmacotherapy, with a prescription if appropriate. If the smoker would like additional assistance, the clinician should refer to a trained nurse or specialist smokers’ clinic for further advice and support (see below).
Intensive interventions Intensive interventions are usually provided by smoking cessation specialists, generally in the context of a specialist smokers’ clinic. The main effect of such interventions is to improve a motivated smoker’s chances of stopping.43 Intensive interventions usually involve a formal assessment (including a motivational assessment) followed by a program of four to six sessions, each lasting from 10 minutes to 1 hour, delivered to groups or on an individual basis.47 Because intensive interventions require a substantial time commitment, they work best with smokers who are highly motivated to stop; indeed, the relatively high success achieved by such interventions may in part be due to the selected nature of the smokers who use them.48 In the UK more brief one-to-one support is known as an “intermediate intervention”; usually this consists of two sessions lasting 10 to 30 minutes, with additional weekly follow-up in person or by telephone for at least 4 weeks.43,49 Both intensive and intermediate interventions should deliver strong encouragement to smokers to use pharmacotherapy as appropriate. There are no evidence-based guidelines for what elements intensive interventions should contain. Generally, guidelines recommend providing support based upon teaching problem-solving skills, providing social support45 and coping with the symptoms of withdrawal (Table 48.2). In addition, some evidence suggests that pairing smokers together when they stop smoking (“buddying up”) can improve cessation rates,50 presumably by encouraging mutual support.
Table 48.2. Common components of counseling for smoking cessation (adapted from References 42 and 43)
Theme
Examples
Abstinence
Total abstinence from smoking is essential: “Not even one puff”. Any smoking increases the likelihood of a full relapse
Past attempts to stop
Patients should use their previous experience of trying to stop smoking to identify strategies that have and have not helped in the past
Identify potential challenges
Patients should anticipate difficult situations that are likely to be associated with a strong urge to smoke, e.g. “favorite cigarette”, triggers for smoking (after a meal, with coffee, on the telephone etc.), stress or emotional upset, being with other smokers, alcohol
Prepare coping strategies
Patients should use strategies to tackle difficult situations, e.g. to distract from urges to smoke, to cope with stress (e.g. lifestyle changes) and to avoid potential temptations
Alcohol
Alcohol can cause relapse – patients should limit or avoid drinking alcohol while trying to stop smoking
Other smokers
Stopping smoking is more difficult if family or friends are also smokers – patients should encourage friends and family to quit with them or avoid smoking in their presence
Reasons, benefits and rewards
Identify a patient’s reasons for stopping smoking; stress the benefits to health and finances; patients can save the money they would have spent on cigarettes to reward themselves for success
Smoking Cessation
The “withdrawal orientated model”, developed at the Maudsley Hospital in London and based on a group intensive intervention of six weekly hour-long sessions used in conjunction with nicotine replacement therapy, has a long-term success rate of 20 to 30%.47 The Lung Health Study has shown that a program of prolonged group intensive intervention with nicotine replacement therapy can lead to 1-year cessation rates as high as 35% compared with 9% in controls receiving no intervention,8 although the high cessation rate in the control group reflects the fact that participants in this trial were highly motivated to stop smoking. Recent reviews have found no significant difference between the efficacy of intensive interventions given either to groups or on an individual basis, so on grounds of costeffectiveness preference is generally given to the group approach. Groups may also have the advantage of encouraging mutual support among smokers. However, some of the benefits of group interventions are offset by difficulties in recruiting and retaining sufficient participants. In the UK in particular, groups have been found to be unsustainable when serving the needs of a single general practice,51 and most groups are now run as part of specialist smoking cessation services currently being established throughout the UK to serve health authority areas with typical populations of 500,000. This target population gives rise to between about 300 to 800 smokers willing to participate in group therapy each year,42 which is clearly just a tiny minority of all smokers; this is the major disadvantage of the intensive approach. Self-help and other supplementary materials Written self-help materials do appear to be of some benefit when compared with no intervention, increasing the relative odds of cessation by a factor of 1.23 (95% confidence intervals 1.02 to 1.49),51a and have the advantage that they have the potential to reach a greater number of smokers than advice delivered by a clinician.The additional benefit of selfhelp materials when given together with other interventions is unclear. Some research has shown that materials tailored to the individual smoker are more effective than generic materials, and that telephone support is of additional benefit.52 Such materials are widely available and can be downloaded from the World Wide Web from organizations such as the US Department of Health and Human Services,52 Quit UK,54 and Action on Smoking and Health.55 Pharmacotherapy Pharmacotherapy should almost always be used in smoking cessation as an adjunct to counseling, rather than as an alternative. The two main pharmacological interventions used in smoking cessation are nicotine replacement therapy and bupropion hydrochloride (sustained-release); other pharmacotherapies are also available and will be discussed below. Nicotine replacement therapy Nicotine replacement therapy has been used for smoking cessation for over 20 years. Its main mode of action is
513
thought to be the reduction of symptoms of the nicotine withdrawal syndrome. It is also thought that nicotine replacement therapy may provide a coping mechanism, and make cigarettes less rewarding to smoke.56 No form of nicotine replacement therapy can completely eliminate the symptoms of withdrawal, possibly because no nicotine replacement therapy has yet been developed that can mimic the rapid and high levels of arterial nicotine achieved when cigarette smoke is inhaled14,57 (Fig. 48.3). Of all smoking cessation interventions, nicotine replacement therapy has been subjected to the most rigorous assessment. The most recent Cochrane reviews of the evidence available suggest that nicotine replacement therapy leads to almost a doubling of long-term cessation rates achieved by nonpharmacological intervention (odds ratio 1.71, 95% confidence intervals 1.60 to 1.83), independently from the intensity of the counseling given or setting.58 Therefore, in specialist clinic interventions which can achieve 20% cessation rates, approximately half of the success is attributable to intensive counseling support, and half to nicotine replacement therapy.43 Currently, evidence for the efficacy of nicotine replacement therapy is limited to adults who smoke ten or more cigarettes per day. Six forms of nicotine replacement therapy products are available at present (Table 48.3). There is no evidence to suggest that any product is significantly better than another,59 or that any particular product can be matched to particular smokers.60 Therefore, the choice of which product to use should be guided by a clinician’s judgment and patient preference. However, there is evidence that 4 mg gum is more effective than 2 mg gum in those smoking 20 or more cigarettes per day,58 and that higher dose patches are more effective than low-dose patches in those smoking more than ten cigarettes per day.61 There is also recent evidence that combinations of therapies such as patch and nasal spray,62 or patch and inhaler62 are more effective than single agents alone. Although the use of combined therapies is currently unlicensed, the evidence that does exist suggests that such combinations are safe.64 There is evidence that nicotine replacement therapy, and nicotine gum in particular, can help to control the weight gain commonly experienced after cessation.65 In terms of duration of therapy, 8 weeks therapy appears to be as effective as longer courses; there is no evidence to suggest that tapered withdrawal of nicotine replacement therapy is better than abrupt withdrawal.58 Nicotine is a vasoconstrictor and nicotine replacement therapy is, therefore, contraindicated in acute cardiovascular events such as unstable cardiac disease, acute myocardial infarction or stroke, but has been shown to be safe in stable cardiac disease.66,67 Nicotine replacement therapy should also be used with caution in pregnant and breastfeeding women. Theoretically nicotine from nicotine replacement therapy is safer than that from cigarettes, since it is not accompanied by the other products of tobacco consumption,14 but complete avoidance of all nicotine should be the objective in pregnancy and breastfeeding, and indeed 30%
514
Asthma and Chronic Obstructive Pulmonary Disease
Cigarette (nicotine delivery, 1 – 2 mg)
15
Cigarette (nicotine delivery, 1 – 2 mg)
80 60
10 40 5 20
Plasma nicotine concentration (ng/mL)
0
0
Oral snuff 15
15
10
10
5
5
0
0
Nasal spray (nicotine delivery, 1 mg)
Polacrilex (nicotine delivery, 4 mg)
Transdermal nicotine (nicotine delivery, 15 mg)
15
15
10
10
5
5
0
0 0
30
60
90
120
0
30
60
90
120
600
Minutes Fig. 48.3. Schematic diagram showing rise in venous blood nicotine levels after smoking a cigarette or using oral snuff, and after using different nicotine replacement products, following overnight abstinence from cigarettes. Polacrilex refers to nicotine gum. Reproduced from Reference 57 with permission.
of pregnant women succeed in stopping smoking during pregnancy without nicotine replacement therapy.68 However, for those who cannot stop smoking without pharmacotherapy and wish to try nicotine replacement therapy, it is probably advisable to limit use to short-acting products so that any potential toxicity is minimized. The risk of dependence on nicotine replacement therapy is small, although a minority of patients who quit successfully do use it long-term.69,70 Long-term use of nicotine replacement therapy is not thought to be associated with any significant harmful effects.8 Research is also currently underway to investigate the role of nicotine replacement therapy in assisting smokers to reduce the number of cigarettes they smoke each day, although currently, nicotine
replacement therapy is not recommended in those who are still smoking. Bupropion Bupropion hydrochloride is an atypical antidepressant with dopaminergic and adrenergic activities71 that has been used in North America for some years as an antidepressant. Bupropion has been licensed more recently for use in smoking cessation, firstly in the USA and latterly in the European Union.72 Interest in the effect of bupropion in smoking cessation arose from anecdotal reports that patients taking bupropion for depression found it easier to stop smoking. Two preliminary reports73,74 and two subsequent major clinical trials75,76 have demonstrated efficacy in smokers
Table 48.3. Pharmacotherapies for smoking cessation
Dosage
Duration
Availability
Nicotine gum (polacrilex)
Sore mouth/throat Indigestion
2 or 4 mg/piece Maximum of 15 pieces/day
12 weeks maximum
UK: prescription and OTC (2 mg gum GSL) US: OTC only
Nicotine transdermal patch
Local skin rash Insomnia (24 hour patch)
25 mg/16 hours
8 weeks
Prescription and OTC
21 mg/24 hours 14 mg/24 hours 7 mg/24 hours
4 weeks then 2 weeks then 2 weeks
Nicotine nasal spray
Nasal irritation
500 lg/spray Maximum of 64 sprays daily
3 months
Prescription only
Nicotine inhaler
Sore mouth/throat
10 mg/cartridge Maximum of 12 cartridges/day
3 months
UK: prescription and OTC US: prescription only
Nicotine sublingual tablet
Sore mouth/throat
2 mg/tablet Maximum 40/day
3 months
UK: prescription and OTC
Nicotine lozenge
Sore mouth/throat
1 mg/lozenge Maximum 25/day
3 months
UK: prescription and OTC
Insomnia Dry mouth
150 mg once daily for 3 days then 6 days 150 mg twice daily (started 1–2 weeks before quit date)
8 weeks
Prescription only
Precautions/ Contraindications
Nicotine replacement therapy
Unstable cardiac disease Acute cerebrovascular disease Pregnancy/breastfeeding
Bupropion
History of seizure or eating disorder
Smoking Cessation
Adverse effects
Pharmacotherapy
OTC indicates over the counter. GSL indicates general sales list, i.e. available for sale outside pharmacies. Information derived from manufacturers’ product data sheets and summary of product characteristics.
515
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Asthma and Chronic Obstructive Pulmonary Disease
antagonist), and sensory replacement (such as ascorbic acid aerosol or citric acid inhalers that recreate the sensation of smoking).46
given bupropion in conjunction with regular counseling support. The first of these studies compared placebo with 100, 150 or 300 mg/day of sustained-release bupropion for 7 weeks in a parallel group study on a total of 615 smokers, and reported cessation rates at 1 year of 12.4, 19.6, 22.9 and 23.1% respectively.75 This effect was independent of any current or previous evidence of depression.77,77a The second study compared sustained-release bupropion 150 mg twice daily (once daily for the first 3 days), either alone or in conjunction with transdermal nicotine, with nicotine alone or placebo.76 Sustained cessation for 1 year was achieved in 5.6% with placebo, 9.8% with transdermal nicotine, 18.4% with bupropion alone, and 22.5% with combined bupropion and nicotine. Bupropion alone was significantly more effective than placebo or transdermal nicotine, and not significantly less effective than bupropion plus nicotine patch. Bupropion significantly reduced weight gain during the drug treatment period, although this effect was subsequently lost. The evidence available is insufficient to show clearly whether bupropion is more effective than nicotine replacement therapy,43,52 so at present there is no obvious first choice between these therapies. The effectiveness of bupropion given with lower levels of counseling support is also not yet established. Until such evidence becomes available, therefore, the decision to use either nicotine replacement therapy or bupropion can probably be based on medical contraindications and patient preference. The main sideeffects of bupropion are insomnia and dry mouth; there is also a low risk of seizure (one in 1000 patients) similar to other antidepressants, so bupropion is contraindicated in those with a history of seizures, and is also contraindicated in those with a history of eating disorders. The combination of bupropion and nicotine replacement therapy carries a theoretical risk of hypertension, and it is recommended that blood pressure is checked weekly during combined therapy.72 The dosage regimen for bupropion is given in Table 48.3.
Who should deliver smoking cessation interventions? A recent update of the Cochrane reviews shows that smoking cessation interventions delivered by doctors are effective (odds ratio for cessation versus no intervention 1.69, 95% confidence intervals 1.45 to 1.98).83 However, in the majority of clinical settings the bulk of smoking cessation interventions are delivered by other health professionals, particularly nurses. The Cochrane reviews confirm that smoking cessation interventions delivered by nurses are effective (odds ratio 1.43, 95% confidence intervals 1.24 to 1.66), but that they are not effective when given as part of a routine screening health check.84 This difference may in part be due to the fact that specific smoking cessation interventions may attract smokers more motivated to stop than those seen during other more general health promotion measures. Combined data from two recent randomized trials in the UK have also shown that pharmacists, trained to provide structured behavioral support with nicotine replacement therapy, can improve cessation rates.85,86 Currently the benefits of other health professionals providing smoking cessation interventions in addition to their usual duties is unclear.43,52
Other drugs Many other drugs have been tested for their effectiveness in helping smokers to stop.46 Of these, clonidine (an a2-nonadrenergic agonist) has been demonstrated to be of proven value in smoking cessation,78 but has gained little use, probably due to significant side-effects, particularly sedation and postural hypotension. Two recent trials have shown that nortriptyline (a tricyclic antidepressant) is also effective in smoking cessation.79,80 Side-effects of nortriptyline include anticholinergic symptoms, nausea, and sedation. Neither drug is licensed in the UK for smoking cessation, although recent US guidelines recommend that clonidine and nortriptyline can be used as second-line agents, in those intolerant or unwilling to use nicotine replacement therapy or bupropion. Other possible therapies for smoking cessation include antidepressants with adrenergic activity (such as doxepin), monoamine oxidase inhibitors, mecamylamine (a nicotine
Setting of the intervention There is clear evidence that brief interventions delivered in primary care are effective, that both general practitioners and primary care nurses should deliver these (the latter in the context of smoking cessation interventions only) and that they should be given with pharmacotherapy as appropriate. Intensive interventions are not viable at a single practice level, but referral to a specialist clinic for more intensive help should be available.43 In hospital, as with primary care, brief interventions are also effective and should be delivered to all smokers attending hospital. More intensive help should also be made available to both in-patients and out-patients, ideally to be delivered by a hospital-based smoking cessation specialist. Pharmacotherapy should be used in out-patients, as appropriate.43 There is clear evidence that intensive interventions delivered by specialist smokers’ clinics are highly effective,
Alternative therapies Alternative therapies such as acupuncture or hypnotherapy appear to be popular in as much as they are widely available and appear commercially successful. Evidence for their efficacy is limited: review of the 20 trials of acupuncture suggests some benefit, but that this is likely to be due to a placebo effect;81 there is no evidence to support any benefit from hypnotherapy.82
OTHER ISSUES
Smoking Cessation
and that such clinics should offer both group and individual treatment, using pharmacotherapy as appropriate.43 It is important that clinicians in all settings systematically identify smokers, to allow smoking cessation interventions to be appropriately targeted.43 Patients with respiratory disease The Lung Health Study demonstrated that an intensive intervention with nicotine replacement therapy was highly effective for smokers with mild asymptomatic COPD.8 However, few studies have looked specifically at smoking cessation in patients with manifest respiratory disease.These studies have tended to focus on in-patients with smokingrelated diseases87,88 or on out-patients attending chest clinics,89 and their results have been mixed. All studies used only brief/intermediate interventions; two used nicotine replacement therapy and both of these were limited in their findings by small sample sizes.87,88 Other studies of hospitalized patients have shown that patients with smoking-related diseases are less successful at stopping smoking than other hospital patients.90 It is possible that because the association between smoking and chronic respiratory disease is so wellrecognized in the general population, many smokers who develop chronic respiratory symptoms give up smoking before presenting to specialist medical services. If so, then those who continue to smoke will represent a hard core of the most dependent smokers who find it especially difficult to stop, and/or those who are least motivated to succeed.
S M O K I N G C E S S AT I O N I N P R A C T I C E Over two-thirds of smokers say that they would like to give up smoking, and one-third will make an attempt to stop smoking every year.4 Unfortunately, most smokers who try to stop do so using willpower alone, a method with at best a 3% long-term success rate among those who try.43 The key to putting the evidence for the effectiveness of smoking cessation into practice is to develop an integrated
517
system of smoking cessation that identifies those smokers motivated to stop as part of routine clinical care, motivates those smokers to try stopping, and aims to improve their chance of succeeding with counseling and pharmacotherapy. The most important elements of practical smoking cessation can be thought of in terms of the five As, a way of integrating smoking cessation into routine practice (Table 48.4) .45 These are designed to be delivered as part of a brief intervention. The five As are outlined in more detail below. Ask about smoking Smoking is of such importance as a risk factor for patients that it is essential that all smokers be identified. Smoking should be treated as a vital sign to be assessed and recorded in all patients’ medical records. Clinicians should develop a system to ensure that every patient’s smoking status is recorded, ideally as part of an expanded set of vital signs. Advise all smokers to stop smoking Clinicians should give a clear, strong and personalized message about stopping smoking, stressing the harmful effects of smoking on present and future health, relating smoking to the patient’s own health or illness, and offering help. Once advice has been given, it should be noted in a patient’s records together with the patient’s response.43 Assess the smoker’s willingness to stop smoking Clinicians should determine whether the patient is currently willing to stop smoking. Those motivated to stop should be provided with assistance to do so most effectively; unmotivated smokers should be encouraged where possible. This distinction between motivated and unmotivated smokers is of important practical value if a clinician is to avoid wasting valuable time providing assistance and pharmacotherapy to a smoker who is unready or unwilling to stop. When assessing smokers it is helpful to have an understanding of some of the psychological aspects of smoking. One psychological model in widespread use in smoking cessation is the transtheoretical model of change, often
Table 48.4. The five As. Brief smoking cessation strategies for routine practice (adapted from Reference 45)
STEP
ACTION
Ask about smoking
Systematically assess smoking status. Smoking should be a vital sign
Advise all smokers to stop
Give a clear, strong and personalized message to stop smoking
Assess willingness to stop
Determine whether the smoker is ready to stop currently or soon. Provide assistance to motivated smokers; motivate those unwilling to stop
Assist motivated smokers to stop
Help smoker with a quit plan, counseling, pharmacotherapy and additional materials
Arrange follow-up
Follow-up soon after the quit date. Assess success and difficulties. Consider referring for a more intensive intervention if there is relapse
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Asthma and Chronic Obstructive Pulmonary Disease
known as the cycle or stages of change92 which describes a continuum of attitudes that a smoker may hold. Some smokers are contented and have not even considered stopping smoking (those in the precontemplation stage); others are considering stopping smoking (the contemplation stage), before then actively preparing to stop in the next 30 days (the preparation stage). Once a smoker has stopped smoking (the action stage), they may succeed and remain abstinent (the maintenance stage) or may fail (relapse), returning to one of the previous stages (Fig. 48.4). In terms of this psychological model, smokers in the preparation and action stages will require assistance, while those in precontemplation and contemplation stages may require further motivation to make an attempt to stop smoking, but would be unlikely to benefit from receiving additional assistance at the present. Assist motivated smokers in stopping smoking Give assistance to smokers motivated to stop, specifically with a “quit plan”, referral for counseling and providing pharmacotherapy as appropriate.Those smokers who request additional assistance should be referred to a specialist clinic. Quit plans are commonly used in smoking cessation, and provide a framework to help a smoker make adequate preparations before giving up smoking. Features of a quit plan may include:45 • Set a quit date: ideally within the next 1 to 2 weeks; • Tell family,friends and colleagues about stopping smoking; • Anticipate challenges in advance, particularly symptoms of withdrawal; • Remove all tobacco-related products from your environment.
Finally, the smoker’s suitability for pharmacotherapy should be assessed. Unless contraindicated, nicotine replacement therapy (suitable for smokers who smoke ten or more cigarettes per day) or bupropion (suitable for those who smoke 15 or more cigarettes per day) should be offered and prescribed as necessary. Clear advice regarding the side-effects and benefits of pharmacotherapy should be given.43,45 Alternatives, such as clonidine or nortriptyline, should be reserved only for those patients intolerant or unwilling to use nicotine replacement therapy or bupropion.45 Arrange follow-up Arrange follow-up to monitor progress and prevent relapse. The first follow-up visit should take place during the first week after the quit date, which is the time of greatest risk of relapse. Weekly follow-up sessions for at least 4 weeks are recommended.43 Follow-up can be performed in person or by telephone, with the aim of confirming abstinence (ideally verified by measurement of carbon monoxide in expired air), reinforcing previous counseling and monitoring use and problems with pharmacotherapy. Many patients will relapse – it is important to stress the cyclical nature of smoking and that further attempts may be successful. If a patient experiences severe withdrawal symptoms, difficulties with pharmacotherapy, or is particularly interested in more intensive interventions, consider referring for more intensive help from a specialist clinic. More detailed information about the content and operation of such intensive interventions is beyond the remit of this chapter, but information is available elsewhere.47
S U M M A RY Precontemplation Contented smoker
Contemplation
Smoking
Smoking is the most important cause of COPD and worsens the symptoms of asthma, and stopping smoking is clearly beneficial to patients with both COPD and asthma. Smoking is an addictive, chronic behavior due to addiction to nicotine, a substance as addictive as heroin and cocaine.There is substantial evidence for the effectiveness of smoking cessation interventions – the key to putting this evidence into practice is to make smoking cessation a routine part of clinical care.
Willing to stop
REFERENCES Action Relapse
Preparation
Stopping
Maintenance Remaining abstinent Fig. 48.4. Transtheoretical model of change. Italicized boxes indicate different stages. Adapted from Reference 92.
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b2-Adrenoceptor Agonists
Chapter
49
Ian P. Hall Division of Therapeutics, University Hospital, Nottingham, UK
b2-agonists have been the mainstay bronchodilator agents used for the treatment of asthma and COPD since the development of inhaled isoprenaline preparations in the 1960s. While the initial preparations were marketed at relatively high doses and had little b2-selectivity the sideeffect profile of theses agents was markedly improved by the development of short-acting b2-selective agents such as salbutamol and terbutaline. More recently, long-acting b2selective agents have assumed an increasingly important role in the management of asthma and to a lesser extent COPD.
MECHANISM OF ACTION b2-agonists bind to the b2-adrenoceptor which is present in the cell membrane of a number of airway cells including airway smooth muscle, airway epithelial cells, inflammatory cells including mast cells, vascular and endothelium and vascular smooth muscle.1 However, the major site of action of b2-agonists in the airways is the airway smooth muscle cell. Following binding of b2-agonist to the b2-adrenoceptor on airway smooth muscle a signaling cascade is triggered which results in a number of events, all of which contribute to relaxation of airway smooth muscle (Table 49.1).2,3 The majority of these events are dependent on elevation of cell cyclic AMP content, which is brought about following binding of b2-agonist to the b2-adrenoceptor by stimulation of adenylyl cyclase as a result of activation of the G protein coupled to the b2-adrenoceptor, Gs.4 This exists as a heterotrimeric complex but following stimulation of the b2adrenoceptor Gs dissociates releasing free a-subunits which are able to stimulate adenylyl cyclase. Adenylyl cyclase exists in a number of different isoforms although there is at least some evidence suggesting that adenylyl cyclase VI is important in airway smooth muscle; however most of the other adenylyl cyclase isoforms are also present in this tissue.5 Adenylyl cyclase catalyzes the formation of cyclic AMP from ATP. Cyclic AMP is able to convert protein kinase A from an inactive form to the active form in which the catalytic and regulatory subunits dissociate. The catalytic subunit of
protein kinase A then phosphorylates key targets within the cell bringing about the majority of the physiological effects of b2-adrenoceptor stimulation. However, there is at least some evidence to suggest that cyclic AMP independent actions may also occur; for example, direct stimulation by Gsa of the BK channel present in the airway smooth muscle cell membrane has been described.2 This is relevant because the BK channel (a voltage-gated potassium channel) is thought to be important in modulating changes in cell membrane potential following stimulation with b2-agonist, and thus can contribute to the relaxant response of b2adrenoceptor stimulation. The intracellular effects of b2-adrenoceptor stimulation are relatively shortlived. Cyclic AMP is broken down by phosphodiesterase isoenzymes present in the cell, with type 3 and type 4 phosphodiesterase activities believed to be the most important in regulating cyclic AMP content in airway smooth muscle and type 4 phosphodiesterase being physiologically important in many inflammatory cells including eosinophils. Continued stimulation by Gsa is prevented by the free Gsa rapidly reassociating with bc to reconstitute the heterotrimeric Gs complex (Fig. 49.1).
Table 49.1. Mechanisms underlying airway smooth muscle relaxation by b2 adrenoceptor agonists
•
Inhibition of spasmogen-induced inositol 1,4,5 trisphosphate production
•
Inhibition of spasmogen-induced rises in intracellular free calcium
•
Activation of calcium-activated K+ channels
•
Alteration of sensitivity of contractile apparatus
•
Increased extrusion/re-uptake of calcium from cytoplasm
•
Hyperpolarization of cell membrane
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Asthma and Chronic Obstructive Pulmonary Disease
β2 AGONIST
Phe 290 VI
VII RECEPTOR ACTIVATION
γ
GDP
γ
α
V
I
Ser 207 Ser 204
α β
β
GDP
III
II
IV
Exocite binding
GTP
Pi
Asp 73 γ α
ⴙ β
GTP
DOWNSTREAM EFFECTS Fig. 49.1. G-protein regulatory cycle of activation and deactivation for transmission of the signal from receptor to effector. When GDP is bound the heterotrimeric G-protein is inactive, receptor stimulation causes conformational change in both it and the G-protein which decreases GDP binding affinity. GTP is abundant in the cell and replaces GDP; the active conformation of the Ga subunit dissociates from bc. This activated state remains until GDP is hydrolysed to GDP whereby the subunits reassociate.
STRUCTURE AND FUNCTIONAL R E L AT I O N S H I P S O F b2 - A G O N I S T S A N D T H E b2 - A D R E N O C E P T O R The b2-adrenoceptor is a member of the G protein coupled receptor super family with the typical seven transmembrane spanning domains (Fig. 49.2).6,7 The binding site for b2agonists consists of residues in at least three of the a-helices which pass through the cell membrane. The prolonged duration of action of salmeterol is believed to be due to binding of the lipophilic tail to residues deep in the fourth transmembrane domain.8,9 This process is essentially irreversible. The explanation for the prolonged duration of action of formoterol is less clear although it has been proposed that because of its lipophilicity formoterol partitions in the cell membrane which forms a reservoir allowing prolonged interaction with the receptor.10 The most commonly used b2-agonists in clinical practice are listed in Table 49.2. All the clinically important b2-agonists consist of a benzene ring with a chain of two carbon atoms and either an amine head or a substituted amine head. If a hydroxyl (OH)
Asp 113
Fig. 49.2. Cross sectional view of transmembrane spanning domains of the b2-adrenoreceptor core. The b2 agonist ligand is shown sitting in the binding pocket in the receptor. Key amino acid residues for binding of ligand are shown, Amino acids in transmembrane domain IV are implicated in salmeterol exocite binding.
group is present at positions 3 or 4 on the benzene ring the structure is a catechol nucleus and hence the agent a catecholamine. If these hydroxyl groups are substituted or repositioned the drug is generally less potent than the synthetic catecholamine isoprenaline, which is a full agonist at b2-adrenoceptors. This potential disadvantage may be outweighed by the relative resistance of substituted catecholamines to metabolic degradation by the enzyme catechol – 0-methyltransferase (COMT). Examples of such agents are salbutamol and terbutaline with salbutamol only being a partial agonist. As mentioned above, the prolonged duration of action of salmeterol is due to a long side chain substitution which is believed to bind to an additional site in the fourth transmembrane spanning domain of the receptor. Substitutions on the a carbon atom help block oxidation by monoamine oxidase (MAO).
Table 49.2. Frequently used b2-adrenoceptor agonists
Short-acting b2-adrenoceptor agonists Salbutamol (albuterol)a Terbutaline Tenoterol Long-acting b2-adrenoceptor agonists Salmeterol Formoterol a
USA name
b2-Adrenoceptor Agonists
The effects of catecholamines such as adrenaline (noradrenaline) and isoprenaline are terminated by uptake into either sympathetic nerve endings (uptake 1) or other innervated tissues such as smooth muscle (uptake 2). The dominant enzyme present in innervated tissues is COMT whereas the dominant metabolic degradation route in sympathetic nerve endings is through oxidation by MAO. In addition to degradation, exogenously administered b2-agonists can be conjugated to sulfates or glucuronides in the liver, or the lung. Following ingestion the drugs are partially conjugated during first past metabolism which accounts for roughly 50% of the metabolism of the short-acting drug salbutamol.
CLINICAL PHARMACOLOGY OF b 2- A G O N I S T S General pharmacology b2-adrenoceptor agonists are predominantly used in the treatment of airflow obstruction because of their bronchodilator properties.These differ markedly between asthma and COPD (Table 49.3); indeed, reversibility of airflow obstruction with inhaled b2-agonist is often used as a diagnostic marker of asthma and helps distinguish asthma from COPD in patients where the distinction is in doubt (e.g. chronic “asthmatics” who have smoked, or previous smokers who develop symptoms of wheeze in later life). However, as well as reversing airflow obstruction in asthmatic individuals b2-agonists also protect against bronchoconstrictor challenge.11 Because of this latter effect b2-agonists have been considered to have potential antiinflammatory actions (see below). In-vitro b2-agonists prevent mediator release from inflammatory cells including mast cells, an effect which if present in human airways would be expected to reduce airway inflammation.12,13 However, the concentrations of these agents required to demonstrate these effects is in general much higher than those seen in the lungs in vivo.
S H O R T- T E R M E F F E C T S O F b 2 - A G O N I S T S IN ASTHMA AND COPD As mentioned above, the ability of b2-adrenoceptor agonists to reverse airflow obstruction is a hallmark of asthma, with
523
reversibility 15% being considered diagnostic. b2-agonists do produce a measurable bronchodilator effect in normal individuals and in patients with other diseases characterized by airflow obstruction such as COPD and bronchiectasis, although the magnitude of these effects is generally much smaller. In normal individuals bronchodilator responses are generally only observable by measuring specific airway conductance. This contrast between the marked effects of b2-agonists in asthmatic patients and the minimal effects in normal individuals led early investigators to hypothesize that a primary defect in the b2-adrenoceptor signaling pathway was the actual cause of asthma. This hypothesis would not explain many of the inflammatory features present in the disease, but interest in the potential for a primary abnormality of b2-adrenoceptors to contribute in part to the pathophysiology of asthma resurfaced following the description of polymorphic variation within the b2-adrenoceptor (see below). In addition to having a bronchodilator action b2-agonists in asthmatics protect against bronchoconstrictor stimuli.14–17 One feature demonstrated by most (but not all) asthmatics is nonspecific airway hyperreactivity to inhaled irritant challenge including allergen. The most frequently used stimuli are histamine and methacholine although abnormal responses are also seen to exercise, allergen and other challenges. The inhaled dose of histamine and other agents required to provoke a 20% fall in FEV1 (PC 20) is increased markedly (usually by about three doubling doses) by previous treatment with a short-acting b2-agonist. While a degree of such bronchial hyperreactivity can also be demonstrated in other diseases including COPD, bronchiectasis, cystic fibrosis and left ventricular failure this is usually far less marked than in asthmatic subjects.
L O N G - T E R M E F F E C T S O F b 2- A G O N I S T S IN ASTHMA AND COPD While regular treatment of inhaled or nebulized b2-agonist is frequently used in the management of moderate or severe COPD, despite relatively small improvements in symptoms, controversy has reigned over the long-term use of regular b2agonist in the management of asthma.18,19 This controversy originated from discussions following epidemics of asthma
Table 49.3. b2-agonists in asthma and COPD
Asthma
COPD
Bronchodilator response greater than 15% change in FEV1
Bronchodilator response less than 15% change in FEV1
Bronchodilator hyperreactivity present
Bronchial hyperreactivity usually absent
b2-agonist protects against nonspecific airway challenge Marked symptomatic benefit with b2-agonist
Small or moderate symptomatic benefit with b2-agonist
Effective in long-term management
No disease-modifying effects
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Asthma and Chronic Obstructive Pulmonary Disease
deaths in New Zealand in the late 1960s and late 1970s which were linked to the prescribing of high-dose isoprenaline and fenoterol, respectively. Several studies subsequently concentrated on the possibility that tachyphylaxis may develop as a result of inhaled b2-agonists in asthma. In general, studies attempting to demonstrate tachyphylaxis to the bronchodilator effects of b2-agonists have failed to identify clinically important loss of responsiveness although small effects have been observed when looked for carefully (see for example, Reference 20). However, in contrast, the bronchoprotective effects of b2-agonists against nonspecific airway challenge show tachyphylaxis which generally develops within 24 hours.21,22 Thus, the magnitude of the protective effect against exercise, histamine challenge or methacholine challenge is reduced in magnitude compared with the level of initial protection following administration of b2-agonist for periods of over 24 hours. However, there is still overall protection against bronchoconstrictor challenge even if this is less than the protection seen in the initial hours after treatment. Thus, while it seems clear that tachyphylaxis develops to the bronchoprotective effects of b2-agonists against nonspecific airway challenge, this is only partial, and one would presume that patients would still be better despite this tachyphylaxis than if they were not taking b2-agonist at all. The main concern therefore has revolved around patients taking intermittent treatment or discontinuing treatment. Small rebound increases in airway reactivity have been demonstrated following the cessation of b2-agonist therapy.23 Clinical studies comparing regular (e.g. four times a day) short-acting b2-agonist versus “as required” b2-agonist have not shown clinically important differences despite earlier reports that asthma control deteriorated following regular treatment.24,25 None the less, there is no reason to suppose regular treatment is better than “as required” usage which remains the preferred way of prescribing b2-agonists in asthma. The controversy regarding b2-agonists resurfaced with the introduction into the marketplace of long-acting b2-agonists. Initial concerns that salmeterol might worsen asthma control in the long term have not been proven to be true. This initially seems surprising, given the fact that salmeterol is a partial agonist and essentially binds irreversibly with the b2adrenoceptor. Interestingly, the wheel has now come full circle with the other commonly used long-acting b2-agonist, formoterol, having undergone recent studies for use as an “as required” agent. Although mild COPD is often treated with “as required” b2-agonist regular high-dose inhaled or nebulized b2-agonists have been much more widely used in COPD than in asthma. While small improvements in lung function and symptomatic improvement have been demonstrated in severe COPD, the overall effect on lung function has generally been small, which is hardly surprising given the fixed nature of the airflow obstruction in the majority of patients. There have been no data suggesting deterioration in lung function following chronic administration of high doses of b2-agonist in COPD (these would be difficult to observe in short-term studies in
any case) although there have been concerns about other effects of high doses of b2-agonist in this setting. In particular, high-dose nebulized b2-agonists are known to cause hypokalaemia and both supraventricular and ventricular arrhythmias26 and there have been concerns that these may occur in patients on regular high-dose nebulized bronchodilator therapy for either asthma or COPD at home.
b 2 - A D R E N O C E P T O R P O LY M O R P H I S M I N ASTHMA AND COPD As mentioned above, the identification of polymorphic variation within the gene for the b2-adrenoceptor reawakened interest in the possibility that primary abnormalities of b2adrenoceptor signaling pathways may be involved in the pathogenesis of these airway diseases. The gene for the b2adrenoceptor is situated on chromosome 5q31–33 in a region showing linkage to intermediate phenotypes for asthma and/or atopy.27 The b2-adrenoceptor gene and its immediate controlling regions show a high degree of polymorphic variation with nine single nucleotide type polymorphisms (SNPs) having been identified within the coding region of the gene and a further eight in the immediate 5 prime untranslated region (reviewed in Reference 28). Of the nine coding region polymorphisms five are degenerate (i.e. do not alter the amino acid code of the receptor).29 However, the other four all result in single amino acid substitutions. While the polymorphism at codon 34 (Val34Met) is rare and appears to have no functional effects, the other three nondegenerate polymorphisms appear to produce functional alteration in receptor behavior. Thus, the rare Thr164Ile polymorphism results in reduced affinity for catechol ligands and an altered receptor sequestration profile.30 Interestingly, Thr164 is very close to the salmeterol binding site within the fourth transmembrane spanning domain of the receptor and it seems likely that the isoleucine 164 substitution may alter the binding characteristics of salmeterol to the b2-adrenoceptor. However, the allelic frequency of this polymorphism is only around 2–3% in Caucasian populations, hence homozygous individuals are very rare and to date have not been adequately studied. In contrast, the two N-terminal polymorphisms at codon 16 (Arg16Gly) and 27 (Gln27Glu) are common. While neither alter agonist binding properties of the receptor both result in altered down-regulation profiles following longterm agonist exposure. Thus, the Gly 16 and Gln 27 forms of the receptor show increased receptor down-regulation following agonist exposure while the Glu 27 form of the receptor appears to be partially protected from downregulation.9 These effects have been shown both in transformed cell systems and in primary cultures of human airways smooth muscle. Of the 5 prime untranslated region polymorphisms the strongest evidence for possible functional effects is for the 47 T–C SNP (single nucleotide polymorphism) which alters the terminal amino acid in a short open reading frame which codes for the b-upstream peptide
b2-Adrenoceptor Agonists
(also know as the b2-adrenoceptor 5 prime leader cistron); this peptide is believed to be important in maintaining a “brake” on receptor expression and the Cys19Arg polymorphism in this peptide may possibly increase translational inhibition of the b2-adrenoceptor.31,32 The role of b2-adrenoceptor polymorphism has been extensively studied in asthma but less so in COPD. To date, the majority of studies have failed to demonstrate an association between b2-adrenoceptor polymorphism and asthma per se, although weak association with IgE and the degree of bronchial hyperresponsiveness has been seen in some (but not in all) studies.33 These effects may, in part, be due to linkage disequilibrium with other important genes on chromosome 5q such as the nearby Th2 cytokine locus. The possibility that these polymorphisms may contribute to the development of COPD has not been reported upon to date, although studies in this area are currently in progress. The other potential importance of b2-adrenoceptor polymorphism is in pharmacogenetic studies. The possibility that b2-adrenoceptor polymorphism may predict treatment response, particularly following long-term exposure to agonists due to the altered down-regulation profile of individuals carrying particular genotypes (e.g. Gly16, Gln27), has been studied by a number of groups. Initial studies demonstrated an association between Gly16 and subsensitivity to the bronchodilator effects of formoterol following chronic dosing and also a reduced bronchodilator response to salbutamol.20,34 Gly16 has also been shown to be associated with nocturnal asthma. However, more recent studies have failed to identify a relationship between Gly16 and development of severe asthma,35 and in general, it appears that the effects of these polymorphisms upon treatment response are likely to be relatively small and of doubtful clinical significance overall. It is also possible that the combination of groups of polymorphisms around this region (i.e. the haplotype of an individual at this locus) may be the main determinant of functional effects rather than single polymorphisms in isolation.36 It will be interesting to determine whether these polymorphisms are relevant to treatment response in COPD; intuitively, one might imagine this could be the case given the higher doses of agents used in COPD although, to date, no published data are available on this issue.
S U M M A RY b2-adrenoceptor agonists remain the most important bronchodilator therapies available for the management of both asthma and COPD. The response to b2-agonist is markedly greater in asthma than in COPD due to the reversible nature of airflow obstruction in asthma. In addition, in asthma, b2-agonists provide marked protection against nonspecific bronchial challenge. Extensive polymorphic variation exists within the b2-adrenoceptor but at present there are few data to suggest a causal role for b2-
525
adrenoceptor polymorphism in the development of asthma or COPD. Polymorphic variation in the b2-adrenoceptor may, however, be important in determining treatment response although the overall magnitude of these effects appears to be small.
REFERENCES 1. Davis C, Conolly ME, Greenacre JK. Beta-adrenoceptors in human lung, bronchus and lymphocytes Br. J. Clin. Pharm. 1980; 10:425. 2. Kume H, Hall IP, Washabow RJ, Takagi K, Kotlikoff MI. b-Adrenergic agonists regulate KCa channels in airway smooth muscle cAMP dependent mechanisms. J. Clin. Invest. 1994; 93:371. 3. Torphy TJ, Hall IP. Cyclic AMP and the control of airways smooth muscle tone. In: Airways Smooth Muscle: Biochemical Control of Contraction and Relaxation, (eds Raeburn D and Giembycz MA), p. 215. Basel: Birkhauser Verlag, 1994. 4. Johnson M. The b-adrenoceptor. Am. J. Respir. Crit. Care Med. 1999; 158:S146. 5. Billington CK, Hall IP, Stuart J, Mundell JLP et al. Inflammatory and contractile agents sensitize specific adenylyl cyclase isoforms in human airway smooth muscle. Am. J. Respir. Cell Mol. Biol. 1999; 21:597–606. 6. Dohlman HG, Bouvier M, Benovic JL, Caron MG, Lefkowitz RJ. The multiple membrane spanning topography of the b2adrenergic receptor. J. Biol. Chem. 1987; 262:14282. 7. Emorine J, Marullo S, Delavier-Klutchko C, Kaveri SV, DurievTrautmann O, Strosberg AD. Structure of the gene for human b2-adrenergic receptor: Expression and promoter characterisation. Proc. Natl Acad. Sci. USA 1987; 84:6995. 8. Green SA, Spasoff AP, Coleman RA, Johnson M, Liggett SB. Sustained activation of a G protein-coupled receptor via “anchored” agonist binding: Molecular localisation of the salmeterol exocite within the b2-adrenergic receptor. J. Biol. Chem. 1996; 271:24029. 9. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of b2adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 1995; 13:25. 10. Lofdahl CG, Svedmyr N. Formoterol fumarate, a new b2adrenoceptor agonist. Allergy 1989; 44:264. 11. Tattersfield AE. Effect of beta agonists and anticholinergic drugs on bronchial reactivity. Am. Rev. Respir. Dis. 1987; 136:S64. 12. Assem ESK, Schild HO. Inhibition by sympathomimetic amines of histamine release induced by antigen in passively sensitized human lung. Nature 1969; 224:1028. 13. Howarth PH, Durham SR, Lee TH, Kay AB, Church MK, Holgate ST. Influence of albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating mediator responses to allergen bronchial provocation in asthma. Am. Rev. Respir. Dis. 1985; 132:986. 14. Cheung D, Timmers MC, Zwinderman AH, Bel EH, Dijkman JH, Sterk PJ. Long-term effects of a long-acting b2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness with mild asthma. N. Engl. J. Med. 1992; 327:1198. 15. Twentyman OP, Finnerty JP, Harris A, Palmer J, Holgate ST. Protection against allergen-induced asthma by salmeterol. Lancet 1990; 336:1338. 16. Twentyman OP, Finnerty JP, Holgate ST. The inhibitory effect of nebulized albuterol on the early and late asthmatic reactions and increase in airway responsiveness provoked by inhaled allergen in asthma. Am. Rev. Respir. Dis. 1991; 144:782. 17. Wong BJ, Dolovich J, Ramsdale EH et al. Formoterol compared with beclomethasone and placebo on allergen-induced asthmatic responses. Am. Rev. Respir. Dis. 1992; 146:1156.
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18. Sears MR, Taylor DR, Print CG et al. Regular inhaled b-agonist treatment in bronchial asthma. Lancet 1990; 336:1391. 19. Taylor DR, Sears MR, Herbison GP et al. Regular inhaled bagonist in asthma: effects on exacerbations and lung function. Thorax 1993; 48:134. 20. Tan S, Hall IP, Dewar J, Dow E, Lipworth B. Association between b2-adrenoceptor polymorphism and susceptibility to bronchdilator desensitisation in moderately severe stable asthmatics. Lancet 1997; 350:995. 21. Connor BJ, Aikman SL, Barnes BJ. Tolerance to the nonbronchodilator effects of inhaled b2-agonists in asthma. N. Engl. J. Med. 1992; 327:1204. 22. Ramage L, Lipworth BJ, Ingram CG, Cree IA, Dhillon DP. Reduced protection against exercise-induced bronchoconstriction after chronic dosing with salmeterol. Respir. Med. 1994; 88:363. 23. Wahedna I, Wong CS, Wisniewski AFZ, Pavord ID, Tattersfield AE. Asthma control during and after cessation of regular b2-agonist treatment. Am. Rev. Respir. Dis. 1993; 148:707. 24. Drazen JM, Israel E, Boushey HA et al. for the National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. N. Engl. J. Med. 1996; 335:841. 25. van Schayck CP, Dompeling E, van Herwaarden CLA et al. Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomised controlled study. Br. Med. J. 1991; 303:1426. 26. Wong CS, Pavord ID, Williams J, Britton JR, Tattersfield AE. Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma. Lancet 1990; 336:1396. 27. Kobilka BK, Dixon RAF, Frielle T et al. cDNA for the human b2adrenergic receptor: A protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc. Natl Acad. Sci. USA 1987; 84:46.
28. Fenech A, Hall IP. Pharmacogenetics of asthma. Br. J. Clin. Pharmacol. 2000 (in press). 29. Reihsaus E, Innis M, MacIntyre N, Ligghett SB. Mutations in the gene encoding for b2-adrenergic receptor in normal and asthmatic subjects. Am. J. Respir. Cell Mol. Biol. 1993; 8:334. 30. Green SA, Cole G, Jacinto M, Innis M, Liggett SB. A polymorphism of the human b2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J. Biol. Chem. 1993; 268:23116. 31. McGraw DW, Forbes SL, Kramer LA, Liggett SB. Polymorphisms of the 5 leader cistron of the human b2-adrenergic receptor regulate receptor expression. J. Clin. Invest. 1998; 102:1927. 32. Scott MG, Swan C, Wheatley AP, Hall IP. Identification of novel polymorphisms within the promoter region of the human b2-adrenergic receptor gene. Br. J. Pharmacol. 1999; 126:841–4. 33. Dewar JC, Wilkinson J, Wheatley A et al. The glutamine 27 b2adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families. J. Allergy Clin. Immunol. 1997; 100:261. 34. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the b2adrenoceptor and response to albuterol in children with and without a history of wheezing. J. Clin. Invest. 1997; 100:3184. 35. Weir TD, Malleck N, Sandford AJ et al. Genetic polymorphisms of the b2-adrenergic receptor in fatal and near fatal asthma. Am. J. Respir. Crit. Care Med. 1998; 158:787. 36. Drysdale CM, McGraw DW, Stack CB et al. Complex promoter and coding region b2-adrenergic receptor haplotypes alter receptor expressions and predict in vivo responsiveness. Proc. Natl Acad. Sci. USA 2000; 97:10483–8.
Chapter
Anticholinergic Bronchodilators
50
Steven E. Cattapan and Nicholas J. Gross Loyola University Stritch School of Medicine, Edward Hines Jr. VA Hospital, Hines, IL, USA
Anticholinergic agents, such as atropine, exist in the roots, seeds, and leaves of many plants; as such, they have been used in herbal remedies for many centuries. Seventeenthcentury Aryuvedic literature documents the treatment of asthma with Datura stramonium, a plant commonly known as jimsonweed, which contains atropine. In 1802, this therapy was introduced into Europe by General Gent who, while stationed in Madras, found that smoking Datura stramonium alleviated his asthma.1 In 1859, it was reported that severe bronchospasm was successfully treated by the injection of atropine into the vagus nerve.2,3 Unfortunately, naturally occurring anticholinergics produce many sideeffects that result in poor acceptability by patients. Thus, following the discovery of adrenaline in the 1920s, the use of anticholinergics was largely supplanted by adrenergic agents and later by methylxanthines. Interest in anticholinergics returned with better understanding of the role of the parasympathetic system in controlling airway tone, and with the development of synthetic congeners of atropine that are topically active but much less prone to produce side-effects.4
R AT I O N A L E F O R U S E O F ANTICHOLINERGIC B R O N C H O D I L AT O R S Autonomic control of airway caliber In human airways, most of the efferent autonomic nerves are cholinergic5 (Chapter 34). Branches of the vagus nerve travel along the airways and synapse at peribronchial ganglia, from which short post-ganglionic nerves travel to smooth muscle cells and mucous glands, predominantly in the central airways. The release of acetylcholine from varicosities and terminals of the post-ganglionic nerves activates muscarinic receptors, thereby stimulating smooth muscle contraction, releasing mucus from mucus glands, and possibly accelerating ciliary beat frequency. In resting animals, a low level of cholinergic, vagal (bronchomotor) tone has been demonstrated. This cholinergic activity can be augmented
by a variety of stimuli by means of the neural pathways shown in Fig. 50.1. Afferent activity can arise from irritant receptors and C fibers located anywhere in the upper and lower airways, and probably also from the esophagus and carotid bodies. These impulses are transmitted along vagal afferents, through the vagal nuclei, and then to vagal efferents and the larger airways that receive vagal innervation. Stimuli to which these receptors respond include mechanical irritation, many irritant gases, aerosols, particles, cold dry air, and specific mediators such as histamine and bronchoconstricting eicosanoids.6,7 There is evidence that cholinergic bronchomotor tone is increased in both asthma8 and chronic obstructive pulmonary disease (COPD).9 By competing with acetylcholine at muscarinic receptors, anticholinergic agents inhibit tonic and phasic cholinergic
CNS ? Vagal afferents
Vagal efferents Naso pharynx
Larynx
Fig. 50.1. Diagrammatic representation of vagal reflex pathways from irritant receptors through vagal afferents, central nervous system (CNS), and vagal efferents to effector cells in the airways. Reproduced from Reference 4, with permission.
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Asthma and Chronic Obstructive Pulmonary Disease
activity and permit airways to dilate; however, airflow limitation is seldom completely reversed, as vagal activity probably accounts for only a part of the airflow obstruction in patients with asthma or COPD. Anticholinergics do not inhibit other mediators of smooth muscle contraction, nor do they affect the numerous other mechanisms of airway obstruction in asthma and COPD. Muscarinic receptor subtypes in airways At least three muscarinic receptor subtypes are expressed in human lung, and they appear to have different physiological functions (Fig. 50.2). Our current understanding is that M1 receptors, located in peribronchial ganglia, facilitate cholinergic transmission and enhance bronchoconstriction; M3 receptors, located on smooth muscle cells and submucosal glands, mediate smooth muscle contraction and mucus secretion.10 M2 receptors, in contrast, are autoreceptors whose stimulation provides feedback inhibition of further acetylcholine release from cholinergic nerves, and thus tend to limit vagal bronchoconstriction. M2 receptors are selectively damaged by certain viruses as well as by some eosinophil products, which may account for the bronchospasm associated with viral infections and asthma.11,12 Another possible implication of this schema is that currently available anticholinergic bronchodilators, none of which is selective for muscarinic receptor subtypes, may be suboptimal. Attempts to develop selective anticholinergic agents have resulted in one, tiotropium bromide, that dissociates more rapidly from M2 receptors, rendering it functionally selective for both M1 and M3 receptors.13-15
PHARMACOLOGY Anticholinergic agents are classified as tertiary or quaternary ammonium compounds, depending on whether the nitrogen atom on the tropane ring is 3-valent or 5-valent, respectively (Fig. 50.3). Naturally occurring anticholinergic agents, such as atropine and scopolamine, are tertiary ammonium compounds. They are freely soluble in water and lipids and well absorbed from mucosal surfaces and the
M2 M3
M1
ACh Airway smooth muscle
Ganglion
Cholinergic nerve M1
M2
M3
Fig. 50.2. Muscarinic receptor subtypes in airways. M1 receptors are localized to parasympathetic ganglia, M2 receptors to post-ganglionic cholinergic nerves (autoreceptors), and M3 receptors to airway smooth muscle. Reproduced from Reference 80, with permission.
skin. They are thus widely distributed in the body and cross the blood–brain barrier, counteracting parasympathetic activity in almost every system and producing widespread dose-related systemic effects. Atropine, for example, in the dose that results in bronchodilatation (1.0–2.5 mg in adults) frequently produces skin flushing, mouth dryness and possibly tachycardia. In slightly higher doses, it produces blurred vision, urinary retention and mental effects such as irritability, confusion and hallucinations. The therapeutic margin of atropine and its natural congeners is thus small, making these agents difficult to use. Quaternary ammonium compounds are all synthetic, e.g. ipratropium bromide. The charge associated with the 5valent nitrogen atom renders these molecules poorly absorbable from mucosal surfaces. Such agents are fully anticholinergic at the site of deposition and will, for example, dilate the pupil if delivered to the eye or dilate the bronchi if inhaled. However, they are not sufficiently absorbed from these sites to produce either detectable blood levels or systemic effects, even when delivered in supramaximal doses.16 Quaternary agents can thus be regarded for practical purposes as topical forms of atropine. The group includes, in addition to ipratropium: • • • •
oxitropium bromide (Oxivent) atropine methonitrate glycopyrrolate bromide (Robinul) tiotropium bromide (Spiriva).
The last agent, tiotropium, is of particular interest in that it is a functionally selective antagonist of the muscarinic receptor subtypes that mediate bronchoconstriction (see above) and is also extremely long-acting.13,14 The long halflife of tiotropium allows for once-daily dosing. Thus, it is likely that tiotropium will prove more convenient and provide more consistent bronchodilation than the currently recommended three- to four-times daily administration of ipratropium bromide. Furthermore, the prolonged protection against cholinergic bronchoconstriction may improve control of nocturnal bronchoconstriction, where cholinergic mechanisms appear to be important. For these reasons, tiotropium may prove preferable to currently available agents. Indeed, in a recent randomized trial of 288 patients with stable COPD, tiotropium was more effective than ipratropium at improving trough, average, and peak lung function over a 13-week period.17 Pharmacokinetics Atropine is quantitatively absorbed from the airways, reaching peak blood levels in 1 hour. The half-life in the circulation is about 3 hours in adults, but longer in children and the elderly.4 Small concentrations can be measured in the feces and in breast milk. Radiolabeling studies of ipratropium in humans show that, following oral or inhaled doses, the serum levels are very low, with a peak at about 1–2 hours and a half-life of about 4 hours. Most of the drug is excreted unchanged in the urine. Following inhalation,
529
Anticholinergic Bronchodilators
Tertiary ammonium compounds CH3
CH3 N
N
Atropine
O
O
CH2 OH
C
CH
O Hysoscine (scopolamine)
O
O
CH2 OH
C
CH
Quaternary ammonium compounds
Br- H2O
CH(CH3)2
Br- H2O
H3C N
O Ipratropium bromide
O
C
CH2 OH CH
H3C
N
CH3
O
O Tiotropium bromide
O
OH
S
C
S
Fig. 50.3. Structures of some anticholinergic agents.
CLINICAL EFFICACY
delivered by turbuhaler was equipotent to 20 lg delivered by MDI.19 The optimal dose of oxitropium MDI is approximately 200 lg. For less commonly used agents, the optimal doses are as follows: atropine, 0.025–0.04 mg/kg; atropine methonitrate, 0.015–0.02 mg/kg; glycopyrrolate, 0.02 mg/kg. In separate studies,14,20 tiotropium was administered in doses ranging from 10 to 80 lg and from 4.5 to 36 lg; in both studies, dose-related improvements in airflow were discernible.
Dose–response The dose–response of anticholinergic agents given by various inhalational methods is provided in a previous review.18 For ipratropium bromide in nebulized solution, the optimal dose is 500 lg in adults and 125–250 lg in children. By metered dose inhaler (MDI), the optimal dose in young adults with asthma is 40–80 lg, but in older patients with COPD the optimal dose is much higher, possibly 160 lg, particularly when airways obstruction is severe. Newer inhalers will employ a dry powder form without propellants, rather than the suspension that is currently used. The optimal dose of the dry powder form may be a little lower than that for the suspension. For instance, 10 lg of ipratropium
Protection against specific stimuli When given in advance of bronchospastic stimuli, anticholinergic agents provide variable degrees of protection.4 They protect more or less completely against cholinergic agonists such as methacholine. In asthmatics, they can prevent bronchospasm induced by b-blocking agents and by psychogenic factors. They provide only partial protection against bronchospasm due to most other stimuli, e.g. histamine,21,22 prostaglandins, nonspecific dusts and irritant aerosols, exercise and hyperventilation with cold dry air. In most of the latter instances, adrenergic agents usually provide greater protection. Ipratropium has no prophylactic effect on leukotriene-induced asthma.23
the bronchodilator effect is somewhat longer than that of atropine, probably because it is not removed from the airways by absorption. Most of an oral dose is recovered in the feces, a small amount as inactive metabolites in the urine. Very little reaches the central nervous system. A similar distribution is likely for tiotropium.
530
Asthma and Chronic Obstructive Pulmonary Disease
commercially available and effective at reducing rhinorrhea;29 thus, in these patients, it may reduce asthma symptoms.
Stable asthma A very large number of studies have compared the bronchodilator potential of the anticholinergic agents with that of adrenergic agents in patients with asthma. While many of these studies are flawed by the fact that they used recommended doses rather than optimal doses, they provide useful information about the comparative actions of these bronchodilators.24 Fig. 50.4, which is typical of most such studies, illustrates many of these points. Anticholinergic agents are slower to reach peak effect, typically 1–2 hours, compared with about 15 minutes for many adrenergic agents. At their peak effect, they almost invariably result in less bronchodilation. The quaternary forms may be slightly longer acting than agents such as salbutamol. Among asthmatic patients, however, there is substantial variation in responsiveness, some patients responding very little to anticholinergic agents, others responding to them almost as well as to adrenergic agents. It has been difficult to identify subgroups of asthmatic patients who are likely to have the greatest response to anticholinergic therapy. The bronchodilating effect of ipratropium may increase with age, in contrast to the decline in response to salbutamol.25 However, children aged 10–18 years have been shown to benefit26 (see below). Individuals with intrinsic asthma and those with a longer duration of asthma may also respond better than individuals with extrinsic asthma,27 although these factors appear to be poor predictors of response. An individual trial remains the best way to identify responsiveness.28 Recently, attention has focused on the role post-nasal drip may play in promoting asthma. Ipratropium nasal spray is
Increase in FEV1 above baseline (mL BTPS)
Pediatric airways disease For acute severe asthma in children, two well-conducted trials in the 1980s showed that the addition of ipratropium
Salbutamol Ipratropium
800 700
Acute severe asthma Most studies suggest that b-agonists are more effective bronchodilators in the setting of acute severe asthma, and that an anticholinergic agent should not be used as the sole initial bronchodilator. The question arises whether an anticholinergic agent can add to the bronchodilatation achieved by the adrenergic agent. In 1987, Rebuck et al.30 found that the combination of 500 lg nebulized ipratropium with 1.25 mg nebulized fenoterol resulted in significantly more bronchodilatation over the first 90 minutes of treatment than either agent alone. Moreover, patients with more severe airway obstruction obtained the greatest benefit from the combination. In the past decade, many studies have addressed this same question. A meta-analysis31 of ten such studies (total of 1377 patients) concluded that the addition of ipratropium reduced hospital admissions (relative risk 0.73) and increased FEV1 by 7.5% (on average 100 cc, 95% CI 50–149 ml) when compared with groups receiving b2 stimulants alone. These benefits were both statistically and clinically significant.32 It seems appropriate to recommend that both classes of bronchodilators be given in acute severe asthma, especially in the early hours of treatment32 and particularly in patients with more severe airflow obstruction.
*
*
*
* *
600 500 400 300 200 100 0 30
60
90
120
180
240
300
360
420
480
Time (minutes)
Fig. 50.4. Increase in forced expiratory volume in 1 second (FEV1) of 25 patients with asthma after inhalation of 200 lg salbutamol by metered dose inhaler (MDI) or 40 lg ipratropium by MDI on separate days. All patients received an additional dose of salbutamol at 480 minutes. Asterisks denote significant differences (P < 0.05). Reproduced from Reference 24, with permission.
531
Anticholinergic Bronchodilators
Asthmatics
0.8
IFT 0.6 Mean increase (liters)
accelerated the rate of improvement in airflow over salbutamol alone.33,34 Subsequent studies35–40 yielded conflicting results regarding the efficacy of combined therapy, although some of these studies lacked statistical power. A systematic review41 of ten studies concluded that combination therapy with multiple doses of ipratropium was safe, improved lung function, and reduced hospitalization rates, especially in children with severe asthma. As in adult status asthmaticus, therefore, the combination of ipratropium with an adrenergic agent is probably more effective than salbutamol monotherapy, particularly in severe exacerbations. In stable childhood asthma, the evidence to support the addition of ipratropium to salbutamol is less clear. Two consensus reports reviewed the published evidence, which is not extensive, and concluded that although ipratropium was safe for the pediatric population, its benefit compared with an adrenergic agent alone was slight at best.42,43 There are scattered reports of ipratropium use in other pediatric conditions such as cystic fibrosis, viral bronchiolitis, exerciseinduced bronchospasm and bronchopulmonary dysplasia, but these do not provide strong and consistent evidence for the benefit of ipratropium over alternative bronchodilators.
FT 0.4
0.2 I
1
2
3
Time (hours)
Bronchitics 0.4 Mean increase (liters)
Stable COPD A large number of studies have compared anticholinergic agents with other bronchodilators in patients with COPD.44,45 Although patients with COPD usually do not exhibit as much improvement in airflow limitation to any agent or combination of agents as do patients with asthma, most studies show that the anticholinergic agent is a more potent bronchodilator than other agents in COPD.28,46–48 After large cumulative doses, the anticholinergic agent alone achieves all the available bronchodilatation.49 In this regard, COPD patients contrast sharply with asthmatic patients. Lefcoe and associates50 performed one of a few studies in which bronchodilator responsiveness was compared between patients with asthma and COPD who had similar baseline airflows. As illustrated in Fig. 50.5, patients with bronchitis had a better response to ipratropium than to the combination of fenoterol and theophylline (change in FEV1 0.29 L versus 0.18 L), whereas in asthmatics ipratropium was a less effective bronchodilator than the combination.50 Why? In asthma, airflow obstruction results from airway inflammation that is, at least partially, modified by adrenergic agents but not by anticholinergics; in COPD, the major reversible component is bronchomotor tone, which is best reversed by anticholinergic agents.49 Accordingly, ipratropium is currently recommended as first-line treatment for stable COPD in the most recent official statements of the European Respiratory Society51 and the American Thoracic Society.52 It should be noted, however, that the clinical utility of ipratropium (and possibly other bronchodilators) is limited to the short-term relief of symptoms and that it has no demonstrated longterm effect on the natural history of COPD. In the Lung Health Study, a large multicenter longitudinal trial of healthy smokers, regular use of ipratropium had no
IFT I 0.2
FT P 1
2 Time (hours)
3
Fig. 50.5. Increase in forced expiratory volume in 1 second (FEV1) of 15 patients with asthma (upper panel) and 15 patients with chronic bronchitis (lower panel). P, placebo metered dose inhaler (MDI); I, ipratropium 40 lg MDI; F T, fenoterol 5 mg plus oxtriphylline 400 mg oral. Reproduced from Reference 50, with permission.
discernible effect on smoking-related accelerated decline in lung function.53 Acute exacerbations of COPD Four studies comparing the efficacy of bronchodilators in acute exacerbations of COPD have failed to discern a difference among adrenergic agents, anticholinergic agents, or their combination.30,54–56 None the less, published guidelines from the American Thoracic Society, European Respiratory Society, and British Thoracic Society all recommend combination therapy with adrenergic and anticholinergic agents.51,52,57
532
Asthma and Chronic Obstructive Pulmonary Disease
Effects on sleep quality Sleep disturbance is common among patients with chronic bronchitis and asthma. In the Tucson Epidemiological Study, 41% of patients with obstructive airways disease reported at least one symptom of disturbed sleep.58 Patients with stable COPD frequently experience nocturnal oxygen desaturation, particularly during REM sleep, even in the absence of concomitant obstructive sleep apnea.59 This contributes to the development of pulmonary hypertension, polycythemia and cardiac arrhythmias.60 Sleep disturbance in children with asthma is associated with psychological problems and impairment of memory.61 A randomized double-blinded study involving 36 patients with moderate to severe COPD showed that ipratropium increased total sleep time, decreased the severity of nocturnal desaturation, and improved the patient’s perceptions of sleep quality.62 Combinations with other bronchodilators Combinations of different classes of bronchodilators often provide more bronchodilatation than single agents, and this effect is seen in many of the studies cited. However, since most clinical studies are performed with recommended rather than optimal doses of the agents, the effects of multiple classes of agents may simply be additive rather than potentiating. None the less, since anticholinergic, adrenergic and methylxanthine agents work by different mechanisms, affect different-sized airways and have different pharmacodynamic and pharmacokinetic properties, their combination is rational and is likely to result in improved bronchodilatation. No unfavorable interactions between these three classes of agents have been reported, so the greater bronchodilation achieved by their combination is achieved without increasing the risk of side-effects. In practice, it is common to use two or even all of these agents simultaneously to manage severe airways obstruction. Single MDIs combining different classes of inhaled bronchodilators have been in use since at least the 1950s. The combination of ipratropium and the b2-agonist fenoterol (Berodual® and DuoVent®) has been widely used since the l970s. Because of the concerns about the safety of fenoterol, a new combination MDI containing ipratropium and salbutamol, both in recommended dosage, has been developed (Combivent®). For patients who need two agents, a single MDI containing both agents is likely to be less expensive than two MDIs, more convenient for the patient to use, and therefore likely to improve patient compliance. Clinical trials with this combination in patients with COPD63–65 suggest it possesses all the advantages mentioned above. A post hoc review of two trials, involving 1067 patients over an 85-day period, concluded that the combination approach appears to be cost-effective.66 Bronchodilation is greater during the first 4–5 hours after administration, but not much prolonged over that achieved by single agents, and no increase in side-effects is incurred. Similarly, in 863 patients with moderately severe COPD, nebulization of a combination of ipratropium bromide and albuterol sulfate (Dey combination, Dey LP, Napa, CA,
USA) resulted in 30% more improvement in bronchodilation than was seen by albuterol alone, and 32% more than with ipratropium alone. However, the 6-minute walking distance was unchanged.67
SIDE-EFFECTS Atropine produces numerous systemic side-effects related to the inhibition of physiological functions of the parasympathetic system, as mentioned above. These effects occur in doses at or only slightly above the bronchodilator dose. Atropine is contraindicated in patients with glaucoma or prostatism. The principal advantage of quaternary anticholinergic agents is that they are so poorly absorbed from mucosa that the risk of such effects is insignificant. Even massive, inadvertent overdosage of one such agent resulted in trivial effects.17 Ipratropium, the most widely studied quaternary anticholinergic, has been exonerated after extensive exploration for atropine-like side-effects.68 It can, for example, be given to patients with glaucoma without affecting intraocular tension69 (provided it is not sprayed directly into the eye). It has been found not to affect urinary flow characteristics in older men. Nor has it been found to alter the viscosity and elasticity of respiratory mucus, or mucociliary clearance, as does atropine.70 It has negligible effects on hemodynamics, minute ventilation,71 and the pulmonary circulation.72 Consequently, quaternary anticholinergics do not carry the risk of worsening hypoxemia, as do adrenergic agents,73–75 an important consideration in exacerbations of asthma and COPD. In normal clinical use, the only side-effects of ipratropium are dryness of the mouth, a brief coughing spell, and paradoxical bronchoconstriction. Paradoxical bronchoconstriction This last effect occurs in perhaps 0.3% of patients and has been variously attributed to hypotonicity of the nebulized solution, idiosyncrasy to the bromine radical, the benzalkonium preservative,76,77 and a selective effect on the M2 receptor. Paradoxical bronchoconstriction, which may also occur with other anticholinergic agents, warrants withdrawal of the drug from the patient. Other than these effects, very extensive investigation and the worldwide use of ipratropium for over two decades demonstrate a remarkably low incidence of untoward reactions. There is no reason at present to believe that the safety profile of the newer quaternary anticholinergic agents will be different from that of ipratropium.
C L I N I C A L R E C O M M E N D AT I O N S The use of anticholinergic bronchodilators is best limited to the poorly absorbed quaternary forms, e.g. ipratropium, oxitropium, atropine methonitrate, glycopyrrolate, and tiotropium, administered by inhalation. They are sometimes
Anticholinergic Bronchodilators
useful in stable asthma as adjuncts to other bronchodilator therapy, and have a demonstrated role in combination with adrenergic agents in the treatment of acute severe asthma. Their principal indication is the long-term management of stable COPD, where they are probably the most efficacious bronchodilators. Because of their slow onset of action they are best used on a regular, maintenance basis, rather than p.r.n.The usual dose of ipratropium, two puffs of 20 lg each, is probably suboptimal78 for many patients with COPD and can safely be doubled or quadrupled.79
20.
21. 22.
23.
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40. Qureshi F, Pestian J, Davis P, Zaritsky A. Effect of nebulized ipratropium on the hospitalization rates of children with asthma. N. Engl. J. Med. 1998; 339:1030–5. 41. Plotnick L, Ducharme F. Should inhaled anticholinergics be added to b2 agonists for treating acute childhood and adolescent asthma? A systematic review. Br. Med. J. 1998; 317:971–7. 42. Warner JO, Gotz M, Landau LI, Levison H, Milner AD, Pedersen S. Management of asthma: a consensus statement. Arch. Dis. Child. 1989; 64:1065–79. 43. Hargreave FE, Dolovich J, Newhouse MT. The assessment and treatment of asthma: a conference report. J. Allergy Clin. Immunol. 1990; 85:1098–111. 44. Thiessen B, Pedersen OF. Maximal expiratory flows and forced vital capacity in normal, asthmatic and bronchitic subjects after salbutamol and ipratropium bromide. Respiration 1982; 43:304–16. 45. Passamonte PM, Martinez AJ. Effect of inhaled atropine or metaproterenol in patients with chronic airway obstruction and therapeutic serum theophylline levels. Chest 1984; 85:610–15. 46. Bleecker ER, Britt EJ. Acute bronchodilating effects of ipratropium bromide and theophylline in chronic obstructive pulmonary disease. Am. J. Med. 1991; 91:24S–7. 47. Braun SR, McKenzie WN, Copeland C, Knight L, Ellersieck M. A comparison of the effect of ipratropium and albuterol in the treatment of chronic obstructive airway disease [published erratum appears in Arch. Intern. Med. 1990 Jun; 150:1242]. Arch. Intern. Med. 1989; 149:544–7. 48. Tashkin DP, Ashutosh K, Bleecker ER, Britt EJ, Cugell DW, Cummiskey JM. Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. A 90-day multi-center study. Am. J. Med. 1986; 81:81–90. 49. Gross NJ, Skorodin MS. Role of the parasympathetic system in airway obstruction due to emphysema. N. Engl. J. Med. 1984; 311:421–5. 50. Lefcoe NM, Toogood JH, Blennerhassett G, Baskerville J, Paterson NA. The addition of an aerosol anticholinergic to an oral beta agonist plus theophylline in asthma and bronchitis. A doubleblind single dose study. Chest 1982; 82:300–5. 51. Siafakas NM, Vermeire P, Pride NB, Paoletti P, Gibson J, Howard P. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur. Respir. J. 1995; 8:1398–420. 52. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am. J. Respir. Crit. Care Med. 1995; 152:S77–121. 53. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994; 272:1497–505. 54. Karpel JP, Pesin J, Greenberg D, Gentry E. A comparison of the effects of ipratropium bromide and metaproterenol sulfate in acute exacerbations of COPD. Chest 1990; 98:835–9. 55. Patrick DM, Dales RE, Stark RM, Laliberte G, Dickinson G. Severe exacerbations of COPD and asthma. Incremental benefit of adding ipratropium to usual therapy. Chest 1990; 98:295–7. 56. Koutsogiannis Z, Kelly A. Does high dose ipratropium bromide added to salbutamol improve pulmonary function for patients with chronic obstructive airways disease in the emergency department? Aust. N. Z. J. Med. 2000; 30:38–40. 57. BTS guidelines for the management of chronic obstructive pulmonary disease: The COPD Guideline Group of the Standards of Care Committee of the BTS. Thorax 1997; 52(S5):S1–28. 58. Klink M, Quan SF. Prevalence of reported sleep disturbances in a general adult population and their relationship to obstructive airways diseases. Chest 1987; 91:540–6. 59. Douglas NJ, Calverley PM, Leggett RJ, Brash HM, Flenley DC, Brezinova V. Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet 1979; 1:1–4.
60. Douglas NJ. Sleep in patients with chronic obstructive pulmonary disease. Clin. Chest Med. 1998; 19:115–25. 61. Stores G, Ellis AJ, Wiggs L, Crawford C, Thomson A. Sleep and psychological disturbance in nocturnal asthma. Arch. Dis. Child 1998; 78:413–19. 62. Martin RJ, Bucher-Bartleson BL, Smith P et al. Effect of ipratropium bromide treatment on oxygen saturation and sleep quality in COPD. Chest 1999; 115:1338–45. 63. Petty TL. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. COMBIVENT Inhalation Aerosol Study Group. Chest 1994; 105:1411–19. 64. Ikeda A, Nishimura K, Koyama H, Izumi T. Bronchodilating effects of combined therapy with clinical dosages of ipratropium bromide and salbutamol for stable COPD: comparison with ipratropium bromide alone. Chest 1995; 107:401–5. 65. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. The COMBIVENT Inhalation Solution Study Group. Chest 1997; 112:1514–21. 66. Friedman M, Serby CW, Menjoge SS, Wilson JD, Hilleman DE, Witek TJ Jr. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest 1999; 115:635–41. 67. Gross N,Tashkin D, Miller R, Oren J, ColemanW, Linberg S. Inhalation by nebulization of albuterol-ipratropium combination (Dey combination) is superior to either agent alone in the treatment of chronic obstructive pulmonary disease. Dey Combination Solution Study Group. Respiration 1998; 65:354–62. 68. Gross NJ. Ipratropium bromide. N. Engl. J. Med. 1988; 319:486–94. 69. Watson WT, Shuckett EP, Becker AB, Simons FE. Effect of nebulized ipratropium bromide on intraocular pressures in children. Chest 1994; 105:1439–41. 70. Pavia D, Bateman JR, Sheahan NF, Clarke SW. Effect of ipratropium bromide on mucociliary clearance and pulmonary function in reversible airways obstruction. Thorax 1979; 34:501–7. 71. Tobin MJ, Hughes JA, Hutchison DC. Effects of ipratropium bromide and fenoterol aerosols on exercise tolerance. Eur. J. Respir. Dis. 1984; 65:441–6. 72. Chapman KR, Smith DL, Rebuck AS, Leenen FH. Haemodynamic effects of inhaled ipratropium bromide, alone and combined with an inhaled beta 2-agonist. Am. Rev. Respir. Dis. 1985; 132:845–7. 73. Ashutosh K, Dev G, Steele D. Nonbronchodilator effects of pirbuterol and ipratropium in chronic obstructive pulmonary disease. Chest 1995; 107:173–8. 74. Gross NJ, Bankwala Z. Effects of an anticholinergic bronchodilator on arterial blood gases of hypoxaemic patients with chronic obstructive pulmonary disease. Comparison with a betaadrenergic agent. Am. Rev. Respir. Dis. 1987; 136:1091–4. 75. Khoukhaz G, Gross NJ. Effects of salmeterol on arterial blood gases in patients with stable chronic obstructive pulmonary disease. Comparison with albuterol and ipratropium. Am. J. Respir. Crit. Care Med. 1999; 160:1028–30. 76. Beasley R, Fishwick D, Miles JF, Hendeles L. Preservatives in nebulizer solutions: risks without benefit. Pharmacotherapy 1998; 18:130–9. 77. Boucher M, Roy MT, Henderson J. Possible association of benzalkonium chloride in nebulizer solutions with respiratory arrest. Ann. Pharmacother. 1992; 26:772–4. 78. Gross NJ, Petty TL, Friedman M, Skorodin MS, Silvers GW, Donohue JF. Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease. A three-center study. Am. Rev. Respir. Dis. 1989; 139:1188–91. 79. Leak A, O’Connor T. High dose ipratropium bromide is it safe? Practitioner 1988; 232:9–10. 80. Barnes PJ, Minette P, Maclagan J. Muscarinic receptor subtypes in airways. Trends Pharmacol. Sci. 1988; 9:412–16.
Chapter
Theophylline
51
Peter J. Barnes National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
Theophylline remains one of the most widely prescribed drugs for the treatment of airway diseases worldwide since it is inexpensive. In many industrialized countries, however, theophylline has become a third-line treatment that is only used in poorly controlled patients. This has been reinforced by various guidelines to therapy. Some have even questioned whether theophylline is indicated in any patients with asthma,1 although others have emphasized the special beneficial effects of theophylline which still give it an important place in the management of asthma and COPD.2 However, the frequency of side-effects and the relative low efficacy of theophylline have recently led to reduced usage, since inhaled b2-agonists are far more effective as bronchodilators and inhaled corticosteroids have a greater anti-inflammatory effect. Despite the fact that theophylline has been used in asthma therapy for over 60 years, there is still considerable uncertainty about its mode of action in asthma and its logical place in therapy. Because of problems with side-effects, there have been attempts to improve on theophylline, and recently there has been increasing interest in selective phosphodiesterase (PDE) inhibitors, which have the possibility of improving the beneficial and reducing the adverse effects of theophylline.
MOLECULAR MECHANISMS OF ACTION Although theophylline has been in clinical use for more than 60 years both its mechanism of action at a molecular level and its site of action remain uncertain. Several molecular mechanisms of action have been proposed, although many of these appear to occur only with higher concentrations of theophylline than effective clinically (Table 51.1). Phosphodiesterase inhibition Theophylline is a weak and nonselective inhibitor of PDEs, which break down cyclic nucleotides in the cell, thereby leading to an increase in intracellular cyclic 35 adenosine monophosphate (cAMP) and cyclic 3,5 guanosine monophosphate (cGMP) concentrations (Fig. 51.1). However, the degree of inhibition is small at concentrations of theophylline that are therapeutically relevant. Thus total PDE activity in human lung extracts is inhibited by only 5–10% by therapeutic concentrations of theophylline.5 There is convincing in-vitro evidence that theophylline relaxes airway smooth muscle by inhibition of PDE activity, but relatively high concentrations are needed for maximal relaxation.6 Similarly, the inhibitory effect of theophylline on mediator release from alveolar macrophages appears to be mediated by inhibition of PDE activity in these cells.7 There is no evidence that airway smooth muscle of inflammatory
C H E M I S T RY Table 51.1. Mechanisms of action of theophylline
Theophylline is a methylxanthine similar in structure to the common dietary xanthines caffeine and theobromine. Several substituted derivatives have been synthesized but none has any advantage over theophylline,3 apart from the 3propyl derivative, enprofylline, which is more potent as a bronchodilator and may have fewer toxic effects.4 Many salts of theophylline have also been marketed, the most common being aminophylline, the ethylene diamine salt used to increase solubility at neutral pH so that intravenous administration is possible. Other salts, such as choline theophyllinate, do not have any advantage and others, such as acepifylline, are virtually inactive.3
• Phosphodiesterase inhibition (nonselective) • Adenosine receptor antagonism (A1, A2A, A2B receptors) • Stimulation of catecholamine release • Mediator inhibition (prostaglandins, TNF-a) • Inhibition of intracellular calcium release • Inhibition of NF-jB (↓ nuclear translocation) • ↑ Histone deacetylase activity (↑ efficacy of corticosteroids)
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RRRRRRRRRRRRRRf RRRRR
0
Theophylline
0 GTP
PDE3,4,7
PDE5
3',5'cAMP
3',5'cGMP
{@
GMP
Bronchodilatation
j Inflammatory cells
Fig 5 1 . 1 . Effect of phosphodiesterase (PDE) inhibitors in the breakdown of cyclic nucleotides in airway smooth muscle and inflammatory cells.
cells concentrate theophylline to achieve higher intracellular than circulating concentrations. Inhibition of P D E should lead to synergistic interaction with P-agonists, but this has not been convincingly demonstrated in vivo. However, this might be because relaxation of airway smooth muscle by Pagonists may involve direct coupling of P-receptors via a stimulatory G-protein to the opening of potassium channels, without the involvement of cyclic AMR* At least ten isoenzyme families of P D E have now been recognized and some (PDE3, P D E 4 , PDE5) are more important in smooth muscle relaxation.^''" However, there is no convincing evidence that theophylline has any greater inhibitory effect on the P D E isoenzymes involved in smooth muscle relaxation. It is possible that P D E isoenzymes may have an increased expression in asthmatic airways, either as a result of the chronic inflammatory process, or as a result of therapy. Elevation of cyclic A M P by P-agonists may result in increased P D E activity, thus limiting the effect of Pagonists. Indeed, alveolar macrophages from asthmatic patients appear to have increased P D E activity." This would mean that theophylline might have a greater inhibitory effect on P D E in asthmatic airways than in normal airways. Support for this is provided by the lack of bronchodilator effect of theophylline in normal subjects, compared with a bronchodilator effect in asthmatic patients. '^ Adenosine receptor antagonism Theophylline is a potent inhibitor of adenosine receptors at therapeutic concentrations (both Aj and Aj receptors, although it is less effective against A3 receptors), suggesting that this could be the basis for its bronchodilator effects." Although adenosine has little effect on normal human airway smooth muscle in vitro, it constricts airways of asthmatic patients via the release of histamine and leukotrienes, suggesting that adenosine releases mediators from mast cells.'''The receptor involved appears to be an A3 receptor in
rat mast cells,'^ but in humans there is evidence for the involvement of an AJB receptor.'* Adenosine causes bronchoconstriction in asthmatic subjects when given by inhalation." T h e mechanism of bronchoconstriction is indirect and involves release of histamine from airway mast cells.'''"'* The bronchoconstrictor effect of adenosine is prevented by therapeutic concentrations of theophylline." However, this only confirms that theophylline is capable of antagonizing the effects of adenosine at therapeutic concentrations, and this does not necessarily indicate that this is important for its anti-asthma effect. However, adenosine antagonism is likely to account for some of the side-effects of theophylline, such as central nervous system stimulation, cardiac arrhythmias, gastric hypersecretion, gastroesophageal reflux, and diuresis. Endogenous catecholamine release Theophylline increases the secretion of adrenaline from the adrenal medulla,'^ although the increase in plasma concentration is small and insufficient to account for any significant bronchodilator effect.^" Mediator inhibition Theophylline antagonizes the effect of some prostaglandins on vascular smooth muscle in vitro,^^ but there is no evidence that these effects are seen at therapeutic concentrations or are relevant to its airway effects. Theophylline inhibits the secretion of tumor necrosis factor-a (TNF-a) by peripheral blood monocytes,^^ and increases the secretion of the anti-inflammatory cytokine interleukin (IL)-IO.^^ However, these effects are not seen in alveolar macrophages obtained by bronchoalveolar lavage from patients treated with theophylline.^''Theophylline may also interfere with the action of T N F - a , which may be involved in inflammation in severe asthma and in C O P D . A related compound, pentoxifylline, prevents TNF-a-induced lung injury and
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Theophylline
enhanced hypoxic pulmonary vasoconstriction,25 but its mechanism of action is not yet understood. Calcium ion flux There is some evidence that theophylline may interfere with calcium mobilization in airway smooth muscle.Theophylline has no effect on entry of calcium ions (Ca2+) via voltagedependent channels, but it has been suggested that it may influence calcium entry via receptor-operated channels, release from intracellular stores, or have some effect on phosphatidylinositol turnover (which is linked to release of Ca2+ from intracellular stores). There is no direct evidence in favor of this, other than an effect on intracellular cyclic AMP concentration due to its PDE inhibitory action. An early study suggesting that theophylline may increase Ca2+ uptake into intracellular stores26 has not been followed up. Effect on transcription Theophylline prevents the translocation of the proinflammatory transcription factor NF-jB into the nucleus, thus potentially reducing the expression of inflammatory genes in asthma and COPD.27 Recent studies suggest that theophylline increases the activity of histone deacetylase, which is recruited by corticosteroids to the transcription complex to switch off inflammatory genes.28 This action of theophylline occurs at therapeutically relevant concentrations and is not mediated via PDE inhibition of adenosine antagonism. It predicts a synergistic action between theophylline and corticosteroids. Effects on apoptosis Prolonged survival of granulocytes due to a reduction in apoptosis may be important in perpetuating chronic inflammation in asthma (eosinophils) and COPD
(neutrophils).Theophylline inhibits apoptosis in eosinophils and neutrophils in vitro.29 This is associated with a reduction in the anti-apoptotic protein bcl-2.30 This effect is not mediated via PDE inhibition, but in neutrophils may be mediated by antagonism of adenosine A2A receptors.31
CELLULAR EFFECTS Theophylline has several effects that may contribute to its clinical efficacy in the treatment of asthma and COPD (Fig. 51.2). Airway smooth muscle effects The primary effect of theophylline is assumed to be relaxation of airway smooth muscle and in-vitro studies have shown that it is equally effective in large and small airways.32 In airways obtained at lung surgery, approximately 25% of preparations fail to relax with a b-agonist, but all relax with theophylline.33 The molecular mechanism of bronchodilatation is almost certainly related to PDE inhibition, resulting in an increase in cyclic AMP.6 The bronchodilator effect of theophylline is reduced in human airways by the toxin charybdotoxin, which inhibits large conductance Ca2+activated K+ channels (maxi-K channels), suggesting that theophylline opens maxi-K channels via an increase in cyclic AMP.34 Theophylline acts as a functional antagonist and inhibits the contractile response of multiple spasmogens. In airways obtained at post-mortem from patients who have died from asthma the relaxant response to b-agonists is reduced, whereas the bronchodilator response to theophylline is no different from that seen in normal airways.35 There is evidence that b-adrenoceptors in airway smooth muscle of patients with fatal asthma become uncoupled,36 and
Inflammatory cells
Structural cells Airway smooth muscle
Eosinophil Numbers (apoptosis)
Bronchodilatation
T lymphocytes Cytokines, traffic
Endothelial cell
Mast cell
Theophylline
Leak
Mediators
Macrophage
Respiratory muscles
Cytokines Strength ?
Fig. 51.2. Multiple effects of theophylline.
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theophylline may therefore have a theoretical advantage over b-agonists in severe asthma exacerbations. However, theophylline is a weak bronchodilator at therapeutically relevant concentrations, suggesting that some other target cell may be more relevant for its anti-asthma effect. In human airways the EC50 for theophylline is approximately 1.5 104 M, which is equivalent to 67 mg/L assuming 60% protein binding.33 However, as discussed above, it is important to consider the possibility that PDE activity nay be increased in asthmatic airways so that theophylline may have a greater effect than expected. In-vivo intravenous aminophylline has an acute bronchodilator effect in asthmatic patients, which is most likely to be due to a relaxant effect on airway smooth muscle.37 The bronchodilator effect of theophylline in chronic asthma is small in comparison with b-agonists, however. Several studies have demonstrated a small protective effect of theophylline on histamine, methacholine or exercise challenge.38–41 This protective effect does not correlate well with any bronchodilator effect and it is interesting that in some studies the protective effect of theophylline is observed at plasma concentrations of 10 mg/L. These clinical studies suggest that theophylline may have anti-asthma effects which are unrelated to any bronchodilator action. Anti-inflammatory effects Whether theophylline has significant anti-inflammatory effects in asthma or COPD is still unresolved.42 Theophylline inhibits histamine release from human basophils in vitro43 and mediator release from chopped human lung,44 although high concentrations are necessary and it is likely that this effect involves an increase in cyclic AMP concentration due to PDE inhibition. Theophylline also has an inhibitory effect on superoxide anion release from human neutrophils45 and inhibits the feedback stimulatory effect of adenosine on neutrophils in vivo.46 At therapeutic concentrations in-vitro theophylline may increase superoxide release via an inhibitory effect on adenosine receptors, since endogenous adenosine might normally exert an inhibitory action on these cells.47 Similar results are also seen in guinea-pig and human eosinophils.48 At therapeutic concentrations there is an increased release of superoxide anions from eosinophils, which appears to be mediated via inhibition of adenosine A2 receptors and is mimicked by the adenosine antagonist 8-phenyltheophylline. Inhibition of eosinophil superoxide generation occurs only at high concentrations of theophylline (104 M) which are likely to inhibit PDE. Similar results have also been obtained in human alveolar macrophages.7 Macrophages lavaged from patients taking theophylline have been found to have a reduced oxidative burst response,49 but there is no reduction in the release of the pro-inflammatory cytokines TNF-a or GM-CSF.24 Theophylline inhibits neutrophil chemotaxis via inhibition of adenosine A2A receptors.50 In-vivo theophylline inhibits mediator-induced airway microvascular leakage in rodents when given in high doses,51 although this is not seen at therapeutically relevant
concentrations.52 Theophylline has an inhibitory effect on plasma exudation in nasal secretions induced by allergen in patients with allergic rhinitis, although this could be secondary to inhibition of mediator release.53 In allergen challenge studies in asthmatic patients intravenous theophylline inhibits the late response to allergen, while having relatively little effect on the early response.54 A similar finding with allergen challenge has been reported after chronic oral treatment with theophylline.55 This has been interpreted as an effect on the chronic inflammatory response. This is supported by a reduced infiltration of eosinophils into the airways after allergen challenge following low doses of theophylline.56 In patients with nocturnal asthma low-dose theophylline inhibits the influx of neutrophils and, to a lesser extent, eosinophils seen in the early morning.57 Oral theophylline also inhibits the late response to toluene diisocyanate in TDI-sensitive asthmatics,58 but has no effect on the subsequent increase in methacholine responsiveness. Similarly, theophylline has no effect on the increased airway responsiveness which follows allergen challenge,59 and does not reduce airway responsiveness in asthmatic patients after chronic administration.60 These studies indicate that theophylline on its own may have effects on acute inflammation in the airways, but may be less effective on the chronic inflammatory process. In patients with COPD theophylline reduces the proportion of neutrophils in induced sputum and reduces the concentration of IL-8, suggesting that it may have an antiinflammatory effect unlike corticosteroids.61 Immunomodulatory effects T lymphocytes are now believed to play a central role in coordinating the chronic inflammatory response in asthma. For many years theophylline has been shown to have several actions on T lymphocyte function, suggesting that it might have an immunomodulatory effect in asthma. Theophylline has a stimulatory effect on suppressor (CD8) T lymphocytes, which may be relevant to the control of chronic airway inflammation,62,63 and has an inhibitory effect on graft rejection.64 In-vitro theophylline inhibits IL-2 synthesis in human T lymphocytes, an effect that is secondary to a rise in intracellular cyclic AMP concentration.65,66 At high concentrations theophylline inhibits proliferation in CD4 and CD8 cells, an effect that is mediated via inhibition of PDE4.67 Theophylline also inhibits the chemotactic response of T lymphocytes, an effect that is also mediated through PDE inhibition.68 In allergen-induced airway inflammation in guinea-pigs, theophylline has a significant inhibitory effect on eosinophil infiltration,69 suggesting that it may inhibit the T cell-derived cytokines responsible for this eosinophilic response. Theophylline has been reported to decrease circulating concentrations of IL-4 and IL-5 in asthmatic patients.70 In asthmatic patients low-dose theophylline treatment results in an increase in activated circulating CD4 and CD8 T cells, but a decrease in these cells in the airways, suggesting that it may reduce the trafficking of activated T cells into the airways.71 This is
Theophylline
539
supported by studies in allergen challenge, where low-dose theophylline decreases the number of activated CD4 and CD8 T cells in bronchoalveolar lavage fluid after allergen challenge and this is mirrored by an increase in these cells in peripheral blood.72 These effects are seen even in patients treated with high doses of inhaled corticosteroids, indicating that the molecular effects of theophylline are likely to be different from those of corticosteroids. Theophylline induces apoptosis of T lymphocytes, thus reducing their survival.73 This effect may be mediated via PDE4 inhibition, so may not be relevant to clinical doses of theophylline. The therapeutic range of theophylline was based on measurement of immediate bronchodilatation in response to the acute administration of theophylline.37 However, it is possible that the nonbronchodilator effects of theophylline, which may reflect some anti-inflammatory or immunomodulatory effect, may be exerted at lower plasma concentrations and that different molecular mechanisms may be involved.74
bronchoconstriction, higher concentrations may be required to produce bronchodilatation.78 Theophylline is rapidly and completely absorbed, but there are large interindividual variations in clearance, due to differences in hepatic metabolism (Table 51.2). Theophylline is metabolized in the liver by the cytochrome P450/P448 microsomal enzyme system, and a large number of factors may influence hepatic metabolism. Theophylline is predominantly metabolized by the CYP1A2 enzyme, while at higher plasma concentrations CYP2E1 is also involved.79
Extrapulmonary effects For a long time it has been suggested that theophylline may exert its effects in asthma and COPD via some action outside the airways. It may be relevant that theophylline is ineffective when given by inhalation until therapeutic plasma concentrations are achieved.75 This may indicate that theophylline has effects on cells other than those in the airway. One possible target cell is the platelet, and theophylline has been demonstrated to inhibit platelet activation. An effect of theophylline which remains controversial is its action on respiratory muscles. Aminophylline increases diaphragmatic contractility and reverses diaphragm fatigue.76 This effect has not been observed by all investigators and there are now doubts about the relevance of these observations to the clinical benefit provided by theophylline in COPD.77
Reduced clearance Reduced clearance is found in liver disease, pneumonia and heart failure, and doses need to be reduced to half and plasma levels monitored carefully.80 Increased clearance is also seen with certain drugs including erythromycin, certain quinolone antibiotics (ciprofloxacin, but not ofloxacin), allopurinol, cimetidine (but not ranitidine), serotonin uptake inhibitors (fluvoxamine), and the 5-lipoxygenase inhibitor zileuton, which interfere with CYP 1A2 function. Thus, if a patient on maintenance theophylline requires a course of erythromycin, the dose of theophylline should be halved. Viral infections and vaccination may also reduce clearance, and this may be particularly important in children. Owing to these variations in clearance individualization of theophylline dosage is required and plasma concentrations should be measured 4 hours after the last
PHARMACOKINETICS
Table 51.2. Factors affecting clearance of theophylline
There is a close relationship between the acute improvement in airway function and serum theophylline concentration. Below 10 mg/L therapeutic effects (at least in terms of rapid improvement in airway function) are small and above 25 mg/L additional benefits are outweighed by side-effects, so that the therapeutic range has usually been taken as 10–20 mg/L (55–110 lM).3 It is now apparent that nonbronchodilator effects of theophylline may be seen at plasma concentrations of 10 mg/L and that clinical benefit may be derived from these lower concentrations of theophylline. This suggests that it may be necessary to redefine the therapeutic range of theophylline based on anti-asthma effect, rather than the acute bronchodilator response that requires a higher plasma concentration. The dose of theophylline required to give therapeutic concentrations varies between subjects, largely because of differences in clearance. In addition, there may be differences in bronchodilator response to theophylline and, with acute
Increased clearance Increased clearance is seen in children (1–16 years), and in cigarette and marijuana smokers. Concurrent administration of phenytoin and phenobarbitone increases activity of P450, resulting in increased metabolic breakdown, so that higher doses may be required.
Increased clearance • Enzyme induction (rifampicin, phenobarbitone, ethanol) • Smoking (tobacco, marijuana) • High-protein, low-carbohydrate diet • Barbecued meat • Childhood Decreased clearance • Enzyme inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton) • Congestive heart failure • Liver disease • Pneumonia • Viral infection and vaccination • High-carbohydrate diet • Old age
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dose with slow-release preparations when steady state has usually been achieved. There is no significant circadian variation in theophylline metabolism,81 although there may be delayed absorption at night, which may relate to the supine posture.82
R O U T E S O F A D M I N I S T R AT I O N Intravenous Intravenous aminophylline has been used for many years in the treatment of acute severe asthma. The recommended dose is now 6 mg/kg given intravenously over 20–30 minutes, followed by a maintenance dose of 0.5 mg/kg/hour. If the patient is already taking theophylline, or there are any factors which decrease clearance, these doses should be halved and the plasma level checked more frequently. Oral Plain theophylline tablets or elixir, which are rapidly absorbed, give wide fluctuations in plasma levels and are not recommended. Several effective sustained-release preparations are now available which are absorbed at a constant rate and provide steady plasma concentrations over a 12–24 hour period.83 Although there are differences between preparations, these are relatively minor and of no clinical significance. Both slow-release aminophylline and theophylline are available and are equally effective (although the ethylene diamine component of aminophylline has very occasionally been implicated in allergic reactions). For continuous treatment twice daily therapy (approximately 8 mg/kg twice daily) is needed, although some preparations are designed for once daily administration. For nocturnal asthma a single dose of slow-release theophylline at night is often effective,84,85 and often more effective than an oral slow-release b-agonist preparation. Once optimal doses have been determined plasma concentrations usually remain stable, providing no factors which alter clearance change. Other routes Aminophylline may be given as a suppository, but rectal absorption is unreliable and proctitis may occur, so is best avoided. Inhalation of theophylline is irritant and ineffective. Intramuscular injections of theophylline are very painful and should never be given. The inhaled route is ineffective.
CLINICAL USE Acute severe asthma Intravenous aminophylline has been used in the management of acute severe asthma for over 50 years, but this use has been questioned in view of the risk of adverse effects compared with nebulized b2-agonists. In patients with acute asthma intravenous aminophylline is less effective than nebulized b2-agonists,86 and should therefore be reserved for those patients who fail to respond to b-agonists. There is
some evidence that the use of aminophylline in the emergency room reduces subsequent admissions to hospital with acute asthma.87 In a meta-analysis of 13 acceptably designed clinical trials to compare nebulized b-agonists with or without intravenous aminophylline there was no overall additional benefit from adding aminophylline.88 This indicates that aminophylline should not be added routinely to nebulized b-agonists. Indeed, addition of aminophylline may only increase side-effects.89 Several deaths have been reported after intravenous aminophylline. In one study of 43 asthma deaths in southern England there was a significantly greater frequency of toxic theophylline concentrations (21%) compared with matched controls (7%).90 These concerns have lead to the view that intravenous aminophylline should be reserved for the few patients with acute severe asthma who fail to show a satisfactory response to nebulized b2-agonists. When intravenous aminophylline is used it should be given as a slow intravenous infusion with careful monitoring and a plasma theophylline concentration should be measured prior to infusion. Chronic asthma In most guidelines for asthma management theophylline is used as an additional bronchodilator if asthma remains difficult to control after high doses of inhaled corticosteroids.91 The introduction of long-acting inhaled b2-agonists has further threatened the position of theophylline since the side-effects of these agents may be less frequent that those associated with theophylline and long-acting inhaled b2agonists are more effective controllers than theophylline.92 Whether theophylline has some additional benefit over its bronchodilator action is now an important consideration. In chronic studies, oral theophylline appears to be as effective as sodium cromoglycate in controlling young allergic asthmatics93 and provides additional control of asthma symptoms even in patients talking regular inhaled steroids.94 In one study in which a group of difficult adolescent asthmatic patients were controlled with oral and inhaled steroids, nebulized b2-agonists, inhaled anticholinergics and cromones, in addition to regular oral theophylline, withdrawal of the oral theophylline resulted in a marked deterioration of asthma control which could not be controlled by further increase in steroids and only responded to reintroduction of theophylline.95 This suggests that there may be a group of severe asthmatics who particularly benefit from theophylline. In a controlled trial of theophylline withdrawal in patients with severe asthma controlled only on high doses of inhaled corticosteroids, there was a significant deterioration in symptoms and lung function when placebo was substituted for the relatively low maintenance dose of theophylline.71 There is also evidence that addition of theophylline improves asthma control to a greater extent than b2agonists in patients with severe asthma treated with high-dose inhaled steroids.96 This suggests that theophylline may have a useful place in the optimal management of moderate to severe asthma and appears to provide additional control above that provided by high-dose inhaled steroids.97
Theophylline
Theophylline may be a useful treatment for nocturnal asthma and a single dose of a slow-release theophylline preparation given at night may provide effective control of nocturnal asthma symptoms.84,98 There is evidence that slow release theophylline preparations are more effective than slow release oral b-agonists and inhaled b-agonists in controlling nocturnal asthma.85,99,100 Theophylline is approximately equal in efficacy to salmeterol in controlling nocturnal asthma, but the quality of sleep is better with salmeterol compared with theophylline.101 The mechanism of action of theophylline in nocturnal asthma may involve more than long-lasting bronchodilatation, and could involve inhibition of some components of the inflammatory response, which may increase at night.57 Several studies have demonstrated that adding low-dose theophylline to inhaled corticosteroids in patients who are not controlled gives better asthma control than doubling the dose of inhaled corticosteroids. This has been demonstrated in patients with moderate to severe and mild asthma.102–104 Interestingly, there is a greater degree of improvement in forced vital capacity than FEV1, possibly indicating an effect on peripheral airways. Since the improvement in lung function was relatively slow, this suggests that the effect of the added theophylline may be anti-inflammatory rather than bronchodilator, particularly as the plasma concentration of theophylline in this study was 10 mg/mL. This study suggests that low-dose theophylline may be preferable to increasing the dose of inhaled steroids when asthma is not controlled on moderate doses of inhaled steroids; such a therapeutic approach would be much less expensive than adding long-acting inhaled b2-agonists.
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action of b-agonists and theophylline. b-agonists may cause relaxation of airway smooth muscle via several mechanisms. Classically, they increase intracellular cyclic AMP concentrations, which have been believed to be an essential event in the relaxation response. It has recently become clear that bagonists may cause bronchodilatation, at least in part, by opening maxi-K channels in airway smooth muscle cells.8,34 Maxi-K channels are opened by low concentrations of b2agonists, which are likely to be therapeutically relevant. There is now evidence that b-receptors may be coupled directly to maxi-K channels via the a-subunit of Gs,110 and therefore may induce relaxation without any increase in cyclic AMP, thus accounting for a lack of synergy. Another reason for the lack of synergy may be that cells other than airway smooth muscle may be the main target for the antiasthma effect of theophylline. Repeated administration of b2-agonists may result in tolerance. While this may be explained by down-regulation of b2-receptors an additional mechanism may involve upregulation of PDE enzymes (especially PDE4D) which then break down cyclic AMP more readily.111 Theophylline may therefore theoretically prevent the development of tolerance, although this has not yet been studied clinically. Theophylline may provide useful additional bronchodilatation in patients with COPD, even when maximally effective doses of a b-agonist have been given. This means that, if adequate bronchodilatation is not achieved by a b-agonist alone, theophylline may be added to the maintenance therapy with benefit.
SIDE-EFFECTS COPD Theophylline may also benefit patients with COPD, increasing exercise tolerance, although without any improvement in spirometric values unless combined with an inhaled bagonist.105,106 However, theophylline may reduce trapped gas volume, suggesting an effect on peripheral airways, and this may explain why some patients with COPD may obtain considerable symptomatic improvement without any increase in spirometric values.107 Although the effect of theophylline on respiratory muscle weakness has been believed to be important in contributing to symptomatic improvement in patients with COPD,76 this seems unlikely as several investigators have failed to confirm any effect on respiratory muscle function at therapeutic concentrations of theophylline.77 The demonstration that theophylline reduces neutrophils in induced sputum of patients with COPD suggests that theophylline may have some anti-inflammatory effect.61 Interaction with b-agonists If theophylline exerts its effects by PDE inhibition then a synergistic interaction with b-agonists would be expected. Many studies have investigated this possibility, but while there is good evidence that theophylline and b-agonists have additive effects, true synergy is not seen.108,109 This can now be understood in terms of the molecular mechanisms of
There is no doubt that theophylline provides clinical benefit in obstructive airway disease, but the main limitation to its use is the frequency of adverse effects.112 Unwanted effects of theophylline are usually related to plasma concentration and tend to occur when plasma levels exceed 20 mg/L. However, some patients develop side-effects even at low plasma concentrations. To some extent, side-effects may be reduced by gradually increasing the dose until therapeutic concentrations are achieved. The commonest side-effects are headache, nausea and vomiting, abdominal discomfort and restlessness. There may also be increased acid secretion, gastroesophageal reflux and diuresis. There has recently been concern that theophylline, even at therapeutic concentrations, may lead to behavioral disturbance and learning difficulties in schoolchildren,113 although it is difficult to design adequate controls for such studies. At high concentrations, convulsions and cardiac arrhythmias may occur and there is concern that intravenous aminophylline administered in the emergency room may be a contributory factor to the deaths of some patients with severe asthma.90 Some of the side-effects of theophylline (central stimulation, gastric secretion, diuresis, and arrhythmias) may be due to adenosine receptor and these may therefore be
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avoided by PDE inhibitors. The commonest side-effects of theophylline are nausea and headaches, which may be due to inhibition of certain PDEs (e.g. PDE4 in the vomiting center).114
FUTURE OF THEOPHYLLINE Although theophylline has recently been used much less in developed countries, there are reasons for thinking that it may come back into fashion for the treatment of chronic asthma, with the recognition that it may have an antiinflammatory and immunomodulatory effect when given in low doses (plasma concentration 5–10 mg/L).74 At these low doses the drug is easier to use, side-effects are uncommon and the problems of drug interaction are less of a problem, thus making the clinical use of theophylline less complicated. Theophylline appears to have an effect that is different from those of corticosteroids and may therefore be a useful drug to combine with low-dose inhaled steroids. The molecular mechanism of anti-inflammatory effects of theophylline is now becoming clearer and it seems likely that there is a synergistic interaction with the anti-inflammatory mechanism of corticosteroids. This interaction may underlie the beneficial effects of theophylline when added to inhaled corticosteroids. As slow-release theophylline preparations are cheaper than long-acting inhaled b2-agonists and antileukotrienes, this may justify the choice of low-dose theophylline as the add-on therapy for asthma control. In addition, compliance with oral therapy is likely to be greater than with inhaled therapies.115 This suggests that low-dose theophylline may find an important place in modern asthma management in patients with moderate asthma as well as in patients with severe asthma. In COPD there is evidence for an anti-inflammatory action of theophylline and it may therefore be preferable to high-dose inhaled corticosteroids which have been shown to have no anti-inflammatory effects in patients with COPD.116
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115. Kelloway JS, Wyatt RA, Adlis SA. Comparison of patients’ compliance with prescribed oral and inhaled asthma medications. Arch. Int. Med. 1994; 154:1349–52. 116. Culpitt SV, Nightingale JA, Barnes PJ. Effect of high dose inhaled steroid on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1635–9.
Chapter
Corticosteroids
52
Peter J. Barnes National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
Corticosteroids are by far the most effective therapy currently available for asthma and improvement with corticosteroids is one of the hallmarks of asthma. Inhaled corticosteroids have revolutionized asthma treatment and have become the mainstay of therapy for patients with chronic disease.1,2 By contrast, corticosteroids are largely ineffective in COPD.3 We now have a much better understanding of the molecular mechanisms whereby corticosteroids suppress inflammation in asthma and why they may be ineffective in COPD and in rare patients with asthma who are resistant to corticosteroids. This chapter discusses current understanding of the mechanism of action of corticosteroids and how corticosteroids are used in the management of airway diseases.
MOLECULAR MECHANISMS Corticosteroids are highly effective anti-inflammatory therapy in asthma and the molecular mechanisms involved in suppression of airway inflammation in asthma are now better understood.4 Corticosteroids are effective in asthma because they block many of the inflammatory pathways that are abnormally activated in asthma and they have a wide spectrum of anti-inflammatory actions. Glucocorticoid receptors Corticosteroids bind to a single class of glucocorticoid receptor (GR) which is localized to the cytoplasm of target cells. Corticosteroids bind at the C-terminal end of the receptor, whereas the N-terminal end of the receptor is involved in gene transcription. Between these domains is the DNA-binding domain which has two finger-like projections formed by a zinc molecule bound to four cysteine residues that bind to the DNA double helix. The inactive GR is bound to a protein complex that includes two molecules of 90 kDa heat shock protein (hsp90) and various other proteins which act as “molecular chaperones” preventing the unoccupied GR from moving into the nuclear compartment. Once corticosteroids bind to GR, conformational changes in the receptor structure result in dissociation of these chaperone molecules, thereby exposing nuclear localization
signals on GR, resulting in rapid nuclear localization of the activated GR-corticosteroid complex and its binding to DNA (Fig. 52.1). Two GR molecules bind to DNA as a dimer, resulting in changed transcription. A splice variant of GR, termed GR-b, has been identified that does not bind corticosteroids, but binds to DNA and may theoretically interfere with the action of corticosteroids.5 Increased gene transcription Corticosteroids produce their effect on responsive cells by activating GR to directly or indirectly regulate the transcription of certain target genes.6 The number of genes per cell directly regulated by corticosteroids is estimated to be between 10 and 100, but many genes are indirectly regulated through an interaction with other transcription factors. GR dimers bind to DNA at consensus sites termed glucocorticoid response elements (GREs) in the 5-upstream promoter region of steroid-responsive genes. This interaction changes the rate of transcription, resulting in either induction or repression of the gene. Interaction of the activated GR homodimer with GRE usually increases transcription, resulting in increased protein synthesis. GR may increase transcription by interacting with a large coactivator molecule, CREB binding protein (CBP), which is bound at the start site of transcription and switches on RNA polymerase, resulting in formation of messenger RNA (mRNA) and then synthesis of protein. Binding of activated GR to CBP results in increased acetylation of core histones around which DNA is wound within the chromosomal structure.7 This results in the binding and activation of RNA polymerase, which then results in mRNA formation. Decreased gene transcription In controlling inflammation, the major effect of corticosteroids is to inhibit the synthesis of inflammatory proteins, such as cytokines. This was originally believed to be through interaction of GR with negative GREs, resulting in repression of transcription. However, negative GREs have rarely been demonstrated. GR may also affect the synthesis of some proteins by reducing the stability of mRNA, through effects on ribonucleases that break down mRNA.
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Glucocorticoid
GR
Lipocortin-1 β2-Adrenoceptors
mRNA
Cytokines iNOS, COX2 Adhesion mols
X
hsp90
GRβ
Nucleus
GRE
GRE
Steroid-responsive target genes
Fig. 52.1. Classical model of corticosteroid action. Corticosteroids enter the cell and bind to cytoplasmic glucocorticoid receptors (GR) that are complexed with two molecules of a 90 kDa heat shock protein (hsp90). GR translocates to the nucleus where, as a dimer, it binds to a glucocorticoid recognition element (GRE) on the 5’-upstream promoter sequence of steroid-responsive genes. GREs increase transcription, whereas nGREs may decrease transcription, resulting in increased or decreased messenger RNA (mRNA) and protein synthesis. An isoform of GR, GR-b, binds to DNA, but is not activated by corticosteroids.
Interaction with transcription factors Activated GRs may bind directly with several other activated transcription factors as a protein–protein interaction. This could be an important determinant of corticosteroid responsiveness and is a key mechanism whereby corticosteroids switch off inflammatory genes. Most of the inflammatory genes that are activated in asthma do not appear to have GREs in their promoter regions yet are repressed by corticosteroids. There is increasing evidence that corticosteroids inhibit the effects of transcription factors that regulate the expression of genes that code for inflammatory proteins, such as cytokines, inflammatory enzymes, adhesion molecules and inflammatory receptors. These “inflammatory” transcription factors include activator protein-1 (AP-1) and nuclear factor-jB (NF-jB), which may regulate many of the inflammatory genes that are switched on in asthmatic airways.8,9 Effects on chromatin structure There is increasing evidence that corticosteroids may have effects on the chromatin structure. DNA in chromosomes is wound around histone molecules in the form of nucleosomes. Several transcription factors interact with large coactivator molecules, such as CBP and the related molecule p300, which bind to the basal transcription factor apparatus. Several transcription factors bind directly to CBP, including AP-1, NF-jB and GR10 (Fig. 52.2). At a microscopic level, chromatin may become dense or opaque due to the winding
or unwinding of DNA around the histone core. CBP and p300 have histone acetylation activity which is activated by the binding of transcription factors, such as AP-1 and NF-jB. Acetylation of histone residues results in unwinding of DNA coiled around the histone core, thus opening up the chromatin structure, which allows transcription factors to bind more readily, thereby increasing transcription. Repression of genes reverses this process by histone deacetylation.11 Deacetylation of histone increases the winding of DNA round histone residues, resulting in dense chromatin structure and reduced access of transcription factors to their binding sites, thereby leading to repressed transcription of inflammatory genes. Activated GR may bind to several transcription co-repressor molecules that associate with proteins that have histone deacetylase activity (HDACs), resulting in deacetylation of histone, increased winding of DNA round histone residues and thus reduced access of transcription factors to their binding sites and therefore repression of inflammatory genes. In addition, activated GR recruits HDACs to the transcription start site, resulting in deacetylation of histones, and a decrease in inflammatory gene transcription.7 Target genes in inflammation control Corticosteroids may control inflammation by inhibiting many aspects of the inflammatory process in asthma through increasing the transcription of anti-inflammatory genes and decreasing the transcription of inflammatory genes (Table 52.1).
Corticosteroids
NF-κB
STATs
CBP inhibitors E1A
AP-1 CBP/p300
CREB
Pol II
HAT
Corticosteroid GR
Histone acetylation Histone Ac Ac Ac Ac Ac Ac deacetylation
Repressive chromatin Decreased transcription Inflammatory gene repression
Active chromatin Increased transcription Inflammatory gene expression
Fig. 52.2. Effect of corticosteroids on chromatin structure. Transcription factors, such as STATs, AP-1 and NF-jB bind to co-activator molecules, such as CREB binding protein (CBP) or p300, which have intrinsic histone acetyltransferase (HAT) activity, resulting in acetylation (Ac) of histone residues. This leads to unwinding of DNA and allows increased binding of transcription factors resulting in increased gene transcription. Glucocorticoid receptors (GR) after activation by corticosteroids bind to a glucocorticoid receptor co-activator which is bound to CBP. This results in deacetylation of histone, with increased coiling of DNA around histone, thus preventing transcription factor binding leading to gene repression.
Table 52.1. Effect of corticosteroids on gene transcription
Increased transcription Lipocortin-1 (phospholipase A2 inhibitor) b2-Adrenoceptor Secretory leukoprotease inhibitor Clara cell protein (CC10, phospholipase A2 inhibitor) IL-1 receptor antagonist IL-1R2 (decoy receptor) IjB-a (inhibitor of NF-jB) Decreased transcription Cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-12, IL-13, IL-16, IL-17, IL-18, TNF-a, GM-CSF, SCF) Chemokines (IL-8, RANTES, MIP-1a, MCP-1, MCP-3, MCP-4, eotaxin) Inducible nitric oxide synthase (iNOS) Inducible cycloxygenase (COX-2) Cytoplasmic phospholipase A2 (cPLA2) Endothelin-1 NK1-receptors, NK2-receptors Adhesion molecules (ICAM-1, E-selectin)
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Anti-inflammatory proteins Corticosteroids may suppress inflammation by increasing the synthesis of anti-inflammatory proteins. For example, corticosteroids increase the synthesis of lipocortin-1, a 37 kDa protein that has an inhibitory effect on phospholipase A2 (PLA2), and therefore may inhibit the production of lipid mediators. Corticosteroids induce the formation of lipocortin-1 in several cells and recombinant lipocortin-1 has acute anti-inflammatory properties. However, lipocortin-1 does not appear to be increased by inhaled corticosteroid treatment in asthma.12 Corticosteroids increase the expression of other potentially anti-inflammatory proteins, such as interleukin (IL)-1 receptor antagonist (which inhibits the binding of IL-1 to its receptor), secretory leukoprotease inhibitor (which inhibits proteases, such as tryptase), neutral endopeptidase (which degrades bronchoactive peptides such as kinins), CC-10 (an immunomodulatory protein), an inhibitor of NF-jB (IjB-a) and IL-10 (an anti-inflammatory cytokine). b2-Adrenoceptors Corticosteroids increase the expression of b2-adrenoceptors by increasing the rate of transcription and the human b2receptor gene has three potential GREs. Corticosteroids double the rate of b2-receptor gene transcription in human lung in vitro, resulting in increased expression of b2 receptors.13 This also occurs in vivo in nasal mucosa with treatment with topical corticosteroids.14 This may be relevant in asthma as corticosteroids may prevent down-regulation of b-receptors in response to prolonged treatment with b2agonists. In rats, corticosteroids prevent down-regulation and reduced transcription of b2-receptors in response to chronic b-agonist exposure.15 Cytokines The inhibitory effect of corticosteroids on cytokine synthesis is likely to be of particular importance in the control of inflammation in asthma. Corticosteroids inhibit the transcription of many cytokines and chemokines that are relevant in asthma (Table 52.1). These inhibitory effects are due, at least in part, to an inhibitory effect on the transcription factors that regulate induction of these cytokine genes, including AP-1 and NF-jB. For example, eotaxin which is important in selective attraction of eosinophils from the circulation into the airways is regulated in part by NF-jB and its expression in airway epithelial cells is inhibited by corticosteroids.16 Many transcription factors are likely to be involved in the regulation of inflammatory genes in asthma in addition to AP-1 and NF-jB. IL-4 and IL-5 expression in T-lymphocytes plays a critical role in allergic inflammation, but NF-jB does not play a role, whereas the transcription factor nuclear factor of activated T cells (NF-AT) is important.17 AP-1 is a component of the NF-AT transcription complex, so that corticosteroids inhibit IL-5, at least in part by inhibiting the AP-1 component of NF-AT. There may be marked differences in the response of different cells and of different cytokines to the inhibitory
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action of corticosteroids and this may be dependent on the relative abundance of transcription factors within different cell types. Thus, in alveolar macrophages and peripheral blood monocytes, GM-CSF secretion is more potently inhibited by corticosteroids than IL-1b or IL-6 secretion. Inflammatory enzymes Nitric oxide (NO) synthase may be induced by proinflammatory cytokines, resulting in NO production. NO may amplify asthmatic inflammation and contribute to epithelial shedding and airway hyperresponsiveness through the formation of peroxynitrite. The induction of the inducible form of NOS (iNOS) is inhibited by corticosteroids. In cultured human pulmonary epithelial cells, pro-inflammatory cytokines result in increased expression of iNOS and increased NO formation, due to increased transcription of the iNOS gene, and this is inhibited by corticosteroids acting through inhibition of NF-jB. Corticosteroids inhibit the synthesis of several other inflammatory mediators implicated in asthma through an inhibitory effect on the induction of enzymes, such as cyclo-oxygenase-2 and cytosolic PLA2.18,19 Inflammatory receptors Corticosteroids also decrease the transcription of genes coding for certain receptors. Thus the gene for the NK1receptor, which mediates the inflammatory effects of tachykinins in the airways, has an increased expression in asthma and is inhibited by corticosteroids, probably via an inhibitory effect on AP-1.20 Corticosteroids also inhibit the transcription of the NK2-receptor, which mediates the bronchoconstrictor effects of tachykinins21 and bradykinin B1 and B2 receptors.22 Adhesion molecules Adhesion molecules play a key role in the trafficking of inflammatory cells to sites of inflammation.The expression of many adhesion molecules on endothelial cells is induced by cytokines and corticosteroids may lead indirectly to a reduced expression via their inhibitory effects on cytokines, such as IL1b and TNF-a. Corticosteroids may also have a direct inhibitory effect on the expression of adhesion molecules, such as ICAM-1 and E-selectin at the level of gene transcription. ICAM-1 andVCAM-1 expression in bronchial epithelial cell lines and monocytes is inhibited by corticosteroids.23 Apoptosis Corticosteroids markedly reduce the survival of certain inflammatory cells, such as eosinophils. Eosinophil survival is dependent on the presence of certain cytokines, such as IL-5 and GM-CSF. Exposure to corticosteroids blocks the effects of these cytokines and leads to programmed cell death or apoptosis, although the corticosteroid-sensitive molecular pathways have not yet been defined.24 By contrast, corticosteroids decrease apoptosis in neutrophils and thus prolong their survival.25 This may contribute to the lack of anti-inflammatory effects of corticosteroids in COPD where neutrophilic inflammation is predominant.
Effects on cell function Corticosteroids may have direct inhibitory actions on several inflammatory cells and structural cells that are implicated in asthma (Fig. 52.3). Macrophages Corticosteroids inhibit the release of inflammatory mediators and cytokines from alveolar macrophages in vitro. Inhaled corticosteroids reduce the secretion of chemokines and proinflammatory cytokines from alveolar macrophages from asthmatic patients, whereas the secretion of IL-10 is increased.26 Eosinophils Corticosteroids have a direct inhibitory effect on mediator release from eosinophils, although they are only weakly effective in inhibiting secretion of reactive oxygen species and eosinophil basic proteins. More importantly, corticosteroids induce apoptosis by inhibiting the prolonged survival due to IL-3, IL-5 and GM-CSF,24 resulting in an increased number of apoptotic eosinophils in induced sputum of asthmatic patients.27 There is a delay in the apoptosis of eosinophils in asthma, which is reversed by treatment with corticosteroids.28 One of the best described actions of corticosteroids in asthma is a reduction in circulating eosinophils, which may reflect an action on eosinophil production in the bone marrow. T-lymphocytes T helper 2 lymphocytes (Th2) play an important orchestrating role in asthma through the release of the cytokines IL-4, IL-5, IL-9 and IL-13 and may be an important target for corticosteroids in asthma therapy. Corticosteroids increase apoptosis in T cells, although the molecular mechanisms are not yet certain. Mast cells While corticosteroids do not appear to have a direct inhibitory effect on mediator release from lung mast cells, chronic corticosteroid treatment is associated with a marked reduction in mucosal mast cell numbers. This may be linked to a reduction in IL-3 and stem cell factor (SCF) production, which are necessary for mast cell expression at mucosal surfaces. Mast cells also secrete various cytokines (TNF-a, IL-4, IL-5, IL-6 and IL-8), and this may also be inhibited by corticosteroids.29 Dendritic cells Dendritic cells in the epithelium of the respiratory tract appear to play a critical role in antigen presentation in the lung as they have the capacity to take up allergen, process it into peptides and present it via MHC molecules on the cell surface for presentation to uncommitted T-lymphocytes. In experimental animals the number of dendritic cells is markedly reduced by systemic and inhaled corticosteroids, thus dampening the immune response in the airways.30
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Corticosteroids
Inflammatory cells
Structural cells
Eosinophil
Epithelial cell
Numbers (apoptosis)
Cytokines Mediators T lymphocyte
Endothelial cell
Cytokines Leak Mast cell
Corticosteroids
Numbers
Airway smooth muscle β2-Receptors Cytokines
Macrophage
Mucus gland
Cytokines Mucus secretion Dendritic cell Numbers
Fig. 52.3. Cellular effect of corticosteroids.
Neutrophils Neutrophils, which are not prominent in the biopsies of asthmatic patients, are not sensitive to the effects of corticosteroids. Indeed, systemic corticosteroids increase peripheral neutrophil counts which may reflect an increased survival time due to an inhibitory action of neutrophil apoptosis.25 High doses of inhaled corticosteroids have no effect on airway neutrophilia induced by ozone.31 Endothelial cells GR gene expression in the airways is most prominent in endothelial cells of the bronchial circulation and airway epithelial cells. Corticosteroids do not appear to directly inhibit the expression of adhesion molecules, although they may inhibit cell adhesion indirectly by suppression of cytokines involved in the regulation of adhesion molecule expression. Corticosteroids may have an inhibitory action on airway microvascular leak induced by inflammatory mediators.This appears to be a direct effect on postcapillary venular epithelial cells. Although there have been no direct measurements of the effects of corticosteroids on airway microvascular leakage in asthmatic airways, regular treatment with inhaled corticosteroids decreases the elevated plasma proteins found in bronchoalveolar lavage fluid of patients with stable asthma. Epithelial cells Epithelial cells may be an important source of many inflammatory mediators in asthmatic airways and may drive and amplify the inflammatory response in the airways through
the secretion of proinflammatory cytokines, chemokines and inflammatory peptides. Airway epithelium may be one of the most important cellular targets for inhaled corticosteroids in asthma32,33 (Fig. 52.4). Inhaled corticosteroids inhibit the increased expression of many inflammatory proteins in airway epithelial cells.32 An example is iNOS, which has an increased expressed in airway epithelial and inflammatory cells in asthma and is reduced by inhaled corticosteroids.34 This is reflected by a reduction in the elevated levels of exhaled NO in asthma after inhaled corticosteroids.35 Mucus secretion Corticosteroids inhibit mucus secretion in airways and this may be a direct action of corticosteroids on submucosal gland cells. Corticosteroids may also inhibit the expression of mucin genes, such as MUC2 and MUC5AC.36 In addition, there are indirect inhibitory effects due to the reduction in inflammatory mediators which stimulate increased mucus secretion.
E F F E C T S O N A S T H M AT I C I N F L A M M AT I O N Corticosteroids are remarkably effective in controlling the inflammation in asthmatic airways and it is likely that they have multiple cellular effects. Biopsy studies in patients with asthma have now confirmed that inhaled corticosteroids reduce the number and activation of inflammatory cells in the airway mucosa and in bronchoalveolar lavage.32 These
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life of patients with asthma and allow many patients to lead normal lives, improve lung function, reduce the frequency of exacerbations and may prevent irreversible airway changes. They were first introduced to reduce the requirement for oral corticosteroids in patients with severe asthma and many studies have confirmed that the majority of patients can be weaned off oral corticosteroids.40
Inhaled corticosteroids Epithelial cells
Cytokines IL-1β IL-6 GM-CSF RANTES Eotaxin MIP-1α
Enzymes iNOS COX2 cPLA2
Peptides ET-1
Adhesion monecules ICAM-1
Inflammation
Fig. 52.4. Inhaled corticosteroids may inhibit the transcription of several “inflammatory” genes in airway epithelial cells and thus reduce inflammation in the airway wall.
effects may be due to inhibition of cytokine synthesis in inflammatory and structural cells and suppression of adhesion molecules.The disrupted epithelium is restored and the ciliated to goblet cell ratio is normalized after 3 months of therapy with inhaled corticosteroids. There is also some evidence for a reduction in the thickness of the basement membrane, although in asthmatic patients taking inhaled corticosteroids for over 10 years, the characteristic thickening of the basement membrane was still present. Effects on airway hyperresponsiveness By reducing airway inflammation inhaled corticosteroids consistently reduce airway hyperresponsiveness (AHR) in asthmatic adults and children.37 Chronic treatment with inhaled corticosteroids reduces responsiveness to histamine, cholinergic agonists, allergen (early and late responses), exercise, fog, cold air, bradykinin, adenosine and irritants (such as sulfur dioxide and metabisulfite). The reduction in AHR takes place over several weeks and may not be maximal until several months of therapy. The magnitude of reduction is variable between patients and is in the order of one to two doubling dilutions for most challenges and often fails to return to the normal range. This may not reflect suppression of the inflammation, but persistence of structural changes which cannot be reversed by corticosteroids. Inhaled corticosteroids not only make the airways less sensitive to spasmogens, but they also limit the maximal airway narrowing in response to spasmogens.
CLINICAL EFFICACY OF INHALED CORTICOSTEROIDS IN ASTHMA Inhaled corticosteroids are very effective in controlling asthma symptoms in asthmatic patients of all ages and severity.38,39 Inhaled corticosteroids improve the quality of
Studies in adults As experience has been gained with inhaled corticosteroids they have been introduced in patients with milder asthma, with the recognition that inflammation is present even in patients with mild asthma. Inhaled anti-inflammatory drugs have now become first-line therapy in any patient who needs to use a b2-agonist inhaler more than once a day and this is reflected in national and international guidelines for the management of chronic asthma. In patients with newly diagnosed asthma inhaled corticosteroids (budesonide 600 lg twice daily) reduced symptoms and b2-agonist inhaler usage and improved lung function.These effects persisted over the 2 years of the study, whereas in a parallel group treated with inhaled b2-agonists alone there was no significant change in symptoms or lung function.41 In another study, patients with mild asthma treated with a low dose of inhaled corticosteroid (budesonide 400 lg daily) showed fewer symptoms and a progressive improvement in lung function over several months and many patients became completely asymptomatic.42 There was also a significant reduction in the number of exacerbations. Although the effects of inhaled corticosteroids on AHR may take several months to reach a plateau, the reduction in asthma symptoms occurs more rapidly.43 High-dose inhaled corticosteroids have now been introduced for the control of more severe asthma. This markedly reduces the need for maintenance oral corticosteroids and has revolutionized the management of more severe and unstable asthma. Inhaled corticosteroids are the treatment of choice in nocturnal asthma, which is a manifestation of inflamed airways, reducing night-time awakening and reducing the diurnal variation in airway function. High doses of inhaled corticosteroids may also substitute for a course of oral steroids in controlling acute exacerbations of asthma. High-dose fluticasone propionate (2000 lg daily) was as effective as a course of oral prednisolone in controlling acute exacerbations of asthma in general practice.44 Although doubling the dose of inhaled corticosteroids is recommended for mild exacerbation of asthma, this does not appear to be useful, but a four-fold increase in dose appears to be effective.45 Inhaled corticosteroids effectively control asthmatic inflammation, but must be taken regularly. When inhaled corticosteroids are discontinued there is usually a gradual increase in symptoms and airway responsiveness back to pretreatment values,43 although in patients with mild asthma who have been treated with inhaled corticosteroids for a long time, symptoms may not recur in some patients.46 Reduction in the dose of inhaled corticosteroids is associated with an
Corticosteroids
increase in symptoms and this is preceded by an increase in exhaled NO and sputum eosinophils.47 Studies in children Inhaled corticosteroids are equally effective in children. In an extensive study of children aged 7–17 years there was a significant improvement in symptoms, peak flow variability and lung function compared with a regular inhaled b2agonist which was maintained over the 22 months of the study,48 but asthma deteriorated when the inhaled corticosteroids were withdrawn.49 There was a high proportion of drop-outs (45%) in the group treated with inhaled b2agonist alone. Inhaled corticosteroids are more effective than a long-acting b2-agonist in controlling asthma in children.50 Inhaled corticosteroids are also effective in younger children. Nebulized budesonide reduces the need for oral corticosteroids and also improved lung function in children under the age of 3.51 Inhaled corticosteroids given via a large volume spacer improve asthma symptoms and reduce the number of exacerbations in preschool children and in infants. Dose–response studies Surprisingly, the dose–response curve for the clinical efficacy of inhaled corticosteroids is relatively flat and, while all studies have demonstrated a clinical benefit of inhaled corticosteroids, it has been difficult to demonstrate differences between doses, with most benefit obtained at the lowest doses used.38,40,52 This is in contrast to the steeper dose– response for systemic effects, implying that while there is little clinical benefit from increasing doses of inhaled corticosteroids the risk of adverse effects is increased. However, the dose–response effect of inhaled corticosteroids may depend on the parameters measured and, while it is difficult to discern a dose–response when traditional lung function parameters are measured, there may be a dose–response effect in prevention of asthma exacerbations. Thus, there is a significantly greater effect of budesonide 800 lg daily compared with 200 lg daily in preventing severe and mild asthma exacerbations.53 Normally, a four-fold or greater difference in dose has been required to detect a statistically significant (but often small) difference in effect on commonly measured outcomes such as symptoms, PEF, use of rescue b2-agonist and lung function, and even such large differences in dose are not always associated with significant differences in response. These findings suggest that pulmonary function tests or symptoms may have a rather low sensitivity in the assessment of the effects of inhaled corticosteroids. This is obviously important for the interpretation of clinical comparisons between different inhaled corticosteroids or inhalers. It is also important to consider the type of patient included in clinical studies. Patients with relatively mild asthma may have relatively little room for improvement with inhaled corticosteroids, so that maximal improvement is obtained with relatively low doses. Patients with more severe asthma or with unstable asthma may have more room for improvement and may therefore show a
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greater response to increasing doses, but it is often difficult to include such patients in controlled clinical trials. More studies are needed to assess whether other outcome measures such as AHR or more direct measurements of inflammation, such as sputum eosinophils or exhaled NO, may be more sensitive than traditional outcome measures such as symptoms or lung function tests.54–56 Higher doses of inhaled corticosteroids are needed to control AHR than to improve symptoms and lung function, and this may have a better long-term outcome in terms of reduction in structural changes of the airways.57 Prevention of irreversible airway changes Some patients with asthma develop an element of irreversible airflow obstruction, but the pathophysiological basis of these changes is not yet understood. It is likely that they are the result of chronic airway inflammation and that they may be prevented by treatment with inhaled corticosteroids. There is some evidence that the annual decline in lung function may be slowed by the introduction of inhaled corticosteroids.58 Increasing evidence also suggests that delay in starting inhaled corticosteroids may result in less overall improvement in lung function in both adults and children.59–61 These studies suggest that introduction of inhaled corticosteroids at the time of diagnosis is likely to have the greatest impact.60,61 Several large studies are now underway to assess the benefit of very early introduction of inhaled corticosteroids in children and adults. So far there is no evidence that early use of inhaled corticosteroids is curative and even when inhaled corticosteroids are introduced at the time of diagnosis, symptoms and lung function revert to pretreatment levels when corticosteroids are withdrawn.59 Reduction in mortality Inhaled corticosteroids may reduce the mortality from asthma, but prospective studies are almost impossible to conduct. In a retrospective review of the risk of mortality and prescribed anti-asthma medication, there was a significant protection provided by regular inhaled corticosteroid therapy.62 Comparison between inhaled corticosteroids Several inhaled corticosteroids are currently prescribable in asthma, although their availability varies between countries. There have been relatively few studies comparing efficacy of the different inhaled corticosteroids, and it is important to take into account the delivery system and the type of patient under investigation when such comparisons are made. Because of the relatively flat dose–response curve for the clinical parameters normally used in comparing doses of inhaled corticosteroids, it may be difficult to see differences in efficacy of inhaled corticosteroids. Most comparisons have concentrated on differences in systemic effects at equally efficacious doses, although it has often proved difficult to establish dose equivalence. There are few studies comparing different doses of inhaled corticosteroids in asthmatic patients. Budesonide has been compared with BDP
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and in adults and children appears to have comparable antiasthma effects at equal doses, whereas FP appears to be approximately twice as potent as BDP and budesonide. Studies have consistently shown that fluticasone propionate (FP) and budesonide have less systemic effects than BDP, triamcinolone and flunisolide.63 A new inhaled corticosteroid mometasone also has less systemic effects.64
CLINICAL USE OF INHALED CORTICOSTEROIDS IN ASTHMA Inhaled corticosteroids are now recommended as first-line therapy for all patients with persistent symptoms. Inhaled corticosteroids should be started in any patient who needs to use a b2-agonist inhaler for symptom control more than three times a week. It is conventional to start with a low dose of inhaled corticosteroid and to increase the dose until asthma control is achieved. However, this may take time and a preferable approach is to start with a dose of corticosteroids in the middle of the dose range (400 lg twice daily) to establish control of asthma more rapidly.65 Once control is achieved (defined as normal or best possible lung function and infrequent need to use an inhaled b2-agonist) the dose of inhaled corticosteroid should be reduced in a step-wise manner to the lowest dose needed for optimal control. It may take as long as 3 months to reach a plateau in response and any changes in dose should be made at intervals of 3 months or more. When daily doses of 800 lg daily are needed, a large volume spacer device should be used with an MDI and mouth washing with a dry powder inhaler in order to reduce local and systemic side-effects. Inhaled corticosteroids are usually give as a twice daily dose in order to increase compliance. When asthma is unstable, four times daily dosage is preferable.66 For patients who require 400 lg daily, once daily dosing appears to be as effective as twice daily dosing, at least for budesonide.67 The dose of inhaled corticosteroid should be increased to 2000 lg daily if necessary, but higher doses may result in systemic effects. It may be preferable to add a low dose of oral corticosteroid, since higher doses of inhaled corticosteroids are expensive and have a high incidence of local sideeffects. Nebulized budesonide has been advocated in order to give an increased dose of inhaled corticosteroid and to reduce the requirement for oral corticosteroids,68 but this treatment is expensive and may achieve its effects largely via systemic absorption. Add-on therapy Conventional advice was to increase the dose of inhaled corticosteroids if asthma was not controlled, on the assumption that there was residual inflammation of the airways. However, it is now apparent that the dose–response effect of inhaled corticosteroids is relatively flat, so that there is little improvement in lung function after doubling the dose of inhaled corticosteroids. An alternative strategy is to add some other class of controller drug.
Long-acting inhaled b2-agonists In patients in general practice who are not controlled on BDP 200 lg twice daily, addition of salmeterol 50 lg twice daily was more effective than increasing the dose of inhaled corticosteroid to 500 lg twice daily, in terms of lung function improvement, use of rescue b2-agonist use and symptom control.69 This has been confirmed in several other studies.70 Similar results have been found with another longacting inhaled b2-agonist formoterol, which in addition reduced the frequency of mild and severe asthma exacerbations.53 This has led to the development of fixed combinations of corticosteroids and long-acting b2-agonists, such as FP and salmeterol (seretide/advair/vianni) and budesonide with formoterol (symbicort), which may be more convenient for patients.71,72 These fixed combination inhalers also ensure that patients do not discontinue their inhaled corticosteroids when a long-acting bronchodilator is used. Theophylline Addition of low doses of theophylline (giving plasma concentrations of <10 mg/L) are more effective than doubling the dose of inhaled budesonide, either in mild or severe asthma.73–75 Anti-leukotrienes Similar data are now emerging with anti-leukotrienes,76 although this is less effective than addition of long-acting b2agonists.77 Mechanisms The reason why add-on controller treatments are more effective than higher doses of inhaled corticosteroids remains to be elucidated, but does suggest that there is a reversible component of asthma that is not steroid-sensitive inflammation. As discussed above, the dose–response curve for inhaled corticosteroids efficacy is relatively shallow and control of inflammation may be achieved at low doses in most patients. The add-on therapies may be working on some other component, in asthma that is not sensitive to inhibition by inhaled corticosteroids. This may be an abnormality in airway smooth muscle itself (as a result of remodelling) or edema of the airway wall. In the case of long-acting b2-agonists, there may also be a positive effect of b2-agonists on the anti-inflammatory effects of corticosteroids. b2-Agonists increase the nuclear translocation of GR and this might enhance the anti-inflammatory effects of corticosteroids78 with enhanced suppression of cytokines.79 Cost-effectiveness Although inhaled corticosteroids may be more expensive than short-acting inhaled b2-agonists, they are the most cost-effective way of controlling asthma, since reducing the frequency of asthma attacks will save on total costs.80 Inhaled corticosteroids also improve the quality of life of patients with asthma and allow many patients a normal lifestyle, thus saving costs indirectly.81
Corticosteroids
Corticosteroid-sparing therapy In patients who have serious side-effects with maintenance corticosteroid therapy, there are several treatments which have been shown to reduce the requirement for oral corticosteroids.82 These treatments are commonly termed corticosteroid-sparing, although this is a misleading description that could be applied to any additional asthma therapy (including bronchodilators). The amount of corticosteroid sparing with these therapies is not impressive. Several immunosuppressive agents have been shown to have corticosteroid effects, including methotrexate, oral gold and cyclosporin A. These therapies all have side-effects that may be more troublesome than those of oral corticosteroids and are therefore only indicated as an additional therapy to reduce the requirement of oral corticosteroids.83 None of these treatments is very effective, but there are occasional patients who appear to show a good response. Because of side-effects, these treatments cannot be considered as a way to reduce the requirement for inhaled corticosteroids. Several other therapies, including azathioprine, dapsone and hydroxychloroquine have not been found to be beneficial. The macrolide antibiotic troleandomycin is also reported to have corticosteroid-sparing effects, but this is only seen with methylprednisolone and is due to reduced metabolism of this corticosteroid, so that there is little therapeutic gain.84
PHARMACOKINETICS The pharmacokinetics of inhaled corticosteroids is important in determining the concentration of drug reaching target cells in the airways and in the fraction of drug reaching the
systemic circulation and therefore causing side-effects.40 Beneficial properties in an inhaled corticosteroid are a high topical potency, a low systemic bioavailability of the swallowed portion of the dose and rapid metabolic clearance of any corticosteroid reaching the systemic circulation. After inhalation, a large proportion of the inhaled dose (80–90%) is deposited on the oropharynx and is then swallowed and therefore available for absorption via the liver into the systemic circulation (Fig. 52.5). This fraction is markedly reduced by using a large volume spacer device with a metered dose inhaler (MDI) or by mouth washing and discarding the washing with dry powder inhalers. Between 10 and 20% of inhaled drug enters the respiratory tract, where it is deposited in the airways and this fraction is available for absorption into the systemic circulation. Most of the early studies on the distribution of inhaled corticosteroids were conducted in healthy volunteers, and it is not certain what effect inflammatory disease, airway obstruction, age of the patient or concomitant medication may have on the disposition of the inhaled dose.There may be important differences in the metabolism of different inhaled corticosteroids. BDP is metabolized to its more active metabolite beclomethasone monopropionate in many tissues including lung, but there is no information about its absorption or metabolism of this metabolite in humans. Flunisolide and budesonide are subject to extensive first-pass metabolism in the liver so that less reaches the systemic circulation. Little is known about the distribution of triamcinolone. FP is almost completely metabolized by first-pass metabolism, which reduces systemic effects. When inhaled corticosteroids were first introduced it was recommended that they should be given four times daily, but several studies have now demonstrated that twice daily
MDI ~10–20% inhaled Mouth and pharynx ~80–90% swallowed ( spacer/mouth wash)
Systemic circulation
Lungs
Absorption from GI tract GI tract
Liver
Inactivation in liver “first pass” Fig. 52.5. Pharmacokinetics of inhaled corticosteroids.
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administration gives comparable control, although four times daily administration may be preferable in patients with more severe asthma. However, patients may find it difficult to comply with such frequent administration unless they have troublesome symptoms. For patients with mild asthma who require 400 lg daily, once daily therapy may be sufficient.
SIDE-EFFECTS OF INHALED CORTICOSTEROIDS The efficacy of inhaled corticosteroids is now established in short- and long-term studies in adults and children, but there are still concerns about side-effects, particularly in children and when high inhaled doses are needed. Several side-effects have been recognized (Table 52.2). Local side-effects Side-effects due to the local deposition of the inhaled corticosteroid in the oropharynx may occur with inhaled corticosteroids, but the frequency of complaints depends on the dose and frequency of administration and on the delivery system used. Dysphonia The most common complaint is of hoarseness of the voice (dysphonia) and may occur in over 50% of patients using MDI. Dysphonia is not appreciably reduced by using spacers, but may be less with dry powder devices. Dysphonia may be due to myopathy of laryngeal muscles and is reversible when treatment is withdrawn.85 For most patients it is not troublesome, but may be disabling in singers and lecturers. Oropharyngeal candidiasis Oropharyngeal candidiasis (thrush) may be a problem in some patients, particularly in the elderly, with concomitant oral corticosteroids and more than twice daily Table 52.2. Side effects of inhaled corticosteroids
Local side-effects Dysphonia Oropharyngeal candidiasis Cough Systemic side-effects Adrenal suppression Growth suppression Bruising Osteoporosis Cataracts Glaucoma Metabolic abnormalities (glucose, insulin, triglycerides) Psychiatric disturbances
administration.86 Large volume spacer devices protect against this local side-effect by reducing the dose of inhaled corticosteroid that deposits in the oropharynx. Other local complications There is no evidence that inhaled corticosteroid, even in high doses, increases the frequency of infections, including tuberculosis, in the lower respiratory tract. There is no evidence for atrophy of the airway epithelium and even after 10 years of treatment with inhaled corticosteroids there is no evidence for any structural changes in the epithelium. Cough and throat irritation, sometimes accompanied by reflex bronchoconstriction, may occur when inhaled corticosteroids are given via a metered dose inhaler.These symptoms are likely to be due to surfactants in pressurized aerosols as they disappear after switching to a dry powder corticosteroid inhaler device. Systemic side-effects The efficacy of inhaled corticosteroids in the control of asthma is undisputed, but there are concerns about systemic effects of inhaled corticosteroids, particularly as they are likely to be used over long periods and in children of all ages.38,63 The safety of inhaled corticosteroids has been extensively investigated since their introduction 30 years ago.40 One of the major problems is to decide whether a measurable systemic effect has any significant clinical consequence and this necessitates careful long-term follow-up studies. As biochemical markers of systemic corticosteroid effects become more sensitive, then systemic effects may be seen more often, but this does not mean that these effects are clinically relevant. There are several case reports of adverse systemic effects of inhaled corticosteroids, and these may be idiosyncratic reactions, which may be due to abnormal pharmacokinetic handling of the inhaled corticosteroid. The systemic effect of an inhaled corticosteroid will depend on several factors, including the dose delivered to the patient, the site of delivery (gastrointestinal tract and lung), the delivery system used and individual differences in the patient’s response to the corticosteroid. Recent studies suggest that systemic effects of inhaled corticosteroid are less in patients with more severe asthma, presumably as less drug reaches the lung periphery.87,88 Effect of delivery systems The systemic effect of an inhaled corticosteroid is dependent on the amount of drug absorbed into the systemic circulation. Approximately 90% of the inhaled dose from an MDI deposits in the oropharynx and is swallowed and subsequently absorbed from the gastrointestinal tract. Use of a large volume spacer device markedly reduces the oropharyngeal deposition, and therefore the systemic effects of inhaled corticosteroids, although this is less important when oral bioavailability is minimal, as with FP. For dry powder inhalers similar reductions in systemic effects may be achieved with mouth-washing and discarding the fluid. All patients using a daily dose of 800 lg of an inhaled
Corticosteroids
corticosteroid should therefore use either a spacer or mouth washing to reduce systemic absorption. Approximately 10% of an MDI enters the lung and this fraction (which presumably exerts the therapeutic effect) may be absorbed into the systemic circulation. As the fraction of inhaled corticosteroid deposited in the oropharynx is reduced, the proportion of the inhaled dose entering the lungs is increased. More efficient delivery to the lungs is therefore accompanied by increased systemic absorption, but this is offset by a reduction in the dose needed for optimal control of airway inflammation. For example, a multiple dry powder delivery system, the Turbuhaler, delivers approximately twice as much corticosteroid to the lungs as other devices, and therefore has increased systemic effects. However, this is compensated for by the fact that only half the dose is required. Hypothalamic–pituitary–adrenal axis Corticosteroids may cause hypothalamic–pituitary–adrenal (HPA) axis suppression by reducing corticotrophin (ACTH) production, which reduces cortisol secretion by the adrenal gland. The degree of HPA suppression is dependent on dose, duration, frequency and timing of corticosteroid administration.There is no evidence that cortisol responses to the stress of an asthma exacerbation or insulininduced hypoglycemia are impaired, even with high doses of inhaled corticosteroids. However, measurement of HPA axis function provides evidence for systemic effects of an inhaled corticosteroid. Basal adrenal cortisol secretion may be measured by a morning plasma cortisol, 24 hour urinary cortisol or by plasma cortisol profile over 24 hours. Other tests measure the HPA response following stimulation with tetracosactrin (which measures adrenal reserve) or stimulation with metyrapone and insulin (which measure the response to stress). There are many studies of HPA axis function in asthmatic patients with inhaled corticosteroids, but the results are inconsistent as they have often been uncontrolled and patients have also been taking courses of oral corticosteroids (which may affect the HPA axis for weeks).40 BDP, budesonide and FP at high doses by conventional MDI (>1600 lg daily) give a dose-related decrease in morning serum cortisol levels and 24 hour urinary cortisol, although values still lie well within the normal range. However, when a large volume spacer is used, doses of 2000 lg daily of BDP or budesonide have little effect on 24-hour urinary cortisol excretion. Stimulation tests of HPA axis function similarly show no consistent effects of doses of 1500 lg or less of inhaled corticosteroid. At high doses (>1500 lg daily) budesonide and FP have less effect than BDP on HPA axis function. In children no suppression of urinary cortisol is seen with doses of BDP of 800 lg or less. In studies where plasma cortisol has been measured at frequent intervals there was a significant reduction in cortisol peaks with doses of inhaled BDP as low as 400 lg daily, although this does not appear to be dose-related in the range 400–1000 lg. The clinical significance of these effects is not certain, however.
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Overall, the studies which are not confounded by concomitant treatment with oral corticosteroids, have consistently shown that there are no significant suppressive effects on HPA axis function at doses of 1500 lg in adults and 400 lg in children. Effects on bone metabolism Corticosteroids lead to a reduction in bone mass by direct effects on bone formation and resorption and indirectly by suppression of the pituitary–gonadal and HPA axes, effects on intestinal calcium absorption, renal tubular calcium reabsorption and secondary hyperparathyroidism.89 The effects of oral corticosteroids on osteoporosis and increased risk of vertebral and rib fractures are well known, but there are no reports suggesting that long-term treatment with inhaled corticosteroids is associated with an increased risk of fractures. Bone densitometry has been used to assess the effect of inhaled corticosteroids on bone mass. Although there is evidence that bone density is less in patients taking high-dose inhaled corticosteroids, interpretation is confounded by the fact that these patients are also taking intermittent courses of oral corticosteroids. Changes in bone mass occur very slowly and several biochemical indices have been used to assess the short-term effects of inhaled corticosteroids on bone metabolism. Bone formation has been measured by plasma concentrations of bone-specific alkaline phosphatase, serum osteocalcin or procollagen peptides. Bone resorption may be assessed by urinary hydroxyproline after a 12-hour fast, urinary calcium excretion and pyridinium cross-link excretion. It is important to consider the age, diet, time of day and physical activity of the patient in interpreting any abnormalities. It is also necessary to choose appropriate control groups as asthma itself may have an effect on some of the measurements, such as osteocalcin. Inhaled corticosteroids, even at doses up to 2000 lg daily, have no significant effect on calcium excretion, but acute and reversible dose-related suppression of serum osteocalcin has been reported with BDP and budesonide when given by conventional MDI in several studies. Budesonide consistently has less effect than BDP at equivalent doses and only BDP increases urinary hydroxyproline at high doses. With a large volume spacer even doses of 2000 lg daily of either BDP or budesonide are without effect on plasma osteocalcin concentrations, however. Urinary pyridinium and deoxypyridinoline cross-links, which are a more accurate and stable measurement of bone and collagen degradation, are not increased with inhaled corticosteroids (BDP >1000 lg daily), even with intermittent courses of oral corticosteroids. It is important to monitor changes in markers of bone formation, as well as bone degradation, as the net effect on bone turnover is important. There has been particular concern about the effect of inhaled corticosteroids on bone metabolism in growing children. A very low dose of oral corticosteroids (prednisolone 2.5 mg) causes significant changes in serum osteocalcin and urinary hydroxyproline excretion, whereas daily BDP and budesonide at doses up to 800 lg daily have no
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effect. It is important to recognize that the changes in biochemical indices of bone metabolism are less than those seen with even low doses of oral corticosteroids. This suggests that even high doses of inhaled corticosteroids, particularly when used with a spacer device, are unlikely to have any long-term effect on bone structure. Careful long-term follow-up studies in patients with asthma are needed. There is no evidence that inhaled corticosteroids increase the frequency of fractures. Long-term treatment with highdose inhaled corticosteroids has not been associated with any consistent change in bone density. Indeed, in elderly patients there may be an increase in bone density due to increased mobility. Effects on connective tissue Oral and topical corticosteroids cause thinning of the skin, telangiectasiae and easy bruising, probably as a result of loss of extracellular ground substance within the dermis, due to an inhibitory effect on dermal fibroblasts. There are reports of increased skin bruising and purpura in patients using high doses of inhaled BDP, but the amount of intermittent oral corticosteroids in these patients is not known. Easy bruising, in association with inhaled corticosteroids, is more frequent in elderly patients90 and there are no reports of this problem in children. Long-term prospective studies with objective measurements of skin thickness are needed with different inhaled corticosteroids. Ocular effects Long-term treatment with oral corticosteroids increase the risk of posterior subcapsular cataracts and there are several case reports describing cataracts in individual patients taking inhaled corticosteroids.40 In a recent crosssectional study in patients aged 5–25 years, taking either inhaled BDP or budesonide, no cataracts were found on slit-lamp examination, even in patients taking 2000 lg daily for over 10 years.91 However, epidemiological studies have identified an increased risk of cataracts in patients taking high-dose inhaled steroids over prolonged periods.92 A slight increase in the risk of glaucoma in patients taking very high doses of inhaled corticosteroids has also been identified.93 Growth There has been particular concern that inhaled corticosteroids may cause stunting of growth and several studies have addressed this issue. Asthma itself (as with other chronic diseases) may have an effect on the growth pattern and has been associated with delayed onset of puberty and decceleration of growth velocity that is more pronounced with more severe disease. However, asthmatic children appear to grow for longer, so that their final height is normal. The effect of asthma on growth makes it difficult to assess the effects of inhaled corticosteroids on growth in cross-sectional studies, particularly as courses of oral corticosteroids are a confounding factor. Longitudinal studies have demonstrated that there is no significant effect of
inhaled corticosteroids on statural growth in doses of up to 800 lg daily and for up to 5 years of treatment.40A metaanalysis of 21 studies, including over 800 children, showed no effect of inhaled BDP on statural height, even with higher doses and long duration of therapy94 and in a large study of asthmatics treated with inhaled corticosteroids during childhood, there was no difference in statural height compared with normal children.95 Another long-term follow-up study showed no effect of corticosteroids on final height in children treated over several years.96 Short-term growth measurements (knemometry) have demonstrated that even a low dose of an oral corticosteroid (prednisolone 2.5 mg) is sufficient to give complete suppression of lower leg growth. However inhaled budesonide up to 400 lg is without effect, although some suppression is seen with 800 lg and with 400 lg BDP. The relationship between knemometry measurements and final height are uncertain, since low doses of oral corticosteroid that have no effect on final height cause profound suppression. Metabolic effects Several metabolic effects have been reported after inhaled corticosteroids, but there is no evidence that these are clinically relevant at therapeutic doses. In adults, fasting glucose and insulin are unchanged after doses of BDP up to 2000 lg daily and in children with inhaled budesonide up to 800 lg daily. In normal individuals, high-dose inhaled BDP may slightly increase resistance to insulin. However, in patients with poorly controlled asthma high doses of BDP and budesonide paradoxically decrease insulin resistance and improve glucose tolerance, suggesting that the disease itself may lead to abnormalities in carbohydrate metabolism. Neither BDP 2000 lg daily in adults nor budesonide 800 lg daily in children have any effect on plasma cholesterol or triglycerides. Hematological effects Inhaled corticosteroids may reduce the numbers of circulating eosinophils in asthmatic patients, possibly due to an effect on local cytokine generation in the airways. Inhaled corticosteroids may cause a small increase in circulating neutrophil counts. Central nervous system effects There are various reports of psychiatric disturbance, including emotional lability, euphoria, depression, aggressiveness and insomnia, after inhaled corticosteroids. Only eight such patients have so far been reported, suggesting that this is very infrequent and a causal link with inhaled corticosteroids has usually not been established. Safety in pregnancy Based on extensive clinical experience, inhaled corticosteroids appear to be safe in pregnancy, although no controlled studies have been performed. There is no evidence for any adverse effects of inhaled corticosteroids on the pregnancy, the delivery or on the fetus.97,98 It is important to
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recognize that poorly controlled asthma may increase the incidence of perinatal mortality and retard intra-uterine growth, so that more effective control of asthma with inhaled corticosteroids may reduce these problems.
SYSTEMIC CORTICOSTEROIDS Oral or intravenous corticosteroids may be indicated in several situations. Prednisolone, rather than prednisone, is the preferred oral corticosteroid, as prednisone has to be converted in the liver to the active prednisolone. In pregnant patients prednisone may be preferable, as it is not converted to prednisolone in the fetal liver, thus diminishing the exposure of the fetus to corticosteroids. Enteric-coated preparations of prednisolone are used to reduce side-effects (particularly gastric side-effects) and give delayed and reduced peak plasma concentrations, although the bioavailability and therapeutic efficacy of these preparations is similar to uncoated tablets. Prednisolone and prednisone are preferable to dexamethasone, betamethasone or triamcinolone, which have longer plasma half-lives and therefore an increased frequency of adverse effects. Short courses of oral corticosteroids (30–40 mg prednisolone daily for 1–2 weeks or until the peak flow values return to best attainable) are indicated for exacerbations of asthma, and the dose may be tailed off over 1 week once the exacerbation is resolved. The tail-off period is not strictly necessary, but some patients find it reassuring. Maintenance oral corticosteroids are only needed in a small proportion of asthmatic patients with the most severe asthma that cannot be controlled with maximal doses of inhaled corticosteroids (2000 lg daily) and additional bronchodilators. The minimal dose of oral corticosteroid needed for control should be used and reductions in the dose should be made slowly in patients who have been on oral corticosteroids for long periods (e.g. by 2.5 mg per month for doses down to 10 mg daily and thereafter by 1 mg per month). Oral corticosteroids are usually given as a single morning dose, as this reduces the risk of adverse effects since it coincides with the peak diurnal concentrations. There is some evidence that administration in the afternoon may be optimal for some patients who have severe nocturnal asthma.99 Alternate day administration may also reduce adverse effects, but control of asthma may not be as good on the day when the oral dose is omitted in some patients. Intramuscular triamcinolone acetonide (80 mg monthly) has been advocated in patients with severe asthma as an alternative to oral corticosteroids.100,101 This may be considered in patients in whom compliance is a particular problem, but the major concern is the high frequency of proximal myopathy associated with this fluorinated corticosteroid. Some patients who do not respond well to prednisolone are reported to respond to oral betamethasone, presumably because of pharmacokinetic handling problems with prednisolone.
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Acute severe asthma Intravenous hydrocortisone is given in acute severe asthma, with a recommended dose of 200 mg IV. While the value of corticosteroids in acute severe asthma has been questioned, others have found that they speed the resolution of attacks.102 There is no apparent advantage in giving very high doses of intravenous corticosteroids (such as methylprednisolone 1 g). Indeed, intravenous corticosteroids have occasionally been associated with an acute severe myopathy.103 No difference in recovery from acute severe asthma was seen whether IV hydrocortisone in doses of 50, 200 or 500 mg 6 hourly were used104 and another placebo-controlled study showed no beneficial effect of IV corticosteroids.105 Intravenous corticosteroids are indicated in acute asthma if lung function is <30% predicted and in whom there is no significant improvement with nebulized b2-agonist. Intravenous therapy is usually given until a satisfactory response is obtained and then oral prednisolone may be substituted. Oral prednisolone (40–60 mg) has a similar effect to intravenous hydrocortisone and is easier to administer.102,106 Oral prednisolone is the preferred treatment for acute severe asthma, providing there are no contraindications to oral therapy.107 There is some evidence that high doses of nebulized corticosteroids may also be effective in acute exacerbations of asthma, with a more rapid onset of action.108
C O R T I C O S T E R O I D - R E S I S TA N T A S T H M A Although corticosteroids are highly effective in the control of asthma and other chronic inflammatory or immune diseases, a small proportion of patients with asthma fail to respond even to high doses of oral glucocorticoids.109,110 Resistance to the therapeutic effects of corticosteroids is also recognized in other inflammatory and immune diseases, including rheumatoid arthritis and inflammatory bowel disease. Corticosteroid-resistant patients, although uncommon, present considerable management problems. Recently, new insights into the mechanisms whereby corticosteroids suppress chronic inflammation have shed new light on the molecular basis of corticosteroid-resistant asthma. Corticosteroid-resistant asthma is defined as a failure to improve FEV1 or PEF by >15% after treatment with oral prednisolone 30–40 mg daily for 2 weeks, providing the oral steroid is taken (verified by plasma prednisolone level or a reduction in early morning cortisol level).These patients are not Addisonian and they do not suffer from the abnormalities in sex hormones described in the very rare familial glucocorticoid resistance. Plasma cortisol and adrenal suppression in response to exogenous cortisol is normal in these patients, so they suffer from side-effects of corticosteroids. Complete corticosteroid resistance in asthma is very rare, with a prevalence of <1:1000 asthmatic patients. Much more common is a reduced responsiveness to corticosteroids, so that large inhaled or oral doses are needed to control asthma adequately (corticosteroid-dependent asthma). It is likely that there is a range of responsiveness to
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corticosteroids and that corticosteroid-resistance is at one extreme of this range. It is important to establish that the patient has asthma, rather than COPD, “pseudoasthma” (a hysterical conversion syndrome involving vocal cord dysfunction), left ventricular failure or cystic fibrosis that do not respond to corticosteroids. Asthmatic patients are characterized by a variability in PEF and, in particular, a diurnal variability of >15% and episodic symptoms. It is also important to identify provoking factors (allergens, drugs, psychological problems) that may increase the severity of asthma and its resistance to therapy. Biopsy studies have demonstrated the typical eosinophilic inflammation of asthma in these patients.110 Mechanisms of corticosteroid resistance There may be several mechanisms for resistance to the effects of corticosteroids. Certain cytokines (particularly IL-2, IL-4 and IL-13) may induce a reduction in affinity of glucocorticoid receptors in inflammatory cells such as T-lymphocytes, resulting in local resistance to the antiinflammatory actions of corticosteroids.110 Another mechanism is an increased activation of the transcription factor AP-1 by inflammatory cytokines, so that AP-1 may consume activated glucocorticoid receptors and thus reduce their availability for suppression of inflammation at inflamed sites.111 There is an increased expression of c-Fos, one of the components of AP-1.112 The reasons for this excessive activation of AP-1 by activating enzymes is currently unknown, but may be genetically determined. Another proposed mechanism is an increase in expression of GR-b, which then interferes with DNA binding of GR,113,114 but any increase in GR-b is insufficient to account for reduced responsiveness to corticosteroids.115
CORTICOSTEROIDS IN COPD Although inhaled corticosteroids are highly effective in asthma, they provide little benefit in COPD, despite the fact that airway and lung inflammation is present.3 Effect on inflammation This may reflect that the inflammation in COPD is not suppressed by corticosteroids, with no reduction in inflammatory cells, cytokines or proteases in induced sputum even with oral corticosteroids.116,117 Corticosteroids do not suppress neutrophilic inflammation in the airways and corticosteroids may prolong the survival of neutrophils.31 There is some evidence that the airway inflammation in COPD is corticosteroid-resistant, as corticosteroids have no inhibitory effect on inflammatory proteins, such as cytokines, that are normally suppressed by corticosteroids. This lack of response to corticosteroids may be explained in part by the inhibitory effect of cigarette smoking on histone deacetylases, thus interfering with an important anti-inflammatory action of corticosteroids.118
Clinical studies Four large studies conducted over 3 years have demonstrated no beneficial effect of inhaled corticosteroids on the decline in lung function in patients from mild to moderate COPD.119–122 There is some evidence for a reduction in more severe exacerbations with high doses of inhaled corticosteroids,121,123 but the effect is small and rather similar to the effect of bronchodilators in this respect. Some patients with COPD (approximately 10%) show some response to inhaled corticosteroids and it is likely that these are patients who have concomitant asthma. Indeed there corticosteroid responders are more likely to have sputum eosinophils and an increase in exhaled NO, which are features of asthmatic inflammation.124 These patients should be treated as if they have asthma.The remaining majority of patients are unlikely to derive much benefit from inhaled corticosteroids and indeed there are good reasons for not prescribing these drugs. They are often given in high doses as this has a risk of systemic side-effects in a vulnerable patient population, who are elderly, relatively immobile, may have a poor diet and have comorbid conditions, all of which increase the risk of side-effects, such as osteoporosis and cataracts. In addition high doses of inhaled corticosteroids are relatively expensive. In the management of acute exacerbations there is evidence that oral corticosteroids increase the rate of recovery, although the effects are relatively small.125,126
FUTURE DIRECTIONS Inhaled corticosteroids are now used as first-line therapy for the treatment of persistent asthma in adults and children in many countries, as they are the most effective treatments for asthma currently available.40 While many patients, particularly with more severe asthma, remain undertreated, there is also a danger of overtreatment and many patients with mild asthma who may require very low doses of inhaled corticosteroids are inappropriately treated with high doses. It is essential that inhaled corticosteroids are slowly reduced to the minimal dose required to control asthma. An important clinical development is the recognition that asthma is better controlled by addition of an alternative class of treatment (long-acting inhaled b2-agonists, low-dose theophylline, anti-leukotrienes) than on increasing the dose of inhaled steroid. The recent introduction of fixed combination inhalers with long-acting b2-agonists is an important advance as it greatly simplifies asthma management and provides very effective control. Improvement in techniques for the noninvasive monitoring of airway inflammation may be valuable in the future for assessing the requirement for inhaled corticosteroids.127 New corticosteroids Budesonide and FP have been important advances in inhaled corticosteroid therapy as they have reduced systemic effects because of greater first-pass hepatic metabolism than
Corticosteroids
BDP. New inhaled corticosteroids in development, such as mometasone, show a similar improved profile.128 However, all currently available corticosteroids are absorbed from the lungs into the systemic circulation and therefore inevitably have some systemic component. A class of steroids was developed that was metabolized in the lung, but such so-called “soft” steroids, such as tipredane and butixocort, did not prove to be clinically effective, probably because they were metabolized too rapidly in the airways. A new steroid ciclesonide is a prodrug that releases active corticosteroids in the lungs after enzymatic action. Ciclesonide appears to have good efficacy and is now in clinical development.129 Steroids that are metabolized by enzymes in the circulation may be the safest type of inhaled corticosteroid and novel esterified corticosteroids are now in clinical development. However, it is still not certain whether the anti-inflammatory effects of inhaled corticosteroids in asthma are mediated entirely by local antiinflammatory effects in the airways, and it is possible that there is a systemic component, for example on bone marrow eosinophil precursors or on regional lymph nodes. Furthermore, it is not clear whether inhaled corticosteroids are distributed from their point of deposition in the airways to more peripheral airways via the local circulation. If this is the case then corticosteroids that are degraded by enzymes in the circulation may not reach small airways that are inflamed in asthma. Understanding the molecular mechanisms of action of corticosteroids has led to the development of a new generation of corticosteroids. As discussed above, a major mechanism of the anti-inflammatory effect of corticosteroids appears to be direct inhibition of transcription factors, such as NF-jB and AP-1 that are activated by proinflammatory cytokines (transrepression). By contrast, the endocrine and metabolic effects of steroids that are responsible for the systemic side effects of corticosteroids are likely to be mediated via DNA binding (transactivation). This has led to a search for novel corticosteroids that selectively transrepress, thus reducing the potential risk of systemic side-effects. Since corticosteroids bind to the same GR, this seems at first to be an unlikely possibility, but while DNA binding involved a GR homodimer, interaction with transcription factors AP-1 and NF-jB involves only a single GR. A separation of transactivation and transrepression has been demonstrated using reporter gene constructs in transfected cells using selective mutations of the glucocorticoid receptor. Furthermore, some steroids, such as the antagonist RU486, have a greater transrepression than transactivation effect. Indeed, the topical steroids used in asthma therapy today, such as FP and budesonide, appear to have more potent transrepression than transactivation effects, which may account for their selection as potent anti-inflammatory agents.130 Recently, a novel class of steroids has been described in which there is potent transrepression with relatively little transactivation. These “dissociated” steroids, including RU24858 and RU40066 have anti-inflammatory effects in vitro,131 although there is little separation of anti-inflammatory effects and systemic
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side-effects in vivo.132 This suggests that the development of steroids with a greater margin of safety is possible and may even lead to the development of oral steroids that do not have significant adverse effects.
REFERENCES 1. Barnes PJ. Inhaled glucocorticoids for asthma. N. Engl. J. Med. 1995; 332:868–75. 2. Barnes PJ. Efficacy of inhaled corticosteroids in asthma. J. Allergy Clin. Immunol. 1998; 102:531–8. 3. Barnes PJ. Inhaled corticosteroids are not helpful in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 161:342–4. 4. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin. Sci. 1998; 94:557–72. 5. Bamberger CM, Bamberger AM, de Castr M, Chrousos GP. Glucocorticoid receptor b, a potential endogenous inhibitor of glucocorticoid action in humans. J. Clin. Invest. 1995; 95:2435–41. 6. Reichardt HM, Kaestner KH, Tuckermann J et al. DNA binding of the glucocorticoid receptor is not essential for survival. Cell 1998; 93:531–41. 7. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits IL-1b-induced histone H4 acetylation on lysines 8 and 12. Mol. Cell Biol. 2000; 20:6891–903. 8. Barnes PJ, Karin M. Nuclear factor-jB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 1997; 336:1066–71. 9. Barnes PJ, Adcock IM. Transcription factors and asthma. Eur. Respir. J. 1998; 12:221–34. 10. Kamei Y, Xu L, Heinzel T et al. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 1996; 85:403–14. 11. Wolffe AP, Hayes JJ. Chromatin disruption and modification. Nucleic. Acids. Res. 1999; 27:711–20. 12. Hall SE, Lim S, Witherden IR et al. Lung type II cell and macrophage annexin I release: differential effects of two glucocorticoids. Am. J. Physiol. 1999; 276:L114–21. 13. Mak JCW, Nishikawa M, Barnes PJ. Glucocorticosteroids increase b2-adrenergic receptor transcription in human lung. Am. J. Physiol. 1995; 12:L41–6. 14. Baraniuk JN, Ali M, Brody D et al. Glucocorticoids induce b2adrenergic receptor function in human nasal mucosa. Am. J. Respir. Crit. Care Med. 1997; 155:704–10. 15. Mak JCW, Nishikawa M, Shirasaki H, Miyayasu K, Barnes PJ. Protective effects of a glucocorticoid on down-regulation of pulmonary b2-adrenergic receptors in vivo. J. Clin. Invest. 1995; 96:99–106. 16. Lilly CM, Nakamura H, Kesselman H et al. Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids. J. Clin. Invest. 1997; 99:1767–73. 17. Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Annu. Rev. Immunol. 1997; 15:707–47. 18. Newton R, Kuitert LM, Slater DM, Adcock IM, Barnes PJ. Cytokine induction of cytosolic phosholipase A2 and cyclooxygenase-2 mRNA by proinflammatory cytokines is suppressed by dexamethasone in human epithelial cells. Life Sci. 1997; 60:67–78. 19. Newton R, Seybold J, Kuitert LME, Bergmann M, Barnes PJ. Repression of cyclooxygenase-2 and prostaglandin E2 release by dexamethasone occurs by transcriptional and posttranscriptional mechanisms involving loss of polyadenylated mRNA. J. Biol. Chem. 1998; 273:32312–21.
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20. Adcock IM, Peters M, Gelder C, Shirasaki H, Brown CR, Barnes PJ. Increased tachykinin receptor gene expression in asthmatic lung and its modulation by steroids. J. Mol. Endocrinol. 1993; 11:1–7. 21. Katsunuma T, Mak JCW, Barnes PJ. Glucocorticoids reduce tachykinin NK2-receptor expression in bovine tracheal smooth muscle. Eur. J. Pharmacol. 1998; 344:99–107. 22. Haddad EB, Fox AJ, Rousell J et al. Post-transcriptional regulation of bradykinin B1 and B2 receptor gene expression in human lung fibroblasts by tumor necrosis factor-a: modulation by dexamethasone. Mol. Pharmacol. 2000; 57:1123–31. 23. Atsuta J, Plitt J, Bochner BS, Schleimer RP. Inhibition of VCAM-1 expression in human bronchial epithelial cells by glucocorticoids. Am. J. Respir. Cell Mol. Biol. 1999; 20:643–50. 24. Walsh GM. Mechanisms of human eosinophil survival and apoptosis. Clin. Exp. Allergy 1997; 27:482–7. 25. Meagher LC, Cousin JM, Seckl JR, Haslett C. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J. Immunol. 1996; 156:4422–8. 26. John M, Lim S, Seybold J et al. Inhaled corticosteroids increase IL-10 but reduce MIP-1a, GM-CSF and IFN-c release from alveolar macrophages in asthma. Am. J. Respir. Crit. Care Med. 1998; 157:256–62. 27. Woolley KL, Gibson PG, Carty K, Wilson AJ, Twaddell SH, Woolley MJ. Eosinophil apoptosis and the resolution of airway inflammation in asthma. Am. J. Respir. Crit. Care Med. 1996; 154:237–43. 28. Kankaanranta H, Lindsay MA, Giembycz MA, Zhang X, Moilanen E, Barnes PJ. Delayed eosinophil apoptosis in asthma. J. Allergy Clin. Immunol. 2000; 106:77–83. 29. Williams CM, Galli SJ. The diverse potential effector and immunoregulatory roles of mast cells in allergic disease. J. Allergy Clin. Immunol. 2000; 105:847–59. 30. Nelson DJ, McWilliam AS, Haining S, Holt PG. Modulation of airway intraepithelial dendritic cells following exposure to steroids. Am. J. Respir. Crit. Care Med. 1995; 151:475–81. 31. Nightingale JA, Rogers DF, Chung KF, Barnes PJ. No effect of inhaled budesonide on the response to inhaled ozone in normal subjects. Am. J. Respir. Crit. Care Med. 2000; 161:479–86. 32. Barnes PJ. Mechanism of action of glucocorticoids in asthma. Am. J. Respir. Crit. Care Med. 1996; 154:S21–7. 33. Schweibert LM, Stellato C, Schleimer RP. The epithelium as a target for glucocorticoid action in the treatment of asthma. Am. J. Respir. Crit. Care Med. 1996; 154:S16–20. 34. Saleh D, Ernst P, Lim S, Barnes PJ, Giaid A. Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid. FASEB J. 1998; 12:929–37. 35. Kharitonov SA, Yates DH, Barnes PJ. Regular inhaled budesonide decreases nitric oxide concentration in the exhaled air of asthmatic patients. Am. J. Respir. Crit. Care Med. 1996; 153:454–7. 36. Kai H,Yoshitake K, Hisatsune A, Kido T, Isohama Y, Takahama K, Miyata T. Dexamethasone suppresses mucus production and MUC-2 and MUC-5AC gene expression by NCI-H292 cells. Am. J. Physiol. 1996; 271:L484–8. 37. Barnes PJ. Effect of corticosteroids on airway hyperresponsiveness. Am. Rev. Respir. Dis. 1990; 141:S70–6. 38. Kamada AK, Szefler SJ, Martin RJ et al. Issues in the use of inhaled steroids. Am. J. Respir. Crit. Care Med. 1996; 153:1739–48. 39. Barnes PJ. Therapeutic strategies for allergic diseases. Nature 1999; 402:B31–8. 40. Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids: an update. Am. J. Respir. Crit. Care Med. 1998; 157:S1–53. 41. Haahtela T, Jarvinen M, Kava T et al. Comparison of a b2-agonist terbutaline with an inhaled steroid in newly detected asthma. N. Engl. J. Med. 1991; 325:388–92.
42. Juniper EF, Kline PA, Vanzieleghem MA, Ramsdale EH, O’Byrne PM, Hargreave FE. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am. Rev. Respir. Dis. 1990; 142:832–6. 43. Vathenen AS, Knox AJ, Wisniewski A, Tattersfield AE. Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma. Am. Rev. Respir. Dis. 1991; 143:1317–21. 44. Levy ML, Stevenson C, Maslen T. Comparison of short courses of oral prednisolone and fluticasone propionate in the treatment of adults with acute exacerbations of asthma in primary care. Thorax 1996; 51:1087–92. 45. Foresi A, Morelli MC, Catena E. Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group. Chest 2000; 117:440–6. 46. Juniper EF, Kline PA, Vanzielegmem MA, Hargreave FE. Reduction of budesonide after a year of increased use: a randomized controlled trial to evaluate whether improvements in airway responsiveness and clinical asthma are maintained. J. Allergy Clin. Immunol. 1991; 87:483–9. 47. Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am. J. Respir. Crit. Care Med. 2000; 161:64–72. 48. van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, Duiverman EJ, Pocock SJ, Kerrebijn KF. Effects of 22 months of treatment with inhaled corticosteroids and/or b2-agonists on lung function, airway responsiveness and symptoms in children with asthma. Am. Rev. Respir. Dis. 1992; 146:547–54. 49. Waalkens HJ, van Essen-Zandvliet EE, Hughes MD et al. Cessation of long-term treatment with inhaled corticosteroids (budesonide) in children with asthma results in deterioration. Am. Rev. Respir. Dis. 1993; 148:1252–7. 50. Simons FE. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. N. Engl. J. Med. 1997; 337:1659–65. 51. Ilangovan P, Pedersen S, Godfrey S, Nikander K, Novisky N, Warner JO. Nebulised budesonide suspension in severe steroiddependent preschool asthma. Arch. Dis. Child. 1993; 68:356–9. 52. Busse WW, Chervinsky P, Condemi J et al. Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma. J. Allergy Clin. Immunol. 1998; 101:457–63. 53. Pauwels RA, Lofdahl C-G, Postma DS et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N. Engl. J. Med. 1997; 337:1412–18. 54. Lim S, Jatakanon A, John M et al. Effect of inhaled budesonide on lung function and airway inflammation. Assessment by various inflammatory markers in mild asthma. Am. J. Respir. Crit. Care Med. 1999; 159:22–30. 55. Jatakanon A, Lim S, Chung KF, Barnes PJ. An inhaled steroid improves markers of inflammation in asymptomatic steroidnaive asthmatic patients. Eur. Respir. J. 1998; 12:1084–8. 56. Jatakanon A, Kharitonov S, Lim S, Barnes PJ. Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Thorax 1999; 54:108–14. 57. Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk PJ. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am. J. Respir. Crit. Care Med. 1999; 159:1043–51. 58. Dompeling E, Van Schayck CP, Molema J, Folgering H, van Grusven PM, van Weel C. Inhaled beclomethasone improves the course of asthma and COPD. Eur. Respir. J. 1992; 5:945–52. 59. Haahtela T, Järvinsen M, Kava T et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N. Engl. J. Med. 1994; 331:700–5.
Corticosteroids
60. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Resp. Med. 1994; 5:369–72. 61. Selroos O, Pietinalcho A, Lofroos A-B, Riska A. Effect of early and late intervention with inhaled corticosteroids in asthma. Chest 1995; 108:1228–34. 62. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N. Engl. J. Med. 2000; 343:332–6. 63. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch. Intern. Med. 1999; 159:941–55. 64. Nathan RA, Nayak AS, Graft DF et al. Mometasone furoate: efficacy and safety in moderate asthma compared with beclomethasone dipropionate. Ann. Allergy Asthma Immunol. 2001; 86:203–10. 65. Barnes PJ. Inhaled glucocorticoids: new developments relevant to updating the Asthma Management Guidelines. Resp. Med. 1996; 90:379–84. 66. Malo J-L, Cartier A, Merland N et al. Four-times-a-day dosing frequency is better than twice-a-day regimen in subjects requiring a high-dose inhaled steroid, budesonide, to control moderate to severe asthma. Am. Rev. Respir. Dis. 1989; 140:624–8. 67. Jones AH, Langdon CG, Lee PS et al. Pulmicort Turbohaler once daily as initial prophylactic therapy for asthma. Respir. Med. 1994; 88:293–9. 68. Otulana BA, Varma N, Bullock A, Higenbottam T. High dose nebulized steroid in the treatment of chronic steroid-dependent asthma. Resp. Med. 1992; 86:105–8. 69. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994; 344:219–24. 70. Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). Br. Med. J. 2000; 320:1368–73. 71. Chapman KR, Ringdal N, Backer V, Palmqvist M, Saarelainen S, Briggs M. Salmeterol and fluticasone propionate (50/250 lg) administered via combination diskus inhaler: As effective as when given via separate diskus inhalers. Can. Respir. J. 1999; 6:45–51. 72. Shapiro G, Lumry W,Wolfe J et al. Combined salmeterol 50 lg and fluticasone propionate 250 lg in the Diskus device for the treatment of asthma. Am. J. Respir. Crit. Care Med. 2000; 161:527–34. 73. Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O’Connor BJ, Barnes PJ. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N. Engl. J. Med. 1997; 337:1412–18. 74. Ukena D, Harnest U, Sakalauskas R et al. Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur. Respir. J. 1997; 10:2754–60. 75. Lim S, Jatakanon A, Gordon D, Macdonald C, Chung KF, Barnes PJ. Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice. Thorax 2000; 55:837–41. 76. Laviolette M, Malmstrom K, Lu S et al. Montelukast added to inhaled beclomethasone in treatment of asthma. Am. J. Respir. Crit. Care Med. 1999; 160:1862–8. 77. Nelson HS, Busse WW, Kerwin E et al. Fluticasone propionate/ salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. J. Allergy Clin. Immunol. 2000; 106:1088–95. 78. Eickelberg O, Roth M, Lorx R et al. Ligand-independent activation of the glucocorticoid receptor by b2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells. J. Biol. Chem. 1999; 274:1005–10.
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79. Pang L, Knox AJ. Synergistic inhibition by b2-agonists and corticosteroids on tumor necrosis factor-a-induced interleukin-8 release from cultured human airway smooth-muscle cells. Am. J. Respir. Cell Mol. Biol. 2000; 23:79–85. 80. Barnes PJ, Jonsson B, Klim J. The costs of asthma. Eur. Respir. J. 1996; 9:636–42. 81. van Schayk CP, Dompeling E, Rutten MP, Folgering H, van den Boom G, van Weel C. The influence of an inhaled steroid on quality of life in patients with asthma or COPD. Chest 1995; 107:1199–205. 82. Hill SJ, Tattersfield AE. Corticosteroid sparing agents in asthma. Thorax 1995; 50:577–82. 83. Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults. Cochrane Database Syst. Rev. 2000; 2:CD000391. 84. Nelson HS, Hamilos DL, Corsello PR, Levesque NV, Buchameier AD, Bucher BL. A double-blind study of troleandamycin and methylprednisolone in asthmatic patients who require daily corticosteroids. Am. Rev. Respir. Dis. 1993; 147:398–404. 85. Williamson IJ, Matusiewicz SP, Brown PH, Greening AP, Crompton GK. Frequency of voice problems and cough in patients using pressurised aersosol inhaled steroid preparations. Eur. Respir. J. 1995; 8:590–2. 86. Toogood JA, Jennings B, Greenway RW, Chung L. Candidiasis and dysphonia complicating beclomethasone treatment of asthma. J. Allergy Clin. Immunol. 1980; 65:145–53. 87. Brutsche MH, Brutsche IC, Munawar M et al. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet 2000; 356:556–61. 88. Harrison TW, Wisniewski A, Honour J, Tattersfield AE. Comparison of the systemic effects of fluticasone propionate and budesonide given by dry powder inhaler in healthy and asthmatic subjects. Thorax 2001; 56:186–91. 89. Efthimou J, Barnes PJ. Effect of inhaled corticosteroids on bone and growth. Eur. Respir. J. 1998; 11:1167–77. 90. Roy A, Leblanc C, Paquette L et al. Skin bruising in asthmatic subjects treated with high does of inhaled steroids: frequency and association with adrenal function. Eur. Respir. J. 1996; 9:226–31. 91. Simons FER, Persaud MP, Gillespie CA, Cheang M, Shuckett EP. Absence of posterior subcapsular cataracts in young patients treated with inhaled glucocorticoids. Lancet 1993; 342:736–8. 92. Cumming RG, Mitchell P, Leeder SR. Use of inhaled corticosteroids and the risk of cataracts. N. Engl. J. Med. 1997; 337:8–14. 93. Garbe E, LeLorier J, Boivin J-F, Suissa S. Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma. JAMA 1997; 227:722–7. 94. Allen DB, Mullen M, Mullen B. A meta-analysis of the effects of oral and inhaled corticosteroids on growth. J. Allergy Clin. Immunol. 1994; 93:967–76. 95. Silverstein MD, Yunginger JW, Reed CE et al. Attained adult height after childhood asthma: effect of glucocorticoid therapy. J. Allergy Clin. Immunol. 1997; 99:466–74. 96. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N. Engl. J. Med. 2000; 343:1064–69. 97. Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D. The safety of asthma and allergy medications during pregnancy. J. Allergy Clin. Immunol. 1997; 100:301–6. 98. Schatz M. Asthma and pregnancy. Lancet 1999; 353:1202–4. 99. Beam WR, Ballard RD, Martin RJ. Spectrum of corticosteroid sensitivity in nocturnal asthma. Am. Rev. Respir. Dis. 1992; 145:1082–6. 100. McLeod DT, Capewell SJ, Law J, MacLaren W, Seaton A. Intramuscular triamcinolone acetamide in chronic severe asthma. Thorax 1985; 40:840–5.
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101. Ogirala RG, Aldrich TK, Prezant DJ, Sinnett MJ, Enden JB, Williams MH. High dose intramuscular triamcinolone in severe life-threatening asthma. N. Engl. J. Med. 1991; 329:585–9. 102. Engel T, Heinig JH. Glucocorticoid therapy in acute severe asthma – a critical review. Eur. Respir. J. 1991; 4:881–9. 103. Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am. J. Respir. Crit. Care Med. 1995; 150:11–16. 104. Bowler SD, Mitchell CA, Armstrong JG. Corticosteroids in acute severe asthma: effectiveness of low doses. Thorax 1992; 47:584–7. 105. Morell F, Orkiols R, de Gracia J, Curul V, Pujol A. Controlled trial of intravenous corticosteroids in severe acute asthma. Thorax 1992; 47:588–91. 106. Harrison BDN, Stokes TC, Hart GJ, Vaughan DA, Ali NJ, Robinson AA. Need for intravenous hydrocortisone in addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure. Lancet 1986; i:181–4. 107. British Thoracic Society. The British guidelines on asthma management. Thorax 1997; 52(Suppl 1):S1–21. 108. Devidayal, Singhi S, Kumar L, Jayshree M. Efficacy of nebulized budesonide compared to oral prednisolone in acute bronchial asthma. Acta Paediatr. 1999; 88:835–40. 109. Barnes PJ, Greening AP, Crompton GK. Glucocorticoid resistance in asthma. Am. J. Respir. Crit. Care Med. 1995; 152:125S–40S. 110. Szefler SJ, Leung DY. Glucocorticoid-resistant asthma: pathogenesis and clinical implications for management. Eur. Respir. J. 1997; 10:1640–7. 111. Adcock IM, Brown CR, Shirasaki H, Barnes PJ. Effects of dexamethasone on cytokine and phorbol ester stimulated c-Fos and c-Jun DNA binding and gene expression in human lung. Eur. Respir. J. 1994; 7:2117–23. 112. Lane SJ, Adcock IM, Richards D, Hawrylowicz C, Barnes PJ, Lee TH. Corticosteroid-resistant bronchial asthma is associated with increased c-Fos expression in monocytes and Tlymphocytes. J. Clin. Invest. 1998; 102:2156–64. 113. Hamid QA, Wenzel SE, Hauk PJ et al. Increased glucocorticoid receptor b in airway cells of glucocorticoid-insensitive asthma. Am. J. Respir. Crit. Care Med. 1999; 159:1600–4. 114. Sousa AR, Lane SJ, Cidlowski JA, Staynov DZ, Lee TH. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor b-isoform. J. Allergy Clin. Immunol. 2000; 105:943–50. 115. Gagliardo R, Chanez P, Vignola AM et al. Glucocorticoid receptor a and b in glucocorticoid dependent asthma. Am. J. Respir. Crit Care Med. 2000; 162:7–13. 116. Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am. J. Respir. Crit. Care Med. 1997; 155:542–8. 117. Culpitt SV, Nightingale JA, Barnes PJ. Effect of high dose inhaled steroid on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1635–9.
118. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. 2001; 10:1110–12. 119. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Longterm effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999; 353:1819–23. 120. Pauwels RA, Lofdahl CG, Laitinen LA et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N. Engl. J. Med. 1999; 340:1948–53. 121. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslen T. Randomised, double-blind, placebo-controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease; the ISOLDE trial. Br. Med. J. 2000; 320:1297–303. 122. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343:1902–9. 123. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimou J. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998; 351:773–80. 124. Papi A, Romagnoli M, Baraldo S et al. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 162:1773–7. 125. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet 1999; 354:456–60. 126. Niewoehner DE, Erbland ML, Deupree RH et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N. Engl. J. Med. 1999; 340:1941–7. 127. Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 163:1693–722. 128. Prakash A, Benfield P. Topical mometasone. A review of its pharmacological properties and therapeutic use in the treatment of dermatological disorders. Drugs 1998; 55:145–63. 129. Taylor DA, Jensen MW, Kanabar V et al. A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5-monophosphate in asthmatic patients. Am. J. Respir. Crit. Care Med. 1999; 160:237–243. 130. Adcock IM, Nasuhara Y, Stevens DA, Barnes PJ. Ligand-induced differentiation of glucocorticoid receptor trans-repression and transactivation: preferential targetting of NF-jB and lack of IjB involvement. Br. J. Pharmacol. 1999; 127:1003–11. 131. Vayssiere BM, Dupont S, Choquart A et al. Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo. Mol. Endocrinol. 1997; 11:1245–55. 132. Belvisi MG, Wicks SL, Battram CH et al. Therapeutic benefit of a dissociated glucocorticoid and the relevance of in vitro separation of transrepression from transactivation activity. J. Immunol. 2001; 166:1975–82.
Chapter
Mediator Antagonists
53
K. Fan Chung and Peter J. Barnes National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
Many inflammatory mediators are involved in the pathophysiology of asthma and COPD, suggesting that antagonists of mediator receptors or inhibitors of their synthesis would be beneficial in treatment. However, the large number of mediators involved and the redundancy of their effects means that inhibitors of single mediators have little or no clinical benefit. However, some mediators appear to be more important than others and inhibitors have some clinical effect. This is particularly true of anti-leukotrienes, the first new class of therapy for asthma introduced in more than 30 years.
ANTI-LEUKOTRIENES Anti-leukotrienes can be divided into cysteinyl-leukotriene (cys-LT) receptor antagonists which antagonize the effects of cyc-LTs, such as LTD4 and leukotriene synthesis inhibitors, which are inhibitors of 5-lipoxygenase (5-LO) enzyme that generates cys-LTs and LTB4 (Fig. 53.1). Antileukotrienes are mainly indicated for the treatment of asthma, and LTB4 inhibitors, such as LTB4 receptor antagonists, have no effect in asthma and are being considered for the treatment of COPD.
Allergen Exercise
Aspirin
PAF
Eos
MC
SO2
Arachidonic acid 5-lipoxygenase
ⴚ
Plasma exudation
5-LO inhibitors zileuton
Cysteinyl-leukotrienes (LTC4, LTD4, LTE4)
Cys-LT1 receptors
Mucus secretion
Fig. 53.1. Inhibition of leukotrienes.
Bronchoconstriction
ⴚ
LT-antagonists pranlukast zafirlukast montelukast
Eos recruitment
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5-Lipoxygenase inhibitors 5-LO is a critical enzyme involved in the generation of leukotrienes. Inhibitors of 5-LO may be classified as direct inhibitors of the enzyme, and indirect inhibitors which interfere with a nuclear membrane docking protein, 5-LO activating protein (FLAP), that is necessary for enzyme activation.1,2 Many hydroxamates and N-hydroxyureas are 5-LO inhibitors, and act by interfering with the redox state of the active binding site. Zileuton is the most extensively investigated and is the only 5-LO inhibitor available for prescription in asthma. The effect of zileuton is similar to that of leukotriene receptor antagonists, and zileuton inhibits allergen- and exercise-induced asthma, as well as aspirininduced asthma.3 It decreases airway hyper-responsiveness and inflammatory cells in nocturnal exacerbations of asthma.4,5 In addition, zileuton inhibits eosinophil influx induced by allergen challenge.6 Zileuton has a short duration of action, and has to be taken four times daily. Its side-effects are mainly on the liver, with frequent abnormalities of liver function tests. Other redox 5-LO inhibitors have been developed, but have not reached the market. Non-redox 5-LO inhibitors and inhibitors of FLAP (e.g. MK-886, MK-591, Bayx1005) have been developed,7,8 but there is no further clinical development. One theoretical advantage of the 5-LO inhibitors on the receptor antagonists is that they inhibit the formation of LTB4, and other 5-LO products, as well as cysteinyl-leukotrienes. This may make the drugs more applicable to other airway diseases where LTB4 may be involved. Cysteinyl-leukotriene antagonists The role of cys-LTs is discussed in Chapter 24 Cys-LTs cause airway obstruction through the stimulation of specific receptors termed the cys-LT receptor type 1 (Cyst-LT1). This a seven-transmembrane spanning, G-protein-coupled receptor, where the gene is mapped to the X chromosome.9 Signaling through cyst-LT1 occurs through stimulation of phosphoinositide hydrolysis.10 A second cysteinylleukotriene receptor, cyst-LT2, has also been characterized, and is found on pulmonary vessels, but its functional role is unclear.11 Many potent cyst-LT1 receptor antagonists are now available for the treatment of asthma, namely zafirlukast12 and montelukast13 in most countries, while pranlukast14 is currently available only in Japan and Korea. Only one anti-leukotriene is a 5-lipoxygenase inhibitor, zileuton, which is available in the USA.15 Effects of leukotriene receptor antagonists Leukotriene receptor antagonists in clinical use inhibit the bronchoconstrictor effects of inhaled cys-LTs. For example, a single 40 mg dose of zafirlukast produces a 100-fold shift of the LTD4 dose–response curve, and significant protection is present for 24 hours.16 Oral administration of leukotriene receptor antagonist inhibits both the early and late response to allergen, and exercise-induced asthma.17,18
Leukotriene receptor antagonists are able to cause bronchodilation, and their effect is additive to that of short-acting b2agonists.19,20 Effects of anti-leukotrienes in asthma In many studies of anti-leukotrienes such as zileuton, zafirlukast, pranlukast and montelukast, their effectiveness has been compared with that of placebo in short-term studies of 4–6 weeks’ duration.12–15 A greater increase in FEV1, a reduction in asthma medication use and in asthma symptoms, with an increase in morning peak flow has been demonstrated in mild-to-moderately severe asthma with some degree of airflow obstruction and usually in cohorts not on inhaled corticosteroid therapy. These findings have been confirmed and extended in longer studies in patients with mild-to-moderate chronic stable asthma with zileuton,21 zafirlukast,22 montelukast,23 all demonstrating clinical benefit. Their additive effect to the bronchodilation achieved with high doses of inhaled b-agonist19,24 indicate that they may have a place in the treatment of acute severe asthma. Clinical benefit has also been demonstrated with the addition of anti-leukotrienes to the patients with poor asthma control, already taking high doses of inhaled corticosteroids.25 Anti-leukotrienes may also reduce to a small extent the doses of inhaled corticosteroids required for asthma control.26 Anti-leukotrienes may reduce the risk of acute severe asthma exacerbations.27,28 The effects of anti-leukotrienes have been compared with these inhaled corticosteroids.29 In a recent meta-analysis, it was concluded that inhaled corticosteroids (250–400 lg beclomethasone dipropionate equivalent per day) provided better improvements in lung function and quality of life, as well as reduction in symptoms, night awakenings and need for rescue b-agonist. The rate of asthma exacerbations was similar when the anti-leukotrienes were compared with inhaled corticosteroids. The possible added benefit of adding leukotrienereceptor antagonist to inhaled corticosteroids has been evaluated. Addition of pranlukast to half the usual dose of inhaled corticosteroids in patients with moderate-to-severe persistent asthma led to maintained control, while the placebo group demonstrated less improved asthma control.30 Montelukast has been shown to maintain control of asthma in patients in whom removal of inhaled corticosteroids caused worsening of asthma.27 The combination of montelukast and inhaled corticosteroids provided the best control. However, adding montelukast in patients with severe asthma who are symptomatic despite high doses of inhaled corticosteroid provides no clinical benefit.31 Anti-leukotrienes are effective in blocking aspirininduced asthmatic responses,32 and may be particularly indicated in patients with aspirin-sensitive asthma. In addition, anti-leukotrienes are particularly effective in inhibiting exercise-induced asthma,18,33,34 without loss of protection with prolonged usage.35 In addition, leukotriene inhibitors may improve concomitant symptoms of seasonal rhinitis.36,37
Mediator Antagonists
Anti-inflammatory effects Cys-LTs can induce airway eosinophilia in patients with asthma.38 Leukotriene-receptor antagonists or synthesis inhibitors can reduce blood and airway eosinophilia associated with poorly controlled asthma,5,27 and reduce airway inflammation associated with allergen-induced airway responses.39 These results indicate that anti-leukotrienes can be considered as an anti-inflammatory therapy for asthma. Safety At the recommended doses, all leukotriene receptor antagonists have not resulted in non-respiratory symptoms nor laboratory abnormalities when compared with placebotreated groups. However, with zileuton, asymptomatic 3fold or greater increases in serum alanine-aminotransferase levels were found in 4.6% of patients receiving zileuton at the standard dose of 600 mg four times per day, compared with 1% of patients receiving standard asthma treatment together with placebo. These elevations usually occurred during the first 3 months of therapy, with sometimes normalization of the values despite continuation of treatment. A rare syndrome of Churg–Strauss, marked by circulating eosinophilia and evidence of tissue or organ infiltration and vasculitis by eosinophils in association with heart failure, cutaneous or gastrointestinal involvement, and peripheral neuropathy has been associated with treatment with zafirlukast and montelukast. Most patients developing Churg–Strauss syndrome have previously received oral glucocorticoid therapy or high-dose inhaled corticosteroid therapy to control their asthma.This may be due to unmasking of vasculitis of Churg–Strauss syndrome, as corticosteroids are tapered with the introduction of leukotriene receptor antagonist therapy.40 Role in COPD There is no evidence that cys-LTs are involved in COPD and no studies of leukotriene antagonists have been reported. LTB4 may play a role in the recruitment of neutrophils in COPD airways and therefore 5-LO inhibitors may have some therapeutic potential. No studies of zileuton or other 5-LO inhibitors in COPD have yet been reported.
A N T I H I S TA M I N E S Histamine mediates most of its effects on airway function via H1-receptors, suggesting that H1-antagonists may have therapeutic effects in airway disease. Non-sedating potent H1-receptor antagonists, such as terfenadine, fexafenadine, loratadine, desloratadine, ebastine and astemizole, may be given in large doses, but while these antihistamines have useful clinical effects in allergic rhinitis, they are far from effective in asthmatic patients, as demonstrated in a metaanalysis of clinical trials.41,42 The effects of antihistamines, even when taken in high doses, are small and clinically insignificant.43 Terfenadine causes about 50% inhibition of the immediate response to allergen, but has no effect on the
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late response.44 Antihistamines cause a small degree of bronchodilatation in asthmatic patients, indicating a certain degree of histamine “tone”, presumably due to the basal release of histamine from activated mast cells, as discussed above.45,46 Chronic administration of terfenadine has a small clinical effect in mild allergic asthmatic patients,47 but is far less effective that other anti-asthma therapies, so that these drugs cannot be recommended in the routine management of asthma. H1-receptor antagonists have not been found to be useful in more severe asthmatic patients.48 Some new antihistamines, such as cetirizine and astemizole have been shown to have beneficial effects in asthma,49,50 but this may be unrelated to their H1-antagonist effects.51 H2-antagonists, such as cimetidine and ranitidine, may be contraindicated in asthma on theoretical grounds, if H2receptors are important in counteracting the bronchoconstrictor effect of histamine. In clinical practice, however, there is no evidence that H2-antagonists have any deleterious effect in asthma. H2-antagonists are of theoretical benefit in patients with gastroesophageal reflux, as they reduce acid reflux, but in practice reflux is rarely associated with worsening of asthma. H3-receptor agonists may have some theoretical benefit in asthma, since they may modulate cholinergic bronchoconstriction and inhibit neurogenic inflammation. Although (R)-a-methylhistamine relaxes rodent peripheral airways in vitro,52 it has no effect when given by inhalation on airway caliber or metabisufite-induced bronchoconstriction in asthmatic patients, indicating that a useful clinical effect is unlikely.53 Anti-histamines have a useful effect in the treatment of rhinitis, and particularly the rhinorrhea. As a large proportion of patients with asthma have concomitant rhinitis, an H1-antagonist may help the overall management of asthma.54 While H1-receptor antagonists alone may be ineffective, some studies suggest that they may have some efficacy in combination with other antagonists. Thus an H1 receptor antagonist when added to an anti-leukotriene was able to inhibit the early and late response to allergen more effectively than the anti-leukotriene alone.55,56 Combination tablets of H1-antagonist and anti-leukotriene (such as montelukast and loratadine) are now in development. There is no evidence that antihistamines have any role in the treatment of COPD.
S E R O T O N I N A N TA G O N I S T S The evidence for involvement of serotonin in asthma is weak. There is no evidence that serotonin is a direct constrictor in human airways and it is not stored in and released from human mast cells, as in rodents. Serotonin receptor antagonists have been studied experimentally in asthmatic patients. Ketanserin, which antagonizes 5HT2 receptors and blocks the bronchoconstrictor effects of serotonin in animals, has no effect on airway function in asthmatic patients, but there is a small inhibitory effect
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on methacholine-induced bronchoconstriction.57 Inhaled ketanserin has no effect on histamine-induced bronchoconstriction, but has a small inhibitory effect on adenosineinduced bronchoconstriction, indicating a possible action on mast cells.58 Tianeptine, which enhances serotonin uptake by platelets, lowers the elevated plasma serotonin levels reported in patients with asthma and is associated with a reduction in asthmatic symptoms.59
THROMBOXANE INHIBITORS Although thromboxane production is increased in asthma and thromboxane analogs are potent bronchoconstrictors in asthmatic patients,60 there is no convincing evidence that thromboxane receptor (TP) antagonists or thromboxane synthase inhibitors are effective in asthma.61 A thromboxane synthase inhibitor (ozagrel) and a receptor antagonist (seratrodast) are used in the treatment of asthma in Japan, but their effects in asthma are minimal.62,63 There is no evidence that thromboxane antagonists are effective in COPD.
PA F A N TA G O N I S T S Although PAF mimics many of the pathophysiological features of asthma. Including induction of airway hyperresponsiveness, PAF antagonists have proved to be very disappointing in asthma therapy. Several potent PAF antagonists have now been tested in bronchial challenge and clinical studies. Apafant (WEB 2086) potently inhibits PAF effects on platelets and the intradermal effects of PAF.64 It also potently inhibits the effects of inhaled PAF on airway function.65 However, there was no effect on the early or late response to allergen or on airway hyper-responsiveness in patients with mild asthma.66 A 3-month study of oral apafant in patients with symptomatic moderate asthma failed to show any effect on lung function, symptoms or on rescue b2-agonist use.67 UK74505 inhibits inhaled PAFinduced bronchoconstriction and its inflammatory effects.68 However, modipafant (UK80067, the racemate of UK74505) had no effect on moderately severe asthmatics taking this drug for 4 weeks.69 A new potent and long-acting PAF receptor antagonist, foropafant (SR27417A), is effective in inhibiting systemic, cellular and pulmonary effects after PAF challenge in patients with mild bronchial asthma.70 However, this antagonist produces a modest, but significant, reduction in the magnitude of the allergen-induced late response, but no effect on the early response, allergeninduced hyper-responsiveness, or on baseline lung function.71 Another PAF antagonist,Y24180, has been shown to reduce airway responsiveness to inhaled methacholine in extrinsic stable asthmatics after oral administration for 2 weeks72 and to decrease the number of activated eosinophils in the bronchoalveolar lavage fluid of asthmatic patients.73 Overall, these clinical data with PAF antagonists suggest
that extracellular PAF plays little or no part in human allergic asthma, despite the convincing data in animal models of asthma. It is possible that intracellular PAF play a more important signaling role, so that inhibitors of PAF synthesis might have more clinical effect. Drugs that inhibit PAF and 5-lipoxygenase have also been developed and it is possible that these dual inhibitors might be more effective.74 There is no evidence that PAF is involved in COPD and no studies with PAF antagonists in this disease have been reported.
B R A D Y K I N I N A N TA G O N I S T S There is convincing evidence for the involvement of bradykinin in asthma, and in particular a role in sensitizing and activating airway sensory nerves. A peptide bradykinin antagonist [D-Arg0,Hyp3,D-Phe7]bradykinin (NPC567) was unable to inhibit the effect of bradykinin on nasal secretions, even when given at the same time as bradykinin,75 presumably because of rapid local metabolism. Icatibant (HOE 140, D-Arg[Hyp3,Thi6,D-Tic7,Oic8]bradykinin is a selective B2-receptor antagonist,76 which is not only potent but has a long duration of action in animals in vivo since it is resistant to enzymatic degradation. This antagonist is potent in inhibiting the bronchoconstrictor and microvascular leakage response to bradykinin77,78 and the effect of bradykinin on airway sensory nerves.79 Clinical studies with icatibant are limited, but there is some evidence that nasal application reduces the nasal blockage induced by allergen in patients with allergic rhinitis.80 In a clinical study of nebulized icatibant in asthma, there was a small improvement in airway function tests after 4 weeks of treatment, but no improvement in asthma symptoms.81 Recently non-peptide antagonists have been identified. WIN 64338 is a non-peptide B2-receptor antagonist that has been shown to block the bronchoconstrictor action of bradykinin in airway smooth muscle in vitro82 and more potent non-peptide antagonists, such as FR167344 have now been developed that have clinical potential.83 Although this compound is not very potent, it may be a lead for the development of more potent non-peptide drugs in the future.84
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43. Simmons FER, Simons KJ.The pharmacology and use of H1-receptorantagonist drugs. N. Engl. J. Med. 1994; 330:1663–70. 44. Hamid M, Rafferty P, Holgate ST. The inhibitory effect of terfenadine and flurbiprofen on early and late-phase bronchoconstriction following allergen challenge in atopic asthma. Clin. Exp. Allergy 1990; 20:261–7. 45. Eiser NM, Mills J, Snashall PD, Guz A. The role of histamine receptors in asthma. Clin. Sci. 1981; 60:363–70. 46. Cookson WOCM. Bronchodilator action of the antihistamine terfenadine. Br. J. Clin. Pharmacol. 1987; 24:120–1. 47. Taytard A, Beaumont D, Pujet JC, Sapene M, Lewis PJ. Treatment of bronchial asthma with terfenadine: A randomised controlled trial. Br. J. Clin. Pharmacol. 1987; 24:743–6. 48. Wood-Baker R, Smith R, Holgate ST. A double-blind, placebo controlled study of the effect of the specific histamine H1-receptor antagonist, terfenadine, in chronic severe asthma. Br. J. Clin. Pharmacol. 1995; 39:671–5. 49. Spector SL, Nicodemus CF, Corren J et al. Comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-to-moderate asthma. J. Allergy Clin. Immunol. 1995; 96:174–81. 50. Busse WW, Middleton E, Storms W et al. Corticosteroid-sparing effect of azelastine in the management of bronchial asthma. Am. J. Respir. Crit. Care Med. 1996; 153:122–7. 51. Walsh GM. The anti-inflammatory effects of cetirizine. Clin. Exp. Allergy 1994; 24:81–5. 52. Burgaud JL, Javellaud J, Oudart N. Bronchodilator action of an agonist for histamine H3-receptors in guinea pig perfused bronchioles and lung parenchymal strips. Lung 1992; 170:95–108. 53. O’Connor BJ, Lecomte JM, Barnes PJ. Effect of an inhaled H3receptor agonist on airway responses to sodium metabisulphite in asthma. Br. J. Clin. Pharmacol. 1993; 35:55–7. 54. Simons FE. Is antihistamine (H1-receptor antagonist) therapy useful in clinical asthma? Clin. Exp.Allergy 1999; 29 (Suppl. 3):98–104. 55. Roquet A, Dahlen B, Kumlin M et al. Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am. J. Respir. Crit. Care Med. 1997; 155:1856–63. 56. Meltzer EO, Malmstrom K, Lu S et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: A randomized, placebo-controlled clinical trial. J. Allergy Clin. Immunol. 2000; 105:917–22. 57. Cazzola M, Assogna G, Lucchetti G, Cicchitto G, D’Amato G. Effect of ketanserin, a new blocking agent of the 5-HT2 receptor, on airway responsiveness in asthma. Allergy 1990; 45:151–3. 58. Cazzola M, Matera MG, Santangelo G et al. Effect of the selective 5-HT2 antagonist ketanserin on adenosine-induced bronchoconstriction in asthmatic subjects. Immunopharmacology 1992; 23:21–8. 59. Lechin F, van der Dijs B, Orozco B et al. The serotonin uptakeenhancing drug tianeptine suppresses asthmatic symptoms in children: a double-blind, crossover, placebo-controlled study. J. Clin. Pharmacol. 1998; 38:918–25. 60. Saroea HG, Inman MD, O’Byrne PM. U46619-induced bronchoconstriction in asthmatic subjects is mediated by acetylcholine release. Am. J. Respir. Crit. Care Med. 1995; 151:321–4. 61. O’Byrne PM, Fuller RW. The role of thromboxane A2 in the pathogenesis of airway hyperresponsiveness. Eur. Resp. J. 1989; 2:782–6. 62. Obase Y, Shimoda T, Matsuo N, Matsuse H, Asai S, Kohno S. Effects of cysteinyl-leukotriene receptor antagonist, thromboxane A2 receptor antagonist, and thromboxane A2 synthetase inhibitor on antigen-induced bronchoconstriction in patients with asthma. Chest 1998; 114:1028–32. 63. Manning PJ, Stevens WH, Cockcroft DW, O’Byrne PM.The role of thromboxane in allergen-induced asthmatic responses. Eur. Respir. J. 1991; 4:667–72.
64. Hayes J, Ridge SM, Griffiths S, Barnes PJ, Chung KF. Inhibition of cutaneous and platelet responses to platelet activating factor by oral WEB 2086 in man. J. Allergy Clin. Immunol. 1991; 88:83–8. 65. Adamus WS, Heuer H, Meade CJ, Kempe ER, Brecht HM. Inhibitory effect of oral WEB 2086, a novel selective PAFacether antagonist, on ex vivo platelet aggregation. Eur. J. Clin. Pharmacol. 1988; 35:237–9. 66. Freitag A,Watson RM, Mabos G, Eastwood C, O’Byrne PM. Effect of a platelet activating factor antagonist, WEB 2086, on allergen induced asthmatic responses. Thorax 1993; 48:594–8. 67. Spence DPS, Johnston SL, Calverley PMA et al. The effect of the orally active platelet-activating factor antagonist WEB 2086 in the treatment of asthma. Am. J. Resp. Crit. Care Med. 1994; 149:1142–8. 68. O’Connor BJ, Uden S, Carty TJ, Eskra D, Barnes PJ, Chung KF. Effect of a potent and specific platelet activating factor (PAF) receptor antagonist on airway and systemic responses to PAF in man. Am. J. Resp. Crit. Care Med. 1994; 150:35–40. 69. Kuitert LM, Hui KP, Uthayarkumar S et al. Effect of the platelet activating factor antagonist UK 74,505 on the early and late response to allergen. Am. Rev. Respir. Dis. 1993; 147:82–6. 70. Gomez FP, Marrades RM, Iglesia R et al. Gas exchange response to a PAF receptor antagonist, SR 27417A, in acute asthma: a pilot study. Eur. Respir. J. 1999; 14:622–6. 71. Evans DJ, Barnes PJ, Cluzel M, O’Connor BJ. Effects of a potent platelet activating factor antagonist, SR27417A, on allergeninduced asthmatic responses. Am. J. Respir. Crit. Care Med. 1997; 156:11–16. 72. Hozawa S, Haruta Y, Ishioka S, Yamakido M. Effects of a plateletactivating factor antagonist Y 24180 on bronchial hyperresponsiveness in patients with asthma. Am. J. Respir. Crit. Care Med. 1995; 152:1198–202. 73. Mizuki M, Komatsu H, Akiyama Y, Iwane S, Tsuda T. Inhibition of eosinophil activation in bronchoalveolar lavage fluid from atopic asthmatics by Y-24180, an antagonist to platelet-activating factor. Life Sci. 1999; 65:2031–9. 74. Cai X, Scannell RT, Yaeger D et al. (/)-Trans-2-[3-methoxy-4(4 - chlorophenylthioethoxy) - 5 - (N-methyl - N - hydroxyureidyl) methylphenyl]-5-(3,4,5trimethoxyphenyl) tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and plateletactivating factor receptor antagonist. J. Med. Chem. 1998; 41:1970–9. 75. Pongracic JA, Naclerio RM, Reynolds CJ, Proud D. A competitive kinin receptor antagonist, [DArg°, Hyp3, DPhe7]-bradykinin, does not affect the response to nasal provocation with bradykin. Br. J. Clin. Pharmacol. 1991; 31:287–94. 76. Wirth K, Hock FJ, Albus U et al. HOE 140, a new potent and long acting bradykinin antagonist: in vivo studies. Br. J. Pharmacol. 1991; 102:774–7. 77. Wirth KJ, Gehring D, Schölkens BA. Effect of HOE 140 on bradykinin-induced bronchoconstriction in anesthetized guinea pigs. Am. Rev. Respir. Dis. 1993; 148:702–6. 78. Sakamoto T, Elwood W, Barnes PJ, Chung KF. Effect of HOE 140, a new bradykinin antagonist, on bradykinin and plateletactivating factor-induced bronchoconstriction and airway microvascular leakage in guinea pig. Eur. J. Pharmacol. 1992; 213:376–83. 79. Miura M, Belvisi MG, Barnes PJ. Effect of bradykinin in airway neural responses in vitro. J. Appl. Physiol. 1992; 73:1537–41. 80. Austin CE, Foreman JC, Scadding GK. Reduction by Hoe 140, the B2 kinin receptor antagonist, of antigen-induced nasal blockage. Br. J. Pharmacol. 1994; 111:969–71. 81. Akbary AM, Wirth KJ, Scholkens BA. Efficacy and tolerability of Icatibant (HOE 140) in patients with moderately severe chronic bronchial asthma. Immunopharmacology 1996; 33:238–42. 82. Scherrer D, Daeffler L, Trifilieff A, Gies J-P. Effects of WIN 64338, a non peptide bradykinin B2-receptor antagonist, on guinea-pig trachea. Br. J. Pharmacol. 1995; 115:1127–8.
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83. Inamura N, Asano M, Hatori C et al. Pharmacological characterization of a novel, orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344. Eur. J. Pharmacol. 1997; 333:79–86.
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Chapter
Antibiotics
54
Sat Sharma and Nicholas Anthonisen Section of Respirology, University of Manitoba, Winnipeg, Canada
After 60 years of availability of antibiotics, surprisingly little is known about their role in obstructive airway diseases. A review of antibiotic therapy will necessarily involve a discussion of the role of bacterial infection in asthma and chronic obstructive pulmonary disease. This chapter presents an appraisal of the bacterial pathogens causing infective exacerbations, trials of antimicrobial therapy, individual antimicrobial agents and guidelines for their judicious use both in asthma and COPD.
ASTHMA A causal relationship between respiratory tract infection, especially viral infection and exacerbations of bronchial asthma is well established in the medical literature.1 In early prospective studies by McIntosh et al.,2 the relationship between exacerbations of wheezing and infection in hospitalized, previously diagnosed asthmatic children was investigated. A significant fraction (42%) was associated with viral respiratory infections, but not with pathogenic bacteria. Prospective studies on acute exacerbations of asthma in the adult population have suggested that approximately 10–20% of acute exacerbations may be attributable to acute viral infection. Berman and coworkers3 convincingly failed to show an association between bacterial respiratory infection and asthma. Transtracheal aspirates from 27 adult asthmatic patients with acute exacerbations showed no correlation between bacterial isolates and asthma symptoms. This suggested that overt bacterial infection of the lower respiratory tract does not contribute to the exacerbation of asthma. However, studies of older children and young adults have shown that infection with atypical bacteria e.g. Mycoplasma and Chlamydia may be responsible for exacerbations. In these studies, rhinovirus was the most important pathogen, followed by influenza A virus, Mycoplasma and Chlamydia.4–6 Several other studies have suggested a relationship between respiratory infections in infancy and development of asthma, although this hypothesis awaits more definite proof.
Mycoplasma Mycoplasma pneumoniae infection is commonly seen in children and young adults, although it may occur in all age groups.7,8 Seggev et al.9 showed that 21% of adults hospitalized with asthma exacerbation had evidence of a recent infection with mycoplasma. The illness may start with nonrespiratory symptoms such as headache and myalgias, and there is frequently pharyngitis and low-grade fever. A nonproductive cough, which tends to be prolonged and severe, is most characteristic. The diagnosis is made based on clinical history and chest radiograph, which shows patchy segmental pulmonary infiltrates. The definitive diagnosis is made by serological studies, particularly a doubling titer in convalescence. Antibiotic therapy is most effective if given within a few days of onset. Erythromycin or tetracycline are equally effective, and treatment is continued for 2–3 weeks. As well as causing exacerbations of asthma, M. pneumoniae pneumonia in nonasthmatics may well induce bronchial hyperresponsiveness which may be transient or persistent.10 Chlamydia The TWAR strain of Chlamydia (Chlamydia pneumoniae) has been shown to be a common cause of atypical pneumonia and is next in frequency to Mycoplasma.11,12 This is an infection primarily of adolescents and adults. The clinical manifestations are similar to those caused by M. pneumoniae. The severity of illness can be quite variable. The diagnosis is difficult to make, as commercial serological tests are generally not available. Chest radiograph shows findings similar to M. pneumoniae infection. Several studies have suggested that C. pneumoniae infection may precipitate acute bronchospasm and, in addition, may also be a risk factor for the development of chronic bronchospasm. The treatment of C. pneumoniae infection requires further study, but erythromycin or tetracycline may be beneficial if given for 10 days or more.
COPD Although a major cause of COPD is cigarette smoking, infectious organisms play several potential roles:13,14 (Chapter 30)
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• Childhood respiratory infections can predispose to the development of COPD in later life.15,16 • Infectious organisms can chronically infect the bronchi and small airways contributing to progressive lung destruction (vicious circle hypothesis).17,18 • Acute exacerbations of COPD, caused by infection, result in considerable morbidity and are the leading cause of mortality in this disease. Despite extensive research over the past few decades, our understanding of lower respiratory tract infection in COPD is incomplete. Evidence for the role of bacterial infection in COPD, individual antimicrobial agents and an evidencebased approach to treatment of infection are discussed in the following sections. Normal microbial flora Various aerobic and anaerobic bacteria inhabit the mucosal surfaces of the upper respiratory tract. These include • • • • •
Neisseria sp., Moraxella catarrhalis, a variety of Streptococcus sp., Streptococcus pneumoniae, Hemophilus sp.
A variety of anerobic bacteria are present around the teeth and gums. Enterobacteriaceae and Pseudomonas sp. are isolated in about 15% of pharyngeal swab cultures taken from normal subjects.19,20 The major bronchi and smaller conducting airways in normal humans are relatively sterile. In a study of 25 normal subjects, samples from multiple sites in the lower respiratory tract were obtained with a protected brush specimen. Most cultures contained bacteria (38 out of 52 specimens, or 73%) similar to those found in the nasopharynx, but the colony counts were often so low (none to five colonies per culture plate) that the cultures probably indicated upper respiratory tract contamination rather than true lower respiratory tract colonization.21 The nasopharyngeal bacteria may be transiently aerosolized or aspirated into the lower respiratory tract but are removed by mucociliary clearance or cough. Pathogenic aerobic Gram-negative rods do not inhabit the upper airways mucosa in normal persons, but may do with alterations in health status such as alcoholism, diabetes, residing in a health-care facility.22 Subconscious aspiration of oropharyngeal secretions allows these microbes to enter the lower airways and alveoli and become a nidus for subsequent infection. Airway colonization in chronic bronchitis Pathogenic bacteria can be cultured from bronchial washings of some 82% of chronic bronchitics compared with normal bronchi which are nearly always sterile.23 Routine sputum cultures obtained from patients with chronic bronchitis commonly contain nonencapsulated H. influenzae and Strep. pneumoniae. In most clinical series, one or both of
these species have been recovered from approximately 30 to 50% of sputum specimens in patients with chronic bronchitis, and anaerobic bacteria were recovered in 17% of transtracheal aspirate specimens.24 Airway colonization with H. influenzae and Strep. pneumoniae is of uncertain significance. These bacteria tend to be present in sputum during quiescent intervals although the frequency of their recovery is increased during acute infectious episodes. Development of purulent sputum is not specifically correlated with the presence of one or the other of these bacteria in quantitative cultures.
THE DIAGNOSIS OF ACUTE E X A C E R B AT I O N O F C H R O N I C BRONCHITIS Clinical diagnosis There is no universally accepted definition of an acute exacerbation of COPD (AECB). AECB is basically a clinical diagnosis. A descriptive definition could be: “an acute, episodic deterioration superimposed on stable COPD with increased dyspnea, reduced daily performance, with or without changes in sputum volume and color, coughing, or body temperature; and/or alterations in mental status”.17,18 The three cardinal symptoms (Table 54.1) (Winnipeg Criteria)25 are • increased dyspnea, • increased sputum purulence, • increased sputum volume. These features should be present without an objectively documented cause such as pneumonia, congestive heart failure, myocardial ischemia, upper respiratory tract infection, recurrent aspiration and pulmonary embolism. These conditions may resemble an acute exacerbation and need to be excluded. Laboratory diagnosis of AECB Microbiological data may play a role in diagnosis and management but must be interpreted with caution. One problem Table 54.1. Classification of exacerbations
Type
Characteristics
1
Increased dyspnea, sputum volume and sputum purulence (all 3 symptoms present)
2
2 of the above 3 symptoms present
3
1 of the above symptoms present + at least 1 of the following: upper respiratory tract infection in the last 5 days, fever, increased wheezing and increased cough
Antibiotics
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is that pathogenic bacteria can be cultured from respiratory secretions in as many as 80% of patients with stable chronic bronchitis, therefore, bacterial colonization complicates the laboratory diagnosis of bacterial infection.
agents recommend early use of these agents based on clinical suspicion and not laboratory confirmation, and COPD patients should probably be treated in the same manner.
Sputum Gram stain The sputum Gram stain has been advocated as a means of objectively demonstrating an increase in bacterial flora and bronchial inflammation. In one study, Baigelman et al.26 compared more than 1000 sputum Gram stains from patients with chronic bronchitis during stable states, acute bacterial infections, acute allergic exacerbations, and recovery from acute bacterial exacerbations. The results showed that fewer than two bacteria per oil-immersion field were found in stable patients, while during exacerbations the sputum revealed 12 organisms per oil-immersion field resembling H. influenzae, eight organisms resembling Strep. pneumonia or 18 organisms resembling M. catarrhalis. Over 99% of patients with chronic bronchitis without clinical evidence of infection fell below these thresholds.These findings suggest that an upper limit may be set for the numbers of micro-organisms seen on a Gram stain of sputum from patients with COPD in the absence of a bacterial infection. Some clinical trials have incorporated the Gram stain as a means of distinguishing bacterial from nonbacterial causes of acute exacerbation. Despite its potential, sputum Gram stain does not alter therapy and is not currently recommended as a routine test.
Chest radiograph Chest X-rays are not routinely recommended in mild to moderate exacerbations, as there is usually no change from baseline. Chest radiography should be performed if the patient has high fever, new abnormalities on auscultation, or is severely ill as characterized by worsening hypoxia, hypercapnia or right heart failure.
Sputum culture The routine sputum culture is less useful than the Gram stain and is often misleading. Studies examining sputum cultures before, during, and after bacterial exacerbations have correlated poorly with clinical parameters and Gram stain results.26,27 Gram-negative bacilli have often been recovered in sputum culture even when they are absent on Gram stain, and clinical recovery has occurred even without specific Gram-negative antibiotic therapy. In one study, more than 50% of sputum cultures remained positive long after clinical recovery.28 The sputum culture may be contributory and should be considered when there is: • failure of initial antibiotic therapy, • patients with chronic bronchial sepsis requiring more than four courses of antibiotic therapy per year, • severe illness or suspected pneumonia. Viral studies Viruses apparently do not play an important role in causing acute exacerbations. Therefore, virological stains, cultures and antibody assays are not routinely recommended in the management of chronic bronchitis because of the expense and relatively low yield. Rapid antigen detection has lowered the turnaround time for identifying respiratory viruses, but the value of these tests in AECB has not been established. Recently chemotherapeutic agents for influenza have become available. The guidelines for use of anti-influenza
ROLE OF BACTERIAL INFECTION COPD is characterized by periodic exacerbations, and acute respiratory infection was the most common cause of death in a prospective study of patients with COPD.29 The role of infection in acute exacerbation of chronic bronchitis is, however, somewhat controversial. Antibiotics are frequently prescribed to these patients but efficacy of this treatment was questioned by Tager and Speizer.30 Several investigators have found increased numbers of bacteria and neutrophils in the sputum during exacerbations.31–33 In some studies34 M. pneumoniae has been isolated in 1 to 10% of patients with acute infections. Bacteria may be the primary cause of the exacerbations; alternatively, they may act as secondary invaders after acute viral or mycoplasma infection. However, evaluating the role of bacterial infection in exacerbations has been a difficult task for a variety of reasons. As the upper airways of many patients with COPD are colonized by H. influenzae, Strep. pneumoniae and M. catarrhalis, the expectorated sputum during exacerbations may be inconclusive. Serologic studies A causal relationship between bacterial infection and acute exacerbation can be inferred by the appearance of an acute antibody response in serum to these bacteria. Documenting a serological response to an organism may demonstrate existence of infection with that organism, but these studies have shown conflicting results. Some have shown no difference between patients with chronic bronchitis and control subjects, other studies have revealed higher titers of antibody to H. influenzae,35 in the serum of patients with chronic bronchitis. However, there was no relationship of titers to exacerbations.36 Such studies generally used the whole organism preparations of unrelated strains as the antigen for serologic studies, and therefore measured a mixture of antibodies to a mixture of antigens. Future studies may utilize antibody response to more specific surface antigens of bacteria to establish the importance of bacterial infection in COPD. Trials of antibiotic therapy in acute exacerbation Another approach to assessing the role of bacterial infection in exacerbations of COPD is to consider the effect of antibiotics on the clinical response (Figs 54.1 and 54.2). A positive
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response to a specific antibiotic prescribed for an exacerbation by a specific organism would provide evidence of a pathogenic role for the bacteria. In a landmark study, Anthonisen and co-workers25 demonstrated, for the first time, that patients could be stratified according to the symptoms to predict a response to antimicrobial therapy. In patients with at least two of the three cardinal symptoms of acute exacerbation (increased sputum purulence, increased sputum volume and increased dyspnea), broad-spectrum antibiotics (amoxicillin, trimethoprim-sulfamethoxazole, doxycycline)
80 70
Placebo group Antibiotic group
P<0.05
P<0.05 P<0.05
60
% Success
50 40 30 20 10 0 All
Type 1 Type 2 Type of exacerbation
Type 3
Fig. 54.1. Rate of successful response to antibiotics or placebo in AECB stratified according to the type of exacerbation. Reproduced from Reference 25, with permission. 35
P<0.05
Placebo Antibiotic
30
% Deterioration
Favors antibiotic
Favors placebo Elmes et al., 1957
25 20
led to improved clinical outcomes, fewer therapeutic failures and a more rapid rate of lung function recovery than did placebo. Overall, the length of illness was 2 days shorter for the antibiotic-treated group as compared with the placebo group. A meta-analysis by Saint et al.37 showed that there were benefits from antibiotic therapy for exacerbations as compared with placebo (Fig. 54.3). In nine prospective randomized trials conducted from 1957 to 1992, the overall effect size (defined as the standard deviation of benefit with therapy versus placebo for the effect measured) favored antibiotics (0.22), and seven of the nine trials showed a benefit for antibiotics. A beneficial effect of antibiotics was demonstrated in studies that included the greatest number of patients and the patients with more severe disease. The demonstration of therapeutic efficacy of antibiotics in exacerbations provides evidence of a pathogenic role for bacteria in exacerbations. Design flaws in the earlier studies, such as small numbers of study patients, unclear selection criteria, uncertain microbiology, nonstandard evaluation criteria and lack of stratification of patients, may account for the discrepancy of outcomes in these studies.38 Although antibiotics provide benefit compared with placebo, further studies are required to assess different classes of antibiotics in specific clinical situations. Several studies have suggested that patients with different severities of chronic lung disease have exacerbations with different organisms. Eller et al.39 found that if patients with better lung function were compared with those with worse lung function (based on FEV1), the bacteriology shifted from pneumococcus and H. influenzae to more complex organisms such as Enterobacteriaceae and Pseudomonas species. Similarly, Miravitlles et al.40 found that H. influenzae and Pseudomonas aeruginosa were more common in patients with FEV1 values of less than 50% of predicted.The patients with worse lung function suffered from more frequent exacerbations and were given repeated antibiotic therapy which likely led to alteration of airway microbial flora.
Berry et al., 1960 Fear and Edwards, 1962
P<0.05
Elmes et al., 1965 Petersen et al., 1967
15
P<0.05
Pines et al., 1972
10
Nicotra et al., 1982 Anthonisen et al., 1987 Jorgensen et al., 1992 Overall
5 0 All
Type 1 Type 2 Type of exacerbation
Type 3
Fig 54.2. Rate of deterioration while on antibiotic or placebo in AECB stratified according to the type of exacerbation. Reproduced from Reference 25, with permission.
⫺1.0
⫺0.5
0
0.5
1.0
1.5
Effect size (SD) Fig 54.3. Overall benefit of antibiotics in the treatment of acute exacerbation of chronic bronchitis. Reproduced from Reference 37, with permission.
Antibiotics
Pathogens Acute exacerbations of COPD are most often caused by infections although other factors may also cause increased dyspnea. Common infectious etiological organisms will be briefly discussed (Table 54.2). Viruses Studies of longitudinal cohorts of COPD patients have examined the role of viruses in acute exacerbations with serial serology and viral cultures of upper and lower respiratory tract secretions. A four-fold increase in titer or a positive viral culture was seen in association with one trial of exacerbations.41,42 The specific viruses and proportion of exacerbations caused by each of these are detailed in Table 54.2. More recently, Soler and associates43 determined the etiology of 50 exacerbations of COPD that required intensive care admission. Adequate serological samples were available in 38 of these episodes. Viral infection was associated with six (15.8%) exacerbations, influenza virus in five and respiratory syncytial virus in one episode. In three of the five influenza infections, a concomitant bacterial pathogen was present. This study suggests that in severe exacerbations, viral infection is less important and these are often complicated by a bacterial infection. Atypical bacteria As these organisms are difficult to culture, serological testing has been used to investigate the role of Chlamydia and Mycoplasma species in acute exacerbations of COPD.
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Mycoplasma infection has been seen only rarely in this setting. C. pneumoniae infection is associated with 5 to 10% of exacerbations. In the study presented by Soler and associates43 of severe exacerbations requiring intensive care, C. pneumoniae infection was present in seven (18%) of 38 cases, although a concomitant bacterial pathogen was present in two of these patients. Bacteria Sputum cultures are positive for aerobic bacteria in about half of the exacerbations of COPD.44 The predominant pathogens and their relative frequency are listed in Table 54.2. Three studies have used bronchoscopic sampling of the lower respiratory tract during exacerbation to avoid oral contamination of the sample. Fagon and colleagues45 studied 54 patients with COPD requiring mechanical ventilation for respiratory failure due to AECB. Bronchoscopy with a protected specimen brush was performed within 24 hours of intubation, before empiric antibiotic therapy. The findings were similar to those of sputum culture. Of the 44 bacterial species isolated, H. parainfluenzae was the most common pathogen (11/44), followed by Strep. pneumoniae (7/44), nontypeable H. influenzae (6/44), and M. catarrhalis (3/44). A variety of other Gram-negative (8/44) and Gram-positive (9/44) bacteria were also present as noted in Table 54.2. Monso and co-workers46 studied two groups of moderately severe COPD patients with bronchoscopic protected specimen brush (PSB) culture in outpatient settings. Forty patients had stable COPD, and 29 patients experienced an
Table 54.2. Pathogens associated with acute exacerbations of COPD
Pathogen class
Frequency of exacerbations (%)
Specific organism
Proportion of pathogen class (%)
Viruses
30–50
Influenza A and B Parainfluenzae 1, 2 and 3 Rhinovirus Coronavirus Adenovirus Respiratory syncytial virus
30–40 20–30 15–25 10–20 5–10 5–10
Atypical bacteria
5–10
C. pneumoniae M. pneumoniae
90–95 5–10
Bacteria
50
Nontypeable H. influenzae S. pneumoniae M. catarrhalis H. parainfluenzae
40–60
P. aeruginosa and Enterobacteriaceae (E. coli, Klebsiella)
15–30 15–30 Isolated frequently but pathogenetic significance unknown Isolated in severe COPD and in recurrent exacerbations
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Asthma and Chronic Obstructive Pulmonary Disease
acute exacerbation. In the stable group, 25% of PSB cultures isolated bacterial pathogens (103 CFU/ml) compared with 51.7% of culture-positive samples in the exacerbation group. Nontypeable H. influenzae was the most common bacterial pathogen in both groups. A study by Soler et al.43 demonstrated that 21 of 50 (42%) patients had positive cultures on bronchoscopic samples during an acute exacerbation. In their study, there was a remarkably high incidence of P. aeruginosa and other Gram-negative bacilli, these were isolated in 28% (14/50) of patients. Based on the remarkably consistent results of these studies, one can conclude that bacteria are recovered in the distal airways in exacerbations of COPD in 50% of the cases and may be responsible for the clinical symptoms observed (Table 54.3).
Initiating factors (e.g. smoking, childhood respiratory disease)
Impaired mucociliary clearance
Damage to airway epithelium
Bacterial colonization
Bacterial products (LOS) Progression of COPD
VICIOUS CIRCLE HYPOTHESIS
Infalmmatory response (cytokines, enzymes, etc.)
Increased elastolytic activity in lung
A considerable body of evidence in the medical literature highlights the importance of bacterial infection and the usefulness of antimicrobial therapy. Cole and Wilson used this evidence to construct the vicious circle hypothesis (Fig. 54.4).54 According to this hypothesis, initiating factors such as cigarette smoke lead to impaired mucociliary clearance in the airways. This is followed by bacterial colonization and release of bacterial products such as lipooligosaccharides, causing direct damage to airway epithelium and inhibiting mucociliary activity.The neutrophils are attracted by chemotactic bacterial factors released by resident phagocytes, complement components, and directly by chemotactic bacterial products. A destructive, cytokine-mediated inflammatory host response is triggered, which enhances the elastolytic activity in the lung, ultimately causing further airway damage. The impairment of the host defense mechanisms predispose to further bacterial infection, thereby establishing the self-perpetuating vicious circle of host and bacterialmediated respiratory tract damage. Previous studies could not demonstrate a role for respiratory infections in the progression of airways obstruction.55–57 However, Kanner et al.58 have recently demonstrated that more rapid decline in
Alteration of elastase–anti-elastase balance Fig 54.4. “Vicious Circle Hypothesis”: The changes in the host defense mechanisms predispose to repeated bacterial infections, thereby establishing the self-perpetuating vicious circle of host and bacterial-mediated respiratory tract damage. Reproduced from Ref. 54, with permission.
lung function occurred with more frequent respiratory tract infections. They found that smokers with mild to moderate COPD suffered from increased numbers of lower respiratory infections as compared with quitters. In addition, one infection per year was associated with an increase in decline of FEV1 of about 7 mL per year.59 Recently, Seemungal et al.60 prospectively followed a cohort of 101 patients with moderate to severe COPD over a 2 year period. In 7.1% of exacerbations, recovery of lung function (PEFR) had not occurred in 91 days.60 Although this model of pathogenesis is popular, more clinical studies and applications of newer techniques are required to study these proposed mechanisms of “Vicious Circle Hypothesis”.
Table 54.3. Important bacterial pathogens in acute exacerbation of chronic COPD
Portion of total isolates Author Ref./year
Number of isolates
H. influenzae
M. catarrhalis
Strep. pneumoniae
Davies et al.47 1986 Basran et al.48 1990 Chodosh49 1992 Aldons50 1991 Bachand51 1991 Lindsay et al.52 1992 Neu et al.53 1993
127.0 60.0 214.0 53.0 8.0 398.0 84.0
58.5 43.3 37.9 70.0 30.0 49.7 46.4
15.0 3.3 22.4 13.0 10.7 19.0 28.6
16.5 25.0 22.4 15.0 21.4 17.0 25.0
Antibiotics
MANAGEMENT OF INFECTIONS IN C O P D E X A C E R B AT I O N Preventative measures Vaccines Annual influenza vaccine reduces morbidity and mortality due to influenza in the elderly by 50%53 and should be given to patients with COPD.The beneficial effect is thought to be the result of prevention of airway epithelial damage predisposing the patient to subsequent bacterial infection.61 The beneficial effect of pneumococcal vaccine in patients with chronic bronchitis has not been firmly established. However, the current recommendations are that patients with COPD receive pneumococcal vaccine at least once in their life and should have one repeat at 5 years.62 It is a prudent policy to follow because of the low cost and few side-effects of the vaccine. Prophylactic antibiotics Only a limited number of studies have examined the role of prophylactic antibiotics in COPD.63,64 In one study of patients with moderate COPD no benefit from prophylactic antibiotics was found with respect to the frequency of exacerbations or to the rate of decline of FEV1 over 4 or 5 years.65 In another large study, no benefit from antibiotic prophylaxis during the winter months was observed.66 The prophylactic use of antibiotics in chronic bronchitis is not supported by clinical trials and is not indicated. Such therapy runs the risk of increasing antimicrobial resistance in the bacterial pathogens responsible for infections.65,66
CHEMOTHERAPEUTIC AGENTS USED IN C O P D E X A C E R B AT I O N There are a large number of antibiotics available to cover the spectrum of bacteria causing COPD exacerbations. It is useful to classify them as first- and second-line agents (Table 54.4). First-line agents are older, cheaper, and available as generics, require multiple doses per day, have a limited spectrum of efficacy and high rates of antimicrobial resistance. Second-line agents are newer, more expensive, require single or twice daily dosing, and have a wider spectrum and lower rates of antimicrobial resistance. They also tend to attain higher levels in bronchial mucosa and sputum, although this has not been established to be a definite advantage. Antimicrobial resistance The last two decades have seen an alarming increase in resistance to commonly used first-generation anti-microbial agents among nontypeable H. influenzae, Strep. pneumoniae, and M. catarrhalis. In a North American survey conducted in 1997, 33.5% of nontypeable H. influenzae isolates and 92.2% of M. catarrhalis isolates produced β-lactamase. In addition, 16.2% of the nontypeable H. influenzae isolates were resistant to co-trimoxazole.67 In a similar North
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American survey, 43.8% of the Strep. pneumoniae isolates were penicillin resistant, with 27.8% displaying intermediate-level and 16% displaying high-level resistance.68 These resistant Strep. pneumoniae isolates demonstrated decreased susceptibility to several other antibiotics including cephalosporins, macrolides, tetracyclines, and trimethoprim– sulfamethoxazole. Resistance rates in Europe vary widely, but in mainland Spain, 31% of H. influenzae isolates were resistant to ampicillin, 16.7% to chloramphenicol, 15% to erythromycin (27.9% in France), 17.2% to tetracycline and 41.3% to co-trimoxazole.69 Most isolates of M. catarrhalis produce beta-lactamase (79% of UK isolates). The penicillin resistance among Strep. pneumoniae is increasingly worldwide, reaching approximately one-third of all isolates in Spain, 26% in France and 15–20% in the United States.70–72 A substantial proportion of bacterial exacerbations of COPD may be caused by pathogens resistant to the traditional antibiotics such as amoxicillin, co-trimoxazole, and tetracycline. Therefore, local patterns of antimicrobial resistance should be considered in choosing empiric therapy for this common mucosal infection. Pharmacokinetic considerations There are profound differences in the penetration of different antibiotics into the tissues and secretions of the respiratory tract, and the implications of these factors for the treatment of exacerbations of chronic bronchitis deserve consideration. Outcome of antimicrobial therapy may depend to a certain extent on the sputum and bronchial mucosal concentration of these agents.73 In general, βlactams attain only 5 to 25% of the serum concentration in Table 54.4. Antibiotics used in the treatment of acute exacerbations of COPD
First-line antibiotics
Second-line antibiotics
Aminopenicillins Ampicillin Amoxicillin Pivampicillin Bacampicillin
2nd generation cephalosporins Cefaclor Cefuroxime axetil
Tetracylines Tetracycline Doxycycline Minocycline Trimethoprim– sulfamethoxazole
3rd generation cephalosporins Cefixime Amoxicillin–clavulanic acid Newer macrolides Clarithromycin Azithromycin Fluoroquinolones Ciprofloxacin Levofloxacin Moxifloxacin
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sputum and bronchial secretions. Erythromycin and tetracyclines achieve a ratio of 50% or more, while fluoroquinolones produce concentrations in bronchial secretions that are 88 to 200% of serum concentrations.74,75 Azithromycin is concentrated 50- to 100-fold in sputum as well as bronchial secretions.76 However, the clinical significance of good penetration into sputum and bronchial tissue has not been demonstrated in AECB. Antimicrobial agents Tetracylines Many of the original trials of antibiotic therapy utilized tetracyclines. Studies performed in the 1960s and 1970s demonstrated that tetracycline therapy was more effective than placebo in milder infections, while derivatives were no more effective than tetracycline itself. Tetracyclines can be used in AECB because they are active against H. influenzae and atypical pathogens, but there have been reports of increasing resistance against pneumococci.77 Oral penicillins and cephalosporins Although early placebo-controlled studies did not show a definite advantage for therapy with ampicillin, amoxicillin has been a widely used agent for management of AECB.78 Oral penicillins and cephalosporins are the drugs of choice in patients with mild to moderate exacerbations in countries where resistance among H. influenzae and pneumococci remains at low levels. Despite their relatively poor activity and suboptimal respiratory pharmacokinetics, cephalexin and cefaclor have been extensively used for the management of AECB. The newer cephalosporins, cefprozil, and cefixime may have some advantages such as activity against resistant pneumococci, but have not been proven to be superior to amoxicillin,79,80 when organisms were fully sensitive to both agents. Amoxicillin–clavulanic acid The addition of clavulanic acid makes the combination resistant to bacterial beta-lactamases, an important concern in patients with AECB. Although most studies of patients with lower respiratory tract infection have shown it to be equivalent to standard comparable agents.81 An overview of the data from clinical trials demonstrates this to be a valuable agent for infections caused by H. influenzae and M. catarrhalis even though the degree of penetration of bronchial mucosa is variable.82 Comparison with cefixime and ciprofloxacin showed greater clinical success but no significant difference in eradication rates.83 Trimethoprim–sulfamethoxazole Although very popular in the 1970s and 1980s trimethoprim–sulfamethoxazole (TMP–SMX) potential for resistance and the increasing availability of safer agents have resulted in the decline of the use of this antibiotic. In older studies, comparisons with oral cephalosporins generally showed equivalent efficacy.84 Recent studies have shown increased resistance of common respiratory pathogens to
TMP-SMX in Europe and the United States, making this antibiotic less useful in the treatment of AECB. Penicillinresistant pneumococci have an 80 to 90% likelihood of being resistant to TMP-SMX.85 Newer macrolides and azalides Erythromycin has poor activity against H. influenzae (MIC 4 to 8 mg/L) and cannot be considered one of the drugs of choice for AECB. Azithromycin and clarithromycin have improved pharmacokinetics and antibacterial activity.86 A 3-day regimen of azithromycin is clinically and microbiologically equivalent to a 10-day course of coamoxiclav.87 The significant advantages of azithromycin are enhanced potency against H. influenzae, once daily administration, an abbreviated 4-day course, and perhaps a reduced frequency of relapse during extended followup.88,89 Clarithromycin has only intermediate activity against H. influenzae but synergy with a metabolite reduces the overall MIC to around 1 mg/L so thus in the therapeutic range.90 Clinical studies of clarithromycin involving 7- to 14-day regimens in patients with mild to moderate infections have shown equivalence with ampicillin.81 A direct comparison with azithromycin and clarithromycin showed no difference in response rates or adverse reactions.91 Fluoroquinolones These agents penetrate well into the respiratory secretions and bronchial mucosa, but clinical relevance is uncertain. Fluoroquinolones are highly active against β-lactamase producing H. influenzae and M. catarrhalis, and therefore are effective in AECB. Despite a relatively high inhibitory concentration against Strep. pneumoniae, ciprofloxacin demonstrated clinical efficacy similar to amoxicillin, clarithromycin, and cefuroxime.92 A variety of newer fluoroquinolones with longer half-lives has become recently available. The newer agents have enhanced activity against pneumococci compared with ciprofloxacin, thus making them an effective therapy in the management of moderate to severe exacerbations. An ideal antibiotic Newer antimicrobial agents have been studied to show equivalence with regimens that have already been approved. Consequently, there are few data showing that one agent is better than the other, because trials have not been designed with this goal in mind. However, there are several theoretical characteristics that would be desirable in selecting an antibiotic: • activity against the most common and most likely etiological pathogens; • resistance to destruction by β-lactamase; • good penetration into the sputum and bronchial mucosa; • a mechanism of action that does not add to inflammatory events in the airway; • easy to take, with few side-effects; • cost effective.
Antibiotics
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cephalosporins or quinolones is suggested, followed by oral therapy with cephalosporins, amoxicillin–clavulanic acid, or quinolones.
Patients with COPD who have poor ventilatory reserve may develop acute respiratory failure as a consequence of an exacerbation. For this reason, it is prudent to identify this high-risk population for whom an aggressive approach can be applied to prevent deterioration. Mechanical ventilation is required in 20 to 60% of these patients and hospital mortality of 10 to 30% has been reported.93 Factors reported to be associated with increased hospital mortality include age greater than 65 years, comorbid respiratory and nonrespiratory organ dysfunction, and admission to an intensive care unit.94 The other factors linked to poor survival are severity of airways obstruction, performance status, and use of oral corticosteriods.95 Following antibiotic therapy for AECB, factors predicting failure of initial therapy (returning to the physician for more treatment), or the need for hospitalization include co-existent cardiopulmonary disease and the number of previous exacerbations. The presence of cardiovascular comorbidity combined with more than four exacerbations in the previous year has a sensitivity of 70% and specificity of 37% in predicting treatment failure.96 Therefore, advanced age, significant impairment of lung function, poor performance status, comorbid conditions, and history of previous frequent exacerbations requiring systemic corticosteroids characterize a high-risk group. Because the cost of failure is high, an aggressive approach to treatment of this high-risk group may improve outcome. Therapy with first-line antibiotics fails in 13% to 25% of exacerbations.97 Therapeutic failure increases cost of care due to extra physician visits, further diagnostic tests and repeated courses of antibiotics, more hospitalizations, and absence from work. Stratification of patients into risk categories may allow physicians to select appropriate antimicrobial therapy to prevent these consequences in an era of increasing resistance to standard therapy. Several stratification schemes have been proposed to improve initial microbial selection. In 1991, Lode98 proposed that patients be divided into three groups:
The authors propose a simpler risk stratification scheme modified from the publications of Wilson,100 Grossman101 and others102 (Table 54.5). People with no underlying lung disease are not included in this classification as the etiology of acute bronchitis is likely viral, and the disease is selflimited. If the symptoms are persistent, macrolide or doxycycline could be prescribed to eradicate potential infection with M. pneumoniae or C. pneumoniae.
• First-degree patients have a relatively short duration of chronic bronchitis with a normal lung function and are infected with the usual pathogens H. influenzae and Strep. pneumoniae. These patients could be treated with oral amoxicillin, doxycycline, co-trimoxazole or a macrolide. • Second-degree patients have a longer history of COPD, several exacerbations each year and impaired lung function. Use of oral cephalosporins, amoxicillin–clavulanic acid, or quinolones was proposed. • The third-degree patients were described as hospitalized patients with significant comorbidity, prolonged history of COPD and severe functional impairment. These patients have frequent infections with Gram-negative pathogens or resistant H. influenzae and Strep. pneumoniae. In hospitalized patients, therapy with intravenous
• Patients with simple AECB have only mild to moderate impairment of lung function (FEV1 > 50% predicted), and have less than four exacerbations per year. Common organisms found are H. influenzae, Strep. pneumoniae and M. catarrhalis, although viral infections often precede bacterial superinfection. Treatment with a β-lactam is usually successful, and the prognosis is excellent. Since the consequences of treatment failure are few, any first-line antimicrobial agent (Table 54.4) can be used. • Patients with complicated AECB have poorer underlying lung function (FEV1 < 50% predicted) or with concurrent significant medical illness (e.g. diabetes mellitus, congestive heart failure, chronic renal disease, chronic liver disease) and/or experience four or more exacerbations per year. H. influenzae, Strep. pneumoniae and M.
In 1994, Balter et al.99 suggested that patients should be categorized into five groups. • Group 1: acute simple bronchitis likely viral induced with no previous respiratory problems. Antibiotic therapy was not recommended for this group unless symptoms persisted for more than 1 week. • Group 2: simple chronic bronchitis with minimal or no impairment of pulmonary function and without any risk factors. Treatment was recommended for patients who have type 1 and type 2 exacerbations. Any antibiotic from the list of first-line agents was suggested as consequences of treatment failure would be few (Table 54.4). • Group 3: moderate to severe chronic bronchitis and other risk factors. Treatment with antibiotics directed towards β-lactamase producing strains of H. influenzae and M. catarrhalis was suggested. • Group 4: similar to group 3 but with other significant comorbid illness such as congestive heart failure, diabetes mellitus, chronic renal failure or chronic liver disease, the treatment guidelines were similar to group 3 patients. • Group 5 patients: with bronchiectasis, and sputum cultures were recommended to target therapy to the identified pathogen.
A S I M P L E C L A S S I F I C AT I O N S C H E M E
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Table 54.5. Risk stratification of patients with acute exacerbations of COPD
Classification
Characteristics
Simple chronic bronchitis
Patients with chronic bronchitis FEV1 > 50% predicted Experience <4 exacerbations/year No comorbid illness
Complicated chronic bronchitis
Patients with chronic bronchitis FEV1 < 50% predicted Experience >4 exacerbations/year Comorbid medical illness: congestive heart failure, diabetes mellitus, chronic renal failure, or chronic liver disease
Chronic bronchial sepsis
Complicated chronic bronchitis + frequent hospitalizations and continuous sputum throughout year
catarrhalis continue to be the predominant organisms. However, since initial treatment failure has major implications, treatment with medications directed towards resistant organisms should be used. The second-line agents such as amoxicillin–clavulanic acid, second- or third-generation cephalosporins, the second-generation macrolides or fluoroquinolones are recommended. • Occasional patients with chronic bronchial sepsis are characterized by repeated exacerbations and often require multiple hospitalizations with respiratory failure. They have poor lung function, are at risk for Pseudomonas infection, and have a poor prognosis. Therefore an aggressive therapeutic approach can be justified. Empirical therapy using a quinolone with anti-pseudomonal activity and the use of sputum culture in this group of patients to identify possible resistant organisms may be employed. All the proposed classification systems although not prospectively tested in clinical trials, place emphasis on identifying high-risk populations so that they can be treated from onset, with antibiotics targeted to the potential resistant organisms in order to reduce the risk of treatment failure (Fig. 54.5).
PHARMACO-ECONOMIC C O N S I D E R AT I O N S Cost-effectiveness in the treatment of COPD exacerbations is of utmost significance in the modern-day practice of medicine. Pharmaco-economic analysis involves determining the extra costs required to achieve an additional unit of clinical benefit. In AECB, therapeutic failure is associated with much higher costs, thus identification of subgroups of patients likely to fail low-cost therapy is important. Various techniques including modeling studies, retrospective analysis
Acute exacerbation of COPD
Type 3
None
Type 1 or 2
Simple exacerbation
Complicated exacerbation
Chronic bronchial sepsis
First-line antibiotic
Second-line antibiotic
Empirical secondline antibiotic or choose antibiotic based on previous sputum culture
Inadequate response to therapy
Reconsider diagnosis Consider sputum culture Consider changing antibiotic
Fig. 54.5. Proposed algorithm for choosing empirical antibiotic therapy in patients with acute exacerbation of COPD. Adapted from Reference 99 and reproduced with permission.
of data bases, and prospective randomized pharmacoeconomic clinical trials have been developed to examine these issues. A retrospective study by Destache and colleagues
Antibiotics
showed that the use of newer antibiotics (cephalosporins, macrolides and fluoroquinolones) when compared with first-line agents, reduced overall costs of treating patients despite higher initial acquisition costs.103 The Canadian Ciprofloxacin Health Economic Study Group104 randomized patients with more than three exacerbations to receive either ciprofloxacin or any nonquinolone-based therapy.The study measured clinical endpoints (days of illness, hospitalizations, time to next exacerbation) blended with quality of life measurements and total respiratory costs. The use of ciprofloxacin in patients with a history of moderate to severe bronchitis and at least four AECB in the previous year offered substantial clinical and economic benefits. Additional future prospective studies are required to determine if the newer antimicrobial agents offer advantages in terms of costs, quality of life and clinical efficacy.
F U T U R E C O N S I D E R AT I O N S Further research is required to find new ways to distinguish between colonization and infective exacerbations of COPD in order to gain a better understanding of the role of infection in the disease.With advances in molecular biology, antigenic structures of bacteria and evaluation of the antibody response to these antigens may become the basis for identifying an AECB. Future therapies may also be directed towards the inflammatory process within the airways that damages the airway mucosa and that leads to greater colonization by pathogenic bacteria. Specific anti-inflammatory mediators directed against various cytokines may interrupt the progressive deterioration of lung function.105 Most clinical trials of antibiotics were performed for licensing, and patients with pathogens resistant to different antimicrobials were excluded. Further comparative trials showed clinical equivalence and not superiority. Future studies of new antimicrobials should examine clinical efficacy more stringently based on a classification system that would help select patients most likely to benefit from an antibiotic such as those falling in the last two categories in Table 54.5, and should only include patients with Winnipeg type I criteria. These studies should also include well-defined prospective economic analyses and quality of life assessment to ascertain the cost utility of the antibiotic in question.
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28. Chodosh S. Acute bacterial exacerbations in bronchitis and asthma. Am. J. Med. 1987; 82(Suppl. 4a):154–60. 29. Burrows B, Earle RH. Course and prognosis of chronic obstructive lung disease. A prospective study of 200 patients. N. Engl. J. Med. 1969; 280:397–404. 30. Tager I, Speizer FE. Role of infection in chronic bronchitis. N. Engl. J. Med. 1975; 292:563–71. 31. Fisher M, Akhtar AJ, Calder MA et al. Pilot study of factors associated with exacerbations in chronic bronchitis. Br. Med. J. 1969; 4:187–93. 32. Medici TC, Chodosh S. The reticuloendothelial system in chronic bronchitis. Am. Rev. Respir. Dis. 1972; 105:792–804. 33. Murphy TF, Sethi S. State of the art: bacterial infection in chronic obstructive lung disease. Am. Rev. Respir. Dis. 1992; 146:1067–83. 34. Burns MW, May JR. Haemophilus influenzae precipitants in the serum of patients with chronic bronchial disorders. Lancet 1967; 1:354–8. 35. Reichek N, Lewin EB, Rhoden DL et al. Antibody responses to bacterial antigens during exacerbations of chronic bronchitis. Am. Respir. Dis. 1970; 101:238–44. 36. Haase EM, Campagnari AA, Sarvar J et al. Strain-specific and immunodominant surface epitopes of the P2 porin protein of non-typeable Haemophilus influenzae. Infect. Immun. 1991; 59:1278–84. 37. Saint S, Bent S, Vittinghoff E et al. Antibiotics in chronic obstructive pulmonary disease exacerbations: a meta-analysis. JAMA 1995; 273:957–60. 38. Nicotra MB, Rivera M, Awe RJ. Antibiotic therapy of acute exacerbations of chronic bronchitis. Ann. Intern. Med. 1982; 97:18–21. 39. Eller J, Ede A, Schaberg T et al. Infective exacerbations of chronic bronchitis: Relation between bacteriologic etiology and lung function. Chest 1998; 113:1542–8. 40. Miravitlles M, Espinosa C, Fernandez-Laso E et al. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Chest 1999; 116:40–6. 41. Buscho RO, Saxtan D, Shultz PS et al. Infections with viruses and Mycoplasma pneumoniae during exacerbations of chronic bronchitis. J. Infect. Dis. 1978; 137:377–83. 42. Smith CB, Golden C, Kenner R et al. Association of viral and Mycoplasma pneumoniae infections with acute respiratory illness in patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1980; 121:225–32. 43. Soler N, Torres A, Ewig S et al. Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation. Am. J. Respir. Crit. Care Med. 1998; 157:1498–505. 44. Ball P. Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest 1995; 108:43s–52s. 45. Fagon J-Y, Chastre J, Trouillet J-L et al. Characterization of distal bronchial microflora during acute exacerbation of chronic bronchitis. Am. Rev. Respir. Dis. 1990; 142:1004–8. 46. Monso E, Ruiz J, Rosell A et al. Bacterial infection in chronic obstructive pulmonary disease. A study of stable and exacerbated outpatients using the protected specimen brush. Am. J. Respir. Crit. Care Med. 1995; 152:1316–20. 47. Davies BI, Maesen FPV, Teengs JP, Baur C. The quinolones in chronic bronchitis. Pharm.Weekbl. Sci. 1986; 8:53–9. 48. Basran GS, Joseph J, Abbas AM, Hughes C, Tillotson GS. Treatment of acute exacerbations of chronic obstructive airways disease – a comparison of amoxycillin and ciprofloxacin. J. Antimicrob. Chemother. 1990; 26(Suppl. F):19–24. 49. Chodosh S. Bronchitis and asthma. In: Gorbach SL, Bartlett JG, Blacklow NR, (eds), Infectious Diseases, pp. 476–85. Philadelphia: WB Saunders, 1992. 50. Aldons PM. A comparison of clarithromycin with ampicillin in the treatment of outpatients with acute bacterial exacerbation of
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chronic bronchitis. J. Antimicrob Chemother. 1991; 27(Suppl. A):101–8. Bachand RT. Comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbations of chronic bronchitis. J. Antimicrob. Chemother. 1991; 27(Suppl. A):91–100. Lindsay G, Scorer HJN, Carnegie CMD. Safety and efficacy of temafloxacin versus ciprofloxacin in lower respiratory tract infections: A randomized double blind trial. J. Antimicrob. Chemother. 1992; 30:89–100. Neu HC, Chick TW. Efficacy and safety of clarithromycin compared to cefixime as outpatient treatment of lower respiratory tract infections. Chest 1993; 104:1393–9. Cole P, Wilson R. Host–microbial interrelationships in respiratory infection. Chest 1989; 95:217S–21S. Fletcher C, Peto R. The natural history of chronic bronchitis and emphysema. Br. Med. J. 1977; 1645–8. Howard P. A long term follow-up of respiratory symptoms and ventilatory function in a group of working men. Br. J. Industr. Med. 1970; 27:326–33. Bates D. The fate of chronic bronchitis: a report of 10 year followup in the Canadian Department of Veteran’s Affairs coordinated study of chronic bronchitis. Am. Rev. Respir. Dis. 1973; 108:1043–65. Kanner R, Renzetti A, Klauber M et al. Variables associated with changes in spirometry in patients with obstructive lung disease. Am. J. Med. 1979; 67:44–50. Kanner RE, Anthonisen NR, Connett JE. Lower respiratory illness promotes FEV1 decline in current smokers but not ex-smokers with mild to moderate COPD: Results from lung health study. Am. J. Respir. Crit. Care Med. 2001; 64:358–64. SeemungalTAR, Donaldson GC, Bhowmik A et al.Time course and recovery of exacerbations in patients with chronic obstructive lung disease. Am. J. Resp. Crit. Med. 2000; 161; 5:1608–18. Nichol KL, Margolis KL, Wuorenma J et al. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N. Engl. J. Med. 1994; 331:778–84. Douglas RG Jr. Prophylaxis and treatment of influenza. N. Engl. J. Med. 1990; 322:443–50. Butler JC, Breinan RF, Campbell JF et al. Pneumococcal polysaccharide vaccine efficacy. An evaluation of current recommendation. JAMA 1993; 270:1826–31. Pridie RB, Datta N, Massey DG et al. A trial of continuous winter chemotherapy in chronic bronchitis. Lancet 1960; 2:723–8. Johnston RN, McNeill RS, Smith DH et al. Five-year winter chemoprophylaxis for chronic bronchitis. Br. Med. J. 1969; 4:265–9. Medical Research Council Working Party on Trials of Chemotherapy in Early Chronic Bronchitis. Value of chemoprophylaxis and chemotherapy in early chronic bronchitis. Br. Med. J. 1966; 1:317–21. Doern GV, Jones RN, Pfaller MA et al. Haemophilus influenzae and Moraxella catarrhalis from patients with community acquired respiratory tract infections: Antimicrobial susceptibility patterns from the SENTRY antimicrobial surveillance program (United States and Canada 1997). Antimicrob. Agents Chemother. 1999; 43:385–9. Doern GV, Pfaller MA, Kugler K et al. Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results from SENTRY antimicrobial surveillance program. Clin. Infect. Dis. 1999; 27:764–70. Kayser FH, Morenzoni G, Santanam P. The second European collaborative study on the frequency of antimicrobial resistance in H. influenzae. Eur. J. Clin. Microbiol. Infect. Dis. 1990; 9:810–17. Powell M, McVey D, Kassim MH et al. Antimicrobial susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis isolated in the UK from sputa. J. Antimicrob. Chemother. 1991; 28:249–59.
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71. Goldstein FW, Garau J. Resistant pneumococci: a renewed threat in respiratory infections. Scand. J. Infect. Dis. 1994; 93(Suppl.): 55–62. 72. Jacoby GA. Prevalence and resistance mechanisms of common bacterial respiratory pathogens. Clin. Infect. Dis. 1994; 18:951–7. 73. Cook PJ, Andrews JM, Woodcock J et al. Concentrations of amoxicillin and clavulanate in lung compartments in adults without pulmonary infection. Thorax 1994; 49:1134–8. 74. Medical Research Council. Value of chemoprophylaxis in chemotherapy in early chronic bronchitis. Br. Med. J. 1966; 1:1317–22. 75. MacFarlane JT, Colville A, Guion A et al. Prospective study of etiology and outcome of adult lower respiratory tract infections in the community. Lancet 1993; 341:511–4. 76. Davey P, Rutherford D, Graham B et al. Repeat consultations after antibiotic prescribing for respiratory infection: a study in one general practice. Br. J. Gen. Pract. 1994; 44:509–13. 77. Mandell LA. Antibiotics for pneumonia therapy. Med. Clin. North Am. 1994; 78:997–1014. 78. Maesen FPV, Geraedts WH, Davies BI. Cefaclor in the treatment of chronic bronchitis. J.Antimicrob. Chemother. 1990; 26:456–8. 79. Verghese A. Efficacy of cefixime in respiratory tract infections. Adv. Ther. 1990; 7:9–15. 80. Ball P. Efficacy and safety of cefprozal versus other beta lactam antibiotics in the treatment of lower respiratory tract infections. Eur. J. Clin. Microbiol. Infect. Dis. 1994; 13:851–6. 81. Bernard Y, Lemenager J, Moral C. A comparative study of amoxicillin and Augmentin in the treatment of bronchopulmonary infections. In: Croydon EAP, Michel ME (eds), Augmentin: clavulanate-potentiated Amoxicillin, pp. 282–90. Amsterdam: Excerpta MEDICA, 1983. 82. Todd PA, Benfield P. Amoxicillin/clavulanic: an update of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1990; 39:264–307. 83. Cazzole M, Vinciguerra A, Beghi GF et al. Comparative evaluation of the clinical and microbiological efficacy of co-amoxiclav vs cefixime or ciprofloxacin in bacterial exacerbation of chronic bronchitis. J. Chemother. 1995; 7:432–41. 84. Mehta S, Parr JH, Morgan DJR. A comparison of cefuroxime and co-trimoxazole in severe respiratory tract infections. J. Antimicrob. Chemother. 1982; 9:479–84. 85. Clavo-Sanchez AJ, Giron-Gonzalez JA, Lopez-Prieto D et al. Multivariate analysis of risk factors for infection due to penicillin resistant and multidrug resistant Streptococcus pneumonia: A multicentre study. Clin. Infect. Dis. 1997; 24:1052–9. 86. Ball AP. Azithromycin in the treatment of lower respiratory tract infections. Rev. Contemp. Pharmacother. 1994; 5:351–7. 87. Hoepelma IM, Mollers MJ, van Schie MH et al. A short (3 day) course of azithromycin tablet versus a 10-day course of amoxicillin-clavulanic acid in the treatment of adults with lower respiratory tract infections and effects on long term outcome. Int. J. Antimicrob. Agents 1997; 9:141–6.
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88. Petrie GR, Choo Kang J, Washton H et al. Azithromycin: an open comparison with amoxicillin in severe exacerbations of chronic bronchitis (Abstract 83). Proceedings of 18th International Congress of Chemotherapy, Stockholm, June 1993. 89. Ball AP. Therapeutic considerations for the management of respiratory tract infections. Infect. Med. 1993; 8(Suppl. a):7–17. 90. Bachand RT. A comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbation of chronic bronchitis. J. Antimicrob. Chemother. 1991; 27(Suppl. a):91–100. 91. Bradbury F. Comparison of azithromycin versus clarithromycin in the treatment of patients with lower respiratory tract infection. J. Antimicrob. Chemother. 1993; 31(Suppl. e):153–62. 92. Ball AP. Evidence for the efficacy of ciprofloxacin in lower respiratory tract infections. Rev. Contemp. Pharmacother. 1992; 3:133–42. 93. Derenne JP, Fleury B, Pariente R. Acute respiratory failure of chronic obstructive lung disease. Am. Rev. Respir. Dis. 1988; 138:1006–33. 94. Anthonisen NR, Wright EC, Hodgkin JE and IPPB trial group. Prognosis in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1986; 133:14–20. 95. Strom K. Survival of patients with chronic obstructive pulmonary disease receiving long-term domiciliary oxygen therapy. Am. Rev. Respir. Dis. 1993; 147:585–91. 96. Ball P, Harris JM, Lowson D et al. Acute infective exacerbations of chronic bronchitis. Quart. J. Med. 1995; 88:61–8. 97. MacFarlane JT, Colville A, Guion A et al. Prospective study of etiology and outcome of adult lower respiratory tract infections in the community. Lancet 1993; 341:511–14. 98. Lode H. Respiratory tract infections: when is antibiotic therapy indicated? Clin.Ther. 1991; 13:149–56. 99. Balter MS, Hyland RH, Low DE et al. Recommendations on the management of chronic bronchitis. Can. Med. Assoc. J. 1994; 151(Suppl.):7–23. 100. Wilson R. Outcome predictors in bronchitis. Chest 1995; 108(Suppl.):53S–7S. 101. Grossman RF. Guidelines for the treatment of acute exacerbation of chronic bronchitis. Chest 1997; 112:310S–13S. 102. Sethi S. Etiology and management of infections in chronic obstructive pulmonary disease. Clinic Pul. Med. 1999; 6:327–32. 103. Destache CJ, Dewan NA, O’Donohue WJ et al. Clinical and economic considerations in acute exacerbations of chronic bronchitis. J. Antimicrob. Chemother. 1999; 43(Suppl. A): 107–13. 104. Grossman R, Mukharjee J,Vaughan D et al. A one year communitybased health economic study of ciprofloxacin vs usual antibiotic treatment in acute exacerbations of chronic bronchitis. The Canadian Ciprofloxacin Health Economic Study Group. Chest 1998; 113:131–41. 105. Ball P. Future antibiotic trials. Sem. Respir. Infect. 2000; 15:82–9.
Long-term Oxygen Therapy
Chapter
55
Bartolome R. Celli Tufts University, Pulmonary and Critical Care, St. Elizabeth’s Medical Center, Boston, MA, USA
The use of oxygen as a therapeutic agent is generally thought to have began in the 1920s.1 Since then, much has been learned about the effects of oxygen and many methods of delivery have been developed. In this chapter, we will review the known effects of chronic oxygen therapy, its indications and the various delivery systems now available.
PAT H O P H Y S I O L O G Y O F O X Y G E N AT I O N To understand the scientific rationale and guidelines concerning oxygen therapy, it is necessary to know about the physiology of gas exchange, transportation of oxygen to tissues and the consequences of tissue hypoxia. Hypoxemia is defined as an abnormally low arterial oxygen tension PaO2. The physiologic causes of hypoxemia include a low inspired partial pressure of oxygen (FiO2), abnormal ventilation–per˙ mismatch), decreased diffusion fusion relationship (V˙ /Q capacity, alveolar hypoventilation, and right to left shunt. Oxygen therapy increases the FiO2 and is the primary treatment for hypoxemia resulting from the first three causes. The hypoxemia of alveolar hypoventilation is best treated by increased ventilation while a true shunt is by definition unresponsive to hyperoxia. Oxygen delivery (DO2) to the tissues is dependent upon the arterial oxygen content (CaO2) and the cardiac output (Q˙ t) as illustrated by the following equation: DO2 CaO2 Q˙ t
(1)
dependent upon any of the above factors and is the most common cause of tissue hypoxia. However, decreased oxygen utilization is another possible cause of hypoxia. This is demonstrated by shunting at the capillary level in sepsis or more dramatically by mitochondrial poisoning secondary to certain substances such as cyanide. The physiologic response to acute hypoxemia is to maintain oxygen transport (Fig. 55.1). At a PaO2 below 55, ventilatory drive increases rapidly leading to a higher arterial PaO2 and hypocapnia. Vascular beds supplying hypoxic tissue vasodilate, resulting in tachycardia, increased cardiac output and oxygen delivery. The lung responds to hypoxemia by vasoconstriction to increase ventilation–perfusion matching and the PaO2. Subsequently, secretion of erythropoietin results in erythrocytosis and improved oxygen carrying capacity.These adaptations improve oxygen delivery. Unfortunately, the short-term benefit of these responses may have a detrimental long-term effect. Prolonged pulmonary vasoconstriction and increased cardiac output can result in pulmonary hypertension, right ventricular failure and decreased survival.2–5 In addition, the increased minute ventilation and increased oxygen cost of breathing (O2 COB) may contribute to chronic malnutrition.6 To interrupt this sequence of events, oxygen therapy has become important in hypoxemic patients.7 We shall review what is known about the long-term effects of oxygen therapy with particular attention to chronic obstructive pulmonary disease (COPD) because this is the only disease in which chronic oxygen therapy has been studied in detail (Table 55.1).
Arterial oxygen content is further determined by CaO2 (Hgb 1.39 % sat/100) (0.003 PaO2) (2) where Hgb is blood hemoglobin concentration in g/100 ml, 1.39 is the maximum amount of oxygen (ml) that can combine with 1 g of hemoglobin, % sat is the amount of oxygen combined with hemoglobin divided by the maximal amount possible, 0.003 is the amount of oxygen (ml) soluble in 100 ml of blood per torr PaO2 in the absence of Hgb, and PaO2 is the partial pressure of oxygen in arterial blood. Tissue hypoxia occurs when the amount of oxygen present cannot meet the metabolic needs. Inadequate oxygen transport is
EFFECTS OF CHRONIC OXYGEN THERAPY Survival Although the cause of death in patients with hypoxic cor pulmonale is uncertain, the factors predicting survival in patients on long-term oxygen have been investigated. In general, variables reflecting worse severity of COPD, such as, reduction of PaO2 or increased PCO2,6-9 lower FEV16,9 and elevated mean pulmonary artery pressure9 correlate with
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Long-term effects
Increased O2 COB
Decreased PaO2
Short-term effects
Increased VE Pulmonary vasoconstriction
Increased V/Q matching
Increased PaO2
Increased PAP
Increased erythropoietin
Increased hematocrit
Increased arterial O2 content
Increased myocardial work
Increased heart rate and stroke volume
Increased cardiac output
Malnutrition
Cor pulmonale Increased oxygen delivery
Death
Fig. 55.1. The short- and long-term physiologic consequences of hypoxemia.
survival.The most important evidence supporting the use of chronic oxygen has been derived from studies investigating its effect on survival.10 In 1970, Neff and Petty11 found a 30–40% decrease in mortality in their severely hypoxic patients on continuous oxygen when they were compared with those in the literature. Subsequently, two large controlled trials studied the effect of oxygen on survival in COPD.4,5 The British Medical Research Council study randomized patients to 15 hours of continuous oxygen each day compared with no oxygen. During the 5-year follow-up, 19 of 42 oxygen therapy patients compared with 30 of 45 controls died. The Nocturnal Oxygen Therapy Trial (NOTT) randomly assigned patients to either 12 or 24 hours of oxygen per day. After 26 months, the mortality of the continuous group (mean 19 hours/day) was one-half that of the 12-hour group. Taken together, these studies found survival to improve proportionally to the number of hours of supplemental oxygen per day. As a result, the current recommendation for hypoxemic patients (PaO2 <55 mm Hg or SaO2 <88%) is continuous 24 hours/day oxygen therapy. In addition, patients with a PaO2 of 55–59 mm Hg or a SaO2 <89% in the presence of cor pulmonale or polycythemia also qualify for long-term continuous oxygen. Because of the lifestyle changes and economic implications of chronic oxygen therapy, patients must meet certain criteria for longer-term prescription. First, patients must be stable, on optimal medical therapy and not smoking. In addition, patients must be observed for at least 3 months to document persistent hypoxemia requiring long-term oxygen. During both the NOTT study4 and a multicenter French study,12 approximately 40% of patients had improved enough after 1 month to no longer qualify for chronic oxygen.
Consequently, patients should be reassessed 1–3 months after initiation of oxygen therapy to determine continued need for its use. Pulmonary hemodynamics Although the reason for increased survival with oxygen is not clear, there is evidence that O2 can improve pulmonary hemodynamics and lead to reduced cardiac work and greater oxygen delivery. Initially, uncontrolled studies in hypoxemic patients suggested that continuous oxygen for 6 to 8 weeks could reduce pulmonary artery hypertension (PAH).13,14 Subsequently, however, the controlled NOTT and MRC studies revealed no definite hemodynamic improvement.4,5 In the MRC trial, the mean pulmonary artery pressure (PAP) remained stable in patients receiving oxygen 15 hours/day, but increased significantly in the control group. In NOTT, there was only a slight decrease in pulmonary vascular resistance (PVR) after 6 months on continuous oxygen while the nocturnal oxygen group had a minimal increase in PVR. However, the results of both these studies may have been flawed by the fact that each was devoted mainly to prognosis, follow-up was short, and not all patients were evaluated. Most recent studies have specifically examined the effect of oxygen therapy on PAH. Weitzenblum and colleagues3 performed right heart catheterizations an average of 41 months prior to oxygen, just before starting oxygen and 31 months after oxygen in 16 severely hypoxemic COPD patients on oxygen therapy. Before oxygen therapy, there was a mean yearly increase in PAP of 1.47 ± 2.3 mm Hg. Following oxygen, pulmonary hypertension improved in 12 of 16 patients as demonstrated by an annual decrease in PAP of 2.15 ± 4.4 mm Hg. Complete normalization of PAP
Long-term Oxygen Therapy
Table 55.1. Known effects of chronic oxygen therapy
Survival Increased in hypoxemic patients with COPD after receiving continuous O2. Pulmonary hemodynamics Decreases pulmonary artery pressure and pulmonary vascular resistance. Increases stroke volume. Exercise Improves exercise endurance. Improves ventilatory muscle function. Decreases minute ventilation. Oxygen cost of ventilation Decreases resting oxygen cost of breathing. Reduces oxygen cost of ventilation during carbon dioxide induced hyperventilation. Neuropsychology Improves neuropsychologic performance. Sleep Improves sleep quality.
rarely occurred, but the changes in PAP were related to differences in PVR. Further analysis of the NOTT data showed that the continuous oxygen therapy group had significant improvements in resting and exercise mean PAP, PVR and stroke volume index after 6 months.2 In addition, the nocturnal oxygen therapy group showed stable hemodynamic variables. However, the absolute differences between the two groups were not significant. Despite this, the authors suggested that further follow-up may show hemodynamic improvement as a factor altering the longevity between the two groups. One investigator has suggested that the reason continuous oxygen therapy improves survival may be due to the detrimental effect of oxygen withdrawal from patients on long-term therapy.15 Selinger and colleagues15 showed that removal of oxygen caused a 31% increase in pulmonary vascular resistance index coupled with a decrease in stroke volume index and oxygen delivery. They propose that the effect of recurrent oxygen withdrawal may be responsible for the worse prognosis of intermittent oxygen therapy. In the longest of all the observational therapeutical oxygen trials, Zelinski and co-workers7 evaluated pulmonary hemodynamics at 2-year intervals for 6 years in a group of 12 patients with hypoxemic COPD. The PAP which was 27 ± 7 torr at entry, decreased to 21 ± 4 at 2 years, to then return to stable values of 26 ± 7 and 26 ± 6 torr at 4 and 6 years, respectively. This was observed in spite of further deterioration of gas exchange with worsening of room air PaO2 and PaCO2. This study lends support to the concept that
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oxygen supplementation to hypoxemic patients halts progression of pulmonary artery hypertension. Many patients continue to worsen despite long-term oxygen. Early identification of those patients who are unlikely to benefit from oxygen would avoid the cost and inconvenience of oxygen in these patients. As a result, various investigators have attempted to correlate an acute hemodynamic response to oxygen with long-term survival. In most studies, acute oxygen delivery (30 minutes to 24 hours) decreases the PAP in a minority of patients.2,16,17 Conversely, others have shown 28% oxygen to reduce PAP >5 mm Hg in greater than half of their patients18,19 and this acute response to oxygen predicted 2-year survival in patients with COPD and cor pulmonale.20 However, Sliwinski et al.17 have found little correlation between acute response to oxygen and long-term survival. They propose that the difference in results of these studies may be attributable to the lack of a pre-entry period in Ashutosh’s study, which may have allowed inclusion of patients who were not stable. Consequently, these patients may have had acute hypoxic vasoconstriction superimposed upon the more irreversible anatomic changes. In their study, responders had lower mean PAP (26 mm Hg) after oxygen compared with the nonresponders (33 mm Hg) suggesting they could have had less severe baseline pulmonary hypertension which might have accounted for their better prognosis. Patients who have an acute hemodynamic response to oxygen may have structural differences in their pulmonary vasculature as compared with those who do not improve. However, an autopsy study examining the pulmonary arteries of patients who died during the NOTT study found no difference in the vascular structure of those who responded to oxygen and those who did not.21 In addition, these authors found structural alterations of the muscular pulmonary arteries in patients with PAH secondary to COPD, but these changes did not correlate with the degree of PAH. Because determination of PAP is invasive, noninvasive methods have been assessed to predict response to oxygen therapy. Ashutosh and Dunsky19 studied exercise V˙ O2max and found a V˙ O2max >6.5 mL/min/kg to predict a fall in PAP >5 mm Hg and 3 year survival on oxygen.19 Attempts to show an acute or chronic benefit of oxygen on RVEF,22,23 and a change in RVEF on oxygen to predict a change in PAP19,23 or survival19 have been disappointing. Therefore, the response of RVEF to oxygen does not appear to predict a beneficial effect of this therapy. The possibility that LTOT could benefit patients with a lesser degree of resting hypoxemia (PaO2 between 56 and 69 torr) was explored by Gorecka et al.24 They prospectively evaluated patients with moderate hypoxemia and observed no difference in mortality between treated and untreated patients. This lack of beneficial effect is further highlighted by the multicenter trial reported by Chouet and co-workers25 who after 2 years of therapy observed no effect on survival or pulmonary artery hemodynamics in a cohort of moderate hypoxemic patients randomized to supplemental oxygen or routine therapy.
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In summary, long-term oxygen has beneficial effects on survival and pulmonary hypertension in patients with COPD and significant hypoxemia. Currently, most studies do not support the ability of acute hemodynamic response to oxygen measured either invasively or noninvasively to predict improvements in PAP, pulmonary vascular changes, or survival. Therefore, long-term oxygen is currently administered to all significantly hypoxemic patients (PaO2 ≤55 torr), since some benefit cannot be ruled out and other therapeutic options are limited. There is no evidence to support the administration of LTOT to patients with mild or transitory hypoxemia. Exercise Ventilatory, rather than circulatory, factors limit maximum exercise performance in most patients with COPD. Performance is most closely related to airflow limitation.26 Other investigators have suggested that the ventilatory muscles may contribute to exercise limitation in COPD.27 The proposed mechanism involves hyperinflation leading to inspiratory muscle dysfunction at an unfavorable length. This requires the muscles to generate pressures, which are close to their maximum capacity, resulting in fatigue. Oxygen therapy has been shown to improve exercise endurance in many studies. Various investigators have found oxygen to increase distance walked,28,29 time on a treadmill,30,31 and time on a cycle ergometer.32,33 The precise mechanisms resulting in improvement are unknown, but a number have been suggested. In hypoxemic patients and those who desaturate with exercise, oxygen therapy results in greater oxygen delivery and utilization by exercising muscles.34–36 However, increased oxygen saturation is not always predictive of improved exercise performance31,32 and other factors may contribute. Some studies have shown oxygen to reduce minute ventilation and respiratory rate for a given workload.32,37 Oxygen has been found to improve exercise ventilatory muscle function, by postponing the onset of fatigue as demonstrated by a delay in the appearance of abdominal paradox and a slower fall in the high to low frequency of the diaphragm electromyogram power spectral density.32,38 Criner and Celli38 found that exercising COPD patients with oxygen resulted in the diaphragm performing more ventilatory work which may prevent overloading of the accessory muscles and contribute to the decrease in dyspnea. Finally, others have suggested that supplemental oxygen may decrease dyspnea and improve endurance by directly reducing chemoreceptor activity from the carotid body.33,39 Currently, qualification for oxygen during exercise requires documentation of a PaO2 less than or equal to 55 mm Hg or an SaO2 <88.40,41 A helpful clue to predicting which patients will desaturate with exercise is the diffusing capacity. Owens and colleagues42 found a diffusing capacity above 55% predicted to be 100% specific in excluding desaturation. Oxygen cost of ventilation Beyond the effect of oxygen on arterial PaO2, there is evidence that oxygen may improve dyspnea by decreasing
airway resistance and work of breathing. Astin and Penman43 studied 18 COPD patients and found a significant association between airway resistance and PaO2. Administration of 30% oxygen for 20 minutes to these patients resulted in an average reduction of airway resistance of 20%. Subsequently, it was also found that 30% oxygen improved flow rates in mildly hypoxemic patients (mean PaO2 = 61 torr).44 Furthermore, atropine caused a similar increase in flow rates that aborted the effect of oxygen. This led the authors to conclude that hypoxemia-related bronchoconstriction may be mediated by vagal tone as had been previously suggested.43,45 In addition to its effects on airways resistance, oxygen via a face mask or transtracheal flow in patients with COPD has also been found to decrease minute ventilation.46,47 As a consequence of these effects, oxygen may lead to a decrease in the work of breathing (WOB) or the oxygen cost of breathing (O2 COB) and thereby improve dyspnea. Astin48 studied the effect of 30% oxygen on 15 patients with COPD and found a decrease in WOB in ten patients and an increase in five patients. Mannix et al.49 calculated the COB induced by breathing 7% carbon dioxide. They found 30% oxygen to decrease the O2 COB by 42% in both COPD patients and controls. In the COPD patients, the decrease in O2 COB was only due to a smaller increment in V˙ O2 for a given level of ventilation, while controls had both a lower V˙ O2 and VE. They concluded that supplemental oxygen decreases the O2 demand of the respiratory muscles. Benditt and co-workers50 observed a decrease in the oxygen cost of breathing with both transtracheal air and oxygen, but the effect was greater with oxygen. Because most patients receive long-term oxygen by a nasal cannula, the effect of nasal flow oxygen on the oxygen cost of breathing was recently assessed.51 At high flows (O2 5 L/min), oxygen significantly decreased the O2 COB while compressed air did not. Based on these results, the improved dyspnea and exercise tolerance with oxygen may be partially due to its effect on WOB and the oxygen cost of breathing. Neuropsychologic effects Beginning in the 1930s and 1940s, aviation research demonstrated the acute effects of mild to severe hypoxia on healthy young men.52 These studies found that even mild hypoxia (PaO2 45–60) could impair judgment, learning and short-term memory in normal subjects. To investigate the effects of chronic hypoxemia, research has focused on the neurobehavioral effects of hypoxemia in patients with COPD. Early work by Krop and colleagues53 demonstrated poorer neuropsychologic performance in a group of COPD patients with a PaO2 <55 mm Hg. Administration of continuous oxygen at 2 L/min by nasal cannula for 4 weeks resulted in significant improvement in eight of ten neuropsychologic tests. Because this study and another54 only looked at a small group of patients without a stabilization period, two large multicenter studies in the United States and Canada examined the neuropsychologic consequences
Long-term Oxygen Therapy
of hypoxemia.55,56 The US Nocturnal Oxygen Therapy Trial studied 203 patients with a mean age of 64 years and PaO2 of 51 torr and found that 42% of patients had moderate to severe impairment of cerebral function.55 The Canadian IPPB Trial examined 100 patients with less hypoxemia (mean PaO2 66 torr) which resulted in more selective impairments.56 The results of both these studies were combined, demonstrating an increase in the rate of deficits from 27% in mild hypoxemia (PaO2 60) to 61% in severe hypoxemia (PaO2 50).57 The NOTT study has evaluated the effect of continuous (19 hours/day) and nocturnal oxygen on neuropsychologic functioning and life quality in 150 COPD patients. The results show an improvement after 6 months in both groups in general alertness, motor speed and hand grip.58 Despite these benefits, patients had no change in emotional status or quality of life. Although improvements after 6 months were no greater on continuous as compared with nocturnal oxygen, a subgroup of patients followed for 12 months showed significantly better neuropsychologic function on continuous oxygen. The poor neuropsychologic performance in hypoxemic COPD patients has been explained by weakness, fatigue and depression. However, there is increasing evidence that brain hypoxia itself is responsible for the impaired function. The conventional belief that mild cerebral hypoxia could impair ATP generation and neuron function has been disproved.59 Some studies suggest that hypoxia can result in reduced synthesis of acetycholine from labeled precursors,61 which is interesting, since there is growing evidence to support the role of acetycholine in memory and learning.62 Sleep In the original description of rapid eye movement (REM) sleep in 1953, it was observed that breathing became more variable during this stage of sleep.63 Subsequently, it was found that decreased chest movement and oxygen saturation occurred in this sleep stage.64 Other groups also demonstrated worsening hypoxemia and carbon dioxide retention during sleep.65,66 Koo and colleagues67 correlated arterial blood gas tension with sleep stage in COPD patients and found that PaO2 decreased shortly after sleep from 64 to 58 mm Hg during non-REM sleep. Upon entering REM sleep, PaO2 fell further to 50 and the PaCO2 rose from 48 to 58 mm Hg. These findings were later confirmed by many others.68–72 The mechanisms of hypoxemia during sleep in COPD include hypoventilation, a reduction in functional residual capacity (FRC), and alterations in ventilation perfusion matching.73 The major cause of hypoxemia during REM sleep is hypoventilation, which appears related to rapid shallow breathing73,74 and long episodes of hypopneas, but not actual apneas.71 In addition, both the hypoxic75,76 and hypercapnic77,78 ventilatory responses are diminished. The cause of REM sleep hypoventilation has not been fully determined, but appears related to altered brain stem
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function during phasic neuronal activity.79 During REM sleep, the ribcage contribution to ventilation decreases by 18–34%,80,81 as a consequence of hypotonia of the intercostal muscles and decreased activity of accessory muscles.82 This may be particularly important in patients with COPD who greatly depend on accessory muscles for breathing.83,84 Though it is generally believed that hypoventilation during REM sleep will result in ventilation– perfusion mismatch,73 its relative importance with regard to REM hypoxemia is unknown. Although some patients with COPD have sleep apnea, there is no evidence that this occurrence is more common than would be expected by chance alone.73 A few studies have measured pulmonary hemodynamics during sleep in COPD and found an increase in PAP with acute desaturation.85–89 In addition, some studies support an association between nocturnal desaturation and pulmonary hypertension (PH) in COPD patients who have a daytime PaO2 60 mm Hg.88,89 Both studies found significantly higher PAP in the patients who desaturated as compared with the non-desaturators. Patients with COPD have poor sleep quality as compared with age-matched controls90,91 and arousals are frequent during periods of desaturation.92 Whether oxygen therapy improves sleep quality in hypoxemic patients is debatable, since various studies have shown conflicting results.90,93 Some studies have found fewer hypoxemic episodes as well as increased total sleep and REM sleep with oxygen.90,94 Although mean nocturnal oxygen saturation (SaO2) and lowest nocturnal SaO2 have been found to correlate with survival, one study found these parameters to have no prognostic value over vital capacity or awake SaO2.94 Furthermore, patients with greater nocturnal hypoxemia than would be predicted, had no difference in survival. Fletcher’s group retrospectively compared survival in COPD patients with a daytime PaO2 60 mm Hg with and without O2 desaturation at night.97 They found an improved survival in those patients without nocturnal desaturation. There was also a trend towards improved survival with nocturnal oxygen in those patients who did desaturate at night. These authors attribute the difference in survival in their study and one by Connaughton et al.95 to the worse daytime PaO2 of the patients in that study (mean PaO2 53 10 mm Hg). They proposed that as the disease becomes more advanced, the daytime SaO2 may become a strong predictor, while sleep SaO2 correlates less well with survival. However, the recent report by Chouet et al.25 suggests that oxygen supplementation at night to mildly hypoxemic patients has a limited, if any, beneficial effect in pulmonary hemodynamics or survival. Presently, patients who are hypoxemic while awake should also be prescribed oxygen during sleep. In addition, patients who are well saturated during wakefulness, but desaturate at night can qualify for oxygen if they have complications attributable to sleep hypoxemia, such as pulmonary hypertension, daytime somnolence or cardiac arrhythmias.40,41.96
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OXYGEN PRESCRIPTION Currently, there are strict guidelines for oxygen prescription based upon resting hypoxemia (PaO2 55 mm Hg or SaO2 88) and hypoxemia induced by sleep or exercise (Table 55.2). Once a patient qualifies for long-term oxygen, prescription requires completion of the Certificate of Medical Necessity for Home Oxygen Therapy form in the USA. This form should be completed before a patient leaves the hospital to ensure inclusion of all information such as patient data, reason for oxygen, blood gases, type of system, and liter flow at rest, exercise and sleep. Long-term oxygen administration can be accomplished with either: • oxygen concentrator • compressed gas • liquid oxygen. Table 55.3 summarizes the advantages and disadvantages of each mode of therapy40,41,96 comparing weight, cost, portability, ease of refill and availability. Because home oxygen is supplied under a fixed reimbursement policy regardless of the system used,94 oxygen vendors will attempt to provide the least expensive system.
Table 55.2. Indications for chronic oxygen therapy
Continuous oxygen Resting PaO2 55 mm Hg or SaO2 88% Resting PaO2 56–59 mm Hg or SaO2 89% in the presence of the following: (1) Dependent edema suggesting congestive heart failure (2) “P” pulmonale on EKG (P wave greater than 3 mm in standard leads II, III, or AVF) (3) Erythrocythemia (hematocrit 56%) Resting PaO2 59 mm Hg or SaO2 89% Only reimbursable with additional documentation justifying the oxygen prescription and a summary of more conservative therapy which has failed. Noncontinuous oxygen Must specify the oxygen flow rate and the number of hours/day During exercise, PaO2 55 mm Hg or an SaO2 88% with low level exertion. During sleep, PaO2 55 mm Hg or an SaO2 88%, with associated complications such as pulmonary hypertension, daytime somnolence and cardiac arrhythmias.
Oxygen concentrator Most patients will require a stationary source of oxygen which is usually provided by an oxygen concentrator. Since concentrators are relatively inexpensive and require less frequent home visits than liquid oxygen, they have become the system of choice for suppliers. These electrically powered devices utilize a molecular sieve to separate oxygen from air resulting in delivery of oxygen to the patient, while nitrogen is returned to the atmosphere. The typical Zeolite sieve achieves oxygen purity of 97% at low flows and 94% at higher flows. However, due to their voltage requirement and their weight, they are primarily a fixed source of oxygen. Consequently, patients need either compressed gas or liquid oxygen as an ambulatory source of oxygen. Compressed gas oxygen Compressed gas oxygen has been provided for many years in high pressure metal or aluminum cylinders. These containers vary in size weighing 90.8, 7.2, 4 and 1.8 kg and provide O2 at 2 L/min flow for 2.4 days, 5.2 hours, 2 hours and 1.2 hours, respectively. The smaller cylinders can be refilled but the process is inefficient and potentially hazardous. The major advantages of compressed gas are its low cost and wide availability. Its disadvantages are the weight of the cylinders, the difficulty refilling and the short oxygen supply time. Liquid oxygen Liquid oxygen is stored at very cold temperatures which reduces its volume to less than 1% of the volume of atmospheric oxygen. Stationary units weigh 140 pounds and can provide 7 days of continuous oxygen at 2 L/min flow. There are portable containers weighing as low as 4 lbs that will last for up to 12 hours at 2 L/min flow. Compared with compressed gas, an equivalent weight container of liquid oxygen is more portable and easier to refill, its liabilities include a higher cost, manufacturer incompatibility and the need for pressure relief venting which wastes unused oxygen.
Table 55.3. Modes of oxygen delivery
System
Advantages
Disadvantages
Gas
Low cost Wide availability Fair portability
Heavy weight Difficult to refill Short supply time
Liquid
Light weight Very portable Easy refill
High cost Vendor incompatibility Pressure venting
Low cost Good availability
Heavy weight Least portable
Concentrator
Long-term Oxygen Therapy
Deciding on which portable system to prescribe depends upon the activity level of the patient. For patients who are more active, liquid oxygen is the ambulatory system of choice since the oxygen lasts longer and the canister is easier to refill and to carry. Lock et al.98 compared liquid and gaseous oxygen and found patients would use liquid oxygen more hours per week (23.5 versus 10 hours) and leave their house more hours per week (19.5 versus 15.5 hours).
O X Y G E N A D M I N I S T R AT I O N D E V I C E S Nasal cannula Patients with COPD and other chronic lung diseases usually receive continuous flow oxygen via a nasal cannula. Delivery at a flow of 2 L/min increases the FiO2 to approximately 27%, which provides an adequate O2 saturation in the majority of patients.40 Although this method is effective, it is quite inefficient. During the respiratory cycle, alveolar gas exchange is limited to early inhalation which accounts for only one-sixth of the cycle. Conversely, alveolar ventilation does not occur during late or dead space inspiration and exhalation.93 Consequently, only oxygen flowing during early inspiration is available to the patient, while the remainder is wasted into the environment. To improve efficiency and mobility, oxygen-conserving devices have been designed to deliver oxygen during early inhalation. These devices include reservoir nasal cannulas, transtracheal catheters and electronic oxygen demand devices. In general, these three devices each result in oxygen savings of two to four times a conventional nasal cannula. For a more detailed review the reader may refer to Ref. 93. Reservoir cannula The reservoir cannula was the first method of oxygen conservation to be used.93,99 This device stores 20 ml of oxygen in a reservoir during expiration and delivers an oxygen bolus at the onset of inspiration. The two available reservoirs are shaped as either a moustache attached to nasal prongs or a pendant placed over the anterior chest wall. The moustache reservoir was developed first, but because of dissatisfaction with its high visible location, the pendant was designed to be hidden by clothing.100 Although this device has better cosmesis, it is still more noticeable than the standard nasal cannula. Electronic demand devices Electronic demand devices sense the beginning of inspiration and deliver a pulse of oxygen during early inhalation.40,101–103 There are several units available with many similarities and differences. Most devices are relatively inexpensive and have built-in rechargeable batteries, and alarms.104 Some systems can be switched manually from demand to continuous flow,104 while others automatically change to continuous flow if an inspiratory signal is not sensed.105 Another demand valve is able to maintain constant oxygen delivery by adjusting the pulse size depending
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on the respiratory rate. A recent comparison of standard nasal cannula, reservoir nasal cannula, and a demand flow device in 15 patients with COPD found no difference in exercise tolerance among the three systems. However, oxygen saturation tended to be lower during the exercise using the demand flow device.106 Transtracheal catheters Transtracheal catheters improve oxygen delivery by bypassing anatomic dead space and utilizing the upper airways as a reservoir during end expiration.107 Heimlich108 developed the first catheter after experiments in dogs demonstrated an increased PaO2 as a catheter was placed more distally. In addition to increased oxygen savings, other advantages of TTO include its relative inconspicuousness, the lack of nasal, auricular or facial skin irritation, its infrequent displacement during exercise and sleep.40,108 In addition, there are patients with refractory hypoxemia on a nasal cannula that have been successfully oxygenated on TTO.109–111 Patient acceptance of transtracheal catheters has been variable with rates ranging from 50 to 96% during 9- to 20month periods.108–113 Complications Complications of TTO vary depending on the system implemented and whether the acute or late phase of treatment is examined. The most common procedure-related problems include subcutaneous emphysema, bronchospasm and paroxysmal coughing.112,114 Frequently encountered late complications and sequelae include dislodged catheters, stomal infections and symptomatic mucous balls. Mucous balls result from oxygen drying the sputum and causing it to adhere to the catheter (110). The greater frequency of mucous balls seen in 10–25% patients with the Scoop catheter (Transtracheal Systems, Denver, CO, USA) appears to be the result of its larger surface area and the presence of side holes which allow accumulation of secretions. Some reports show life-threatening115,116 and even fatal airway obstruction due to mucous balls.117 Many other uncommon complications have been described including broken catheter tips, hemoptysis, keloid formation, hoarseness and cardiac arrhythmias. After an initial burst of enthusiasm, the number of transtracheal earlier initiations has decreased primarily due to the need for continuous supervision and relatively poor long-term compliance.
O X Y G E N A N D A I R T R AV E L Commercial airline travel exposes passengers to hypobaric hypoxia since aircraft cabins are not routinely pressurized to sea level. In patients who have compensated COPD at sea level, lowering the partial pressure of oxygen in the aircraft cabin can produce severe hypoxemia. Physical exertion during the flight can increase the risk of an exacerbation of symptoms. The proportion of patients suffering from complications during air travel is not well known.
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Aircraft are usually pressurized to between 5000 and 7000 feet (1500–2100 m). For the preflight evaluation of most patients, clinicians should consider 8000 feet (2438 m) of altitude above sea levels as realistic “worse case scenario”. Preflight assessment can be accomplished with the following elements: • Estimation of the expected degree of hypoxemia at altitude • Identification of co-morbid disease conditions • Provision of an oxygen prescription if necessary. Documentation of the recent clinical condition and laboratory tests, particularly if the patient is traveling abroad, and counseling are also desirable elements of the preflight patient care.41,118 The two means of estimating the degree of hypoxia at altitude are: • Hypoxia inhalation test (HIT), which is not performed in many clinical laboratories in the United States and is not recommended for routine use • Use of regression formulae. Regression equations offer the opportunity to compare a patient with a group of patients with similar clinical characteristics who have been previously studied during exposure to hypoxia. While regression equations may provide a more physiological basis for the effects of high altitude than the HIT, the regression approach does not assess the individual’s susceptibility to the development of symptoms or electrocardiographic changes during hypoxia. The A-aO2 gradient and a-AO2 ratio generally have no advantages over regression equations. It is currently recommended that the PaO2 during air travel should be maintained above 50 mm Hg.8 While 2–3 liters of oxygen by nasal cannula will replace the inspired oxygen partial pressure lost at 8000 feet compared with sea level,9 lesser increments of oxygen will maintain the PaO2 above 50 mm Hg in many patients. COPD patients receiving continuous oxygen at home will require supplementation during air flight. Such patients should receive greater oxygen supplementation during the flight than at sea level. Increments equivalent to 1–2 liters of oxygen by nasal cannula during flight should suffice for most patients. Patients will also require additional oxygen supplementation if the elevation at the destination is significantly greater than at home. The Federal Aviation Administration requires a physician’s statement of oxygen need in order for a patient to receive continuous oxygen during flight. There is no uniform airline request form, so each airline must be contacted by the patient to determine what is required. As the airlines do not provide oxygen for ground use in the airline terminal, patients who require continuous oxygen should be advised to make plans for such locations. The American Lung Association provides patient education materials for individuals who travel with oxygen entitled “Airline Travel with Oxygen”.
Many ambulatory COPD patients not receiving oxygen at home can tolerate PO2 values below 50 mm Hg for brief periods of time without serious consequences. Stable COPD patients without comorbid disease who have previously traveled without incident and who are currently clinically stable compared with their previous air travel, may be advised to travel by air as there is little risk to them.
S U M M A RY Oxygen therapy has become very important in the treatment of severe COPD. Because long-term oxygen improves survival in hypoxemic COPD, patients with a daytime PaO2 <55 mm Hg or SaO2 <88% qualify for continuous oxygen therapy. Other benefits of oxygen include better exercise tolerance, decreased dyspnea, and improvements in neuropsychological performance. In addition, there appear to be beneficial effects on pulmonary hemodynamics, sleep quality, reduced minute ventilation and work of breathing. The consequences of nocturnal desaturation are not absolutely known. Clinicians should be aware of air travelinduced hypoxemia in COPD and be able to identify those who need oxygen in flight. Once a patient meets the criteria for oxygen prescription, the physician must complete the certificate of Medical Necessity Form specifying the indication for oxygen, type of system and liter flow at rest, exercise and sleep. Patients should be reevaluated at 1 to 3 months to document a persistent need for oxygen therapy. Occasionally, patients should be considered for oxygenconserving devices to decrease oxygen flow, cost and to improve mobility.
REFERENCES 1. Barach AL. The therapeutic uses of oxygen. JAMA 1922; 79:693–8. 2. Timms RM, Khaja FU, Williams GW. Nocturnal oxygen therapy trial group. Hemodynamic response to oxygen therapy in chronic obstructive pulmonary disease. Ann. Intern. Med. 1985; 102:29–36. 3. Weitzenblum E, Sautegeau A, Ehrhart M, Mammosser M, Pelletier A. Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1985; 131:493–8. 4. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. Ann. Intern. Med. 1980; 93:391–8. 5. Medical Research Council Working Party. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1:681–6. 6. Donahue M, Rogers RM, Wilson DO, Pennock BE. Oxygen consumption of the respiratory muscles in normal and in malnourished patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1989; 140:383–91. 7. Zelinski J, Tobiasz M, Hawrylkiewicz I, Sliwnski P, Palasiewicz G. Hemodynamics in COPD patients: A 6-year prospective study. Chest 1998; 113:65–70. 8. Cooper C, Howard P. An analysis of sequential physiologic changes in hypoxic cor pulmonale during long-term oxygen therapy. Chest 1991; 100:76–80.
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9. Skwarski K, Macnee W, Wraith PK, Sliwinski P, Zielinski J. Predictors of survival in patients with chronic obstructive pulmonary disease treated with long-term oxygen therapy. Chest 1991; 100:1522–7. 10. Cooper CB, Waterhouse J, Howard P. Twelve-year clinical study of patients with hypoxic cor pulmonale given long-term domiciliary oxygen therapy. Thorax 1987; 42:105–10. 11. Neff TA, Petty TL. Long-term continuous oxygen therapy in chronic airway obstruction. Ann. Intern. Med. 1970; 72:621–5. 12. Levi-Valensi P, Duwoos H, Racineaux JL. Multicenter study of oxygen therapy: GEMOS preliminary results. Med. Thorac. 1983; 5:502–6. 13. Levine BE, Bigelow DB, Hamstra RD et al. The role of long-term continuous oxygen administration in patients with chronic airway obstruction with hypoxemia. Ann. Intern. Med. 1967; 66:639–50. 14. Abraham AS, Cole RB, Bishop JM. Reversal of pulmonary hypertension by prolonged oxygen administration to patients with chronic bronchitis. Circ. Res. 1968; 24:147–57. 15. Selinger SR, Kennedy TP, Buescher P et al. Effects of removing oxygen from patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1987; 136:85–91. 16. Aber GM Harris AM, Bishop JM. The effect of acute changes in inspired oxygen concentration on cardiac, respiratory and renal function in patients with chronic obstructive airways disease. Clin. Sci. 1964; 26:133–43. 17. Sliwinski P, Hawrylkiewicz I, Gorecka D, Zielinski J. Acute effects of oxygen on pulmonary arterial pressure does not predict survival on long-term oxygen therapy in patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1992; 146:665–9. 18. Anthonisen NR. Home oxygen therapy in chronic obstructive pulmonary disease. Clin. Chest Med. 1986; 7:673–8. 19. Ashutosh K, Dunsky M. Noninvasive tests for the responsiveness of pulmonary hypertension to oxygen. Prediction of survival in patients with chronic obstructive lung disease and cor pulmonale. Chest 1987; 92:393–9. 20. Ashutosh K, Mead G, Dunsky M. Early effects of oxygen administration and prognosis in chronic obstructive pulmonary disease and cor pulmonale. Am. Rev. Respir. Dis. 1983; 127:399–404. 21. Wright JL, Petty T, Thurlbeck WM. Analysis of the structure of the muscular pulmonary arteries in patients with pulmonary hypertension and COPD: National Institutes of Health Nocturnal Oxygen Therapy Trial. Lung 1992; 170:109–24. 22. Macnee W, Wathen CG, Flenley DC, Muir AD. The effects of controlled oxygen therapy on ventricular function in patients with stable and decompensated cor pulmonale. Am. Rev. Respir. Dis. 1988; 137:1289–95. 23. Morrison DA, Henry R, Goldman S. Preliminary study of the effects of low flow oxygen on oxygen delivery and right ventricular function in chronic lung disease. Am. Rev. Respir. Dis. 1986; 133:390–5. 24. Gorecka D, Gorzelak K, Siliwinski P, Tobiasz M, Zielinski J. Effects of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxemia. Thorax 1997; 52:674–9. 25. Chouet A, Weitzenblum E, Kessler R et al. A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease patients. Eur. Respir. J. 1999; 14:1002–8. 26. Jones NL, Jones G, Edwards RHT. Exercise tolerance in chronic airway obstruction. Am. Rev. Respir. Dis. 1971; 103:477–91. 27. Dodd DS, Brancatisano T, Engel LA. Chest wall mechanics during exercise in patients with severe chronic air-flow obstruction. Am. Rev. Respir. Dis. 1984; 129:33–8. 28. Woodcock AA, Gross ER, Geddes DM. Oxygen relieves breathlessness in “pink puffers”. Lancet 1981; 1:907–9. 29. Leggett RJE, Flenley DC. Portable oxygen and exercise tolerance in patients with chronic hypoxic cor pulmonale. Br. Med. J. 1977; 2:84–6.
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30. Cotes JE, Gilson JC. Effect of oxygen on exercise ability in chronic respiratory insufficiency. Lancet 1956; 1:872–6. 31. Bradley BL, Garner AE, Billiu D, Mestas JM, Forman J. Oxygenassisted exercise in chronic obstructive lung disease. The effect on exercise capacity and arterial blood gas tension. Am. Rev. Respir. Dis. 1978; 118:239–43. 32. Bye PTP, Esau SA, Levy RD et al. Ventilatory muscle function during exercise in air and oxygen in patients with chronic airflow limitation. Am. Rev. Respir. Dis. 1985; 132:236–40. 33. Dean NC, Brown JK, Himelman RB, Doherty JJ, Gold WM, Stulbarg MS. Oxygen may improve dyspnea and endurance in patients with chronic obstructive pulmonary disease and only mild hypoxemia. Am. Rev. Respir. Dis. 1992; 146:941–5. 34. Stanek KA, Nagle FJ, Bisgard GE, Burnes WC. Effect of hyperoxia on oxygen consumption in exercising ponies. J. Appl. Physiol. 1979; 46:1115–18. 35. Vyas MN, Banister EW, Morton JW, Grzybowski S. Response to exercise in patients with chronic airway obstruction. II. Effects of breathing 40 percent oxygen. Am. Rev. Respir. Dis. 1971; 103:401–12. 36. Morrison DA, Stovall JR. Increased exercise capacity in hypoxemic patients after long-term oxygen therapy. Chest 1992; 102:542–50. 37. Stein DA, Bradley BL, Miller WC. Mechanisms of oxygen effects on exercise in patients with chronic obstructive pulmonary disease. Chest 1982; 81:6–10. 38. Criner GJ, Celli BR. Ventilatory muscle recruitment in exercise with O2 in obstructed patients with mild hypoxemia. J. Appl. Physiol. 1987; 63:195–200. 39. Guz A, Adams L, Minty K, Murphy K. Breathlessness and the ventilatory drives of exercise, hypercapnoea and hypoxia. Clin. Sci. 1981; 60:17–18. 40. Tiep BL. Long-term home oxygen therapy. Clin. Chest Med. 1990; 11:505–21. 41. American Thoracic Society. Standards for the diagnosis and treatment of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1995; 152:S77–120. 42. Owens GR, Rogers RM, Pennock BE, Levin D. The diffusing capacity as a predictor of arterial oxygen desaturation during exercise in patients with chronic obstructive pulmonary disease. N. Engl. J. Med. 1984 ; 310:1218–21. 43. Astin TW, Penman RWB. Airway obstruction due to hypoxemia in patients with chronic lung disease. Am. Rev. Respir. Dis. 1967; 95:567–75. 44. Libby DM, Briscoe WA, King TKC. Relief of hypoxia-related bronchoconstriction by breathing 30 percent oxygen. Am. Rev. Respir. Dis. 1981; 123:171–5. 45. Nadel JA, Widdicombe JG. Effect of changes in blood gas tensions and carotid sinus pressure on tracheal volume and total lung resistance to airflow. J. Physiol. 1962; 163:13–33. 46. Swinburn CR, Mould H, Stone TN, Corris PA, Gibson GJ. Symptomatic benefit of supplemental oxygen in hypoxemic patients with chronic lung disease. Am. Rev. Respir. Dis. 1991; 143:913–15. 47. Couser JI, Make BJ. Transtracheal oxygen decreases inspired minute ventilation. Am. Rev. Respir. Dis. 1989; 139:627–31. 48. Astin TW. The effect of oxygen inhalation on the work of breathing in patients with chronic obstructive bronchitis. Respiration 1970; 27:51– 62. 49. Mannix ET, Manfredi F, Palange P, Dowdeswell IRG, Farber MO. Oxygen may lower the O2 cost of ventilation in chronic obstructive lung disease. Chest 1992; 101:910–15. 50. Benditt JO, Rassulo J, Celli BR. Work of breathing during direct tracheal O2 administration in patients with severe chronic lung disease. Am. Rev. Respir. Dis. 1990; 14:A883. 51. Tarpy S, Epstein S, Gottlieb D, Celli B. The effect of oxygen and air via nasal cannula on the oxygen cost of breathing in chronic airflow obstruction. Am. Rev. Respir. Dis. 1992; 145:A646.
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52. Luft U. Aviation physiology – the effects of altitude. In: Fenn W, Rahn K (eds), Handbook of Physiology Respiration, 2, p. 1099. Washington, DC: American Physiol. Soc., 1965. 53. Krop HD, Block AJ, Cohen E. Neuropsychologic effects of continuous oxygen therapy in chronic obstructive pulmonary disease. Chest 1973; 64:317–22. 54. Block AJ, Castle JR, Keitt AS. Chronic oxygen therapy. Treatment of chronic obstructive pulmonary disease at sea level. Chest 1974; 65:279–88. 55. Grant I, Heaton RK, Mcsweeny AJ, Adams KM, Timms RM. Neuropsychologic findings in hypoxemic chronic obstructive pulmonary disease. Arch. Intern. Med. 1982; 142:1470–6. 56. Prigatano GP, Parsons OA, Wright E, Levin DC, Hawryluk G. Neuropsychologic test performance in mildly hypoxemic patients with chronic obstructive pulmonary disease. J. Consult. Clin. Psychol. 1983; 51:108–16. 57. Grant I, Prigatano GP, Heaton RK, McSweeny AJ, Wright EC, Adams KM. Progressive neuropsychologic impairment and hypoxemia. Relationship in chronic obstructive pulmonary disease. Arch. Gen. Psych. 1987; 44:999–1006. 58. Heaton RK, Grant I, McSweeny AJ, Adams KM, Petty TL. Psychological effects of continuous and nocturnal oxygen therapy in hypoxemic chronic obstructive pulmonary disease. Arch. Intern. Med. 1983; 143:1941–7. 59. Siesjo B, Johannsson H, Ljunggren B, Norberg K. Brain dysfunction in mild to moderate hypoxia. Am. J. Med. 1981; 70:1247–53. 61. Gibson GE, Shimada M, Blass JP. Alterations in acetylcholine synthesis and in cyclic nucleotides in mild cerebral hypoxia. J. Neurochem. 1978; 31:757–60. 62. Bartus RT. Effects of cholinergic agents on learning and memory in animal models of aging. Aging 1982; 19:271–80. 63. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility and concomitant phenomena during sleep. Science 1953; 118:273–4. 64. Aserinsky E. Periodic respiratory pattern occurring in conjunction with eye movements during sleep. Science 1965; 150:763–6. 65. Robin ED, Whaley RD, Crump CH, Travis DM. Alveolar gas tensions, pulmonary ventilation and blood pH during physiological sleep in normal subjects. J. Clin. Invest. 1958; 37:981–9. 66. Trask CH, Cree EM. Oximeter studies on patients with chronic obstructive emphysema, awake and during sleep. N. Engl. J. Med. 1962; 266:639–42. 67. Koo KW, Sax DS, Snider GL. Arterial blood gases and pH during sleep in chronic obstructive pulmonary disease. Am. J. Med. 1975; 58:663–70. 68. Leitch AG, Clancy LJ, Leggett RJE, Tweeddale P, Dawson P, Evans JI. Arterial blood gas tensions, hydrogen ion, and electroencephalogram during sleep in patients with chronic ventilatory failure. Thorax 1976; 31:730–5. 69. Wynne JW, Block AJ, Hemenway J, Hunt LA, Flick MR. Disordered breathing and oxygen desaturation during sleep in patients with chronic obstructive lung disease (COLD). Am. J. Med. 1979; 66:573–9. 70. Catterall JR, Douglas NJ, Calverley PMA et al. Transient hypoxemia during sleep in chronic obstructive pulmonary disease is not a sleep apnea syndrome. Am. Rev. Respir. Dis. 1983; 128:24–9. 71. Hudgel DW, Martin RJ, Capehart M, Johnson B, Hill P. Contribution of hypoventilation to sleep oxygen desaturation in chronic obstructive pulmonary disease. J. Appl. Physiol. 1983; 55:669–77. 72. Ballard RD, Clover CW, Suh BY. Influence of sleep on respiratory function in emphysema. Am. J. Respir. Crit. Care Med. 1995; 151:945–51. 73. Douglas NJ. Sleep in patients with chronic obstructive lung disease. Clin. Chest Med. 1998; 19:115–25. 74. Douglas NJ, White DP, Pickett CK, Weil JV, Zwillich CW. Respiration during sleep in normal man. Thorax 1982; 37:840–4.
75. Douglas NJ, White DP, Weil JV et al. Hypoxic ventilatory response decreases during sleep in normal men. Am. Rev. Respir. Dis. 1982; 125:286–9. 76. Berthon-Jones M, Sullivan CE.Ventilatory and arousal responses to hypoxia in sleeping humans. Am. Rev. Respir. Dis. 1982; 126:758–62. 77. Douglas NJ, White DP, Weil JV, Pickett CK, Zwillich CW. Hypercapnic ventilatory response in sleeping adults. Am. Rev. Respir. Dis. 1982; 126:758–62. 78. Berthon-Jones M, Sullivan CE.Ventilation and arousal responses to hypercapnia in normal sleeping adults. J. Appl. Physiol. 1984; 57:59–67. 79. Orem J. Medullary respiratory neuron activity: relationship to tonic and phasic REM sleep. J. Appl. Physiol. 1980; 48:54–65. 80. Millman RP, Knight H, Kline LR, Shore ET, Chung D-CC, Pack AI. Changes in compartmental ventilation in association with eye movements during REM sleep. J. Appl. Physiol. 1988; 65:1196–202. 81. Tabachnik E, Muller NL, Bryan AC, Levison H. Changes in ventilation and chest wall mechanics during sleep in normal adolescents. J. Appl. Physiol. 1981; 51:557–64. 82. Tusiewicz K, Moldofsky H, Bryan AC, Bryan MH. Mechanisms of the rib cage and diaphragm during sleep. J. Appl. Physiol. 1977; 43:600–2. 83. Johnson MW, Remmers JE. Accessory muscle activity during sleep in chronic obstructive pulmonary disease. J. Appl. Physiol. 1984; 57:1011–17. 84. Martinez F, Couser J, Celli B. Factors influencing ventilatory muscle recruitment in patients with chronic airflow obstruction. Am. Rev. Respir. Dis. 1990; 142:276–82. 85. Fletcher EC, Gray BA, Levin DC. Nonapneic mechanisms of arterial oxygen desaturation during rapid-eye-movement sleep. J. Appl. Physiol. 1983; 54:632–9. 86. Coccagna G, Lugaresi E. Arterial blood gases and pulmonary and systemic arterial pressure during sleep in chronic obstructive pulmonary disease. Sleep 1978; 1:117–24. 87. Boysen PG, Block AJ, Wynne JW, Hunt LA, Flick MR. Nocturnal pulmonary hypertension in patients with chronic obstructive pulmonary disease. Chest 1979; 76:536–42. 88. Douglas NJ, Calverley PMA, Leggett RJE, Brash HM. Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet 1979; 1:1–4. 89. Fletcher EC, Luckett RA, Miller T, Castrangos C, Kutka N, Fletcher JG. Pulmonary vascular hemodynamics in chronic lung disease patients with and without oxyhemoglobin desaturation sleep. Chest 1989; 95:757–64. 90. Levi-Valensi P, Weitzenblum E, Rida Z et al. Sleep-related oxygen desaturation and daytime pulmonary haemodynamics in COPD patients. Eur. Respir. J. 1992; 5:301–7. 91. Calverley PMA, Brezinova V, Douglas NJ, Catterall JR, Flenley DC. The effect of oxygenation on sleep quality in chronic bronchitis and emphysema. Am. Rev. Respir. Dis. 1982; 126:206–10. 92. Fleetham J, West P, Mezon B, Conway W, Roth T, Kryger M. Sleep arousals, and oxygen desaturation in chronic obstructive pulmonary disease: the effect of oxygen therapy. Am. Rev. Respir. Dis. 1982; 126:429–33. 93. Tiep BL, Lewis MI. Oxygen conservation and oxygen-conserving devices in chronic lung disease: A review. Chest 1987; 92:263–72. 94. Goldstein RS, Ramcharan V, Bowes G, McNicholas WT, Bradley D, Phillipson EA. Effect of supplemental nocturnal oxygen on gas exchange in patients with severe obstructive lung disease. N. Engl. J. Med. 1984; 310:425–9. 95. Connaughton JJ, Catterall JR, Elton RA, Stradling JR, Douglas NJ. Do sleep studies contribute to the management of patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1988; 138:341–4.
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96. Conference Report. New problems in supply, reimbursement, and certification of medical necessity for long-term oxygen therapy. Am. Rev. Respir. Dis. 1990; 142:721–4. 97. Fletcher EC, Donner CF, Midgren B et al. Survival in COPD patients with a daytime PaO2 >60 mm Hg with and without nocturnal oxyhemoglobin desaturation. Chest 1992; 101:649–55. 98. Lock SH, Blower G, Prynne M,Wedzicha JA. Comparison of liquid and gaseous oxygen for domiciliary portable use. Thorax 1992; 47:98–100. 99. Tiep BL, Belman MJ, Mittman C, Phillips RE, Otsap B. A new oxygen-saving nasal cannula. Am. Rev. Respir. Dis. 1983; 130:500–2. 100. Soffer M, Tashkin DP, Shapiro BJ, Littner M, Harvey E, Farr S. Conservation of oxygen supply using a reservoir nasal cannula in hypoxemic patients at rest and during exercise. Chest 1985; 88:663–8. 101. Tiep BL, Belman MJ, Mittman C, Phillips RE, Otsap B. A new pendant storage oxygen-conserving nasal cannula. Chest 1985; 87:381–3. 102. Franco MA, Llompart JA, Teague R, Bloom K, Wilson R. Pulse dose oxygen delivery system. Respir. Care 1984; 29:1034–41. 103. Tiep BL, Nicotra B, Carter R, Phillips R, Otsap B. Lowconcentration oxygen therapy via a demand oxygen delivery system. Chest 1985; 87:636–8. 104. Brook CJ, Bower JS, Davis DM, Zimmer AK. Performance of a demand cannula system during rest, exercise, and sleep in hypoxemic patients. Am. Rev. Respir. Dis. 1986; 133:209A. 105. Shigeoka JW. Oxygen conservers, home oxygen prescriptions, and the role of the respiratory care practitioner. Respir. Care 1991; 36:178–83. 106. Hagarty E, Skorodin M, Langbein L, Hultman C, Jessen J, Maki K. Comparison of three oxygen delivery systems during exercise in hypoxemic patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 155:893–8.
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107. Bower JS, Brook CJ, Zimmer K, Davis D. Performance of a demand oxygen saver system during rest, exercise, and sleep in hypoxemic patients. Chest 1988; 94:77–80. 108. Heimlich HJ. Respiratory rehabilitation with transtracheal oxygen system. Ann. Otol. Rhinol. Laryngol. 1982; 91:643–7. 109. Christopher KL, Spofford BT, Petrun MD, McCarty DC, Goodman JR, Petty TL. A program for transtracheal oxygen delivery: Assessment of safety and efficacy. Ann. Intern. Med. 1987; 107:802–8. 110. Hoffman LA, Dauber JD, Ferson PF, Openbrier DR, Zullo TG. Patient response to transtracheal oxygen delivery. Am. Rev. Respir. Dis. 1987; 135:153–6. 111. Hoffman LA, Johnson JT, Wesmiller SW et al. Transtracheal delivery of oxygen: Efficacy and safety for long-term continuous therapy. Ann. Otol. Rhinol. Laryngol. 1991; 100:108–15. 112. Christopher KL, Spofford BT, Brannin PK, Petty TL. Transtracheal oxygen therapy for refractory hypoxemia. JAMA 1986; 256:494–7. 113. Adamo JP, Mehta AC, Stelmach K, Meeker D, Rice T, Stoller JK. The Cleveland Clinic’s initial experience with transtracheal oxygen therapy. Respir. Care 1990; 35:153–60. 114. Heimlich HJ, Carr GC. The Micro-Trach: A seven-year experience with transtracheal oxygen therapy. Chest 1989; 95:1008–12. 115. Heimlich HJ, Carr GC. Transtracheal catheter technique for pulmonary rehabilitation. Ann. Otol. Rhinol. Laryngol. 1985; 94:502–4. 116. Fletcher EC, Nickeson D, Costrarangos-Galaraza C. Endotracheal mass resulting from a transtracheal oxygen catheter. Chest 1988; 93:438–9. 117. Burton GG, Wagshul FA, Henderson D, Kime SW. Fatal airway obstruction caused by a mucous ball from a transtracheal oxygen catheter. Chest 1991; 99:1520–3. 118. Gong HJ. Airtravel and oxygen therapy in cardiopulmonary patients. Chest 1992; 101:1104–13.
Chapter
Immunomodulators
56
C.J. Corrigan Guy’s, King’s and St. Thomas’ School of Medicine, London, UK
Asthma affects 10% of children and 4% of adults, with an overall prevalence of 6% (3.6 million patients) in the UK. Mortality from asthma is relatively low (1680 deaths in the UK in 1994), but considerable morbidity arises from disease in that minority of patients whose symptoms are inadequately controlled by conventional therapy such as inhaled glucocorticoids and long-acting b2-agonists. In these patients oral glucocorticoids are often employed, but even then patients may remain symptomatic. No existing therapy for asthma is preventative, curative or clearly disease-modifying. Similarly, in COPD no existing therapy has been shown to be preventative, curative or diseasemodifying.
I M M U N O M O D U L AT O RY T H E R A P Y I N ASTHMA Asthma is associated with chronic, cell-mediated inflammation of the bronchial mucosa in which eosinophil-active cytokine products of activated T cells play a prominent role (Chapter 35) (Fig. 56.1). Evidence suggests that glucocorticoids ameliorate asthma at least partly through inhibition of T cells and elaboration of their eosinophil-active cytokine products, particularly interleukin-5 (IL-5).1–3 For this reason, there has been interest in the investigation of other T cell immunomodulatory agents for their possible therapeutic effects in asthma (Chapter 12). Since many of these agents have potentially serious unwanted effects, attention has generally been focused on those asthmatics who continue to have severe disease despite maximal topical, and additional continuous systemic glucocorticoid therapy. Gold salts Evaluation of gold salts in asthma has been based on empirical observation of their “anti-inflammatory” effects in diseases such as rheumatoid arthritis. Actions of gold salts, which may be relevant to a glucocorticoid-sparing effect in asthma, include inhibition of T cell proliferation, IL-5-mediated prolongation of
eosinophil survival,4 IgE-mediated degranulation of mast cells and basophils,5 and leukotriene production by granulocytes.6 Some of these effects may be secondary to inhibition by gold salts of pro-inflammatory transcriptional regulatory proteins, in particular NFjB.7 Two doubleAcute Histamine PGD2 Leukotrienes
MC IgE B
Chronic
Airway obstruction (acute) BHR (chronic)
IL-4 IL-5 Th2
IL-3
Basic proteins Leukotrienes
Act Eo
GM-CSF Cytokines Chemokines
Eo Eotaxin RANTES, etc
Fig. 56.1. Pathogenesis of asthma. Eosinophil-active cytokines secreted by activated, Th2-type T cells (Th2) promote recruitment, priming and prolonged survival of eosinophils (Eo, Act Eo) in the bronchial mucosa. Local production of eosinophil-active CC chemokines such as eotaxin may play a complementary role in this process. Eosinophil products (granule basic proteins and cysteinyl leukotrienes) are thought to damage the mucosa leading to clinical symptoms (variable airways obstruction and bronchial hyperresponsiveness). Acute release of mediators (histamine, prostaglandins, leukotrienes) from mast cells (MC), IgEmediated or otherwise, may exacerbate asthma symptoms on this background of chronic, T cell-mediated inflammation, but this phenomenon is arguably not an essential component of the disease. IgEdependent release of mediators from mast cells is dependent on the presence of allergen-specific IgE in atopic subjects, the synthesis of which is promoted in B cells (B) by IL-4 as well as IL-13.
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blind, placebo-controlled parallel group studies,8,9 in which oral gold salts were administered for 6 months showed a modest, but significant glucocorticoid-sparing effect of the therapy as compared with placebo. Lung function was not improved, and additional anti-asthma therapy not reduced. Not all of the patients showed a significant response. The unwanted effects of oral gold salt therapy include dermatitis, hepatic dysfunction, proteinuria, interstitial pneumonitis and, rarely, blood dyscrasias.10 Nevertheless, it has been concluded in one study11 comparing the glucocorticoid-sparing effects of gold salts, methotrexate and cyclosporin A in severe asthma that gold salts provide the optimal risk/benefit ratio in terms of efficacy and tolerability. Methotrexate Methotrexate is a folic acid analog used at low dosage for its anti-inflammatory activity in an increasing variety of chronic diseases. It exerts a delayed, but sustained therapeutic effect even with intermittent, weekly dosage regimens. This probably reflects its accumulation in cells as polyglutamate complexes, resulting in accumulation of Sadenosyl methionine and adenosine, both of which are inhibitory to T cell function.12 The results of several placebo-controlled trials of methotrexate therapy in severe, oral glucocorticoid-dependent asthma have been summarized in two recent meta-analyses.13,14 In both it was concluded that concomitant weekly methotrexate therapy for a minimum of 3–6 months allows significant (overall 20%, but only in about 60% of responding patients) reduction in oral glucocorticoid requirements, with no significant improvement in lung function. In a more exacting analysis of these trials by the Cochrane reviewers,15 however, it was concluded that existing trial data do not justify the premise that methotrexate is glucocorticoid-sparing. The most serious potential unwanted effect of methotrexate therapy is cumulative hepatic toxicity and hepatic fibrosis, with isolated reports of deaths from opportunistic infections and pnemonitis. Cyclosporin A Cyclosporin A (CsA) is a lipophilic, cyclic undecapeptide derived from the fungus Tolypocladium inflatum. In a complex with the cytoplasmic binding protein cyclophilin, it inhibits calcineurin-mediated dephosphorylation and nuclear translocation of the cytoplasmic subunit of the T cell transcriptional activator NF-AT, thus inhibiting T cell proliferation and cytokine production relatively specifically.16 Two blinded, placebo-controlled trials in severe, glucocorticoid-dependent asthmatics17,18 together, showed that concomitant CsA therapy improved lung function over 3–6 months while reducing oral prednisolone requirements. As with methotrexate, not all patients showed a significant response. Unwanted effects of low dosage CsA therapy include hypertension and renal impairment. Regular monitoring of renal function, blood pressure and whole blood trough concentrations of CsA is necessary. Lymphoprolifer-
ative disorders and serious opportunistic infections appear to be very uncommon. Intravenous immunoglobulin (IVIG) therapy Therapy with intravenous pooled immunoglobulin, originally designed to restore immune deficiency, also appears to have immunomodulatory effects in diseases involving immune effector mechanisms. In a blinded, placebocontrolled parallel group study of oral glucocorticoiddependent asthmatics,19 patients were randomized to receive IVIG or albumin (placebo) intravenously monthly for a total of 6 months (seven infusions). During therapy, oral prednisone requirements were reduced to an almost identical extent in the active and placebo-treated groups, with no significant differences in changes in symptoms, lung function and the frequency of disease exacerbations. In a second, similar blinded trial,20 treatment of patients with both IVIG and placebo allowed significant reduction in oral prednisone dosages, which was significantly greater in the IVIG treated group when only those asthmatics on relatively high initial dosages of oral prednisone were included in the analysis. Another double-blind, placebo-controlled study of IVIG therapy in severe childhood asthma21 failed to show any benefit of IVIG over placebo in terms of changes in symptoms and lung function. The possible mechanisms by which IVIG therapy could exert a beneficial effect in asthma are not clear. Some of the benefits may result from immunoglobulin replacement itself, since a proportion of chronic asthmatics have depressed serum IgG concentrations, although there is little evidence that this results in defective humoral immunity.22 Additionally, IVIG has been shown to increase T cell susceptibility to glucocorticoid inhibition in vitro,23 to abrogate IgE synthesis by B cells in vitro,24 and to contain other potential immunomodulatory products including soluble CD4, CD8 and HLA molecules and cytokines. In summary, the evidence that IVIG therapy is of any benefit in glucocorticoid-dependent asthma is at present equivocal. It is very expensive and is associated with a high incidence of unpleasant urticarial and anaphylactic reactions, as well as fever and aseptic meningitis. Summary: the worth of current immunomodulatory therapy Many reservations remain about the use of currently available immunomodulatory therapy for the treatment of severe, glucocorticoid-dependent asthma since: • Not all patients respond, and response cannot be predicted a priori • The high incidence of unwanted effects makes it difficult to assess overall benefit/risk ratios even in asthmatics who are able to reduce oral glucocorticoids • There is a risk of opportunistic infection and (at least theoretically) neoplasia • There are many relative or absolute contraindications to therapy, such as pregnancy
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Immunomodulators
• There is lack of knowledge about the long-term effects, beneficial or otherwise, of therapy.
I M M U N O M O D U L AT O RY T H E R A P Y F O R COPD
In view of all these observations, it is clear that any further investigation of immunomodulatory therapy for asthma should be performed within the confines of a controlled trial. There is an urgent need to produce a global definition of precisely which patients are suitable for such trials, and what constitutes an appropriate trial of therapy.
Key elements of the pathogenesis of COPD include:
N E W E R I M M U N O M O D U L AT O R S Tacrolimus (FK506) is a macrolide derived from the soil organism Streptomyces tsukudaiensis which, despite having a different structure to CsA, similarly inhibits NF-AT activation.16 Sirolimus (rapamycin) is another macrolide derived from Streptomyces hygroscopius. It inhibits IL-2 signaling at least partly by inhibiting phosphorylation/activation of the kinase p70 S6 (p70S6k), and by inhibiting the enzymatic activity of the cyclin-dependent kinase cdk2-cyclin E complex.25 Other new immunomodulatory drugs, the inhibitory actions of which are relatively specific for T cells, continue to appear, including brequinar sodium and mycophenolate mofetil (inhibitors of de novo synthesis of pyrimidines and purines respectively, particularly in T cells), leflunomide and the napthopyrans. Whether or not these drugs will offer opportunities for the therapy of severe asthma with a more favorable benefit/risk ratio remains to be seen.
• Chronic exposure to cigarette smoke (a causal factor in more than 90% of cases in the UK) • Individual (possibly inherited) susceptibility since only 10–20% of heavy smokers develop symptomatic disease • A smoking-induced inflammatory cellular infiltrate in the airways, more marked peripherally, comprising of neutrophils, CD8 T cells and variable numbers of eosinophils.29,30 The amount of this infiltrate is closely related to total smoke (pack years) exposure, but not so closely related to the presence/absence of COPD, although some studies31 seem to demonstrate a COPDspecific, elevated influx of CD8 T cells • Excessive production of proteinases, which digest the lung parenchyma, and overwhelm endogenous antiproteinases which normally protect against this. The principal proteinases are elastase and other serine proteinases from neutrophils, and matrix metalloproteinases (a group of over 20 related neutral endopeptidases) from macrophages and epithelial cells. A working hypothesis for the pathogenesis of COPD is shown in Fig. 56.2. At present, this remains largely theoretical. In particular, there is little or no hard evidence for a
Smoke
LTB4
ⴙ
MMP
Chemotaxis
HUMANIZED ANTIBODIES AS I M M U N O M O D U L AT O R S I N A S T H M A
ⴙ
Macrophage TNF-α
Chimeric humanized monoclonal antibodies with high target specificity and affinity and low antigenicity are now undergoing clinical trials. Examples include: • Anti-IgE antibody, which inhibits the binding of IgE to its high-affinity receptor. Preliminary trials suggest that this antibody reduces free serum IgE concentrations, target organ sensitivity to allergen provocation26 and oral glucocorticoid requirements in severe asthmatics.27 • Anti-CD4 antibody, which was shown transiently and specifically to reduce circulating numbers of CD4 T cells in the peripheral blood, with improvement of lung function and reduction of symptoms in a group of chronic, severe asthmatics.28 It seems likely that a range of such monoclonal antibodies with more restricted target specificity (for example, antiIL-5 antibodies) will appear and undergo assessment in the near future for their possible benefits in asthma therapy (see Chapter 62).
Elastase
IL-8, LTB4
IL-8
CD8 T cell
Neutrophil IL-8
Epithelial cell
ⴙ Antiproteases
Fig. 56.2. Pathogenesis of COPD. Cigarette smoke activates alveolar macrophages, and may produce an initial neurogenic neutrophil leak into the airways, amplified by local release of neutrophil chemoattractants such as leukotriene B4 (LTB4), both from neutrophils themselves and secondary to the effects of their proteinases on macrophages. Neutrophil chemoattracting CXC chemokines, of which IL-8 is prototypical, may be released from neutrophils and macrophages, as well as bronchial epithelial cells in response to cigarette smoke. The T cell- and macrophage-derived cytokine TNF-a, which further augments IL-8 secretion, has been measured in induced sputum from COPD patients. Although T cells, particularly CD8 cells, may also be attracted by CXC chemokines including IL-8, the role of these cells, if any, remains obscure. While it is easy to see how proteinases derived from neutrophils and macrophages may overwhelm endogenous anti-proteinases to cause emphysema, it is less clear how they could cause obliterative bronchiolitis of the small airways.
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role for T cells. As with asthma (Fig. 56.1), the scheme takes no account of why the process persists in some individuals but not others. Glucocorticoids as prototype immunomodulators in COPD Glucocorticoids, which are so effective in most (but not all, as we have seen) patients with asthma, appear to be ineffective in reducing airway inflammation and proteinase expression in COPD,32 neither do they significantly reduce the accelerated decline in lung function which characterizes the disease.33 This raises the question whether or not COPD is a disease susceptible to immunomodulation in a manner similar to asthma. There is no good evidence to date that COPD inflammation is driven by T cell cytokines. Furthermore, in stark contrast to other granulocytes, including eosinophils, glucocorticoids are generally facilitatory to neutrophil differentiation and survival.34 It may be the case that COPD is not susceptible to T cell-directed immunomodulatory strategies. Alternative therapeutic strategies in COPD If the scheme in Fig. 56.2 approximates to the truth, it may be inferred that therapeutic approaches to COPD may involve the use of inhibitors of macrophage and neutrophil function, leukotriene inhibitors and inhibitors of cytokines or chemokines and/or their actions on target cells, and measures which increase proteinase inhibition (Chapter 62). It should not be forgotten that, at present, the only effective therapeutic maneuver for COPD is smoking cessation.
REFERENCES 1. Corrigan CJ, Haczku A, Gemou-Engesaeth V et al. CD4 T lymphocyte activation in asthma is accompanied by increased serum concentrations of interleukin-5: effect of glucocorticoid therapy. Am. Rev. Respir. Dis. 1993; 147:540–7. 2. Doi S, Gemou-Engesaeth V, Kay AB et al. Polymerase chain reaction quantification of cytokine messenger RNA expression in peripheral blood mononuclear cells of patients with severe asthma: effect of glucocorticoid therapy. Clin. Exp. Allergy 1994; 24:854–67. 3. Corrigan CJ, Hamid Q, North J et al. Peripheral blood CD4, but not CD8 T lymphocytes in patients with exacerbation of asthma transcribe and translate messenger RNA encoding cytokines which prolong eosinophil survival in the context of a Th2-type pattern: effect of glucocorticoid therapy. Am. J. Respir. Cell. Mol. Biol. 1995; 12:567–78. 4. Suzuki S, Okubo M, Kaise S et al. Gold sodium thiomalate selectively inhibits interleukin-5 mediated eosinophil survival. J. Allergy Clin. Immunol. 1995; 96:251–6. 5. Marone G, Columbo M, Galeone D et al. Modulation of the release of histamine and arachidonic acid metabolites from human basophils and mast cells by auranofin. Agents Actions 1986; 18:100–2. 6. Parente JE, Wong K, Davis P et al. Effects of gold compounds on leukotriene B4, leukotriene C4 and prostaglandin E2 production by polymorphonuclear leukocytes. J. Rheumatol. 1986; 13:47–51. 7. Bratt J, Belcher J, Vercellotti GM et al. Effects of anti-rheumatic gold salts on NF-kappa B mobilisation and tumour necrosis
factor-alpha-induced neutrophil-dependent cytotoxicity for human endothelial cells. Clin. Exp. Immunol. 2000; 120:79–84. 8. Nierop G, Gijzel WP, Bel EH et al. Auranofin in the treatment of steroid dependent asthma: a double blind study. Thorax 1992; 47:349–54. 9. Bernstein IL, Bernstein DI, Dubb JW et al. A placebo-controlled multicenter study of auranofin in the treatment of patients with corticosteroid-dependent asthma. Auranofin Multicenter Drug Trial. J. Allergy Clin. Immunol. 1996; 98:317–24. 10. Tomioka H, King TE. Gold-induced pulmonary disease: clinical features, outcome, and differentiation from rheumatoid lung disease. Am. J. Respir. Crit. Care Med. 1997; 155:1011–20. 11. Bernstein IL, Bernstein DI, Bernstein JA. How does auranofin compare with methotrexate and cyclosporin as a corticosteroidsparing agent in severe asthma? Biodrugs 1997; 8: 205–15. 12. Cronstein BN. Methotrexate and its mechanism of action. Arthritis Rheum. 1996; 39:1951–60. 13. Aaron SD, Dales RE, Pham B. Management of steroid-dependent asthma with methotrexate: a meta-analysis of randomised clinical trials. Respir. Med. 1998; 92:1059–65. 14. Marin MG. Low-dose methotrexate spares steroid usage in steroiddependent chronic asthmatic patients: a meta-analysis. Chest 1997; 112:29–33. 15. Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent in adult asthma (Cochrane review). In: The Cochrane Library, Issue 3, Oxford:Update software, 2000. 16. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol.Today 1992; 13:136–42. 17. Alexander AG, Barnes NC, Kay AB. Trial of cyclosporin in corticosteroid-dependent chronic severe asthma. Lancet 1992; 339:324–8. 18. Lock SH, Kay AB, Barnes NC. Double blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma. Am. J. Respir. Crit. Care Med. 1993; 153:509–14. 19. Kishiyama JL, Valacer D, Cunningham-Rundles C et al. A multicentre, randomised, double blind, placebo-controlled trial of high-dose intravenous immunoglobulin for oral corticosteroiddependent asthma. Clin. Immunol. 1999; 91:126–33. 20. Salmun LM, Barlan I, Wolf HM et al. Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: a double blind, placebo-controlled, randomised trial. J. Allergy Clin. Immunol. 1999; 103:810–15. 21. Niggemann B, Leupold W, Schuster A et al. Prospective, doubleblind, placebo-controlled, multicentre study on the effect of high-dose intravenous immunoglobulin in children and adolescents with severe bronchial asthma. Clin. Exp. Allergy 1998; 28:205–10. 22. Lack G, Ochs HD, Gelfand EW. Humoral immunity in steroiddependent children with asthma and hypogammaglobulinaemia. J. Pediatr. 1996; 129:898–903. 23. Spahn JD, Leung DYM, Chan MTS et al. Mechanisms of glucocorticoid reduction in subjects treated with intravenous immunoglobulin. J. Allergy Clin. Immunol. 1999; 103:421–6. 24. Sigman K, Ghibu F, Sommerville W et al. Intravenous immunoglobulin inhibits IgE production in human B lymphocytes. J. Allergy Clin. Immunol. 1998; 102:421–7. 25. Dumont FJ, Su Q. Mechanism of action of the immunosuppressant rapamycin. Life Sci. 1995; 58:373–95. 26. Fahy JV, Fleming HE, Wong HH et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am. J. Respir. Crit. Care Med. 1997; 155:1828–34. 27. Milgrom H, Fick RB, Su JQ et al.Treatment of allergic asthma with monoclonal anti-IgE antibody. N. Engl. J. Med. 1999; 341:1966–73. 28. Kon OM, Sihra BS, Compton CH et al. Randomised, doseranging, placebo-controlled study of chimeric anti-CD4 (keliximab) in chronic severe asthma. Lancet 1998; 352:1109–13.
Immunomodulators
29. Lams BEA, Sousa AR, Rees PJ et al. Immunopathology of the small airways submucosa in smokers with and without chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 158:1518–23. 30. Lams BEA, Sousa AR, Rees PJ et al. Immunopathology of the large airways submucosa in smokers with and without chronic obstructive pulmonary disease. Eur. Respir. J. 2000; 15:512–16. 31. Saetta M, Di Stefano A, Turato G et al. CD8+ T lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 157:822–6.
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32. Culpitt SV, Nightingale JA, Barnes PJ. Effect of high dose inhaled steroid on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1635–9. 33. Burge PS, Calverley PMA, Jones PW et al. Randomised double blind, placebo-controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br. Med. J. 2000; 320:1297–303. 34. Meagher LC, Cousin JM, Seckl JR et al. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J. Immunol. 1996; 156:4422–8.
Pulmonary Vasodilators
Chapter
57
Richard N. Channick and Lewis J. Rubin Division of Pulmonary and Critical Care Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
Pulmonary hypertension is a common complication of severe COPD and contributes substantively to both its morbidity and mortality.1 In general, the presence and severity of pulmonary vascular disease correlates closely with indices of the degree of severity of chronic airflow obstruction and hypoxemia. Patients with an FEV1 less than 1 L or a PaO2 <55 torr usually have some degree of altered pulmonary hemodynamic state. Furthermore, acute exacerbations of COPD which result in worsening gas exchange are likely to produce acute deteriorations in pulmonary hemodynamics, which further compromise oxygen transport to peripheral tissues. Although the perturbations in pulmonary hemodynamics tend to be less severe in COPD as compared to other pulmonary vascular diseases such as primary pulmonary hypertension (PPH) or chronic thromboembolic pulmonary hypertension (CTEPH), the presence of pulmonary hypertension in COPD is an ominous prognostic sign, with a survival which is similar to inoperable lung cancer.1 Accordingly, considerable effort has been made in understanding the pathogenesis of pulmonary hypertension in COPD and in attempting to develop strategies for its treatment.
PAT H O G E N E S I S O F P U L M O N A RY HYPERTENSION IN COPD Several factors contribute to the development of pulmonary hypertension in COPD: • Loss of cross-sectional vascular surface area. As a result of the widespread destruction of airways and lung parenchyma typical of emphysema, there is also concomitant loss of vasculature, leading to an increase in perfusion pressure to accommodate pulmonary blood flow. In addition, increases in pulmonary blood flow, such as those that occur with physical activity, are associated with further increases in pulmonary artery pressure owing to the loss of vascular distensibility and the inability to recruit unused vasculature. This process is, by its very nature, irreversible.2
• Dynamic pulmonary vasoconstriction. The muscular pulmonary arteries respond with constriction to a variety of stimuli that are common in COPD (Chapter 19). Of these, hypoxia is the most potent and frequent stimulus for pulmonary vasoconstriction; hypoxic pulmonary vasoconstriction (HPV) is unique to pulmonary artery smooth muscle cells and is due to inhibition of an oxygen (or redox)-sensitive membrane-bound K+ channel, leading to cell depolarization and increased intracellular Ca++ concentrations.3 Impaired endothelial function may also be present and further contributes to the vasoconstriction resulting from diminished production of endothelialderived relaxing factors such as nitric oxide (NO) and prostacyclin (PGI2). • Pulmonary vascular remodeling. As a result of vasoconstriction and altered endothelial function, severe COPD results in the elaboration of a variety of promoters of vascular growth and remodeling (Chapter 19). Among these, endothelin, platelet-derived growth factor, and transforming growth factor have been suggested as playing major roles in the evolution of the chronically hypertensive pulmonary vascular bed. In concert, these and other mitogens promote endothelial and smooth muscle proliferation and extension of smooth muscle cells into the smaller, peripheral vessels.4 Although this remodeling process may be modified by restoration of normoxic conditions, the amelioration is usually incomplete. It is clear that the mechanisms by which chronic hypoxia induces pulmonary vascular remodeling are complex. One proposed schema is shown in Fig. 57.1.
PAT H O P H Y S I O L O G Y O F P U L M O N A RY HYPERTENSION IN COPD As a result of the aforementioned processes, the narrowing of the vascular lumen produces elevations in pulmonary artery pressure and pulmonary vascular resistance. Furthermore, pressures increase further with exercise or with acute exacerbations associated with deteriorations in gas
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Tissue responses to ischemia
Vasoconstrictor
Perspective series
Shear stress Precapillary artery muscularization
Chronic hypoxia H
IF
-α
Isc
in d
he
Production of VSMC growth factors
HI
ep
m ia
F1 end α e nt
/r e p e
Fewer precapillary arteries
Reactive oxygen species
re s p o
nses rf u si o n inju r y ?
VSMC hypertrophy VSMC growth Endothelial cellderived VSMC?
Protease activity Apoptosis Inflammatory response
Fig. 57.1. Possible mechanisms of hypoxia-induced pulmonary vascular remodeling. Reproduced from Reference 4.
exchange. The increased right ventricular afterload may eventually lead to impaired right ventricular output and, if severe and progressive, right ventricular failure ensues. Although the term cor pulmonale is frequently used to describe right heart failure, it is more appropriately used to define pulmonary vascular disease in the setting of respiratory disease; right heart failure is a late and unusual complication of cor pulmonale, particularly in the present era of widespread availability of supplemental oxygen therapy for chronic hypoxemia.
VA S O D I L AT O R T H E R A P Y F O R P U L M O N A RY H Y P E R T E N S I O N I N C O P D Rationale The rationale for the use of vasodilators in cor pulmonale is based on the premise that active vasoconstriction is a key element in its pathogenesis, and that some systemic vasodilators also exert this effect on the pulmonary circulation. Indeed, a variety of systemic antihypertensive agents have been shown to reduce pulmonary artery pressure in experimental animals with pulmonary hypertension produced by acute hypoxic ventilation or the administration of pulmonary vasoconstrictor agents.5 Unfortunately, as described above, the pulmonary hypertensive state is the result of more than simple vasoconstriction, with remodeling playing a pivotal role. Thus, antihypertensive drugs that also have vascular remodeling effects, such as angiotensinconverting enzyme or angiotensin synthesis inhibitors and endothelin receptor blockers, may be particularly attractive agents to treat hypertensive pulmonary vascular disease.6 In animal models of chronic pulmonary hypertension, both of these classes of drugs attenuate the vascular remodeling produced by a variety of pulmonary vascular injuries.7 However, to date there have been few clinical trials evaluating these agents in patients with cor pulmonale (Table 57.1).
Table 57.1. Pulmonary vasodilators in COPD
Existing agents
New agents
Oxygen Hydralazine Oral nitrates Calcium channel blockers Nitric oxide Prostacyclin
ACE inhibitors Endothelin antagonists
CLINICAL STUDIES Oxygen It is important to remember that supplemental oxygen, a selective pulmonary vasodilator, is the only pulmonary “vasodilator” which has been demonstrated to improve survival in COPD, although the hemodynamic effects are variable.8–10 It is likely that the favorable impact of oxygen therapy on survival in COPD is due to a variety of effects, including optimizing myocardial and other peripheral tissue oxygen delivery. Oral vasodilators Several studies have evaluated other vasodilators in patients with COPD. Studies, until recently, focused on oral vasodilators, including hydralazine,11 oral nitrates, and calcium channel antagonists.12–19 Several small reports have consistently demonstrated an acute pulmonary vasodilating effect from the administration of calcium channel blockers, including nifedipine,12–15 felodipine,16,17 verapamil,18 and diltiazem.18 However the magnitude of this effect is quite variable, ranging from 10 to 30%, depending on the study. In addition, nifedipine has been shown to reduce PaO2, presumably by inhibition of HPV and worsening V/Q matching,
Pulmonary Vasodilators
an effect which is magnified during exercise and with supplemental oxygen administration.12 Possibly mitigating the worsening of arterial oxygenation by nifedipine, however, are data demonstrating improvement in cardiac output and oxygen delivery during nifedipine administration.12,19 Given the modest hemodynamic effects, at least at rest, of oral vasodilators, and the relatively mild nature of the pulmonary hypertension, at least at rest, observed in COPD, it is reasonable to question whether oral vasodilators have any long-term clinical utility in these patients. To date, there have been no large placebo-controlled trials addressing this issue. There are several controlled studies, however. Vestri and coworkers20 found that, compared to a well-matched control group, no significant objective improvement occurred with 1 year of nifedipine. Interestingly, a significant improvement in dyspnea was seen in the nifedipine group. Similarly, Domenighetti et al.14 found that, even in a subgroup of COPD patients with marked acute pulmonary vasodilation in response to nifedipine (43% decrease in PAP mean), clinical deterioration over 12 months occurred. Sajkov et al.,16 in a 12-week study of another calcium channel antagonist, felodipine, found reductions in pulmonary arterial pressure and pulmonary vascular resistance that were felt to be significant (22% and 30%, respectively). However, exercise capacity was not improved. One theoretical limitation of pulmonary vasodilator therapy, in general, is that although the presence of pulmonary hypertension is an ominous prognostic sign in COPD, it may merely serve as a marker of disease severity and not contribute substantively, per se, to symptom limitation or survival. Unlike patients with other forms of pulmonary vascular disease such as PPH, CTEPH, and connective tissue disease, patients with cor pulmonale are primarily symptom-limited not by the cardiovascular process but by the airway and parenchymal lung disease.21 Right ventricular function is not normal, but is usually not severely depressed, although the compensatory mechanisms may fall short during acute exacerbations of airway disease. Accordingly, improving the pulmonary hemodynamic state may not result in improved activity tolerance or survival in this disease. Another concern regarding vasodilator use is that cor pulmonale is typically a disease of older patients, a population that is also prone to have coexistent coronary artery disease. Vasodilators can increase cardiac work if tachycardia is produced, while at the same time they can also “steal” blood flow away from areas of anatomic obstruction, leading to worsening cardiac ischemia. Finally, systemically administered agents exert nonselective cardiovascular effects, including systemic hypotension, tachycardia, and potentially negative inotropic myocardial effects. While these effects may be dose-related, they can occur in patients even at low doses and can limit the utility of vasodilators. In conclusion, presently available data suggest that oral calcium channel blockers do cause acute reductions in pulmonary artery pressure and pulmonary vascular resist-
607
ance, and modest increases in cardiac output in COPD patients. However, there is no convincing evidence of any improvement in exercise capacity or outcome in these patients. Nitric oxide More recently, interest has focused on inhaled pulmonary vasodilators such as nitric oxide. The theoretical advantage of an inhaled pulmonary vasodilator is that its delivery to better ventilated lung regions might actually improve gas exchange, by shifting perfusion to these well-ventilated regions. This, in fact, occurs in ARDS,22 in which marked increases in PaO2 occur in over two-thirds of patients given inhaled NO. The data in COPD, however, are conflicting. Both improvement23–25 and deterioration26,27 in resting arterial oxygenation have been reported in COPD patients given inhaled NO, despite comparable degrees of pulmonary vasodilation. These “conflicting” results may, in fact, reflect ˙ disturbances seen in COPD. the heterogeneity of the V˙/Q ˙ areas are present, inhaled NO For instance, if more low V˙/Q ˙ may reach some of these lung units and actually worsen V˙/Q matching, a phenomenon reproduced in an animal study by Hopkins et al.28 On the other hand, if the predominant disturbance is shunt, inhaled NO would tend to improve oxygenation by shifting perfusion away from non-ventilated regions. The effects of inhaled NO on gas exchange during exercise may, in fact, be even more important. Roger and colleagues24 found that inhaled NO, despite worsening oxygenation at rest, actually prevented exercise induced O2 desaturation in patients with COPD, possibly due to preferential distribution of NO to well-ventilated regions during exercise. However, despite potential beneficial effects of inhaled NO during exercise in COPD patients, exercise limitation is generally not due to either O2 desaturation or pulmonary hypertension. Thus, it is uncertain whether or not chronic NO administration would benefit these patients. Suggested guidelines for the use of vasodilators in COPD Current experience does not support the widespread use of systemically active vasodilators in cor pulmonale, owing to the hazards described above and the dearth of studies demonstrating sustained clinical benefit. Nevertheless, there are selected patients who appear to have alterations in pulmonary hemodynamics which are out of proportion to the severity of chronic respiratory disease and in whom conventional approaches to therapy are only partially successful. In those patients, if evidence of significant pulmonary vasoreactivity can be demonstrated in response to acutely inhaled NO or intravenous prostacyclin, the administration of a calcium channel blocking agent such as nifedipine or diltiazem may be warranted. Doses should be titrated based on individual tolerance, as guided by pulse, blood pressure, and oxygen saturation. The development or worsening of pedal edema may be indicative of the salt and
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water retention effects or the negative inotropic effects of these drugs, and differentiating between these may be challenging. Administration of a diuretic may be useful, but caution should be exercised so as not to reduce intravascular volume excessively, since the right ventricle is preload dependent; furthermore, excessive diuresis can produce a contraction metabolic alkalosis which results in respiratory compensation – further worsening the already compromised ventilatory state in these patients. The effects of vasodilator therapy should be monitored using some clinically meaningful parameter, such as objective testing of cardiopulmonary exercise tolerance, noninvasive evaluation of right heart size and function using echocardiography, or invasive measurements of cardiopulmonary hemodynamics. Theoretically, the use of pulmonary vasodilators in the setting of acute cor pulmonale may be more appealing than their use in the chronic state, owing to the acute and therefore potentially reversible component and the impact of this alteration on morbidity and mortality. Unfortunately, no clinical trials have addressed the role of vasodilators in this population; furthermore, the deleterious effects of vasodilators may be particularly problematic in this setting. The use of more selective agents, such as NO by inhalation, would be preferred in the acutely decompensated patient. The impact of this therapy, however, remains unproven.
S U M M A RY While pulmonary hypertension remains a serious complication of chronic obstructive pulmonary disease, effective therapy has been elusive. It is likely that pharmacological agents that exert both vasodilator and antiproliferative effects are most likely to produce sustained improvement in cardiopulmonary hemodynamics, although the impact of this therapy on symptoms and survival in COPD remains unknown. In addition, delivery of these agents in a manner that facilitates selectivity of their effects to the pulmonary vasculature, such as by the inhaled route would be preferable in order to minimize the adverse effects of systemic vasodilatation. As our understanding of the molecular basis for the pulmonary vascular remodeling in COPD unfolds, targeted therapy should be feasible and could be combined with other modalities in order to both prevent and treat the vascular complications of end-stage chronic obstructive pulmonary disease.
REFERENCES 1. Traver G, Kline M, Burrows B. Predictors of mortality in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1979; 119: 895–902. 2. Rubin LJ, Tod ML, Yoshimura K. Effects of nitrendipine and hypoxia on pulmonary vascular resistance in emphysema. Am. Rev. Respir. Dis. 1990; 142: 625–30.
3. Wang J, Juhaszova M, Rubin LJ et al. Hypoxia inhibits gene expression of voltage-gated K channel alpha subunits in pulmonary artery smooth muscle cells. J. Clin. Invest. 1997; 100:2347–53. 4. Voelkel NF, Tuder RM. Hypoxia-induced pulmonary vascular remodeling: a model for what human disease? J. Clin. Invest. 2000; 106:733–8. 5. Young T, Lundquist L, Chesler E, Weir E. Comparative effects of nifedipine, verapamil and diltiazem on experimental pulmonary hypertension. Am. J. Cardiol. 1983; 51:195–200. 6. Rubin LJ. The renin-angiotensin system and the “lesser circulation”: A role in cor pulmonale? Chest 1996; 110:584–5. 7. DiCarlo VS, Chen S, Meng QC et al. Endothelin receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in the rat. Am. J. Physiol. 1995; 269:E1037–43. 8. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1:681–6. 9. Tims R, Khaja F, Williams G. Hemodynamic response to oxygen therapy in chronic obstructive pulmonary disease. Ann. Intern. Med. 1985; 102:29–36. 10. Weitzenblum E, Oswald M, Mirhom R, Kessler R, Apprill M. Evolution of pulmonary haemodynamics in COLD patients under long-term oxygen therapy. Eur. Respir. J. 1989; 2(Suppl. 7):669S–73S. 11. Dal Nogare A, Rubin LJ. Effects of hydralazine on exercise capacity in pulmonary hypertension secondary to chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1986; 133:385–9. 12. Kennedy TP, Michael JR, Huang CK et al. Nifedipine inhibits hypoxic pulmonary vasoconstriction during rest and exercise in patients with chronic obstructive pulmonary disease. A controlled double-blind study. Am. Rev. Respir. Dis. 1984; 129:544–51. 13. Agostoni P, Doria E, Galli C, Tamborini G, Guazzi MD. Nifedipine reduces pulmonary pressure and vascular tone during shortbut not long-term treatment of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1989; 139:120–5. 14. Domenighetti GM, Saglini VG. Short- and long-term hemodynamic effects of oral nifedipine in patients with pulmonary hypertension secondary to COPD and lung fibrosis. Deleterious effects in patients with restrictive disease. Chest 1992; 102:708–14. 15. Burghuber OC. Nifedipine attenuates acute hypoxic pulmonary vasoconstriction in patients with chronic obstructive pulmonary disease. Respiration 1987; 52:86–93. 16. Sajkov D, McEvoy RD, Cowie RJ et al. Felodipine improves pulmonary hemodynamics in chronic obstructive pulmonary disease. Chest 1993; 103:1354–61. 17. Bratel T, Hedenstierna G, Nyquist O, Ripe E.The use of a vasodilator, felodipine as an adjuvant to long-term oxygen treatment in COLD patients. Eur. Respir. J. 1990; 3:46–54. 18. Gassner A, Sommer G, Fridrich L, Magometschnigg D, Priol A. Differential therapy with calcium antagonists in pulmonary hypertension secondary to COPD. Hemodynamic effects of nifedipine, diltiazem, and verapamil. Chest 1990; 98:829–34. 19. Saadjian AY, Philip-Joet FF, Vestri R, Arnaud AG. Long-term treatment of chronic obstructive lung disease by Nifedipine: An 18-month haemodynamic study. Eur. Respir. J. 1988; 1:716–20. 20. Vestri R, Philip-Joet F, Surpas P, Arnaud A, Saadjian A. One-year clinical study on nifedipine in the treatment of pulmonary hypertension in chronic obstructive lung disease. Respiration 1988; 54:139–44. 21. Rubin LJ. Primary pulmonary hypertension. N. Engl. J. Med. 1997; 336:111–17. 22. Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N. Engl. J. Med. 1993; 328:399–405.
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23. Adnot S, Kouyoumdjian C, Defouilloy C et al. Hemodynamic and gas exchange responses to infusion of acetylcholine and inhalation of nitric oxide in patients with chronic obstructive lung disease and pulmonary hypertension. Am. Rev. Respir. Dis. 1993; 148:310–16. 24. Roger N, Barbera JA, Roca J, Rovira I, Gomez FP, RodriguezRoisin R. Nitric oxide inhalation during exercise in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 156:800–6. 25. Yoshida M, Taguchi O, Gabazza EC et al. Combined inhalation of nitric oxide and oxygen in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 155:526–9.
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26. Moinard J, Manier G, Pillet O, Castaing . . Y. Effect of inhaled nitric oxide on hemodynamics and V A/Q inequalities in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1994; 149:1482–7. 27. Barbera JA, Roger N, Roca J, Rovira I, Higenbottam TW, Rodriguez-Roisin R.Worsening of pulmonary gas exchange with nitric oxide inhalation in chronic obstructive pulmonary disease. Lancet 1996; 347:436–40. 28. Hopkins SR, Johnson EC, Richardson RS, Wagner H, De Rosa M, Wagner PD. Effects of inhaled nitric oxide on gas exchange in lungs with shunt or poorly ventilated areas. Am. J. Respir. Crit. Care Med. 1997; 156:484–9.
Chapter
Ventilator Support
58
Samuel L. Krachman Temple University, Philadelphia, PA, USA
Martin J. Tobin LoyolaUniversity of Chicago Stritch School of Medicine and Hines Veterans Administration Hospital, Maywood, IL,USA
In patients with obstructive lung disease, the development of acute respiratory failure is a common cause for admission to the intensive care unit (ICU).1–5 Between 3 and 58% of patients1,2,4,5 require mechanical ventilation, with an associated mortality of 6 to 30%.6–8 The high mortality may be a consequence of both disease severity and complications of mechanical ventilation.
I N D I C AT I O N S F O R V E N T I L AT O R SUPPORT When severe hypoxemia develops in patients with asthma9 and COPD,10 intubation and mechanical ventilation may be necessary to ensure the delivery of a sufficiently high fractional inspired oxygen concentration (FIO2). The development of an acute respiratory acidosis is another major indication for mechanical ventilation,11 although simpler measures can sometimes reverse the process.12 An increase in work of breathing, secondary to an increase in airway resistance13 or an inspiratory threshold load associated with auto- or intrinsic positive end expiratory pressure (PEEPi), often requires mechanical ventilation to rest the respiratory muscles and decrease the oxygen cost of breathing.
I N VA S I V E P O S I T I V E P R E S S U R E V E N T I L AT I O N Modes of mechanical ventilation Controlled ventilation With controlled mechanical ventilation, the ventilator delivers all breaths at a preset rate and the patient cannot trigger the machine. With volume-controlled ventilation, breaths have a preset volume (volume-targeted), whereas with pressure-controlled ventilation breaths are pressure-limited and time-cycled.14 Use of volume-controlled ventilation is largely restricted to patients who are apneic as a result of brain damage, sedation or paralysis.
Assist-control ventilation In the assist-control (AC) mode, the ventilator delivers a breath either when triggered by the patient’s inspiratory effort or independently if such an effort does not occur within a preselected period. All breaths are delivered under positive pressure by the machine, but unlike controlled ventilation the patient’s triggering efforts commonly exceed the preset rate. The amount of active work performed by a patient is critically dependent on the trigger sensitivity and inspiratory flow settings. Even when these settings are optimized, patients actively perform about one-third of the work performed by the ventilator during passive conditions.15,16 Intermittent mandatory ventilation With intermittent mandatory ventilation (IMV), the patient receives periodic positive-pressure breaths from the ventilator at a preset volume and rate, but the patient can also breathe spontaneously between these ventilator breaths.17 With synchronized IMV, the ventilator waits until the patient begins to inhale and then synchronizes the machine breath with the patient’s inspiratory effort. If a patient does not make an effort within a preset time, the ventilator delivers a positive-pressure breath. With IMV, patients frequently have difficulty in adapting to the intermittent nature of assistance. It was previously assumed that respiratory muscle rest was proportional to the number of machine-assisted breaths. Recent studies, however, indicate that inspiratory effort is equivalent for spontaneous and assisted breaths.18–20 At a moderate level of machine assistance, i.e. where the ventilator accounted for 20–50% of the total ventilation, electromyographic activities of the diaphragm and sternomastoid muscles were equivalent for assisted and spontaneous breaths.19 These findings suggest that respiratory center output is pre-programmed and is unable to adjust to breath-tobreath changes in unloading. As a result, IMV may contribute to the development of respiratory muscle fatigue or prevent its recovery.
Asthma and Chronic Obstructive Pulmonary Disease
Pressure support ventilation Pressure support (PS) ventilation is patient-triggered like AC and IMV, but differs in being pressure-targeted and flow-cycled.21 The physician sets a level of pressure that augments every spontaneous effort, and the patient can alter respiratory frequency, inspiratory time and tidal volume. A fall in airway pressure triggers the ventilator, which in turn increases pressure to a preset value. Accordingly, the pressure to inflate the lungs and chest wall is provided jointly by the ventilator and the patient. Unlike the guaranteed volume achieved by AC and IMV, tidal volume varies depending on the set pressure, patient effort and pulmonary mechanics. The lack of guaranteed assistance in the absence of patient effort can cause apnea in patients with an unstable respiratory center output. Cycling to exhalation is triggered by a decrease in inspiratory flow to a preset level, such as 5 L/min or 25% of the peak inspiratory flow. Inspiratory assistance can also be terminated by a small increase in pressure (1–3 cm H2O) above the preset level, resulting from expiratory effort.21 PS is very effective in decreasing the work of inspiration. The degree of inspiratory muscle unloading, however, is variable, with a coefficient of variation of up to 96% among patients.22 In patients with COPD, the variability in the work of breathing can be explained by the inspiratory resistance, minute ventilation, and degree of PEEPi.22 Of note, PS does not decrease PEEPi in patients with COPD.22,23 Instead, increasing levels of PS increase the contribution from PEEPi to the overall work of breathing, accounting for approximately two-thirds of the inspiratory effort.22 The algorithm used to terminate inspiratory assistance during PS can also affect the work of breathing in patients with COPD. Patients with a prolonged time constant require more time for flow to fall to this threshold, and consequently, mechanical inflation may persist into neural expiration. To counteract such neural–mechanical dysynchrony, patients may activate their expiratory muscles at a time when the ventilator is still inflating the thorax, causing the patient to fight the ventilator. There is no consensus for the appropriate level of PS for an individual patient. In one study, the level minimizing activity of the sternomastoid muscles also reversed electromyographic evidence of excessive diaphragmatic stress.21 Commonly, PS is titrated to achieve a decrease in respiratory frequency and an increase in tidal volume. Considerable discrepancy exists among studies as to the preferred target or “optimal” level of PS. Achieving a decrease in respiratory rate to 30/min was recently found to be a better predictor of a decrease in the work of breathing than achieving a tidal volume of 0.6 L.22 Increasing PS to achieve a low respiratory frequency and inspiratory muscle unloading may be accompanied by an increase in expiratory muscle activity, causing the patient to fight the ventilator.22 Thus, selecting the optimal level of PS can be quite complex. Comparison between modes of mechanical ventilation A head-to-head comparison of the common modes of assisted ventilation was recently conducted, with most of the
patients having COPD.20 Compared with spontaneous breathing, AC achieved the largest decrease in the work of breathing. The decrease in the work was greater for PS than for IMV at lower levels of support. Addition of PS of 10 cm H2O to a given level of IMV caused a greater reduction in the work of breathing (Fig. 58.1), not only during the intervening PS breaths, but also during the mandatory IMV breaths.The decrease in work during the mandatory breaths was proportional to the decrease in respiratory drive during the intervening breaths.
V E N T I L AT O R S E T T I N G S Fractional inspired oxygen concentration The lowest FIO2 that achieves satisfactory arterial oxygenation should be selected. With arterial blood samples, a SaO2 target of 90% is appropriate, but with pulse oximetry the same target can be associated with PaO2 values as low as 41 torr in black patients.24 Trigger sensitivity Most ventilators employ pressure triggering, whereby a decrease in circuit pressure is required to initiate the ventilator. With flow-triggering (sometimes termed “flow-by”), a base flow of gas (usually set at 5 to 20 L/min) is delivered during both the expiratory and inspiratory phases of the respiratory cycle.25 With patient effort, gas enters the patient’s lungs and is diverted from the exhalation port. The difference between inspiratory and expiratory base flow is sensed, causing the ventilator to switch phase; sensitivity is usually set at 2 L/min. A decrease in breathing effort is noted with flow triggering in the PS, but not the AC, mode.26
400 IMV PS IMV PS 10 cm H2O
350 PTP/min, cm H2O s/min
612
300 250 200 150 100 50 0 0
20
40
60
80
100
Percent support by primary mode Fig. 58.1. At proportional levels of ventilator assistance, work, as measured by the pressure-time product (PTP/min), was significantly lower for the combination of IMV and PS of 10 cm H2O than for either PS or IMV alone (from Ref. 20, with permission).
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Tidal volume To prevent alveolar overdistension and lung injury, tidal volumes of 5 to 7 ml/kg (or less) have become increasingly popular.27 This ventilator strategy is termed permissive hypercapnia or controlled hypoventilation,28 because it commonly produces an increase in PaCO2. If pH falls below 7.20, some physicians administer intravenous bicarbonate, although its benefit is unproven.28 In patients with severe asthma requiring mechanical ventilation, most studies suggest that permissive hypercapnia decreases mortality.29,30 In a controlled study4 of patients with asthma and acute respiratory failure, pulmonary barotrauma and hypotension were significantly lower in patients electively hypoventilated. Respiratory rate Setting the ventilator rate depends on the mode being employed. With AC ventilation, the ventilator supplies a breath in response to each patient effort; the back-up rate should be set at approximately four breaths below the patient’s spontaneous rate. With IMV, the mandatory rate is initially set high and then gradually decreased according to patient tolerance. As discussed above, this common approach does not ensure adequate rest. With pressuresupport ventilation, the ventilator rate is not set. Inspiratory flow rate In patients with COPD, increasing inspiratory flow to 100 L/min produces better gas exchange, probably because the resulting increase in expiratory time allows more complete emptying of gas-trapped regions.31 Studies in healthy subjects,32 as well as in intubated patients,33 have demonstrated that increasing the inspiratory flow setting causes an immediate increase in respiratory frequency and respiratory drive. Yet, it has been recently demonstrated that imposed ventilator inspiratory time, independent of delivered inspiratory flow and tidal volume, can determine respiratory frequency.34
P O S I T I V E E N D - E X P I R AT O RY P R E S S U R E
increase in PEEPi is secondary to increased elastic recoil, rather than expiratory effort, the addition of external PEEP can decrease the inspiratory threshold load.35,36 Deciding the appropriate amount of external PEEP in patients with airflow limitation can be difficult because of regional inhomogeneities among lung units, each with its own critical closing pressure.37 If application of external PEEP causes an increase in end-expiratory lung volume, decreases in cardiac output and blood pressure are likely to follow.38–41 In general, a level of external PEEP approximately 70% of the PEEPi value is used in patients with COPD.38–41 In contrast to patients with airflow limitation secondary to COPD, PEEP should be avoided in patients with asthma, because it is likely to increase lung volume and decrease cardiac output.42
A N C I L L A RY T H E R A P Y Recent studies have established that it is possible to achieve satisfactory bronchodilation using a metered-dose inhaler (MDI) despite the presence of an endotracheal tube in mechanically ventilated patients. It is essential to follow a specified protocol, use an in-line chamber device,43 and actuate the MDI at the onset of inspiratory airflow. Maximal bronchodilation can be achieved in patients with COPD with as few as four puffs of a sympathomimetic aerosol (Fig. 58.2).44 Analgesic, anxiolytic, and neuromuscular blocking agents are frequently used in mechanically ventilated patients. When selecting an analgesic in a patient with asthma, use of morphine should be avoided because of the risk of histamine 20
4
16
18 ** ** ** **
**
**
16
**
**
**
**
14
0 0 5
In patients with COPD, dynamic hyperinflation results from dynamic airway collapse. The accompanying increase in alveolar pressure is termed PEEPi. To trigger the ventilator in this situation, the patient must first generate a negative inspiratory pressure equal in magnitude to PEEPi and then overcome the trigger sensitivity setting. Provided the
8
**P < 0.001
Rrsmax, cm H2O/L/ses
Triggering the ventilator is more difficult in patients with dynamic hyperinflation. In this situation, the patient must first generate sufficient pressure to offset the elastic recoil associated with hyperinflation, and thereafter overcome the sensitivity threshold. With all modes of ventilation, ineffective triggering increases in proportion to the level of assistance, secondary to a decrease in respiratory drive.20 Breaths preceding the non-triggered effort have a higher volume, shorter expiratory time, and a higher PEEPi.
15 20
40
60
80
Time, min Fig. 58.2. In mechanically ventilated patients with COPD, four puffs of albuterol with a metered dose inhaler (MDI) resulted in a significant decrease in maximal inspiratory airway resistance (Rrsmax) within 5 minutes, with no further improvement after a total of 28 puffs (from Ref. 41, with permission).
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release and worsening bronchospasm.45 Neuromuscular blocking agents can result in prolonged paralysis and the development of an acute myopathy.46,47 The concurrent use of corticosteroids appears to increase the risk. The inadvertent discontinuation of mechanical ventilation in patients receiving a neuromuscular blocking agent will cause complete apnea, leading to cardiopulmonary arrest. Train-offour monitoring is recommended while patients receive neuromuscular blocking agents, although clinical assessment at the bedside is equally important.48
C O M P L I C AT I O N S Patients receiving mechanical ventilation are at risk of numerous complications, including oxygen toxicity, air leaks, infection, endotracheal-tube complications, and decreased cardiac output. These problems occur frequently and they can be life threatening if not promptly detected and treated. Barotrauma The development of extra-alveolar air, in the form of pneumomediastinum, subpleural air cysts, subcutaneous emphysema, pneumothorax, or pneumoperitoneum is termed pulmonary barotrauma. These findings have been found in 14 to 27% of patients with obstructive lung disease receiving mechanical ventilation.4,7,8 Infection Pneumonia develops in 21% of patients receiving mechanical ventilation for over 48 hours.49 In mechanically ventilated patients with COPD, more than 40% of the patients have potentially pathogenic microorganisms present in their upper and lower airways, and have an increased risk of lifethreatening pneumonia.50 The diagnosis of pneumonia is often difficult in patients receiving mechanical ventilation, because clinical criteria are unreliable and airway colonization confounds the identification of causative organisms. Quantitative cultures of specimens obtained by bronchoalveolar lavage or with a protected specimen brush passed through the bronchoscope improve bacteriologic diagnosis,51 and may affect outcome.52 Effects on cardiac output Both PEEP and PEEPi can cause similar decreases in cardiac output, primarily by decreasing venous return. In addition, increases in pulmonary vascular resistance, secondary to alveolar distension and stretching of adjacent vessels, increases right ventricular afterload. As a result, the interventricular septum may shift to the left and decrease left ventricular compliance. Distended lung parenchyma may also increase juxtacardiac pressure and decrease left ventricular compliance. PEEPi has been noted in patients with COPD experiencing hemodynamic embarrassment.53 On discontinuation of mechanical ventilation, hemodynamics improved as the amount of PEEPi decreased.
WEANING About 70% of patients tolerate the first attempt to discontinue mechanical ventilation.54,55 Nevertheless, about 40 to 60% of total ventilator time is devoted to the process of weaning. Pathophysiology of weaning failure In patients with COPD, a decrease in respiratory motor output appears to be a rare cause for failure to wean.13 The major reason that patients with COPD fail weaning trials is because of a progressive increase in work of breathing secondary to increases in resistance, elastance and PEEPi. In contrast, pulmonary mechanics during passive ventilation are virtually indistinguishable in weaning success and weaning failure patients before a weaning trial.56 Respiratory muscle weakness is not a common cause of weaning failure,57 but whether these patients develop muscle fatigue has not been determined. Only a fraction of patients develop abnormal gas exchange, with the development of hypercapnia and/or hypoxemia.58 Rigorous studies of the pathophysiology of weaning failure in patients with asthma have not been conducted. Timing of weaning process Recent studies emphasize that clinical bedside assessment and physician judgment are insufficient in determining the appropriate time to initiate weaning.59 The best predictor of weaning outcome is the measurement of the frequency-totidal volume ratio, a measure of rapid shallow breathing. A frequency-to-tidal volume ratio above 100 breaths/minute/ liter suggests that weaning is not likely to be successful.57 Weaning techniques Four weaning techniques are generally used. With IMV and PS, the level of ventilator assistance is gradually reduced. Pressure support became popular as a means of overcoming the resistance of the endotracheal tube.This line of thinking, however, ignored the fact that the upper airway becomes swollen when an endotracheal tube has been in place, and after extubation patients will experience increased upper airway resistance. Indeed, the work of breathing following extubation is similar to that while breathing on a T-piece.60 The least popular methods are trials of spontaneous breathing performed once a day or several times a day using a Tpiece circuit. Several spontaneous trials have been performed comparing weaning techniques.54,61 IMV has been shown to delay the weaning process. A once-a-day trial of spontaneous breathing resulted in a three-fold increase in the rate of successful weaning compared with IMV, and a two-fold increase in successful weaning compared with PS. More recently, it has been found that outcome for spontaneous breathing trials is similar when they last only for 30 minutes or 2 hours. The use of a daily screen to assess weaning readiness shortens the time to successful extubation.62
Ventilator Support
N O N - I N VA S I V E P O S I T I V E P R E S S U R E V E N T I L AT I O N In patients with COPD and acute respiratory failure, the use of noninvasive positive pressure ventilation results in less frequent intubation, decreased complications, and a shorter hospital stay. In two of these studies, noninvasive positive pressure ventilation caused a decrease in mortality.63–65
CONCLUSIONS Patients with obstructive lung disease commonly develop acute respiratory failure, requiring the institution of mechanical ventilation. Abnormalities in pulmonary gas exchange, lung mechanics and respiratory muscle function contribute to the development of respiratory failure. Adapting ventilator strategies that account for these abnormalities, such as controlled hypoventilation in acute asthma or the application of external PEEP in patients with COPD, may decrease morbidity and possibly improve patient outcome.
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13. Jubran A, Tobin MJ. Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am. J. Respir. Crit. Care Med. 1997; 155:906–15. 14. Marini JJ. Pressure-controlled ventilation. In: Tobin MJ (ed.), Principles and Practice of Mechanical Ventilation, pp. 305–17. New York: McGraw-Hill, 1994. 15. Marini JJ, Capps JS, Culver BH. The inspiratory work of breathing during assisted mechanical ventilation. Chest 1985; 87:612–18. 16. Ward ME, Corbeil C, Gibbons W, Newman S, Macklem PT. Optimization of respiratory muscle relaxation during mechanical ventilation. Anesthesiology 1988; 69:29–35. 17. Sassoon CSH. Intermittent mandatory ventilation. In: Tobin MJ (ed.) Principles and Practice of Mechanical Ventilation, pp. 221–37. New York: McGraw-Hill, 1994. 18. Marini JJ, Smith TC, Lamb VJ. External work output and force generation during synchronized intermittent mechanical ventilation. Am. Rev. Respir. Dis. 1988; 138:1169–79. 19. Imsand C, Feihl F, Perret C, Fitting JW. Regulation of inspiratory neuromuscular output during synchronized intermittent mechanical ventilation. Anesthesiology 1994; 80:13–22. 20. Leung P, Jubran A, Tobin MJ. Comparison of assisted ventilator modes on triggering, patient effort and dyspnea. Am. J. Respir. Crit. Care Med. 1997; 155:1940–8. 21. Brochard L. Pressure support ventilation. In: Tobin MJ (ed.) Principles and Practice of Mechanical Ventilation, pp. 239–57. New York: McGraw-Hill, 1994. 22. Jubran A, Van de Graaff WB, Tobin MJ. Variability of patient– ventilator interaction with pressure support ventilation in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1995; 152:129–36. 23. Appendini L, Patessio A, Zanaboni S et al. Physiologic effects of positive end-expiratory pressure and mask pressure support during exacerbations of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1994; 149:1009–78. 24. Jubran A, Tobin MJ. Reliability of pulse oximetry in titrating supplemental oxygen therapy in ventilator-dependent patients. Chest 1990; 90:1420–5. 25. Hubmayr RD. Setting the ventilator. In: Tobin MJ (ed.) Principles and Practice of Mechanical Ventilation, pp. 191–206. New York: McGraw-Hill, 1994. 26. Aslanian P, El Atrous S, Isabey D et al. Effects of flow triggering on breathing effort during partial ventilatory support. Am. J. Respir. Crit. Care Med. 1998; 157:135–43. 27. Dreyfuss D, Saumon G. Ventilator-induced injury. In: Tobin MJ (ed.) Principles and Practice of Mechanical Ventilation, pp. 793–811. New York: McGraw-Hill, 1994. 28. Tuxen DV. Permissive hypercapnia. In: Tobin MJ (ed.) Principles and Practice of Mechanical Ventilation, pp. 371–92. New York: McGraw-Hill, 1994. 29. Darioli R, Perret C. Mechanical controlled hypoventilation in status asthmaticus. Am. Rev. Respir. Dis. 1984; 129:385–7. 30. Tuxen DV, Williams TJ, Scheinkestel CD, Czarny D, Bowes G. Use of a measurement of pulmonary hyperinflation to control the level of mechanical ventilation in patients with acute severe asthma. Am. Rev. Respir. Dis. 1992; 146:1136–42. 31. Connors AF Jr, McCaffree DR, Gray BA. Effect of inspiratory flow rate on gas exchange during mechanical ventilation. Am. Rev. Respir. Dis. 1981; 124:537–43. 32. Puddy A, Younes M. Effect on inspiratory flow rate on respiratory output in normal subjects. Am. Rev. Respir. Dis. 1992; 146:787–9. 33. Corne S, Gillespie D, Roberts D, Younes M. Effect of inspiratory flow rate on respiratory rate in intubated patients. Am. J. Respir. Crit. Care Med. 1997; 156:304–8. 34. Laghi F, Karamchandani K, Tobin M. Influence of ventilator settings in determining respiratory frequency during mechanical ventilation. Am. J. Respir. Crit. Care Med. 1999; 160:1766–70.
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35. Rossi A, Gottfried SB, Zocchi L et al. Measurement of static compliance of the total respiratory system in patients with acute respiratory failure: the effect of intrinsic positive end-expiratory pressure. Am. Rev. Respir. Dis. 1985; 131:672–7. 36. Smith TC, Marini JJ. Impact of PEEP on lung mechanics and work of breathing in severe airflow obstruction. J. Appl. Physiol. 1988; 65:1488–99. 37. Schnader J. Estimation of auto-PEEP (letter). Chest 1991; 99:520. 38. Petrof BJ, Legare M, Goldberg P, Milic-Emili J, Gottfried SB. Continuous positive airway pressure reduces work of breathing and dyspnea during weaning from mechanical ventilation in severe chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1990; 141:281–9. 39. Georgopoulos D, Giannouli E, Patakas D. Effects of extrinsic positive end-expiratory pressure on mechanically ventilated patients with chronic obstructive pulmonary disease and dynamic hyperinflation. Intens. Care Med. 1993; 19:197–203. 40. Ranieri VM, Guiliani R, Cinnella G. Physiologic effects of positive end-expiratory pressure in patients with chronic obstructive pulmonary disease during acute ventilatory failure and controlled mechanical ventilation. Am. Rev. Respir. Dis. 1993; 147:5–13. 41. Rossi A, Santos C, Roca J, Torres A, Felez MA, Rodriguez-Roisin R. Effects of PEEP on V/Q mismatching in ventilated patients with chronic airflow obstruction. Am. J. Respir. Crit. Care Med. 1994; 149:1077–84. 42. Tuxen DV. Detrimental effects of positive end-expiratory pressure during controlled mechanical ventilation of patients with severe airflow obstruction. Am. Rev. Respir. Dis. 1989; 140:5–9. 43. Dhand R, Tobin MJ. Bronchodilator delivery with metered-dose inhalers in mechanically ventilated patients. Eur. Respir. J. 1996; 9:585–95. 44. Dhand R, Duarte AG, Jubran A et al. Dose response to bronchodilator delivered by metered-dose inhaler in ventilatorsupported patients. Am. J. Respir. Crit. Care Med. 1996; 154:388–93. 45. Wheeler AP. Sedation, analgesia, and paralysis in the intensive care unit. Chest 1993; 104:566–77. 46. Manthous CA, Chatila W. Prolonged weakness after the withdrawal of atracurium. Am. J. Respir. Crit. Care Med. 1994; 150: 1441–3. 47. Leatherman JW, Fluegel WL, David WS, Davies SF, Iber C. Muscle weakness in mechanically ventilated patients with severe asthma. Am. J. Respir. Crit. Care Med. 1996; 153:1686–90. 48. Strange C,Vaughan L, Franklin C, Johnson J. Comparison of trainof-four and best clinical assessment during continuous paralysis. Am. J. Respir. Crit. Care Med. 1997; 156:1556–61. 49. Fagon JY, Chastre J, Hance A et al. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Am. J. Med. 1993; 94:281–8. 50. Soler N, Torres A, Ewig S et al. Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease
51.
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55.
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61.
62.
63.
64.
65.
(COPD) requiring mechanical ventilation. Am. J. Respir. Crit. Care Med. 1998; 157:1498–505. Chastre J, Viau F, Brun P et al. Prospective evaluation of the protected specimen brush for the diagnosis of pulmonary infections in ventilated patients. Am. Rev. Respir. Dis. 1984; 130:924–9. Fagon JY, Chastre J, Wolff M et al. Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. Ann. Intern. Med. 2000; 132:621–30. Pepe PE, Marini JJ. Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction. Am. Rev. Respir. Dis. 1982; 126:166–70. Esteban A, Frutos F,Tobin MJ et al. A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group. N. Engl. J. Med. 1995; 332: 345–50. Esteban A, Alia I, Tobin MJ. Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation. Am. J. Respir. Crit. Care Med. 1999; 159:512–18. Jubran A, Tobin MJ. Passive mechanics of lung and chest wall in patients who failed or succeeded in trials of weaning. Am. J. Respir. Crit. Care Med. 1997; 155:916–21. Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N. Engl. J. Med. 1991; 324:1445–50. Tobin MJ, Perez W, Guenther SM et al. The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am.Rev.Respir.Dis. 1986; 134: 1111–18. Stroetz RW, Hubmayr R. Tidal volume maintenance during weaning with pressure support. Am. J. Respir. Crit. Care Med. 1995; 152:1034–40. Strauss C, Louis B, Isabey D, Lemaire F, Harf A, Brochard L. Contribution of the endotracheal tube and the upper airway to breathing workload. Am. J. Respir. Crit. Care Med. 1998; 157:23–30. Brochard L, Rauss A, Benito S et al. Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am. J. Respir. Crit. Care Med. 1994; 150:896–903. Ely EW, Baker AM, Dunagan DP et al. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N. Engl. J. Med. 1996; 335:1864–9. Bott J, Carroll MP, Conway JH et al. Randomized controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease. Lancet 1993; 341:1555–7. Kramer N, Meyer TJ, Meharg J, Cece RD, Hill NS. Randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure. Am. J. Respir. Crit. Care Med. 1995; 151:1799–806. Brochard L, Mancebo J, Wysocki M et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N. Engl. J. Med. 1995; 333:817–22.
Pulmonary Rehabilitation
Chapter
59
E.F.M. Wouters Faculteit der Geneeskunde-Pulmonology, Universiteit Maastricht, The Netherlands
INTRODUCTION During many decades, the disease states “asthma” and “COPD” were primarily defined as disorders in lung function. Asthma was mainly characterized by wide variations over short periods of time in resistance to flow in intrapulmonary airways. COPD was considered as a disease state characterized by the presence of a generally progressive and irreversible airflow limitation, owing to emphysema or intrinsic airway disease. The primary treatment in both diseases was therefore directed on pharmacological modulation of airflow limitation by bronchodilators and anti-inflammatory agents. Especially in COPD patients pharmacological treatment often does not result in a substantial effect and a functional deficit often persists. Indeed, exercise intolerance is a characteristic and greatly troubling manifestation of COPD and patients with moderate to severe COPD or severe asthma are limited in their abilities to perform usual daily life tasks. The concept of rehabilitation, involving holistic efforts to restore patients with debilitating and disabling disease to an optimally functioning state, is a relatively recent practice in pulmonary medicine. In 1974, a committee of the American College of Chest Physicians defined pulmonary rehabilitation as “an art of medical practice wherein an individually tailored, multidisciplinary program is formulated which through accurate diagnosis, therapy, emotional support and education stabilizes or reverses both physiopathological and psychopathological manifestations of pulmonary diseases and attempts to return the patients to the highest possible functional capacity allowed by his handicap and overall life situation”.1 More recent definitions were formulated by the NIH and by a task force of the European Respiratory Society (ERS). According to the NIH, pulmonary rehabilitation has to be defined as a multidimensional continuum of services directed to persons with pulmonary disease and their families, usually by an interdisciplinary team of specialists, with the goal of achieving and maintaining the individual’s maximum level of independence and functioning in the community.2 According to the ERS task force, pulmonary
rehabilitation is a process which systematically uses scientifically based diagnostic management and evaluation options, to achieve the optimal daily functioning and health-related quality of life of individual patients suffering from impairment and disability, due to chronic respiratory diseases as measured by clinically and/or physiologically relevant outcome measures.3 Although both definitions are primarily applied to patients with COPD, they are clearly also applicable to other patients suffering from chronic respiratory diseases. The new official statement of the ATS on pulmonary rehabilitation, published in 1999, supports this approach by defining pulmonary rehabilitation as a multidisciplinary program of care for patients with chronic respiratory impairment that is individually tailored and designed to optimize physical and social performance and autonomy.4 These definitions refer to the philosophical concept of rehabilitation as the restoration of the individual to the fullest medical, mental, emotional, social and vocational potential of which the person is capable. From the beginning it has been clear that the goals of rehabilitation were multifactorial and included the following: • to decrease and control respiratory symptoms • to increase physical capacity, to improve quality of life • to reduce the psychological impact of physical impairment and disability • to decrease the number of acute exacerbations related to COPD • to prolong life.5 These goals are nowadays considered as outcome parameters for optimal COPD, as well as asthma management in general. Therefore, pulmonary rehabilitation as the application of the whole spectrum of scientifically evaluated nonpharmacological treatment options has to be considered as an integrated part of optimal management of both disease conditions especially for the patients with persistent physiological deficit after optimal pharmacological treatment or persistent impact on psychological functioning or health status. Present insights in determining factors on daily life
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functioning and health status, related to the systemic effects of the disease process of COPD, strengthen this approach to consider this intervention as part of an integrated management process.
ELIGIBILITY CRITERIA Any patient with symptomatic, stable COPD or severe asthma, who is disabled either by the underlying disease, or by related therapy or by complications or by the systemic effects of the disease process should be considered for pulmonary rehabilitation. The ATS statement considers pulmonary rehabilitation indicated for patients with chronic respiratory impairment who despite optimal medical management, are dyspneic, have reduced exercise tolerance, or experience a restriction in activities.4 In fact, based on the defined goals of COPD management by the ATS as well as by the ERS, pulmonary rehabilitation can no longer be considered as a separate intervention but as part of an integrated medical approach for the disabled COPD patient.6,7 Improvement in health status and functional capacity and reduction of symptoms, defined as treatment goals for COPD are not restricted to this specific disease condition, but can be considered as outcome parameters for chronic respiratory diseases as severe asthma. Furthermore, it is important as part of the selection procedure that the patient is not distracted or limited by other serious or unstable medical conditions, that he/she is willing and able to learn about his disease and is motivated to devote the time and effort necessary to benefit from a comprehensive care program.8 Most of these rehabilitation programs can be completed in an outpatient setting. An ERS task force also defined specific selection criteria for in-hospital treatment.3 In-hospital management allows comprehensive diurnal assessment of the individual patient outside the habitual home environment. In-hospital rehabilitation can also be considered for specific intervention strategies or facilitates training of the most disabled patients, e.g. those with supplemental oxygen or patients receiving noninvasive mechanical ventilation. Post-intensive care patients with either disabling respiratory problems or weaning failure after acute respiratory support are also candidates for a comprehensive management program. Selection criteria for inpatient programs according the ERS are summarized in Table 59.1. Improvement of daily life functioning or health status are management goals not restricted to COPD, but applicable in other chronic respiratory conditions as asthma. Asthma is generally considered as one of the non-COPD indications for pulmonary rehabilitation.3,4 Otherwise, most asthma management programs largely rely on pharmocological intervention by administration of bronchodilating and antiinflammatory agents in a stepwise manner.9 Nonpharmacological intervention strategies are largely overlooked in asthma management plans. A survey of clinical control of asthma in Europe highlighted that a considerable percentage
Table 59.1. Selection criteria for inpatient programs
• Need for an integrated 24-hour supervised monitoring management plan, including training, teaching of coping skills, and other aspects of daily life functioning • Behavioral intervention to correct psychosocial problems • Need for specific intervention strategies, such as nutritional therapy • Participation in pre-operative and post-operative rehabilitation programs • Post-intensive care patients with either disabling respiratory problems or weaning failure after acute respiratory support • Identification and assessment of patients for longterm oxygen therapy or long-term home mechanical ventilation • Logistic aspects when outpatient rehabilitation is not available and the traveling distance does not allow the patient to participate in intensive rehabilitation
of children, as well as of adults, is markedly limited in daily life, as well as in social activities.10
COMPONENTS OF N O N P H A R M A C O L O G I C A L T R E AT M E N T Based on the historically defined approach of pulmonary rehabilitation, each patient enrolled in a rehabilitation program has to be considered as a unique individual with specific physio- and psychopathological impairment caused by the underlying disease. Therefore, pulmonary rehabilitation incorporated many different therapeutic modalities applied as a comprehensive, multidisciplinary care program including pharmacological treatment. Specific components in this nonpharmacological approach of patients with asthma or COPD are supported by scientific data supporting the efficacy and effectiveness of the applied intervention procedure. In order to improve quality of life or to promote self-management behavior of chronically ill patients with asthma or COPD, it is also important to consider the different dimensions of the rehabilitation program. In general, a distinction has to be made between: • the aim of the intervention; • the level on which the intervention is focused; • the directness of the intervention.11 For pulmonary rehabilitation in general, these dimensions are described in Table 59.2. Based on this approach, interventions directed at improvement, for example quality of life, have to be focused on
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Table 59.2. Dimensions of pulmonary rehabilitation
Aim of the intervention Reduction and control of respiratory symptoms Improvement in physical functioning Improvement in quality of life Reduction of the number of acute exacerbations Promotion of self-management behavior Improvement of cognition and behavior Reduction of psychological impact of physical impairment and disability Improvement of survival Level of focusing of the intervention Individual Group Environment Directness of the intervention Direct Indirect Supported by educational material
improvement of general psychological, social, practical and physical well-being of the patient. Dependent upon the aim and the phase the patient is in, the interventions can involve physical exercise programs as well as stress-management programs, social skills training or different kinds of counseling and support.The level of focusing of the intervention has to be decided depending on the aim of the intervention and the expected efficiency. Group training is highly appreciated by patients. Psychological group interventions directed at patients and partners can increase efficiency in order to get management goals. Furthermore, interventions can be directed at changing or adaptation of the environment of the asthma or COPD patient.These interventions are often specified by the term “social engineering”, because these interventions are directed at modification of living-, work-, or leisure-time situations and healthy life-styles of the patient from a social or patient perspective.12 Finally, the directness of intervention has to be considered. As part of a comprehensive intervention, indirect interventions can be considered in order to improve social support for the patient or to train other professionals in intervention skills. This theoretical approach of intervention programs is still largely unattainable in most rehabilitation programs, based on the limited resources still now spent on nonpharmacological intervention strategies in asthma, as well as in COPD. In this approach, components of a rehabilitation program are individualized based on a careful assessment of the patient, not limited to lung function testing, but addressing physical and emotional deficits, knowledge of the disease, cognitive and psychosocial functioning, as well as nutritional assessment. Furthermore, this assessment must be an ongoing process during the whole rehabilitation process. Education,
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exercise training, vocational therapy, physical therapy, psychosocial support and nutritional intervention are now generally applied modalities in pulmonary rehabilitation. Education Patient education is generally used as an “umbrella term for various forms of goal-directed and systematically applied communication processes, directed at the improvement of cognition, understanding and motivation, and the improvement of action- and decision-making possibilities of a patient to improve the coping with and recovery of the disease”.13 Ideally, patient education is more than provision of information to the patient, but is a “planned learning experience using a combination of methods such as teaching, counseling and behavior modification techniques which influence patient knowledge and health behavior”.14 Promotion of selfmanagement behavior in asthma or COPD can be directed to improve adherence to medical advice with respect to medication and healthy life-style, directed at the stabilization or retardation of the progression of the clinical picture or at the avoidance of undesirable consequences and complications. Medical advice to chronically ill patients can also be directed at various aspects of cognition and behavior.12 In asthma, studies concerning patient education are directed on improvement of self-management, are restricted to medical outcome measures and are conducted by a wide variety of health care workers not explicitly trained to provide educational intervention.15–26 The outcome variables as measured in different studies are generally restricted to number of attacks, emergency room visits, visits to the physician, knowledge, rehospitalization rate and use of drugs while in most studies no psychosocial outcome variables are included. Therefore, it is very important that an effective educational program in asthma directed at improvement of self-management and quality of life provides information in a structured way and that both psychological as well as medical parameters are included.To involve several dimensions of the multiple problems of the asthmatic patient, a multidisciplinary program is preferred and follow-up sessions seem to be helpful in the prevention of rehospitalization or relapse. Group-directed programs are preferable and programs have to be directed at the environment of the patient.12 Studies concerning patient education in COPD patients are limited.27–33 Most of the reported studies are directed at the improvement of self-management, decrease of medical consumption, decrease of stress and increase of social support and improvement of quality of life. As in asthma, most educational programs are conducted by various professionals, the environment of the patient is generally not involved and most of the studies do not pay attention to the problems of partners. The overall impression in most studies is that programs do have effects on various aspects of COPD. Characteristics like depression, anxiety and optimism, wellbeing, the number and length of hospital admissions and use of health services can be influenced positively by patient education programs. Most of these studies have only shortterm effects. Van den Broek12 reported the effects of a
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patient education group intervention program as part of a pulmonary rehabilitation program. Patients were randomly assigned to an experimental group and a control group. Partners participated in the study. Patients in the control group received medical advice and standard clinical care. The experimental group followed a structured educational program consisting of two components: an informative part and an educational part. The total program was directed at teaching self-management skills. Patients were followed for 12 months after the end of the rehabilitation program. Limited or no effects could be demonstrated on variables for psychological functioning, physical functioning or for social and practical functioning. The following characteristics of an optimal education program for patients with asthma or COPD can be formulated:12 • The program should be conducted by experts specially trained in techniques to change behavioral or irrational cognitions • Information should be provided in a structured way • A group-program is preferable from a health economical perspective, but a combination of an individualized program and a group-program may be most effective • Both participation of the social environment and attention to the problems of the partners should have a high priority to maintain newly acquired skills and cognitions in the home-situation • Both medical and psychosocial parameters have to be emphasized • The responsibility of the patient for his own health must be emphasized • In order to promote the patient’s self-activity and to support the maintenance of behavioral changes in the home-situation, additional materials should be made available to the patient to be used at home • Follow-up sessions are necessary to support the patient and his or her partner in the home-situation • Specific patient education interventions should be implemented in a multidisciplinary program, in addition to standard care to improve physical and psychological functioning • Short- and long-term effects have to be evaluated by valid measurements. Stabilization or reversal of disease-related psychopathology was one of the initially defined goals of pulmonary rehabilitation. Personality traits and intrapsychic conflicts, as well as acute pschychological states as panic, anxiety or depression, are widely recognized problem categories in patients with asthma and COPD. Specific psychosocial intervention strategies are usually required in order to modify these problems. Kaptein and Dekker34 recently reviewed the nature of psychosocial support in different rehabilitation programs. They concluded that relaxation techniques as a predominantly passive form of intervention were the most frequently applied type of psychosocial support, aimed at more controlled and efficient breathing.
The authors concluded that future research is needed to assess the outcome of more specific psychosocial intervention strategies, as well as to delineate the contribution of psychosocial intervention itself over and above pulmonary rehabilitation programs. Exercise training Impaired exercise tolerance is a prominent feature especially in patients suffering from COPD. Exercise limitation especially in patients with COPD is the result of complex changes including a wide spectrum of variables: • reduced expiratory airflow as a consequence of poor elastic recoil • increased airways resistance leading to increased work of breathing and increased ventilatory drive • reduced pulmonary vascular bed and increased pulmonary vascular resistance contributing to exerciseinduced hypoxemia • impaired cardiac output by impediment of right heart filling and left ventricular systolic function and skeletal muscle dysfunction. Leg fatigue attributable to peripheral muscle weakness has now been generally recognized as a common limiting symptom during exercise in COPD.35 Several factors have been suggested to explain the occurrence of skeletal muscle dysfunction in COPD: chronic inactivity and deconditioning, systemic inflammation, systemic corticosteroid administration, hypoxemia, electrolyte disturbances and muscle depletion as a consequence of a chronic process of tissue wasting. COPD-related changes in structure and metabolism of the skeletal muscles are furthermore reported: decreased oxidative capacity,36 a greater proportion of fatigue-susceptible fibers as a consequence of shifts from type 1 fibers to type 2 fibers,37 as well as changes in energyrich phosphagen metabolism.38 Lower capacity for muscle aerobic metabolism is related to an increased lactic acidosis for a given exercise work rate and enhances ventilatory needs by increasing nonaerobic carbon dioxide production. This requirement imposes an additional burden on the respiratory muscles already facing an increased impedance to breathing. Exercise in COPD is also related to an earlyonset of muscle intracellular acidosis.39 Remarkably, opposite changes in diaphragmatic fiber composition are now reported especially in more severe COPD patients towards a higher proportion of fatigue-resistant fibers.40 Besides these changes in intrinsic diaphragmatic muscle structure, mechanical disadvantages and altered muscle fiber length mainly as a consequence of static and dynamic hyperinflation, as well as an altered muscle environment contribute to a dysfunction of inspiratory muscles and especially of the diaphragm in COPD. A possible imbalance between inspiratory muscle function and increased muscle load related to the increased resistive and elastic load is an important determinant of dyspnea, susceptibility to inspiratory muscle fatigue, drive on the respiratory muscles and hypercapnia.41 Towards
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LT*
20
VO2 max*
30
10 0
10 Fig. 59.1. Changes in physiologic responses to an identical exercise task (high constant work rate test) produced by two exercise training strategies in patients with COPD. Left panel. High work rate training group (n 11). Right panel. Low work rate training group (n 8). Note that patients performed the same total work in their training program irrespective of group assignment. Percent change is calculated from the average change in response at the time the pretraining study ended. Vertical lines represent 1 SEM. Decreases in blood lactate, ventilation, O2, uptake, CO2 output, ventilatory equivalent for O2, and heart rate are observed for both training regimens, but decreases are appreciably greater for the high work rate training group. Reproduced with permission from Am. Rev. Respir. Dis. 1991; 143:9–18.
20
*Lactate
30
HR
30
20
% Change with training
% Change
20
10
CS*
0 40
10
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*VE
0
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Heart Rate
Physiological outcome of training in COPD Although exercise training is often considered as the cornerstone of every rehabilitation program, it remained unclear until the 1990s if there were physiological reasons for improvement in exercise tolerance. It was generally thought that these patients were unable to achieve a training intensity sufficiently high to train exercising muscles. Casaburi et al.42 clearly showed evidence that physiologic training responses could be observed in these patients. At a given level of exercise, significant reductions in blood lactate, CO2 production, minute ventilation, O2 consumption and heart rate were observed (Fig. 59.1).
The ventilatory requirement for exercise fell after an effective training program in proportion to the drop in blood lactate at a given exercise stress level. Based on these data and the results of other studies,43 it can be concluded that physiologic adaptation to training develops in these COPD patients. A reduction in lactic acid production by the contracting muscles is probably the main mechanism in the process of adaptation. Early lactic acid production during exercise is reported in COPD patients. A number of factors can contribute to an early increase in lactic acid. It is conceivable that this reflects an increase in skeletal muscle lactic acid production because of an impaired oxidative capacity. Maltais et al.36 demonstrated by muscle biopsy studies that the oxidative capacity of the m. vastus lateralis is reduced in COPD and that this reduction in oxidative capacity is significantly related to this decreased oxidative capacity. Others have demonstrated a relationship between this early lactic acid production and changes in intermediary amino acid metabolism, especially the glutamate concentrations in muscle biopsies.44 The physiologic response to endurance training in patients with COPD was therefore evaluated by analyzing changes in skeletal muscle aerobic enzyme activities. Maltais and his group43 clearly demonstrated an increase in aerobic enzyme activity after an endurance training program and that this improvement in skeletal muscle oxidative capacity was related to the reduction in exercise-induced lactic acidosis in these patients (Fig. 59.2). These results clearly indicated that skeletal muscle adaptations related to physiologic parameters can occur after training even in severe patients with COPD.
Work rate*
this complexity in pathophysiological and metabolic changes especially in COPD patients, the outcome of exercise training as part of a rehabilitation program has to be interpreted. Indeed, pulmonary rehabilitation programs almost include a measure of exercise training, generally based on transfer of standard recommendations for exercise training from healthy subjects to these disabled pulmonary patients frequently ignoring the complexity of bodily changes related to or a consequence of the disease state. Therefore, exercise testing before a training program is generally advised in order to determine the nature of exercise limitation, e.g. cardiocirculatory, ventilatory, diffusion limitation, limitation in the pulmonary circulation, or peripheral muscle limitation. Subsequent exercise training can be prescribed based on the individual limitations of the patient.
Fig. 59.2. The effects of endurance training on Vo2max, and work rate achieved during exercise, on VE, VCO2, heart rate (HR), and lactic acid concentration for identical exercise work rate, on lactate threshold (LT), and on the activity of CS and HADH. Significant changes are indicated by an asterisk. Reported values represent percent changes of the baseline values that occurred after training. (Reproduced with permission from Am. J. Respir. Crit. Care Med. 1996; 154:442–7.)
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Exercise prescription Although exercise training is recognized as an important component of the treatment of patients with COPD, the optimal method of exercise training still remains a matter of debate. In general, exercise training can be divided into two types: aerobic or endurance training and strength training. The majority of the studies of exercise training in COPD have focused on endurance training. However, no clear recommendations for COPD are yet available. However, in normal subjects, clear recommendations are available about duration, intensity and frequency for aerobic training.45,46 According to these recommendations, aerobic training calls for rhythmical, dynamic activity of large muscles, performed three to four times a week for 20–30 min per session at an intensity of at least 50% of maximal oxygen consumption. Such a program of aerobic training is capable of inducing structural and physiological adaptations that provide the trained individual with improved endurance for performance of high-intensity activity. Most of the rehabilitation programs include exercise sessions of at least 30 min, three to five times a week. Although no ideal duration has been established, duration in many programs is around 8 weeks. Limited information is also available regarding physiological outcome of different types of exercise testing. Most studies have investigated the physiological response of continuous training at a given work load in order to stress the oxidative pathways. Otherwise, interval training, alternating high and lower training load, resembles more closely the daily life activity pattern especially in severe COPD patients and this form of training stresses, in addition, the glycolytic pathways. Continuous training especially seems to be related to physiological improvement while interval training had more marked effects on leg pain in COPD patients.47 It still remains questionable how optimal training intensity should be modulated in COPD patients. In healthy subjects training is normally targeted by means of percentage of maximal heart rate (60–90% of predicted) or the percentage of maximal oxygen uptake (50–80% predicted) achieved.45 However, principles of exercise training intensity derived from normals are often not applicable to pulmonary patients who are limited by breathing capacity and dyspnea. Some investigators have reported that high-intensity training can be tolerated by patients with COPD and that they can be trained at an intensity which represents a higher percentage of maximum exercise tolerance than recommended for normals, because these patients can sustain ventilation at high percentages of their maximum breathing capacity.48–50 In some studies, it was even concluded that high intensity training might be superior to low intensity training.42 Indeed, Casaburi et al.42 compared high work rate training versus low work rate training and concluded that physiologic training effects were much less marked in patients who trained at low work rate, even though the total amount of work involved in the training regimen was the same irrespective of the training group to which the patient was assigned. Others concluded that most patients with COPD were unable to achieve high intensity training, defined as a
training intensity of 80% of baseline maximal power output.51 Furthermore, these authors demonstrated that the intensity of training achieved, as a percentage of baseline maximal power output is not influenced by the initial baseline maximal oxygen consumption, age or the degree of airflow limitation. Despite the impossibility of maintaining high-intensity training, significant improvement in exercise capacity was obtained and physiological adaptation to endurance training occurred. The intensity of training can also be dependent on the chosen setting of training. Although patients can tolerate high-intensity training in a monitored setting, low-intensity may be tolerated and maintained better over the long term. Additional research is needed to identify optimal exercise strategies for subgroups of patients with pulmonary disease. Only limited data are available on the effects of strength training in patients with pulmonary disease. Strength training involves the performance of explosive tasks such as weightlifting over a short period of time. Simpson et al.52 reported a 73% increase in cycling endurance time at 80% of maximal power output following 8 weeks of weightlifting training of the upper and lower extremity muscles. Otherwise, no significant changes in maximal cycling exercise capacity or walking distance were observed. Others confirmed that weight training can improve treadmill walking endurance of patients with mild COPD and that this improvement in treadmill endurance correlated with improvements in upper and lower limb isokinetic sustained muscle strength following training.53 The outcome of a combination of strength training and endurance training also needs further evaluation. In one study, a combination of aerobic endurance training and strength training resulted in increases in quadriceps strength, thigh muscle crosssectional area and pectoralis major muscle strength without influence on peak work rate, walking distance or health status.54 Lower extremity training as part of pulmonary rehabilitation Randomized, controlled trials have at present demonstrated that lower extremity training of several types and undertaken in several settings is a critical component of a pulmonary rehabilitation program. Ries et al.48 compared the effects of a comprehensive pulmonary rehabilitation program including exercise reconditioning with those of education alone on physiological and psychosocial outcomes in patients with COPD. Pulmonary rehabilitation consisted of 12 4-hour sessions which included education, physical and respiratory care instruction, psychosocial support and a supervised exercise training, followed by monthly reinforcement sessions for 1 year. The education group received 2hour sessions which included videotapes, lectures and discussions. This comprehensive rehabilitation program produced a significantly greater increase in maximal exercise tolerance, maximal oxygen uptake, exercise endurance, selfefficacy of walking and these effects were associated with a marked reduction of the symptoms of perceived breathlessness, muscle fatigue and shortness of breath.
Pulmonary Rehabilitation
These positive effects of rehabilitation on dyspnea were confirmed by the results of O’Donnell et al.,55 who demonstrated that after rehabilitation there was a significant shift of the relationship between dyspnea and workload downwards, indicating that at any given workload, dyspnea was less. Similar results were reported by Goldstein et al.56 They performed a prospective randomized controlled trial of respiratory rehabilitation in 89 subjects. Exercise activities included interval training, treadmill, upper-extremity training and leisure walking as part of an 8-week inpatient rehabilitation program. Significant improvements in exercise tolerance, measured by submaximal cycle time and walking distance were demonstrated and sustained for 6 months in the rehabilitation group. There were also significant differences in questionnaire assessment of dyspnea and dyspnea index. Assessment of the outcome of pulmonary rehabilitation in COPD was the subject of a meta-analysis by Lacasse et al.57 They reported a significant overall effect of 55.7 m for walking distance and of 8.3 Watts for maximum exercise capacity. The minimum clinically important difference of the walk test is estimated at about 50 m.58 Cambach et al.59 reported data of studies evaluating the effects of pulmonary rehabilitation in patients with asthma, as well as in patients with COPD. These authors reported similar significant improvements of exercise capacity after rehabilitation. These and other results provide convincing evidence that lower extremity training is beneficial in patients with chronic airflow limitation and exercise limitation. Lower extremity training can be recommended on evidence-based scientific criteria to be included in the rehabilitation of patients with asthma and COPD.60 Upper extremity training Patients with COPD frequently report disabling dyspnea for daily activities involving the upper extremities such as combing hair, brushing teeth or shaving. It is known that even in healthy persons, arm exercise is relatively more demanding than leg exercise. Some studies have demonstrated that arm elevation is related to a disproportionate increase in the diaphragmatic contribution to the generation of ventilatory pressures61 and that arm elevation is a fatiguing task for the muscles involved as assessed by electromyographic data. In COPD patients, studies have reported that arm exercise has an effect on breathing pattern amd recruitment of expiratory muscles, as well as on the pattern of metabolic and ventilatory response. Therefore, exercise training of the upper extremities may be beneficial for these patients also from the point of view that exercise training is specific to the muscles and tasks involved in the training. However, relatively few data exist assessing outcomes of upper extremity (UE) training compared with those available for lower extremity training. Studies have demonstrated that UE training leads to improved arm muscle endurance during isotonic arm ergometry62 and that arm training conducted during a pulmonary rehabilitation program led to a reduced metabolic demand associated with arm exercise.61 Based on present findings, it can be concluded that strength
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and endurance training of the UE improves arm function and that these exercises are safe and should be included in rehabilitation programs for patients with pulmonary diseases. Further studies are needed to explore the effects of arm training on functional outcomes, to evaluate different forms of arm exercise training programs and to determine the effect of arm exercise training on respiratory muscle function.60 Ventilatory muscle training There is accumulating evidence in the literature for respiratory muscle dysfunction especially in COPD patients. Four main factors may explain inspiratory muscle dysfunction in COPD: • mechanical disadvantage associated with hyperinflation • altered muscle fiber length as an important determinant of the force-generating capacity • alterations in the intrinsic muscle structure, manifested by changes in fiber type composition and muscle mass • changes in muscle environment manifested by a variety of electrolyte disturbances, changes in oxygen and carbon dioxide tension or levels of inflammatory mediators.63 This imbalance between the function of the inspiratory muscles and the load they are facing plays an important role in the sensation of dyspnea, the level of hypercapnia and could even be an important determinant of survival in COPD. Interventions directed to improve respiratory muscle performance have to affect two possible variables: the force developed during contraction as a fraction of the maximal force (measured by the ratio Pbreath/Pmax) and the duty cycle, represented by the ratio TI/TTOT for the inspiratory muscles. Changes in duty cycle are difficult to obtain. Therefore, interventions directed to improve respiratory muscle performance focus on lowering the ratio Pbreath/Pmax by reducing the load on the respiratory muscles or by improving their force-generating capacity. Ventilatory muscle training is generally practised in order to increase respiratory muscle strength. Two types of training are commonly applied in ventilatory muscle training: normocapnic sustained hyperpnea and inspiratory resistance breathing. During normocapnic hyperpnea, a supernormal target ventilation is required for 15 to 20 minutes, during which carbon dioxide tension is kept constant. This form of training therefore requires complicated equipment to monitor the patients and requires a medical facility in order to train them. Inspiratory resistance training uses small hand-held devices based on a resistance, flow-dependent system or by applying a threshold valve as a flow-independent device. In a meta-analysis on ventilatory muscle training, the effects of inspiratory resistive training have been reviewed.64 The effects of 17 reviewed studies were rather disappointing: non-significant changes in Pmax were reported in 11 studies in which it was evaluated and in respiratory muscle endurance in nine studies in which it was evaluated. These findings demonstrate that control of the training stimulus may be exceedingly important to induce the expected
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physiologic training response. Other studies have now demonstrated that respiratory muscle training, if properly applied, results in improved respiratory muscle strength or endurance.65 This improvement in respiratory muscle function is associated with a decreased sensation of dyspnea. In patients with ventilatory limitation of exercise capacity, the association of target-flow inspiratory muscle training and peripheral muscle exercise training allows for an additional improvement of walking distance and maximal exercise capacity compared with exercise training alone.66,67 However, the role of ventilatory muscle training in improvement of exercise capacity remains controversial because the positive outcome of this form of training on exercise capacity could not be reproduced in patients with better preserved inspiratory muscle function.68,69 Future studies on ventilatory muscle training should take into account the striking differences in muscle structural alterations in lower limb and respiratory muscles in COPD patients, reflecting the degree of activity of these muscles and the load they face: fiber shifts in the diaphragm are already parallel to those observed in endurance training making the diaphragm more resistant to muscle fatigue, a beneficial adaptation of a muscle chronically facing an increased work load.40 Selection of good candidates for muscle training and of training modalities based on pathological and physiological insights in muscle function adaptations can contribute to provide further scientific evidence for this intervention modality.60 Pulmonary rehabilitation and quality of life Health-related quality of life (HRQL), the degree to which the quality of life is affected by the individual’s health status, has become increasingly recognized as an important outcome of interventions in chronic pulmonary diseases as COPD and severe asthma. HRQL and functional status are often used interchangeably. Functional status refers to the individual’s ability to function in such diverse realms as physical, social and emotional and denotes a stronger basis in the ability to perform the tasks of daily life, while HRQL denotes a more subjective experience of the impact of health on the quality of one’s life.70 Comprehensive pulmonary rehabilitation programs have been demonstrated to improve HRQL in COPD patients. In a prospective randomized controlled trial, Goldstein et al.56 demonstrated significant differences in questionnaire assessment of dyspnea, emotional functioning, mastery and dyspnea index, while the fatigue dimension did not change significantly. Others could not demonstrate significant differences in general quality of life, probably related to the insensitivity of the applied scales to detect specific HRQL changes that result from pulmonary rehabilitation.48 Indeed, in a meta-analysis of respiratory rehabilitation in COPD, 10 different instruments were used for assessment of HRQL in 12 trials.57 Evidence of validity and responsiveness of these instruments has only been reported for two of them. From that meta-analysis, it could be concluded that pulmonary reha-
bilitation has positive outcome effects on dyspnea and mastery, whereas for fatigue and emotional function the magnitude of the treatment effect did not exceed the minimum clinically important difference.57 Cambach et al.59 studied the effects of a communitybased pulmonary rehabilitation program for patients with asthma and COPD. They reported similar improvements in HRQL for patients with asthma and COPD. In neither group were improvements in exercise capacity significantly related with improvements in HRQL.59 These and other studies indicate that HRQL instruments provide additional information on the assessment of outcome of pulmonary rehabilitation. Long-term outcome of pulmonary rehabilitation While several studies address the short-term outcome of pulmonary rehabilitation, the long-term outcome of pulmonary rehabilitation has been studied by only a few investigators. Ries et al.48 reported that benefits in exercise performance, dyspnea, exercise-associated symptoms of breathlessness and muscle fatigue and self-efficacy, obtained after an 8-week comprehensive rehabilitation program, could be partially maintained for 1 year with monthly reinforcement, but that the obtained benefits decreased after that time. Continued participation in a supervised training program over an additional 12 weeks was also required for maintenance of the benefit of walking endurance up to 1 year in another study.71 Wijkstra et al.72 demonstrated that incorporation of a session of physiotherapy once weekly or a session of physiotherapy once a month has no significant effects on walking distance, assessed over a period of 18 months.72 A recent randomized controlled trial comparing pulmonary rehabilitation to standard medical care demonstrated that patients with moderate to severe COPD achieved improvements in exercise tolerance and dyspnea lasting up to 2 years following a 12-week outpatient program.73 Some studies have analyzed the long-term outcome of rehabilitation on quality of life. Ketelaars et al.74 evaluated the long-term effect of rehabilitation on HRQL. She reported that patients with moderate HRQL scores upon admission had the greatest decline after 9 months of followup, despite having made substantial gains in HRQL by the end of the initial rehabilitation program. Otherwise, patients with poorer baseline HRQL scores, showed very little improvement during the rehabilitation program and remained severely impaired in HRQL long term. These authors suggested that differentiated aftercare programs may be indicated in order to maintain initial gains in HRQL. Wijkstra et al.72 reported that rehabilitation at home for 3 months followed by once-monthly physiotherapy sessions improves HRQL. Foglio et al.75 evaluated the longterm outcome of pulmonary rehabilitation in a group of asthmatics, as well as COPD patients. Regardless of diagnosis, they found that patients with chronic airflow limitation who underwent a rehabilitation program maintained an improved HRQL 1 year post-discharge despite a partial loss of the improvement in exercise tolerance. They
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confirmed the data of Ketelaars that not all patients may show a clinically significant improvement in HRQL and extended these results to asthmatics. At present it can be concluded that further information is needed about the optimal means and setting to maintain short-term effects of pulmonary rehabilitation on exercise tolerance and HRQL.
S U M M A RY Pulmonary rehabilitation programs in COPD and asthma have clear effects on improvement of exercise tolerance, reduction of symptoms of dyspnea and of health-related quality of life. At present there is no conclusive evidence that these programs would improve survival or reduce medical consumption, although suggestive evidence is present.76 Further studies are needed in order to define the long-term benefits, as well as the optimal program structure, to get the greatest effects. Cost-effectiveness studies are needed, as well as data on more optimal selection procedures, in order to select the best possible candidates for rehabilitation. Exercise training programs have to integrate present knowledge of muscular adaptations in patients with chronic airflow limitation. The shift from empiricism to science in performing pulmonary rehabilitation may result not only in a further improvement in quality of life, but perhaps also in the life expectancy of patients with usually incurable and sometimes inexorably progressive pulmonary disease such as severe asthma and COPD.
REFERENCES 1. Petty TL. Pulmonary rehabilitation. In: Basics of RD. New York: American Thoracic Society, 1975. 2. Fishman AP. Pulmonary rehabilitation research: NIH workshop summary. Am. J. Respir. Crit. Care Med. 1994; 149:825–33. 3. Donner CF, Muir JF. Rehabilitation and chronic care scientific group of the European Respiratory Society: ERSTask Force position paper selection criteria and programmes for pulmonary rehabilitation in COPD patients. Eur. Respir. J. 1997; 10:744–57. 4. Pulmonary rehabilitation-1999: Official statement of the American Thoracic Society. Am. J. Respir. Crit. Care Med. 1999; 159:1666–82. 5. American Thoracic Society. Pulmonary rehabilitation: official American Thoracic Society Position Statement. Am. Rev. Respir. Dis. 1981; 124:663. 6. ATS statement. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1995; 152:S77–120. 7. Siafakas NM, Vermeire P, Pride NB et al. Optimal assessment and management of chronic obstructive pulmonary disease. ERS consensus statement. Eur. Respir. J. 1995; 8:1398–420. 8. Ries AL.What pulmonary rehabilitation can do for your patients. J. Respir. Dis. 1995; 16:R16–24. 9. Global initiative for asthma. NHLB/WHO working group, 1995. 10. Rabe KF, Vermeire PA, Soriano JB et al. Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study. Eur. Respir. J. 2000; 16:802–7. 11. Maes S. Chronische ziekten. [Chronic illnesses]. In: Handboek klinische psychologie. 1993.
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12. Van den Broek AHS. Patient education and chronic obstructive pulmonary disease. Thesis University of Leiden 1995. ISBN 90-802379-1-4. 13. Damoiseaux V. Patiëntenvoorlichting: een terreinverkenning. [Patient education: an exploration]. Symposiumbundel patiëntenvoorlichting. GVO cahiers, University of Maastricht, 1984. 14. Jones K, Tilford S, Robinson Y. Health education. Effectiveness and efficiency. India: Chapman and Hall, 1990. 15. Green LW, Werlin SH, Schauffler HH et al. Research and demonstration issues in self-care: measuring the decline of medicocentrism. Health education monographs. 1977; 5:161–89. 16. Maiman LA, Green LW, Gibson G et al. Education for selftreatment by adult asthmatics. JAMA 1979; 241:1919–22. 17. Heringa P, Lawson LL, Reda D. The effect of a structured education program on knowledge and psychomotor skills of patients using beclomethasone dipropionate aerosol for steroid dependent asthma. Health Edu. Quart. 1987; 14:309–17. 18. Jenkinson D, Davison J, Jones S et al. Comparison of effects of a self-management booklet and audiocassette for patients with asthma. Br. Med. J. 1987; 297:267–70. 19. Snyder SE, Winder JA, Creer TL. Development and evaluation of an adult asthma self-management program: wheezers anonymous. J. Asthma 1987; 24:153–8. 20. Mayo PH, Richman J, Harris HW. Results of a program to reduce admissions for adult asthma. Ann. Intern. Med. 1990; 112:864–71. 21. Ringsberg KC, Wiklund I, Wilhelmsen L. Education of adult patients at an “asthma school”: effects on quality of life, knowledge and need for nursing. Eur. Respir. J. 1990; 3:33–7. 22. Bailey WC, Richards J, Brooks CM et al. A randomized trial to improve self-management practices of adults with asthma. Arch. Intern. Med. 1990; 150:1664–8. 23. Vromans ISY. Omgaan met asthma. [Coping with asthma]. Thesis. Zeist: stichting voor sociale gezondheid/Kerebosch bv, 1990. 24. Huss K, Salerno M, Huss RW. Computer-assisted reinforcement of instruction: effects on adherence in adult atopic asthmatics. Res. Nurs. Health 1991; 14:199–202. 25. Bolton MB, Tilley BC, Kuder J et al. The cost and effectiveness of an education program for adults who have asthma. J. Gen. Intern. Med. 1991; 6:401–7. 26. Schlösser MAG. Self-management and asthma. Thesis. Leiden: DSWO press, 1992. 27. Ashikaga T,Vacek PM, Lewis SO. Evaluation of a community-based education program for individuals with chronic obstructive pulmonary disease. J. Rehab. 1980; April/May/June: 23–7. 28. Brough FK, Schmidt CD, Rasmussen T et al. Comparison of two teaching methods for self-care training for patients with chronic obstructive pulmonary disease. Pat. Couns. Health Edu. 1983; 4:111–6. 29. Jensen PS. Risk, protective factors, and supportive interventions in chronic airway obstruction. Arch. Gen. Psych. 1983; 40:1203–7. 30. Atkins CJ, Kaplan RM, Timms RM et al. Behavioural exercise programs in the management of chronic obstructive pulmonary disease. J. Couns. Clin. Psychol. 1984; 52:591–603. 31. Howland J, Nelson EC, Barlow PB et al. Chronic obstructive airway disease. Impact of health education. Chest 1986; 90:233–8. 32. Tougaard L, Krone T, Sorkanaes A et al. Economic benefits of teaching patients with chronic obstructive pulmonary disease about their illness. Lancet 1992; 339:1517–20. 33. Toshima MT, Kaplan RM, Ries AL. Experimental evaluation of rehabilitation in chronic obstructive pulmonary disease: shortterm effects on exercise endurance and health status. Health Psychol. 1990; 9:237–52. 34. Kaptein AA, Dekker FW. Psychosocial support. Eur. Respir. Mon. 2000; 5:58–69. 35. Killian KJ, Leblanc P, Martin DH et al. Exercise capacity and ventilatory, circulatory, and symptom limitation in patients with airflow limitation. Am. Rev. Respir. Dis. 1992; 146:935.
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36. Maltais F, Simard AA, Simard C et al. Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD. Am. J. Respir. Crit. Care Med. 1996; 153:288. 37. Satta A, Migliori GB, Spanevello A et al. Fibre types in skeletal muscles of chronic obstructive pulmonary disease patients related to respiratory function and exercise tolerance. Eur. Respir. J. 1997; 10:2853. 38. Pouw EM, Schols AMWJ, Van der Vusse GJ et al. Elevated inosine monophosphate levels in resting muscle of patients with stable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 157:453. 39. Wuyam B, Payen JF, Levy P et al. Metabolism and aerobic capacity of skeletal muscle in chronic respiratory failure related to chronic obstructive pulmonary disease. Eur. Respir. 1992; 5:157. 40. Levine S, Kaiser L, Leferovich J et al. Cellular adaptation in the diaphragm in chronic obstructive pulmonary disease. N. Engl. J. Med. 1997; 337:1799. 41. O’Donnell DE, Webb KA. Exertional breathlessness in patients with chronic airflow limitation. The role of lung hyperinflation. Am. Rev. Respir. Dis. 1993; 148:1351–7. 42. Casaburi R, Patessio A, Ioli F et al. Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. Am. Rev. Respir. Dis. 1991; 143:9. 43. Maltais F, Leblanc P, Simard C et al. Skeletal muscle adaptation to endurance training in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1996; 154:442. 44. Engelen M, Schols A, Does J et al. Altered glutamate metabolism is associated with reduced muscle glutathione levels in patients with emphysema. Am. J. Respir. Crit. Care Med. 2000; 161:98–103. 45. American College of Sports Medicine. The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness in healthy adults. Med. Sci. Sports Exerc. 1990; 23:265–74. 46. Casaburi R. Exercise training in chronic obstructive lung disease. In: Casaburi R, Petty TL (eds). Principles and Practice of Pulmonary Rehabilitation, pp. 204–24. Philadelphia: WB Saunders, 1993. 47. Coppoolse R, Schols A, Baarends E et al. Interval versus continuous training in patients with severe COPD. Eur. Respir. J. 1999; 14:258–63. 48. Ries AL, Kaplan RM, Limberg TM et al. Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann. Intern. Med. 1995; 122:823–32. 49. Punzal PA, Ries AL, Kaplan RM et al. Maximum intensity exercise training in patients with chronic obstructive pulmonary disease. Chest 1991; 100:618–23. 50. Ries AL, Archibald CJ. Endurance exercise training at maximal targets in patients with chronic obstructive pulmonary disease. J. Cardiopulm. Rehab. 1987; 7:594–601. 51. Maltais F, LeBlanc P, Jobin J et al. Intensity of training and physiologic adaptation in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 155:555–61. 52. Simpson K, Killian K, McCartney N et al. Randomised controlled trial of weightlifting exercise in patients with chronic airflow obstruction. Thorax 1992; 47:70–5. 53. Clark CJ, Cochrane LM, MacKay E et al. Skeletal muscle strength and endurance in patients with mild COPD and the effects of weight training. Eur. Respir. J. 2000; 15:92–7. 54. Bernard S, Whittom F, LeBlanc P et al. Aerobic and strength training in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 159:896–901. 55. O’Donnell DE, Webb KA, McGuire MA. Older patients with COPD: benefits of exercise training. Geriatrics 1993; 48:59–66.
56. Goldstein RS, Gort EH, Stubbing D et al. Randomised controlled trial of respiratory rehabilitation. Lancet 1994; 344:1394–7. 57. Lacasse Y, Wong E, Guyatt GH et al. Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. Lancet 1996; 348:1115–19. 58. Goldstein RS, Redelmeier DA, Baksh L et al. Subjective comparison ratings of walking ability in patients with COPD. Proceedings of the 5th International Conference on Pulmonary Rehabilitation and Home Ventilation. Denver, Colorado, 1995; 99. 59. Cambach W, Chadwick-Straver RVM, Wagenaar RC et al. The effects of a community-based pulmonary rehabilitation programme on exercise tolerance and quality of life: a randomized controlled trial. Eur. Respir. J. 1997; 10:104–13. 60. Pulmonary Rehabilitation. Joint ACCP/AACVPR evidence-based guidelines. Chest 1997; 112:1363–96. 61. Couser JI, Maryinez FJ, Celli BR. Respiratory response and ventilatory muscle recruitment during arm elevation in normal subjects. Chest 1992; 101:336–40. 62. Ries AL, Ellis B, Hawkins R. Upper extremity exercise training in chronic obstructive pulmonary disease. Chest 1988; 93:688–92. 63. Marchand E, Decramer M. Respiratory muscle function and drive in chronic obstructive pulmonary disease. Clin. Chest Med. 2000; 21:679–92. 64. Smith K, Cook D, Guyatt GH et al. Respiratory muscle training in chronic airflow limitation: a meta-analysis. Am. J. Respir. Crit. Care Med. 1995; 145:533–9. 65. Harver A, Mahler DA, Daubenspeck JA. Targeted inspiratory muscle training improves respiratory muscle function and reduces dyspnea in patients with chronic obstructive pulmonary disease. Ann. Intern. Med. 1989; 111:117. 66. Dekhuijzen PNR, Folgering THM, Van Herwaarden CLA. Targetflow inspiratory muscle training during pulmonary rehabilitation in patients with COPD. Chest 1991; 99:128. 67. Wanke T, Formanek D, Lahrmann H et al. Effects of combined inspiratory muscle and cycle ergometer training on exercise performance in patients with COPD. Eur. Respir. J. 1994; 7:2205. 68. Benditt JO, Wood DE, McCool FD et al. Changes in breathing and ventilatory muscle recruitment patterns induced by lung volume reduction surgery. Am. J. Respir. Crit. Care Med. 1997; 155:279. 69. Larson JL, Covey MK, Wirtz SE et al. Cycle ergometer and inspiratory muscle training in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:500. 70. Curtis R. Assessing health-related quality of life in chronic pulmonary disease. In: Lung Biology in Health and Disease. Pulmonary Rehabilitation, pp. 329–54. New York: Marcel Dekker, 1996. 71. Swerts PM, Kretzers LM, Terpstra Lindeman E et al. Exercise reconditioning in the rehabilitation of patients with chronic obstructive pulmonary disease: a short- and long-term analysis. Arch. Phys. Med. Rehabil. 1990; 71:570–3. 72. Wijkstra PJ, Van der Mark TW, Kraan J et al. Long-term effects of home rehabilitation on physical performance in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1996; 153:1234–41. 73. Guell R, Casan P, Belda J et al. Long-term effects of outpatient rehabilitation of COPD. Chest 2000; 117:976–83. 74. Ketelaars CAJ, Abu-Saad HH, Schlösser MAG et al. Long-term outcome of pulmonary rehabilitation in patients with COPD. Chest 1997; 112:363–9. 75. Foglio K, Bianchi L, Bruletti G et al. Long-term effectiveness of pulmonary rehabilitation in patients with chronic airway obstruction. Eur. Respir. J. 1999; 13:125–32. 76. Bowen JB, Votto JJ, Thrall RS et al. Functional status and survival following pulmonary rehabilitation. Chest 2000; 118:697–703.
Chapter
Surgery
60
John Pepper Royal Brompton Hospital, London, UK
In the early days of thoracic surgery, a variety of procedures were attempted to help patients with emphysema. These included tracheostomy, pneumoperitoneum, autonomic denervation, costochondrectomy and bullectomy. Only bullectomy has survived as an effective operation for a minority of patients with large emphysematous bullae. In 1950, Brantigan and Mueller1 introduced lung volume reduction (LVRS) for patients with end-stage, generalized emphysema. He used thoracotomy and multiple segmental resections, postulating that such a procedure would “restore elastic tension of the remaining lung and the radial tension around the airways to prevent their collapse on expiration”. In a series of 56 patients, Brantigan et al.2 reported that 71% of unilateral and 85% of bilateral procedures resulted in symptomatic improvement. Unfortunately, detailed pulmonary function testing was not documented or easily available at the time. The procedure was not accepted by the medical community because of the poor objective documentation, a mortality rate of 27%, and reports of deterioration over time.3
BULLECTOMY An additional perspective emerges from the literature on giant bullectomy. It is clear from these case series that patients with giant bullae compressing normal underlying lung have large objective improvement in pulmonary function, followed by a decline over time of approximately 20 ml per year, a figure similar to normal individuals. Patients with diffuse emphysema and discrete bullae compressing underlying lung, on the other hand, have a much more variable response. The rate of long-term decline in lung function following bullectomy in these patients is 80–100 ml per year.4,5 This is similar to that of patients with emphysema who did not undergo bullectomy.6 Occasional patients with diffuse emphysema who underwent lung resection were also included in those series. Such patients had a poor response, especially when disease was not associated with regional lung compression.5 Objective data were not available in most reports to easily compare these patients with those
with large bullae and underlying emphysema. In a report containing two patients with diffuse emphysema without large bullae who underwent resection of upper lobe disease, only one had a substantive response to surgery, and the majority of the effect was lost by 2 years.7
L U N G V O L U M E R E D U C T I O N S U R G E RY ( LV R S ) LVRS remained forgotten until the reintroduction of single lung transplantation in the 1980s. In a few instances where the hyperinflated, unoperated lung was found to be compressing the transplanted lung in the early postoperative stage, nonanatomical resection of a portion of the native lung proved life-saving.8 In 1991 Wakabayashi et al.9 reported encouraging results following unilateral laser pneumoplasty via an endoscopic approach in 500 procedures performed on 443 patients. Unfortunately the study was flawed due to inadequate documentation of objective measures of lung function and quality of life. In 1995, Cooper et al.10 reported on bilateral LVRS in 20 patients in whom 20 to 30% of the volume of each lung had been removed through a midline sternotomy. The mean FEV1 improved by 20%, and total lung capacity (TLC), residual volume (RV), and trapped gas were significantly reduced.
L U N G T R A N S P L A N TAT I O N By this time, single lung transplantation had become the most common form of lung transplant performed worldwide, and emphysema the most common indication. The goals of lung transplantation for emphysema are to restore normal lung function, prolong life and limit morbidity from both the procedure and immunosuppression. In contrast, LVRS aims to relieve symptoms and improve exercise capacity. Because of the scarcity of donor organs, lung transplantation is performed for survival and not for quality of life alone. This is an issue in emphysema patients because statistically, patients with relatively severe disease can
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survive for several years. Therefore transplantation should be reserved for patients with FEV1 of 20% of predicted. LVRS is therefore not a true alternative to transplantation, but does not preclude subsequent lung transplant.11 There is no indication for surgery in the management of asthma.
R AT I O N A L E F O R L U N G V O L U M E REDUCTION LVRS is an operation designed to improve the mechanics of lung function, but is unlikely to improve alveolar gas exchange and particularly arterial oxygen tension. A smaller thoracic volume returns the chest wall to a more favorable position on its pressure–volume curve. Reduction in positive alveolar pressure will reduce the inspiratory loading of the respiratory muscles. The diaphragm is returned to a more favorable position with improved length–tension relationships and a reduced radius of curvature. Overall elastic recoil may be improved with subsequent improvement in maximal expiratory flow. This will improve dypsnea beyond the improvement achieved by reducing thoracic volume alone. It is conceivable that the removal of an “overwhelming volume” of emphysematous lung might affect alveolar gas exchange depending upon the prior distribution of perfusion to the areas removed. Alveolar gas exchange could be expected to become more efficient with a reduction in alveolar dead space and venous admixture. Improvement in lung elastic recoil pressure could also affect pulmonary blood flow, either regionally or globally. The resultant capillary recruitment and tethering in areas of re-expanded lung could improve blood flow and overall ventilation–perfusion ratios of the lung, leading to improved alveolar gas exchange. Furthermore, pulmonary vascular resistance could decrease leading to a fall in right ventricular afterload. Restored negative intrathoracic pressure could augment right ventricular preload and improve right ventricular function (Table 60.1). LVRS works in three main ways: • It increases maximal ventilatory capacity which leads to improved ventilatory reserve • It reduces shallow breathing and thus reduces the ratio of dead-space to tidal volume • It increases the diaphragmatic contribution to the inspiratory pressure generation during exercise.12,13 Table 60.1. LVRS: Physiological effects
Respiratory muscle function Lung mechanics Chest wall mechanics Gas exchange Pulmonary circulation
PAT I E N T S E L E C T I O N F O R LV R S The experience of Yusen et al.14 from their first consecutive series of 84 patients undergoing bilateral LVRS revealed that advanced age and hypercapnia were associated with increased operative mortality. Keenan et al.15 studied 57 patients who had lung resected via thoracoscopy with a stapler. Analysis showed that elevated PCO2 and decreased lung diffusing capacity for carbon monoxide (DLCO) were each significantly associated with prolonged hospital stay and higher early mortality. McKenna et al.16 studied 166 patients who underwent thoracoscopic unilateral or bilateral surgery and demonstrated that the initial elevated residual volume (RV) correlated with improved outcome in terms of lung function at 6 months after operation. The weight of tissue resected was correlated with improvement in FEV1 (R 0.55, P 0.0001). No other authors have confirmed these findings and the question of how much lung tissue should be removed has been very difficult to establish. The amount of lung removed is difficult to measure in a meaningful way. If “too much” lung is removed, troublesome broncho-pleural fistulae causing prolonged air leak may result. Alternatively, removal of “too small” an amount of tissue will compromise the result. At the moment this aspect of the procedure relies heavily on surgical judgment. Patients selected for the unilateral procedure have been reported16 to have a higher 1-year mortality than those selected for bilateral surgery (17% versus 2.5%, P 0.01). Factors associated with the higher mortality in the unilateral group included age 75; FEV1 5000 ml; PaO2 50 mm Hg (P 0.0001). In a study of 29 patients in Boston, USA, only preoperative lung resistance during inspiration predicted changes in expiratory flow rates after surgery. Inspiratory lung resistance correlated significantly and inversely with improvement in post operative FEV1 (r 0.63; P 0.001).17 In general, imaging studies have so far proved more useful than lung function tests in identifying those patients who will obtain the greatest benefit from the operation. Geirada et al.18 carried out a retrospective analysis of 50 patients after LVRS. On the basis of inspiratory and expiratory CT scans, they concluded that upper lobe predominance of emphysematous disease, a greater degree of parenchymal compression, a higher amount of regional heterogeneity and a larger percentage of normal or mildly emphysematous lung best predicted improvement after operation. Confirmation came from McKenna et al.’s study16 which also found that emphysema which predominantly affected the upper lobes was associated with an improved operative outcome. For upper lung predominant, lower lung predominant and diffuse emphysema, patients who had bilateral surgery increased their FEV1 by 68 8%, 47 18%, and 37 9%, respectively. Fischer et al.19 correlated pre-operative perfusion lung scans, including quantitative measures of perfusion distribution, with post-operative functional studies. Significantly greater improvement in outcome was found with: heterogeneity; a larger percentage of maximally perfused lung; upper lobe predominance of decreased
629
Surgery
perfusion; and a high degree of matched ventilation and perfusion. Cleverley and colleagues20 found a strong correlation between lung perfusion assessed by high resolution CT and lung perfusion on scintigraphy suggesting that perfusion scintigraphy is superfluous in the pre-operative evaluation of patients with emphysema for LVRS. The operative technique for LVRS has been controversial, but there has been clarification of some issues. Favorable results have been obtained by both thoracoscopic21 or median sternotomy approaches.14 Bilateral is preferable to a unilateral approach and the use of the laser has largely been abandoned because of an unacceptably high incidence of prolonged air leak.
R E S U LT S O F L U N G R E D U C T I O N A recent randomized study of LVRS versus medical treatment of emphysema revealed a significant improvement in FEV1, walking distance and quality of life at 12 months in the surgical group.22 The early mortality in the surgical group was 6% (one of 18). Analysis of the entire study group showed no significant difference in survival between groups (relative risk of death in the surgical as compared with the medical group, 1.74; 95% confidence interval, 0.47 to 6.46; P 0.29). A prospective randomized trial reported by Criner and colleagues23 showed that 6-minute walk dis• tance, total exercise time, and VO2max were higher after LVRS, but did not reach statistical significance. However, when 13 patients crossed over from the medical to the surgical arm these indices measured at 3 months were highly significant when compared with post-rehabilitation data. The operative mortality was 9.4%. A review of 722 patients who underwent LVRS between 1995 and 1996 showed that 12 months after operation, 23% had died.24 A further report from Cooper’s group25 of the outcome of 150 patients showed 51% improvement in FEV1, 28% reduction in residual volume, a reduction in dypsnea, improvement in quality of life, and reduced oxygen dependency. The 90-day mortality was 5%. The most persistent benefit seems to be the reduction in residual volume. The effects of LVRS on maximal exercise capacity seem to peak around 6 months after surgery but the improvement in submaximal exercise performance is sustained for up to 1 year. The relative effects of LVRS and rehabilitation on these variables are difficult to assess (Tables 60.2 and 60.3).
dictable occurrence of ischemia-reperfusion injury, which manifests as a radiographically confirmed infiltrate on the side of the allograft usually in the first 48 hours after transplantation. The cause of this injury is unclear because the incidence of ischemia-reperfusion injury does not correlate well with ischemic times of the donor organ, type of preservation, or other donor-related factors.27 Nevertheless, patients with emphysema tend to have the least complicated post-operative course compared with other groups undergoing single lung transplantation. The time spent on a ventilator, days in ICU, the intensity of ventilator support, use of inotropic drugs, and days required on supplemental oxygen are the least of all patient groups. Early gas exchange and hemodynamics are significantly better.Why is this so? Blood flow is distributed more evenly with an average of two-thirds of the cardiac output perfusing the transplanted lung. In conjunction with lower pulmonary pressures, the amount of edema in the transplanted lung is lower in this patient group. The post-operative FEV1 is generally 50% of predicted, but not as high as that achieved with bilateral transplant,28 although no difference in exercise tolerance following bilateral transplantation has been reported. The 5-year survival is slightly better in bilateral recipients than in their single lung counterpart.29 This may be because there is a greater reserve of lung parenchyma to preserve function against the development of obliterative bronchiolitis. Most centers now apply single lung transplant to emphysema patients without bullous disease who are of smaller stature or older age who might be less tolerant of the bilateral procedure. Hosenpud et al.30 have recently analyzed the survival benefit of lung transplantation for different etiologies. While the clearest survival benefit occurred in the cystic Table 60.2. LVRS: Morbidity and mortality
Air leak Pneumonia GI disturbance Respiratory failure Redo surgery Early death Late death
30–48% 9–22% 2–15% 2.5–13% 2.5–10.5% 2.4–7% 4–17%
Table 60.3. Lung volume reduction surgery
T R A N S P L A N TAT I O N F O R E M P H Y S E M A Single lung transplant is an attractive option for several reasons. Most patients do not have adhesions so that extraction of the lungs is straightforward. The large pleural space provides excellent exposure for implantation. The 1-year survival rate of around 85%26 for this procedure exceeds that for other etiologies and for other forms of lung transplantation. A major cause of post-operative variability is the unpre-
Percentage of real candidates referred for surgery
20–40%
Percentage of patients who improve
50–75%
Hospital mortality
4–23%
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Asthma and Chronic Obstructive Pulmonary Disease
Deconditioning and exercise intolerance can start early in the disease process in patients with mild emphysema. Young31 described the dyspnea spiral, whereby patients withdraw from activities that might provoke dyspnea, thereby facilitating the deconditioning process even before the disease has been recognized. Patients with emphysema following lung transplantation terminate exercise at persistently low peak oxygen consumption and work tolerance, despite apparently significant ventilatory, mechanical and cardiovascular reserve. In one study32 there was no significant difference in maximal workload achieved at 3 months following unilateral versus bilateral lung transplant recipients despite markedly greater improvement in spirometric indices in the bilateral patients. This suggests that a ceiling may exist in maximal performance following surgery that cannot be overcome by further improvements in pulmonary mechanics. In effect, the peripheral musculature has deteriorated to match the exercise capacity imposed by the previously poor level of pulmonary function. In fact, abnormalities in peripheral oxygen extraction have been documented in patients following lung transplantation.33 Maximal oxygen consumption is around 40 to 60% of the predicted value despite the absence of significant cardiac or ventilatory limitations on exercise.34,35
evaluations. In all six domains of health measured by the NHP part 1 (energy, pain, emotional reactions, sleep, social isolation and physical mobility), patients showed statistically significant improvements compared with their pre-transplant levels. Significantly fewer patients reported problems in each area assessed by the NHP part 2 (occupation, work around the house, social life, home life, sex life, hobbies and leisure). Dennis et al.37 found similar improvement in 31 patients receiving heart–lung transplants for cystic fibrosis at Papworth Hospital. Patients showed significant improvement by 3 to 6 months after transplant in each domain of the NHP, except pain. The proportion of patients reporting problems declined after transplantation in five of the seven areas of daily life assessed in part 2 of the NHP. Only occupation remained a problem for many patients after their transplant. Caine et al.38 reporting on a similar group of patients from the same unit, found a small but statistically significant correlation between physical mobility and FEV1. In both the Harefield and Papworth series, the number of transplant recipients reporting health problems in any area, including work, declined to less than 20%. Energy and physical mobility were the most impaired domains for candidates and they significantly improved by 3 to 6 months after transplant. Squier et al.39 examined the predictive value of a baseline measure of Health Related QOL (HRQOL) on the survival of the candidates in the San Diego lung transplant program. They found that HRQOL varied according to the indications for transplant with COPD candidates scoring, on average, worse than CF patients. The situation was different after transplant, patients with COPD tended to enjoy better survival that CF patients. Within each transplant category those with higher baseline HRQOL had a better chance of survival. Such indicators may, in the future, help to refine the candidate selection process in the setting of donor organ scarcity. A report by Gross et al.40 showed a positive impact of lung transplantation on the dimensions of physical function, health perception, social function and role function using a medical outcomes study health survey, MOS-20 Health Profile. The benefits were maintained for 5 years unless BOS supervened. Reported “return to work” rates are disappointing as revealed by one typical study which found 38% “able to work” comparable to other groups.41
QUALITY OF LIFE STUDIES
CONCLUSIONS
Several prospective studies have described the quality of life (QOL) of lung transplant candidates and recipients, but none have studied emphysema patients in isolation. O’Brien et al.36 reported on the QOL outcomes of adult heart–lung recipients from Harefield Hospital. Patients completed the Nottingham Health Profile (NHP) before and after transplantation at 3 month intervals. Twentyeight patients (88% of all 3-month survivors) completed pre-transplant evaluations and 3-month follow-up
The most appropriate surgical treatment for patients with severe emphysema is now more controversial than in previous years. Although the results of single lung transplant for emphysema are better than any form of lung transplant it has been difficult to demonstrate a survival benefit for emphysema as against other forms of parenchymal lung disease. It may be that for subsets of emphysema such as alpha1-antitrypsin deficiency, transplantation does show benefit but this information is not available. In the context of
fibrosis group, no survival benefit was apparent in the emphysema group. Data were analyzed for all patients listed for transplantation in the USA for emphysema, cystic fibrosis, or interstitial fibrosis in the years 1992–1994. In the emphysema group, the risks of transplantation relative to waiting were 2.76, 1.12 and 1.10 at 1 month, 6 months and 1 year, respectively, and the relative risk did not decrease below 1.0 during 2 years of follow-up. The authors concluded that lung transplantation for patients with emphysema is difficult to justify on the grounds of survival considerations alone. The impact of LVRS is difficult to assess at present, but if patients on the transplant list are treated by LVRS this will increase the transplant waiting list mortality, as the early mortality rate for LVRS is around 10%.
E X E R C I S E C A PA C I T Y
Surgery
declining donor lung availability, to achieve an equitable distribution of organs is difficult. There is little doubt that some patients derive considerable benefit from lung volume reduction, but many questions remain to be answered. In the absence of any long-term randomized controlled trials, the relationship between patients selected and the bulk of the emphysema population is not clear. The distribution of response across the population of patients treated by LVRS is unknown. The magnitude of benefit from a health and economics standpoint is also unknown. Answers to some of these questions may emerge in the next few years as clinicians and scientists apply themselves to this common disease.
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REFERENCES
22.
1. Brantigan O, Mueller E. Surgical treatment of pulmonary emphysema. Ann. Surg. 1957; 23:789–804. 2. Brantigan OC, Kress MB, Mueller EA. The surgical approach to pulmonary emphysema. Dis. Chest 1961; 39:485–99. 3. Rogers RM, DuBois AB, Blakemore WS. Effect of removal of bullae on airway conductance and conductance volume ratios. J. Clin. Invest. 1968; 47:2569–78. 4. Pearson MG, Ogilvie C. Surgical treatment of emphysematous bullae: late outcome. Thorax 1983; 38:134–7. 5. Gaensler EA, Jederlinic PJ, Fitzgerald MX. Patient work-up for bullectomy. J.Thorac. Imag. 1986; 1:75–81. 6. Burrows B, Fletcher CM. The emphysematous and bronchial types of chronic airway obstruction: a clinicopathologic study of patients in London and Chicago. Lancet 1966; 1:830–7. 7. Pride NB, Barter CE, Hugh-Jones P. The ventilation of bullae and the effect of their removal on thoracic lung volumes and tests of overall pulmonary function. Am. Rev. Resp. Dis. 1973; 107:83–98. 8. Khaghani A, Al-Khattan KM, Tadjkarimi S, Banner N, Yacoub M. Early experience with single lung transplantation and volume reduction. Eur. J. Cardiothorac. Surg. 1997; 11:604–8. 9. Wakabayashi A, Brenner M, Kayaleh R. Thoracoscopic carbon dioxide laser treatment of bullous emphysema. Lancet 1991; 337:881–3. 10. Cooper J, Trulock E, Triantafillou A et al. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J.Thorac. Cardiovasc. Surg. 1995; 109:106–19. 11. Zenati M, Keenan RJ, Landreneau RJ. Lung reduction as a bridge to lung transplantation in pulmonary emphysema. Ann.Thorac. Surg. 1995; 59:1581–3. 12. Mather PJ, O’Brien G, Kuzma AM, Furukawa S, Criner GJ. Functional adaptation of the right ventricle following bilateral lung volume reduction surgery. Am. J. Respir. Crit. Care Med. 1997; 155:A607. 13. Sciurba FC, Rogers RM, Keenan RJ et al. Improvement in pulmonary function and elastic recoil after lung reduction surgery for diffuse emphysema. N. Engl. J. Med. 1996; 334:1095–9. 14. Yusen R, Trulock E, Pohl M, Biggar DG, Cooper JD. Results of lung volume reduction surgery in patients with emphysema. Semin.Thorac. Cardiovasc. Surg. 1996; 8:99–109. 15. Keenan R, Landreneau R, Sciurba F. Unilateral thorascopic surgical approach for diffuse emphysema. J. Thorac. Cardiovasc. Surg. 1996; 110:308–16. 16. McKenna R, Brenner M, Fischel R. Should lung volume reduction surgery for emphysema be unilateral or bilateral? J. Thorac. Cardiovasc. Surg. 1996; 112:1331–9. 17. Ingenito EP, Evans RB, Loring SH et al. Relation between preoperative inspiratory lung resistance and the outcome of lung
23.
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35. 36.
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volume-reduction surgery for emphysema. N. Engl. J Med. 1998; 338:1181–5. Gierada D, Slone RM, Bae KT, Yusen RD, Lefrak SS, Cooper JD. Pulmonary emphysema: comparison of preoperative quantitative CT and physiologic index values with clinical outcome following lung volume reduction surgery. Radiology 1997; 205:235–42. Fischer K, Slone R, Gierada D, Yusen RD, Cooper JD. Scintigraphic markers of outcome after lung volume reduction surgery as assessed with preoperative lung scans. Am. J. Roent. 1996; 166(Suppl):74–9. Cleverley JR, Desai SR, Wells AU et al. Evaluation of patients undergoing lung volume reduction surgery: ancillary information available from computed tomography. Clin. Radiol. 2000; 55:45–50. Stammberger U, Thurnheer R, Bloch KE et al. Thoracoscopic bilateral lung volume reduction for diffuse pulmonary emphysema. Eur. J. Cardiothorac. Surg. 1997; 11:1005–10. Geddes D, Davies D, Koyama H et al. Effect of lung volume reduction surgery in patients with severe emphysema. N. Engl. J. Med. 2000; 343:239–45. Criner GJ, Cordova FC, Furukawa S et al. Prospective randomised trial comparing bilateral lung volume reduction surgery to pulmonary rehabilitation in severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:2019–27. Fessler HE, Wise RA. Lung volume reduction surgery: is less really more? Am. J. Resp. Crit. Care Med. 1999; 159: 1031–5. Cooper JD, Patterson GA, Sundaresan RS et al. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J. Thorac. Cardiovasc. Surg. 1996; 112:1319–30. Hosenpud JD. The Registry of the International Society for Heart and Lung Transplantation. 14th Official Report 1997. J. Heart Lung Transpl. 1998; 17:656–68. Anderson DC, Glazer HS, Semenkovich JW. Lung transplant oedema: chest radiography after lung transplantation – the first 10 days. Radiology 1995; 195:275–81. Al-Kattan K, Tadjkarimi S, Cox A, Banner N, Khaghani A,Yacoub M. Evaluation of the long term results of single lung versus heart–lung transplantation for emphysema. J. Heart Lung Transpl. 1995; 14:824–31. Sundaresan RS, Shiraishi J, Trulock EP et al. Single or bilateral lung transplantation for emphysema? J.Thorac. Cardiovasc. Surg. 1996; 112:1485–95. Hosenpud JD, Bennett LE, Keck BM, Edwards EB, Novick RJ. Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease. Lancet 1998; 351:24–7. Young A. Rehabilitation of patients with pulmonary disease. Ann. Acad. Med. 1983; 12: 410–16. Orens JB, Becker FS, Lynch JP. Cardiopulmonary exercise testing following allogeneic lung transplantation for different underlying disease states. Chest 1995; 107:144–9. Ross DJ, Waters PF, Mohsenifar Z. Haemodynamic responses to exercise after lung transplantation. Chest 1993; 103:46–53. Williams TJ, Patterson GA, McClean PA, Zamel N, Maurer J. Maximal exercise testing in single and double lung transplant recipients. Am. Rev. Resp. Dis. 1992; 145:101–5. Levy RD, Ernst P, Levine SM. Exercise performance after lung transplantation. J. Heart Lung Transplant 1993; 12:27–33. O’Brien BJ, Banner NR, Gibson S. The Nottingham Health Profile as a measure of quality of life following combined heart and lung transplantation. J. Epidemiol. Comm. Health 1988; 42:232–4. Dennis C, Caine N, Sharples L. Heart–lung transplantation for end stage respiratory disease in patients with cystic fibrosis at Papworth Hospital. J. Heart Lung Transpl. 1993; 12: 893–902.
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38. Caine N, Sharples LD, Dennis C. Measurement of health-related quality of life before and after heart-lung transplantation. J. Heart Lung Transpl. 1996; 15:1047–58. 39. Squier HC, Ries AL, Kaplan RM. Quality of well-being predicts survival in lung transplantation candidates. Am J. Respir. Crit. Care Med. 1995; 152:2032–6.
40. Gross CR, Savil K, Bolman RM, Hertz MI. Long-term health status and quality of life outcomes of lung transplant recipients. Chest 1995; 108:1587–93. 41. Williams TJ, Grossman RF, Maurer JR. Long-term functional follow-up of lung transplant recipients. Clin. Chest Med. 1990; 11:347–58.
Other Therapies
Chapter
61
Neil C. Thomson Department of Respiratory Medicine, Western Infirmary, Glasgow UK
CROMONES The cromones, sodium cromoglycate and nedocromil sodium, were first introduced as prophylactic drugs for asthma over 30 and 15 years ago, respectively. The mechanism of action of the cromones has not been clearly established: • Both drugs act as nonspecific chloride channel blockers in a large range of cell types and through this action these compounds may reduce alterations in cell volume and function.1 • In vitro studies of human inflammatory cells and in vivo studies in experimental animals have shown that both drugs inhibit functions of a variety of inflammatory cells including mast cells, eosinophils, neutrophils, platelets and alveolar macrophages.1–4 Nedocromil sodium has either similar or slightly greater potency to that of sodium cromoglycate. • Both sodium cromoglycate and nedocromil sodium may also have inhibitory effects on sensory nerve endings in the lung, thus preventing the release of tachykinins. Asthma Effects on asthmatic inflammation There is limited and conflicting evidence for the antiinflammatory effects of sodium cromoglycate and nedocromil sodium in asthma: • Chronic treatment has been shown to significantly reduce the percentage of eosinophils in bronchial alveolar lavage specimens following 4 weeks of treatment.5 • An open study of 12 weeks of treatment with inhaled sodium cromoglycate reported a reduction in the numbers of eosinophils, mast cells and T lymphocytes and in the expression of adhesion molecules in bronchial biopsy specimens from nine patients with atopic asthma.6 • A randomized controlled trial of nedocromil sodium for a period of 16 weeks in mild to moderate asthma, however found no significant change in bronchial biopsy eosinophil counts compared with the placebo group.7
Clinical studies Bronchial challenge Sodium cromoglycate and nedocromil sodium are equally effective in attenuating exercise-induced asthma.8 The early and late response to allergen3,9 and the allergeninduced seasonal increase in nonallergic bronchial reactivity can be prevented by both drugs.10 Nedocromil sodium can also produce small reductions in nonseasonal bronchial reactivity.11,12 Clinical asthma Comparison with placebo: In both pediatric and adult asthma, treatment with inhaled sodium cromoglycate has been reported to improve asthma control.13–15 A recent systematic review of 24 randomized controlled trials, however, questioned the efficacy of sodium cromoglycate in children with asthma and concluded that it was no longer justified to recommend sodium cromoglycate as a first-line prophylactic agent in chronic childhood asthma16 (Fig. 61.1). Studies comparing nedocromil sodium with placebo have demonstrated efficacy in both children and adult asthmatic patients.17,18 A small number of clinical trials in adult asthma have compared the two cromones and in most studies the therapeutic effects were found to be comparable.19,20 Comparison with inhaled steroids: The results of most short-to-medium term studies suggest that the improvement in asthma control produced by the cromones is commonly slightly less than that produced by 400 lg of inhaled beclomethasone daily.11,12,21 A large long-term randomized controlled trial in 1041 children aged 5 to 12 years with mildto-moderate asthma compared the anti-asthma effects of 200 lg of budesonide, 8 mg of nedocromil, or placebo twice daily over a 4- to 6-year period.22 Inhaled budesonide provided better control of asthma and improved airway responsiveness when compared with placebo or nedocromil. Neither drug was better than placebo in terms of lung function. Add-on therapy: The addition of inhaled nedocromil sodium to asthmatic patients with symptoms poorly controlled by high-dose (>1000 lg daily) inhaled corticosteroids has been reported to produce small improvements in symptoms, peak flow readings and bronchodilator use.23
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Wheeze: absolute effect size 3
2
1
0
1
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Add-on therapy: There does not appear to be any support for the use of the cromones as additional therapy for patients already receiving inhaled or systemic steroids.
Smith (1968) Hyde (1970) Shioda (1970) Limburg (1971) Fox (1972) Silverman (1972) Hiller (1975) Hiller (1977) Matthew (1977) Edmunds (1980) Glass (1981)
COPD Both sodium cromoglycate and nedocromil sodium are considered to be ineffective in the treatment of COPD, although there are very few published studies.28 A randomized controlled study in patients with COPD reported that nedocromil sodium treatment for 10 weeks had no effect on symptoms, lung function or airway responsiveness to histamine and adenosine. However, the number of dropouts because of exacerbations was fewer with nedocromil sodium compared with placebo.29
Geller (1982) Miraglia (1982) Geller (1983) Henry (1984) Cogswell (1985) Bertelsen (1986) Yuksel (1992) Furfaro (1994) Tasche (1997) 95% CI assuming: Homogeneity Heterogeneity Tolerance int
Fig. 61.1. Sodium cromoglycate in children: 95% confidence intervals of absolute difference for wheeze in sodium cromoglycate group compared with placebo (reproduced with permission from Ref. 16).
Nedocromil sodium does not have a clinically relevant oral corticosteroids sparing effect.24,25 Adverse effects: Sodium cromoglycate and nedocromil sodium are safe drugs and uncommonly cause adverse effects. The main side-effects reported include a distinctive bitter taste, headache and nausea. Place in management The cromones have a very limited role in the management of chronic asthma. First-line prophylactic therapy: The National Institutes of Health expert panel report on the Guidelines for the Diagnosis and Management of Asthma26 suggest that sodium cromoglycate or nedocromil sodium may be considered as initial prophylactic therapy for children, although this recommendation has been challenged recently,16 and as preventative treatment prior to exercise or unavoidable exposure to known allergens. The report emphasizes that safety is the primary advantage of these drugs. The British Guidelines on Asthma Management27 recommend the cromones as alternative anti-inflammatory agents to lowdose inhaled steroids, for example when the patient is unwilling to take inhaled steroids.
VA C C I N E S Influenza vaccines Efficacy A recent study of elderly individuals with chronic lung disease influenza vaccination resulted in a 52% reduction in the rate of hospitalization because of pneumonia or influenza, a 70% reduction in mortality rate from all causes, and an 11% reduction in outpatient visits for all respiratory conditions.30 A systematic review of the limited number of trials of the effect of influenza vaccination in COPD patients concluded that inactivated vaccine might reduce exacerbation rates.31 Vaccination is associated with a decrease in health costs. In asthma the effects of vaccination are less clear-cut.32 Life-attenuated influenza vaccines, administered by intranasal spray, are currently under investigation.33 The results of several studies demonstrate the efficacy and safety of these vaccines in healthy adults. If licensed for use, lifeattenuated influenza vaccines may be particularly useful for preventing influenza in young children. Adverse effects Vaccination is contraindicated in those individuals hypersensitive to eggs, although the risk of reactions is low.34 A small number of placebo-controlled trials have examined the role of inactivated influenza vaccines in precipitating exacerbations of asthma or COPD. These studies have not reported an increase in the exacerbation rate from asthma or COPD in those individuals receiving influenza vaccination compared with placebo.34 However, further randomized controlled trials are needed. Recommendations Health authorities in the United States and in many European countries recommend annual inactivated influenza vaccination for adults and children with chronic pulmonary disease, including asthma.35 Some national guidelines emphasize the importance of targeting elderly individuals with chronic lung disease.28
Other Therapies
Pneumococcal vaccines Efficacy In elderly individuals with chronic lung disease, pneumococcal vaccination has been reported to result in a 43% reduction in the rate of hospitalization because of pneumonia and a reduction of 29% in mortality rate.36 Vaccination is also associated with a reduction in the incidence of invasive pneumococcal disease37 and a decrease in health costs.36 Routine revaccination is not generally recommended because of the increased incidence of adverse reactions. Adverse effects Hypersensitivity reactions may occur. Recommendations Health authorities in some European countries and the United States recommend polyvalent pneumococcal vaccination for all patients with chronic lung disease.37 Some national and international COPD consider that there is insufficient data for its general recommendation,28,38 whereas other guidelines recommend vaccination of all patients with COPD.39 Haemophilus influenza vaccine Oral immunization with Haemophilus (type B) influenza reduces the number of purulent exacerbations in COPD.40 Its routine use is not recommended in the management of asthma or COPD. OM-85 BV (Broncho-Vaxom) OM-85 BV (Broncho-Vaxom) is a mixture of eight bacterial products thought to be important in respiratory infections. It is administered orally and is thought to act as a nonspecific immunostimulant. A randomized controlled study in 381 patients with COPD treatment with OM-85 BV did not reduce the risk of having at least one episode of an acute exacerbation (primary outcome) over a 6-month period compared with placebo. Treatment with OM-85, however, reduced the risk and total number of days of hospitalization for a respiratory problem by 30% and 55%, respectively.41 Further studies are required to confirm these findings.
ANTIVIRAL DRUGS Antiviral drugs used in the treatment of influenza A include amantadine and rimantadine. Both drugs are effective for the prevention and treatment of influenza A infections involving healthy individuals,33 although the efficacy of these agents for patients with asthma or COPD has not been specifically assessed. Neuraminidase inhibitors are a new class of antiviral agents that are active against both influenza A and influenza B. The neuraminidase inhibitors, inhaled zanamivir (Relenza) and oral oseltamivir (Tamiflu) have received regulatory approval in some countries for the treatment of acute influenza. If these agents are started within the first 2
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days after the onset of illness, then treatment will shorten the duration of symptoms by 1 to 1 days and in some studies the need for antibiotics is reduced.33 Antiviral drugs should be considered for patients with asthma and COPD, if started within 2 days of infection, particularly in those who have not been vaccinated.33 It has also been recommended that prophylaxis should be considered in vaccinated members of high-risk groups, including patients with asthma and COPD, because the combination of vaccination and antiviral drug increases protection against influenza.33
ANTIOXIDANTS Antioxidant enzymes form the first line of defense in the lungs. Antioxidants may reduce chronic airway inflammation by neutralizing the damage produced by reactive oxygen species and also possibly by preserving the inhibitory action of antiproteases. Antioxidant genes, however may be upregulated by oxidative stress42 and the dose of administered exogenous antioxidant may need to be titrated so as to avoid suppression of endogenous antioxidant activity.43 Asthma Dietary antioxidants, for example vitamin E, vitamin C and the carotenoids These vitamins are mainly derived from fruit and vegetables. Higher blood, but not dietary vitamin C levels have been associated with fewer asthma symptoms in adults, but not in children.44 Higher vitamin C intake is associated with higher level of lung function.45 In several cross-sectional studies, no clear relationship has been found between dietary and blood levels of vitamin E or beta-carotene and asthma symptoms.44,45 Short-term dietary vitamin C supplementation has been reported to either reduce or to have no effect on bronchial hyperreactivity in asthmatic patients.46,47 Dietary supplementation with vitamins C and E over a 2-week period did not alter exhaled nitric oxide, carbon monoxide or hydrogen peroxide levels or induced sputum eosinophil counts.48 These shortterm studies suggest that supplementation with antioxidant vitamins may not be able to reduce oxidative stress of the airways in asthma, but studies over a longer time are required. Inhaled glutathione In mild asthma, nebulized glutathione was found to induce bronchoconstriction.49 COPD Oxidative stress is increased in smokers and reactive oxygen species may be involved in the pathogenesis of COPD.42,50 There is evidence that endogenous antioxidant capacity is reduced in COPD and so antioxidants may be useful in the treatment of COPD. Dietary antioxidants There is some evidence linking dietary deficiency of antioxidants such as vitamin C, vitamin E and beta-carotene and
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COPD.44,51 There have been no controlled studies of vitamins C or E in COPD. Dietary supplementation, with betacarotene and retiylpalitate for over 10 years did not alter the rate of decline in lung function compared with placebo.52 Beta-carotene and alpha-tocopherol supplements had no benefit on the symptoms of COPD.53 N-acetylcysteine N-acetylcysteine, which is a mucolytic,54 may also act as an antioxidant by providing cysteine intracellularly for increased production of glutathione.55 Antioxidant effects have been reported both in vitro55 and in vivo.54–58 In vitro Nacetylcysteine reduces neutrophil chemotaxis56 and in smokers it reduces the number and activity of bronchoalveolar neutrophils and alveolar macrophages.56 N-acetylcysteine preserves the inhibitory action of antiproteases from oxidative inactivation.59 It has not been established, however whether the clinical effects of N-acetylcysteine and other mucolytics are due to the antioxidant properties of these drugs (see Mucolytic Drugs).
M U C O LY T I C D R U G S Mucolytic drugs such as N-acetylcysteine, methylcysteine and carbocysteine, that reduce the viscosity of mucous in vitro, have been assessed in several clinical trials in COPD. These drugs have not been assessed in asthma. COPD Efficacy A systematic review of 22 randomized controlled trials of mucolytic drugs including N-acetylcysteine found that these drugs reduced the frequency of acute exacerbations of COPD by 0.067 per month (29% reduction) and the total days of disability by 0.56 days per month when compared with placebo.60,61 The number of patients who remained exacerbation-free was greater in the mucolytic group than in the placebo group (OR 2.22, 95% CL 1.93–2.54). The efficacy and side-effect profile was similar between N-acetylcysteine and the other mucolytic drugs. A systematic review of 11 randomized trials comparing oral N-acetylcysteine with placebo administered from 12–24 weeks in patients with chronic bronchitis concluded that active treatment reduced the risk of exacerbations and improved symptoms without an increased risk of sideeffects62 (Fig. 61.2). In nine trials, 48.5% of patients (351 of 723) receiving N-acetylcysteine had no exacerbations compared with 31.2% of patients (229 of 733) receiving placebo (relative benefit 1.56 (95% CL 1.37–1.77). In five trials, 61.4% of patients (286 of 466) receiving N-acetylcysteine reported improved symptoms compared with 34.6% of patients (160 of 462) receiving placebo (relative benefit 1.78 (95% CL 1.54–2.05)). The duration of treatment (12–24 weeks) or cumulative dose of N-acetylcysteine did not influence efficacy. The clinical relevance of these beneficial effects is difficult to quantify. In an open study of patients
Patients with no exacerbation with P (%)
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Patients with no exacerbation with NAC (%) Fig. 61.2. Mucolytics in COPD: absence of any exacerbation with oral N-acetylcysteine (NAC) or placebo (P) in chronic bronchitis. Symbol sizes are proportional to trial sizes. Arrows are weighted means (reproduced with permission from Ref. 62).
with mild to moderate COPD N-acetylcysteine reduced the rate of decline in FEV1 over a 2-year period.63 This effect was seen particularly in those aged over 50 years of age: rate of decline in FEV1 of 30 ml per year compared with 54 ml per year with the untreated patients. Stey and colleagues62 have estimated that of 100 patients with chronic bronchitis taking N-acetylcysteine for 12–24 weeks, 17 would be prevented from having an exacerbation and 26 would note an improvement in symptoms compared with placebo. The long-term use of N-acetylcysteine is probably not justified, however until cost-effectiveness studies have been performed. Recombinant human DNAase (alfadornase) has not been reported to be of benefit in COPD. Adverse effects The main side-effects of mucolytic drugs are gastrointestinal in nature. Recommendations National guidelines do not recommend the use of mucolytic drugs in the management of COPD.28,38,39
MANAGEMENT OF MALNUTRITION COPD Malnutrition (defined as <90% of ideal body weight) is found in 25% of outpatients with COPD and in over 50% of patients admitted to hospital because of COPD.64,65 The mechanisms of weight loss are unclear, although changes in energy balance and systemic inflammation are likely to play a part. The mortality rate is increased in malnourished patients with COPD.66,67 Malnourished patients with COPD exhibit reduced exercise capacity and respiratory muscle function.67 No simple recommendation can be given regarding the “best” test for nutritional assessment.39
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MANAGEMENT OF OBESITY
Treatment group Control group
Peak expiratory flow
% of predicted
95 90 85 80 75 70
Forced expiratory volume in 1 second 90 85 % of predicted
Patients with COPD have increased resting energy requirements due to the increased energy requirements of the ventilatory muscles.68 The energy cost of respiratory muscles can be approximated from the severity of lung hyperinflation.39 These patients are often unable to regain weight despite receiving nutritional support.High-carbohydrate diets should be avoided to prevent excess carbon dioxide production. A meta-analysis of nine randomized controlled trials, of which two were double-blind, concluded that nutritional support (caloric supplementation for at least 2 weeks) had no effect on improving anthropometric measures, lung function or exercise capacity among patients with stable COPD.69 Several national guidelines recommend that if patients are malnourished, attempts should be made to restore nutritional balance,28,39 but that forced nutrition is not recommended at the present time.39
80
*
*
*
*
*
*
*
End of weight reduction programme
6 months
1 year
75 70 65 60
COPD Obesity is also a common feature of COPD and is associated with a poor prognosis, independent of FEV1. The influence of weight reduction on the morbidity and mortality from COPD has not been systematically studied.
C O M P L E M E N TA RY M E D I C I N E In the UK, 48% of 4000 patients with asthma questioned in a National Asthma Campaign survey had used some form of complementary medicine. The therapies most frequently used by patients responding to the survey were breathing techniques, homeopathy and herbal medicines.71 The use of complementary medicine in the management of COPD is unknown. In the USA in 1997, 40% of the general population had used complementary medicine and they visited practitioners of alternative medicine more often than their primary care doctor.72 Asthma Efficacy of complementary medicine The evidence for the efficacy of various types of complementary medicine has been assessed in several reviews73–75 and Cochrane reviews.76–80 Only a small number of studies have been performed using double-blind, randomized controlled trial designs, the criteria used to assess new pharmaceutical drugs for asthma. The lack of randomized, controlled and blinded studies is in part explained by the difficulties in designing trials to investigate the efficacy of a
Forced vital capacity 95 90 % of predicted
Asthma Weight reduction has been shown to improve lung function, and health status in obese people with asthma70 (Fig. 61.3). In addition, weight reduction was associated with a decrease in the number of exacerbations and course of oral steroids.
85 80
*
75 70 65 60 Baseline
End of dieting period
Fig. 61.3. Obesity, weight reduction and asthma: mean morning premedication values for PEF, FEV1 and FVC (% predicted) at different stages during study. Vertical bars show standard errors of the mean. * Changes from baseline shows significant (P < 0.05) difference between groups (reproduced with permission from Ref. 70).
number of these therapies due to problems in identifying an appropriate placebo and blinding the intervention. The choice of outcome measures is also of importance because it is possible that some therapies may improve measures of health status rather than lung function. Many trials of complementary therapies involve small numbers of patients and the power of these studies is low. Based on the current evidence available there are very few data to demonstrate that these therapies work in asthma.73–80 Several reviews of complementary techniques have concluded that acupuncture, homeopathy, breathing techniques and yoga were the therapies most worthy of further investigation.73,74,81 Breathing techniques The Buteyko breathing technique is based on the hypothesis that all patients with asthma hyperventilate at rest, and
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that rectifying this problem, by reducing the rate of breathing, results in an improvement in asthma control. In a recently published report,82 the Buteyko breathing technique was compared with a placebo breathing technique in 39 adult asthmatic patients over a 3-month period. At the end of the trial the Buteyko breathing technique group compared with the placebo breathing technique showed reduction in median beta-agonist usage (904 lg and 57 lg, respectively, P = 0.002). Unfortunately the follow-up arrangements were not identical between the two groups and there was the possibility of greater patient contact in the Buteyko-treated group. Measurements of lung function (FEV1 and end-tidal CO2) and quality of life were unaltered in both groups. Two systematic reviews have concluded that too few studies have been undertaken to make reliable conclusions on the use of breathing techniques for asthma. Homeopathy Homeopathy involves identifying factors that precipitate asthma in an individual and then prescribing a specific homeopathic remedy for that person. In some cases, the remedy may include very small quantities of the allergen to which the patient is allergic, e.g. house dust mite. A small randomized controlled parallel group study in 28 patients with allergic asthma compared oral homeopathic immunotherapy to their principal allergen or identical placebo for a 4-week period.83 All patients continued their unaltered conventional therapy. A daily visual analog scale of overall symptom intensity showed improvements in favor of homeopathic immunotherapy within 1 week of starting treatment which persisted through the treatment period. There were no significant changes in measurement of baseline lung function and bronchial reactivity. A meta-analysis of placebo-controlled trials of homeopathy concluded that there was insufficient evidence that it was clearly efficacious for any single clinical condition.77,84 Acupuncture Acupuncture involves the insertion of needles at specific points of the body. The technique is based on Chinese theories of the bodies balance of energies. The effects of acupuncture were assessed in a randomized, double-blind controlled, cross-over study in 22 patients with asthma.85 There was a statistically significant improvement in assessments of quality of life and reductions in beta-agonist use after both the active and sham interventions, but no change in PEF recordings. A Cochrane review of acupuncture for asthma concluded that there was insufficient evidence to make any recommendations about its use, but highlighted the need for well-controlled studies to assess its effectiveness in asthma.76 Herbal medicines A large range of herbal medicines is used for the treatment of asthma. There are no controlled trials of the effectiveness of these remedies.
Yoga Yoga is an ancient Hindu discipline that promotes increased mental and physical control of the body. One of the eight steps of yoga, pranayama, deals with control of breathing to cause relaxation and improved fitness. The effects of two pranayama yoga breathing exercises were assessed in a randomized, controlled, crossover trial in 18 patients with mild asthma.86 There was a statistically significant reduction in bronchial reactivity to histamine after the active intervention compared with placebo, but no change in baseline lung function tests, symptom scores or beta-agonist use. Chiropractic spinal manipulation Chiropractic spinal manipulation, although used mainly for the treatment of musculoskeletal conditions in the United States and Canada, has been reported to be of benefit in asthma. The rationale for its use in asthma is based on the hypothesis that subluxation of spinal joints causes irritation to spinal nerves and alters chest and airway function. Manipulation of the spine is thought to restore normal mechanical and nerve function and result in an improvement in lung function in asthma. A randomized, controlled trial of chiropractic spinal manipulation in 91 children with mild to moderate asthma was recently reported.87 The children were randomized to receive either active or simulated chiropractic manipulation for 4 months. In both groups there were similar small increases in PEF reading, reductions in symptoms and beta-agonist use, as well as improvements in the quality of life. There were no significant changes in spirometric measurements or airway responsiveness. Thus, in this group of asthmatic children the addition of chiropractic spinal manipulation to their usual medical care provided no benefit. Safety of complementary medicine The safety of complementary therapies is rarely assessed. Although patients often consider these treatments as harmless, this may not always be the case. The health of a patient starting a complementary therapy may be put at risk for several reasons. The patient may abruptly stop their conventional medicines for asthma. Some herbal remedies can cause severe toxic effects due to hepatotoxicity, heavy metal poisoning or to micro-organisms.88 Herbal medicines may contain conventional pharmaceutical drugs, for example, corticosteroids or nonsteroidal anti-inflammatory drugs. Finally, it is known that acupuncture can cause pneumothoraces and transmit hepatitis.
REFERENCES 1. Norris AA, Alton EWFW. Chloride transport and the actions of sodium cromoglycate and nedocromil sodium in asthma. Clin. Exp. Allergy 1996; 2:250–3. 2. Thomson NC. Nedocromil sodium: an overview. Respir. Med. 1989; 83:269–76. 3. Thomson NC. Non-steroidal prophylactic agents: mode of action and place in management. In: Clarke TJH, Godfrey S, Lee TH, Thomson NC (eds), Asthma, 4th edn, pp. 283–303. London: Arnold, 2000.
Other Therapies
4. Corin RE. Nedocromil sodium: a review of the evidence for a dual mechanism of action. Clin. Exp. Allergy 2000; 30:461–8. 5. Diaz P, Galleguillos FR, Gonazelez MC et al. Bronchoalveolar lavage in asthma: The effect of sodium cromoglycate (Cromolyn) on leucocyte counts. J. Allergy Clin. Immunol. 1984; 74:41–8. 6. Hoshino M, Nakamura Y. The effects of inhaled sodium cromoglycate on cellular infiltration into the bronchial mucosa and the expression of adhesion molecules in asthmatics. Eur. Respir. J. 1997; 10:858–65. 7. Manolitsas ND, Wang JH, Devalia JL et al. Regular albuterol, nedocromil sodium and bronchial inflammation in asthma. Am. J. Repir. Crit. Care Med. 1995; 151:1925–30. 8. Kelly KD, Spooner CH, Rowe BH. Nedocromil sodium versus cromoglycate for the pre-treatment of exercise induced bronchoconstriction in asthma. Cochrane Database of Systematic Reviews CD002169, 2000. 9. Holgate ST. Inhaled sodium cromoglycate. Respir. Med. 1996; 90:387–90. 10. Dorward AJ, Roberts JA, Thomson NC. Effect of nedocromil sodium on histamine airway responsiveness in grass-pollen sensitive asthmatics during the pollen season. Clin. Allergy 1986; 16:309–15. 11. Svendsen UG, Frolund L, Madsen F et al. A comparison of the effects of nedocromil sodium and beclomethasone dipropionate on pulmonary function, symptoms, and bronchial responsiveness in patients with asthma. J. Allergy Clin. Immunol. 1989; 84:224–31. 12. Bel EH, Timmers MC, Hermans J et al. The long-term effects of nedocromil sodium and beclomethasone dipropionate on bronchial responsiveness to methacholine in nonatopic asthmatic subjects. Am. Rev. Respir. Dis. 1990; 141:21–8. 13. Brompton Hospital/Medical Research Council Collaborative Trial. Long-term study of disodium cromoglycate in the treatment of severe extrinsic or intrinsic bronchial asthma in adults. Br. Med. J. 1972; 4:383–8. 14. Eigen H, Reid JJ, Dahl R et al. Evaluation of the addition of cromolyn sodium to bronchodilator maintenance therapy in the long-term management of asthma. J. Allergy Clin. Immunol. 1987; 80:612–21. 15. Carlsen K-H, Larsson K. The efficacy of inhaled disodium cromoglycate and glucocorticoids. Clin. Exp. Allergy 1996; 26(Suppl. 4): 8–17. 16. Tasche MJA, Uijen JHJM, Bernsen RMD et al. Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma: a systematic review. Thorax 2000; 55:913–20. 17. Edwards AM, Stevens MT. The clinical efficacy of inhaled nedocromil sodium (Tilade) in the treatment of asthma. Eur. Respir. J. 1993; 6:35–41. 18. Holgate ST. The efficacy and therapeutic position of nedocromil sodium. Respir. Med. 1996; 90:391–4. 19. Boldy DAR, Ayres JG. Nedocromil sodium and sodium cromoglycate in patients aged over 50 years with asthma. Respir. Med. 1993; 87:517–23. 20. Schwartz HJ, Blumenthal M, Brady R et al. A comparative study of the clinical efficacy of nedocromil sodium and placebo. How does cromyln sodium compare as an active control treatment? Chest 1996; 109:945–52. 21. Faurschou P, Bing J, Edman G et al. Comparison between sodium cromoglycate MDI: metered dose inhaler and beclomethasone diproprionate MDI in treatment of adult patients with mild to moderate bronchial asthma. A double-blind, double dummy randomized, parallel-group study. Allergy 1994; 49:656–60. 22. Childhood Asthma Management Program Research Group. Longterm effects of budesonide or nedocromil in children with asthma. N. Engl. J. Med. 2000; 343:1054–63. 23. Svendsen UG, Jorgensen H. Inhaled nedocromil sodium as additional treatment to high dose inhaled corticosteroids in the management of bronchial asthma. Eur. Respir. J. 1991; 4:992–9.
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24. Goldin JG, Bateman ED. Does nedocromil sodium have a steroid sparing effect in adult asthmatic patients requiring maintenance oral corticosteroids? Thorax 1988; 43:982–6. 25. Boulet L-P, Cartier A, Cockcroft DW et al. Tolerance to reduction of oral steroid dosage in severely asthmatic patients receiving nedocromil sodium. Respir. Med. 1990; 84:317–23. 26. National Institutes of Health. Highlights of the Expert Panel Report II: Guidelines for the Diagnosis and Management of Asthma. US Department of Health and Human Services Publication, 1997. 27. British Guidelines on Asthma Management. 1995 review and position statement. Thorax 1997; 52:S1–21. 28. ERS Consensus Statement. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). Eur. Respir. J. 1995; 8:1398–420. 29. de Jong JW, Postma DS, van der Mark TW, Koeter GH. Effects of nedocromil sodium in the treatment of non-allergic subjects with chronic obstructive pulmonary disease. Thorax 1994; 49:1022–4. 30. Nichol KL, Baken L, Nelson A. Relation between influenza vaccination and outpatient visits, hospitalization, and mortality in elderly persons with chronic lung disease. Ann. Intern. Med. 1999; 130:397–403. 31. Poole PJ, Chacko E, Wood-Baker RWB et al. Influenza vaccine for patients with chronic obstructive pulmonary disease (Cochrane Review). In: The Cochrane Library, 4, 2000. Oxford: Update Software. 32. Cates CJ, Jefferson TO, Bara AI et al. Vaccines for preventing influenza in people with asthma (Cochrane Review). In: The Cochrane Library, 4, 2000. Oxford: Update Software. 33. Couch RB. Prevention and treatment of influenza. N. Engl. J. Med. 2000; 343:1778–87. 34. Watson JM, Cordier JF, Nicholson KG. Does influenza immunisation cause exacerbations of chronic airflow obstruction or asthma? Thorax 1997; 52:190–4. 35. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practice (ACIP). Morb. Mortal.Wkly Rep. 2000; 49:1–38. 36. Nichol KL, Baken L, Wuorenma J, Nelson A. The health and economic benefit associated with pneumococcal vaccination of elderly persons with chronic lung disease. Arch. Intern. Med. 1999; 159:2437–42. 37. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practice (ACIP). Morb. Mortal.Wkly Rep. 1997; 46:1–24. 38. British Thoracic Society Standards of Care Committee, Guidelines for the management of chronic obstructive pulmonary disease. Thorax 1997; 52(Suppl. 5):1–26. 39. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1995; 152:S77–120. 40. Clancy R, Cripps A, Murree-Allen K et al. Oral immunisation with killed Haemophilus influenzae for protection against acute bronchitis in chronic obstructive lung disease. Lancet 1985; ii:1395–7. 41. Collet JP, Shapiro P, Ernst P et al. Effects of an immunostimulating agent on acute exacerbations and hospitalization in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 156:1719–24. 42. MacNee W. Oxidants/antioxidants and COPD. Chest 2000; 117(Suppl. 1):303S–17S. 43. Rogers DF, Barnes PJ. COPD: new developments and therapeutic opportunities. Trends Pharm. Sci. 1999; 20:352–4. 44. Grievink L, Smit HA, Brunekreef B. Anti-oxidants and air pollution in relation to indicators of asthma and COPD: a review of the current evidence. Clin. Exp. Allergy 2000; 30:1344–54. 45. Fogarty A, Britton J. The role of diet in the aetiology of asthma. Clin. Exp. Allergy 2000; 30:615–27. 46. Mohsenin V, DuBois AB, Douglas JS. Effect of ascorbic acid on response to methacholine challenge in asthmatic subjects. Am. Rev. Respir. Dis. 1983; 127:143–7.
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47. Malo J-L, Cartier A, Pineau L et al. Lack of acute effects on ascorbic acid on spirometry and airway responsiveness to histamine in subjects with asthma. J. Allergy Clin. Immunol. 1986; 78:1153–8. 48. Horvath I, Kiss A, Chung KF, Barnes PJ.The effect ofVitamin C and E supplementation in airway inflammation/oxidative stress in mild asthma. Am. J. Respir. Crit. Care Med. 2000; 161:A595. 49. Marrades RM, Roca J, Barbera JA et al. Nebulized glutathione induces bronchoconstriction in patients with mild asthma. Am. J. Respir. Crit. Care Med. 1997; 156:425–30. 50. Morrison D, Rahman I, Lannan S, MacNee W. Epithelial permeability, inflammation, and oxidant stress in the airspace of smokers. Am. J. Respir. Crit. Care Med. 1999; 159:473–9. 51. Hu G, Cassano PA. Antioxidant nutrients and pulmonary function: The Third National Health and Nutrition Examination Survey (NHANES III). Am. J. Epidemiol. 2000; 151:975–81. 52. Balmes JR, Ngo L, Keogh J et al. Effect of supplemental betacarotene and retinol on rate of decline in lung function. Am. J. Respir. Crit. Care Med. 1998; 157:A46. 53. Rautalahti M, Virtamo J, Haukka J et al. The effect of alphatocopherol and beta-carotene supplementation on COPD symptoms. Am. J. Respir. Crit. Care Med. 1997; 156:1447–52. 54. Sheffner AL, Medler EM, Bailey KR et al. Metabolic studies with acetylcysteine. Biochem. Pharmacol. 1966; 15:1523–35. 55. Repine JE, Bast A, Lankhorst I. Oxidative stress in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 156:341–57. 56. Kharazmi A, Nielsen H, Schiotz PO. N-acetylcysteine inhibits human neutrophil and monocyte chemotaxis and oxidative metabolism. Int. J. Immunopharmacol. 1988; 10:39–46. 57. Joshi UM, Kodavanti PRS, Mehendale HM. Glutathione metabolism and utilisation of external thiols by cigarette smoke-challenged, isolated rat and rabbit lungs. Toxicol. Appl. Pharmacol. 1988; 96:324–35. 58. Rogers DF, Jeffrey PK. Inhibition by oral N-acetylcysteine of cigarette smoke-induced ‘bronchitis’ in the rat. Exp. Lung. Res. 1986; 10:267–83. 59. Arouma OI, Halliwell B, Hoey BM et al. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. J. Free Rad. Biol. Med. 1989; 6:593–7. 60. Poole PJ, Black PN. Mucolytic agents for chronic bronchitis (Cochrane review). In: The Cochrane Library, 4, 2000. Oxford: Update Software. 61. Multicenter Study Group. Long-term oral acetylcysteine in chronic bronchitis, a double-blind controlled study. Eur. J. Respir. Dis. 1980; 61(Suppl. 111):93–108. 62. Stey C, Steurer J, Bachmann S et al. The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Eur. Respir. J. 2000; 16:253–62. 63. Lundback B, Lindstrom M, Andersson S et al. Possible effect of acetylcysteine on lung function. Eur. Respir. J. 1992; 5(Suppl. 15):289S. 64. Braun SR, Keim RM, Dixon RM et al. The prevalence and determinants of nutritional changes in chronic obstructive pulmonary disease. Chest 1984; 86:558–63. 65. Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body weight in chronic obstructive pulmonary disease: the National Institutes of Health Intermittent Positive-Pressure Breathing Trial. Am. Rev. Respir. Dis. 1989; 139:1435–8. 66. Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1856–61.
67. Kelsen SG, Ference M, Kapoor S. Effects of prolonged undernutrition on structure and function of the diaphragm. J. Appl. Physiol. 1985; 58:1354–9. 68. Donahue M, Rogers RM, Wilson DO, Pennock BE. Oxygen consumption of the respiratory muscles in normal and malnourished patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1989; 140:385–91. 69. Ferreira IM, Brooks D, Lacasse Y et al. Nutritional support for individuals with COPD. Chest 2000; 117:672–8. 70. Stenius-Aarniala B, Poussa T, Kvarnstrom J et al. Immediate- and long-term effects of weight reduction in obese people with asthma: randomised controlled study. Br. Med. J. 2000; 320:827–32. 71. Ernst E. Complementary therapies for asthma: what patients use. J. Asthma 1998; 35:667–71. 72. Eisenberg DM, Davis RB, Ettner SL et al. Trends in alternative medicine use in the United States, 1990–1997. Results of a follow-up national survey. JAMA 1998; 280:1549–640. 73. Lane DJ, Lane TV. Alternative and complementary medicine for asthma. Thorax 1991; 46:787–97. 74. Lewith GT, Watkins AD. Unconventional therapies in asthma: an overview. Allergy 1996; 51:761–9. 75. Vickers AJ, Smith C. Analysis of the evidence profile of the effectiveness of complementary therapies in asthma: a qualitative survey and systematic review. Comp.Ther. Med. 1997; 5:202–9. 76. Linde K, Jobst K, Panton J. Acupuncture for chronic asthma (Cochrane Review). In: The Cochrane Library, 4, 2000. Oxford: Update Software. 77. Linde K, Jobst KA. Homeopathy for chronic asthma (Cochrane Review). In: The Cochrane Library, 4, 2000. Oxford: Update Software. 78. Holloway E, Ram FSF. Breathing exercises for asthma (Cochrane Review). In: The Cochrane Library, 4, 2000. Oxford: Update Software. 79. Dennis J. Alexander technique for chronic asthma (Cochrane Review). In: The Cochrane Library, 4, 2000. Oxford: Update Software. 80. Hondras MA, Linde K, Jones AP. Manual therapy for asthma (Cochrane Review). In: The Cochrane Library, 4, 2000. Oxford: Update Software. 81. Ernst E. Breathing techniques – adjunctive treatment modalities for asthma? A systematic review. Eur. Respir. J. 2000; 15:969–72. 82. Bowler SD, Green A, Mitchell CA. Buteyko breathing techniques in asthma: a blinded randomised controlled trial. Med. J. Aust. 1998; 169:575–8. 83. Reilly D, Taylor MA, Beattie NGM et al. Is evidence for homeopathy reproducible? Lancet 1994; 344:1601–6. 84. Linde K, Clausius N, Ramirez G et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebocontrolled trials. Lancet 1997; 350:834–43. 85. Biernacki W, Peake MD. Acupuncture in treatment of stable asthma. Respir. Med. 1998; 92:1143–5. 86. Singh V,Wisniewski A, Britton J et al. Effect of yoga breathing exercises (pranayama) on airway reactivity in subjects with asthma. Lancet 1990; 335:1381–3. 87. Balon J, Aker PD, Crowther ER et al. A comparison of active and simulated chiropractic manipulation as adjunctive treatment for childhood asthma. N. Engl. J. Med. 1998; 339:1013–20. 88. Bateman J, Chapman RD, Simpson D. Possible toxicity of herbal remedies. Scot. Med. J. 1998; 43:7–15.
Future Therapies
Chapter
62
Peter J. Barnes National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
As indicated in previous chapters, asthma and COPD are different diseases that involve different cells, mediators and inflammatory effects and this results in different treatments. Many new classes of drugs are now in development for asthma and COPD, but not surprisingly these drugs differ between the two diseases.This chapter discusses some of the new drugs in development for asthma and COPD, contrasting the approaches for these two different diseases. In contrast to the large number of drugs now in development for asthma,1,2 there is much less progress in the development of new drugs for COPD,3 reflecting the relative neglect of this disease.
T H E N E E D F O R N E W T R E AT M E N T S Asthma Current asthma therapy is highly effective and the majority of patients can be well controlled with inhaled corticosteroids and short- and long-acting b2-agonists. These treatments are not only effective, but safe and relatively inexpensive. This poses a challenge for the development of new treatments, since they will need to be safer or more effective than existing treatments, or offer some other advantage in long-term disease management. However, there are several problems with existing therapies. • Existing therapies have side-effects as they are nonspecific. Inhaled b2-agonists may have side-effects and there is some evidence for the development of tolerance, especially to their bronchoprotective effects. Inhaled corticosteroids may also have local and systemic side-effects at high doses and there is still a fear of using long-term steroid treatment in many patients. Other treatments, such as theophylline, anticholinergics and antileukotrienes are less effective and are largely used as add-on therapies. • There is still a major problem with poor compliance in the long-term management of asthma, particularly as symptoms come under control with effective therapies.4 It is likely that a once daily tablet or even an infrequent injection may give improved compliance. However, oral
therapy is associated with a much greater risk of systemic side-effects and therefore needs to be specific for the abnormality in asthma. • Patients with severe asthma are often not controlled on maximal doses of inhaled therapies or may have serious side-effects from therapy, especially oral corticosteroids. These patients are relatively resistant to the antiinflammatory actions of corticosteroids and require some other class of therapy to control the asthmatic process. • None of the existing treatments for asthma is diseasemodifying, which means that the disease recurs as soon as treatment is discontinued. • None of the existing treatments is curative, although it is possible that therapies which prevent the immune aberration of allergy may have prospects for a cure in the future. COPD In sharp contrast to asthma there are few effective therapies in COPD, despite the fact that it is a common disease that is increasing world-wide.5 The neglect of COPD by pharmaceutical companies is probably as a result of several factors: • COPD is regarded as largely irreversible and is treated as poorly responsive asthma. • COPD is self-inflicted and therefore does not deserve investment. • There are no satisfactory animal models. • Relatively little is understood about the cell and molecular biology of this disease or even about the relative role of small airways disease and parenchymal destruction. None of the treatments currently available prevent the progression of the disease, and yet the disease is associated with an active inflammatory process that results in progressive obstruction of small airways and destruction of lung parenchyma. Increased understanding of COPD will identify novel targets for future therapy6 (Fig. 62.1). It is clear the new treatments for COPD may be different classes of drug from those in development for asthma, reflecting the
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Stopping smoking bupropion
Immunosuppressants?
Alveolar macrophage CD8+ lymphocyte
MCP-1 Chemokines (IL-8) Mediators (LTBJ
Neutrophil inhibitors PDE4 inhibitors
Neutrophil
Protease inhibitors NE, MMP inhibitors a,-AT, SLPI
Alveolar repair retinoic acid
Mediator antagonists LTB4 inhibitors Chemokine antagonists
Neutrophil elastase Cathepsins Matrix metalloproteinases
Emphysema
Mucus hypersecretion
Mucoregulators
Fig. 6 2 . 1 . Targets for COPD therapy based on current understanding of the inflammatory mechanisms. Cigarette smoke (and other irritants) activate macrophages in the respiratory tract that release neutrophil chemotactic factors, including interleukin-8 (IL-8) and leukotriene B4 (LTB4). These cells then release proteases that break down connective tissue in the lung parenchyma, resulting in emphysema, and also stimulate mucus hypersecretion. These enzymes are normally counteracted by protease inhibitors, including a,-antitrypsin, secretory leukoprotease inhibitor (SLPI) and tissue inhibitor of matrix metalloproteinases (TIMP). Cytotoxic T cells (CD8+) may also be involved in the inflammatory cascade.
markedly differing cellular and molecular between these two diseases.'
mechanisms
cular genomics) and proteins (proteomics) from diseased cells, and through identification of single nucleotide polymorphisms (SNPs) that contribute to the disease process.*
D E V E L O P M E N T OF N E W THERAPIES NEW Several strategies have been adopted in the search for new therapies: • Improvement of an existing class of drug. This is well exemplified by the increased duration of Pj-^gonists with salmeterol and formoterol and of anticholinergics with tiotropium bromide, and with the improved pharmacokinetics of the inhaled corticosteroids fluticasone propionate, mometasone and budesonide, with increased first-pass metabolism and therefore reduced systemic absorption. • Development of novel therapies through better understanding of the disease process. Examples are anti-interleukin (IL)-5 as a potential treatment of asthma and phosphodiesterase (PDE)-4 inhibitors as an antiinflammatory therapy for C O P D . • Serendipitous observations, often made in other therapeutic areas. Examples are tumor-necrosis-a (TNF-a) antagonists for airway diseases, derived from observations in other chronic inflammatory diseases. • Identification of novel targets through gene and protein profiling. This approach will be increasingly used to identify the abnormal expression of genes (mole-
BRONCHODILATORS
Bronchodilators act predominantly by relaxation of airway smooth muscle cells, although additional effects, such as inhibition of bronchoconstrictor mediator and neurotransmitter release may contribute. Pj-Agonists are by far the most effective bronchodilators in asthma and act as functional antagonists, blocking the effect of all bronchoconstrictors. The increased bronchodilator duration of long-acting inhaled Pj-agonists has been an important advance and there is now a search for once daily inhaled Pj-agonists. By contrast, in C O P D anticholinergics appear to be the most effective bronchodilators and there has been a search for selective anticholinergics and drugs with a longer duration. Novel classes of bronchodilator have also been developed (Table 62.1). N e w anticholinergics The receptor that mediates the bronchoconstrictor effect of acetylcholine is the muscarinic M3-receptor, whereas M j receptors on cholinergic nerve terminals inhibit acetylcholine release.' Nonselective anticholinergics that block all muscarinic receptors, such as ipratropium bromide, increase acetylcholine release, which may counteract the blockade of M3 receptors in the muscles. There has therefore been a
Future Therapies
Table 62.1. New bronchodilators
Drug class
Examples
b2-Agonists
Once daily inhaled b2-agonists Tiotropium bromide, glycopyrrolate Levcromakalim, SDZ PC400 Ro 25-1533 Urodilatin
Anticholinergics Potassium channel openers VIP analogs Atrial natriuretic peptides
search for selecting muscarinic antagonists, which block M3 and M1 receptors (that enhance ganglionic reflexes), but spare M2 receptors. It has proved difficult to find drugs that are very selective.10 However, tiotropium bromide dissociates very slowly from M1 and M3 receptors compared with M2 receptors and therefore has kinetic receptor selectivity.11 Tiotropium bromide has a very long duration of action, inhibiting cholinergic nerves in human airway smooth muscle for many times longer than ipratropium bromide12 and providing protection against cholinergic challenge of up to 3 days after a single dose.13 Tiotropium has a prolonged bronchodilator effect in COPD14 and is suitable for once daily dosing. It is effective in controlling symptoms in COPD over a prolonged period.15 Potassium channel openers Potassium (K+) channels play an important role in relaxation of airway smooth muscle. Drugs that promote the opening of K+ channels therefore have bronchodilator effects.16 There are many types of K+ channel and selective K+ channel openers (KCOs) have been developed. KCOs that open ATP-dependent K+ channels, such as levcromakalim, have been tested in asthma, but are disappointing as their vasodilator side-effects prevent an effective dose being given.17 This problem cannot be overcome by inhalation as currently available drugs are absorbed from the lungs. Openers of other K+ channels might be more effective
643
and there is interest in openers of large conductance calcium-activated channels (maxi-K) as these are opened by b2-agonists. Several maxi-K openers are in development.18 KCOs may have additional beneficial effects in airway diseases, and may inhibit sensory nerve function19 and inhibit mucus secretion.20 Atrial natriuretic peptides Atrial natriuretic peptides relax airway smooth muscle by increasing cyclic GMP and there act in a different way to b2agonists which increase cyclic AMP.21 An extended form of ANP, urodilatin is an effective bronchodilator in asthma and may be suitable as an intravenous therapy for the treatment of acute exacerbations of asthma and COPD.22
M E D I AT O R A N TA G O N I S T S Blocking the receptors or synthesis of inflammatory mediators is a logical approach to the development of new treatments for asthma and COPD (Table 62.2). However, in both diseases many different mediators are involved and therefore blocking a single mediator may not be very effective, unless it plays a key role in the disease process.23 Several specific mediator antagonists have been found to be ineffective in asthma, including antagonists/inhibitors of histamine, thromboxane, platelet-activating factor, bradykinin and tachykinins. However, these blockers have often not been tested in COPD, in which different mediators are involved. Anti-leukotrienes Anti-leukotrienes include inhibitors of 5-lipoxygenase and antagonists of leukotriene receptors. In asthma, antileukotrienes may give a significant improvement in asthma symptoms and lung function with a weak anti-inflammatory effect,24 but these drugs are less effective than corticosteroids. Cysteinyl-leukotriene receptor antagonists include montelukast, zafirlukast and pranlukast. They are now widely used in the treatment of asthma, but there is no indication that these drugs will be useful in COPD. However, 5-lipoxygenase (5-LO) inhibitors, such as zileuton, might
Table 62.2. New mediator antagonists for asthma and COPD
Mediator
Antagonists
Asthma
COPD
Leukotriene B4 TNF-a IL-4 IL-5 IL-8 Reactive oxygen species Nitric oxide Endothelins
LY 29311, SC-53228, CP-105,696, SB 201146, BIIL284 Infliximab, etanercept Altrakincept Mepizulimab CXCR2 antagonist: SB 225002 Antioxidants: glutathione analogs, SOD mimetics, nitrones Selective iNOS inhibitors: 1400W ETA/B antagonists: SB 209670, Ro 462005
? (severe) ? Yes Yes No Yes ? ?
Yes ? No No Yes Yes ? ?
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Asthma and Chronic Obstructive Pulmonary Disease
be useful as they block the synthesis of LTB4, a potent neutrophil chemotactic mediator that is increased in COPD.25 Several 5-LO inhibitors, including direct enzyme inhibitors and 5-LO activating protein (FLAP) inhibitors, are in development. Another approach in COPD is to block LTB4 receptors and several antagonists are now in clinical trials. One such antagonist LY293111 had no effect on the allergen response in asthma, but was effective in reducing the influx of neutrophils during the late response.26 Several LTB4 antagonists are now being evaluated in COPD. Endothelin antagonists Endothelin is a peptide mediator which has potent bronchoconstrictor and vasoconstrictor effects.27 There is evidence for increased expression in asthmatic airways and in pulmonary vessels of COPD patients with pulmonary hypertension. Endothelin also stimulates fibrosis and may be involved in the structural remodeling that is found in both asthma and COPD. Several endothelin receptor antagonists are now in clinical development,28 but it may be difficult to assess their effect in airway disease as it may be necessary to measure their effects over very prolonged periods. Anti-oxidants Oxidative stress is important in asthma and COPD, particularly during exacerbations.29 Oxidative stress may activate the proinflammatory transcription factor nuclear factor-jB (NF-jB) which switches on multiple inflammatory genes, and may also damage endogenous anti-proteases.30 Existing antioxidants include vitamins C and E and N-acetylcysteine, but more potent anti-oxidants are in development. It is likely that these drugs would be useful in COPD as oxidative stress is likely to be an important component of the disease, particularly during exacerbations. Nitric oxide synthase inhibitors Nitric oxide (NO) production is increased in asthma as a result of increased inducible NO synthase (iNOS) expression in the airways. NO may have beneficial and detrimental effects in asthma.31 In animal models of allergic inflammation NOS inhibition reduces airway inflammation. Inhalation of the nonselective inhibitor L-NAME and the iNOS selective inhibitor aminoguanidine reduce exhaled NO in asthmatic patients, but have no effect on lung function after a single dose.32 Nebulized L-NAME also has no effect on allergen-induced airway responses, despite a marked reduction in exhaled NO.33 More selective iNOS inhibitors are now in clinical development. The role of NO in COPD is even less certain as levels of exhaled NO are not consistently elevated in COPD,34 although this may reflect the increased oxidative stress and formation of peroxynitrite.
CYTOKINES AND THEIR INHIBITORS Cytokines play a critical role in perpetuating and amplifying the inflammation in asthma and COPD.5,35 Most attention
has focused on inhibition of cytokines, but cytokines themselves might have therapeutic potential. There are several approaches to inhibition of cytokines, including inhibiting their synthesis, blocking with antibodies or soluble receptors and antagonism of their receptors and signal transduction pathways (Fig. 62.2). Some cytokines may play a critical role in the allergic inflammatory process, whereas others play a proinflammatory role in both diseases. Inhibition of Th2 cytokines Cytokines derived from Th2 cells appear to play an important role in allergic inflammation and therefore may be an appropriate target for blockade in asthma. Anti-IL-5 IL-5 plays a pivotal role in eosinophilic inflammation and is also involved in eosinophil survival and priming. It is an attractive target in asthma, as it is essential for eosinophilic inflammation, there do not appear to be any other cytokines with a similar role, and lack of IL-5 in gene knock-out mice does not have any deleterious effect.36 The major strategy for inhibiting IL-5 has been the development of blocking antibodies. IL-5 inhibit eosinophilic inflammation and airway hyperresponsiveness (AHR) in animal models of asthma, including primates. This blocking effect may last for over 3 months after a single injection, making treatment of chronic asthma with such a therapy a feasible proposition. Humanized monoclonal antibodies to IL-5 have been developed and a single injection reduces blood eosinophils for over 3 months and prevents eosinophil recruitment into the airways after allergen challenge.37 However, this treatment has no effect on the early or late response to allergen challenge or on AHR, suggesting that eosinophils may be less important for these responses than previously believed. Long-term clinical studies are now in progress, particularly in patients with more severe disease. Nonpeptide IL-5 receptor antagonists would be an attractive alternative and there is a search for such compounds using molecular modeling of the IL-5 receptor a-chain and through large-scale throughput screening. Anti-IL-4 IL-4 is critical for the synthesis of IgE by B lymphocytes and to the development of Th2 cells. IL-4 receptorblocking antibodies inhibit allergen-induced AHR, goblet cell metaplasia and pulmonary eosinophilia in a murine model.38 Inhibition of IL-4 may therefore be effective in inhibiting allergic diseases. Soluble IL-4 receptors are in clinical development as a strategy to inhibit IL-4. Nebulized soluble IL-4 receptors (altrakincept) have shown clinical efficacy in patients with moderate asthma, and were effective when given as a once weekly nebulization in preventing the deterioration in asthma following reduction in inhaled corticosteroids.39 Both IL-4 and IL-13 are inhibited by a double mutant of IL-4 (Arg121→Asp, Tyr124→Asp, BAY 169996)40 and this double mutant inhibits the inflammatory response to allergen in mice.41 IL-4 and the closely related
Future Therapies
645
Transcription factor Transcription factor inhibitor
Cytokine gene
Antisense oligonucleotide
Synthesis inhibitor mRNA
Monoclonal antibody
Cytokine Receptor
Cell of origin Soluble receptor
Receptor antagonist Target cell
Kinase inhibitor
Signal transduction
Transcription factor inhibitor
Fig. 62.2. Inhibition of cytokine synthesis. Several strategies are available to inhibit the production or effects of cytokines.
cytokine IL-13 signal through a shared surface receptor, which activates a specific transcription factor STAT-6 and deletion of the STAT-6 gene, has a similar effect to IL-4 gene knock-out.42 This has led to a search for inhibitors of STAT-6, although it will be difficult to deliver these intracellularly. An endogenous inhibitor of STATs, suppressor of cytokine signaling (SOCS-1), is a potent inhibitor of IL-4 signaling pathways and offers a new therapeutic target.43 Anti-IL-13 There is increasing evidence that IL-13 in mice mimics many of the features of asthma, including AHR, increased IgE, mucus hypersecretion, fibrosis and release of eotaxin.44 IL-13 signals through the IL-4 receptor a-chain, but may also activate different intracellular pathways,45 so that it may be an important target for the development of new therapies. A soluble IL-13Ra2-Fc fusion protein, which blocks the effects of IL-13 but not IL-4 has been used successfully to neutralize IL-13 both in mice in vivo.46 The IL-13Ra2-Fc fusion protein markedly inhibits eosinophilic inflammation, AHR and mucus secretion induced by allergen exposure. IL-13 is expressed in asthma to a much greater extent than IL-4, indicating that it may be a more important target.47 This suggests that development of IL-13 blockers, such as a humanized IL-13 antibody or the IL-13Ra2 may be a useful approach to the treatment of established allergic diseases.48
Anti-IL-9 IL-9 is produced by Th2 cells and appears to have an amplifying effect on the expression of IL-4 and IL-5.49 This suggests that IL-9 may be a useful upstream target in asthma and humanized monoclonal IL-9 antibodies are now in clinical development. Anti-TNF TNF-a may play a key role in amplifying atopic inflammation, through the activation of NF-jB, AP-1 and other transcription factors. TNF-a production is increased in asthma and COPD, and in the latter may be associated with the cachexia and weight loss that occurs in some patients with severe COPD.50,51 In rheumatoid arthritis and inflammatory bowel disease a blocking antibody to TNF-a (infliximab) has produced remarkable clinical responses, even in patients who are relatively unresponsive to steroids.52 TNF antibodies or soluble TNF-receptors (etanercept) are a logical approach to asthma therapy, particularly in patients with severe disease.There is also a search for small molecule inhibitors of TNF-a, of which the most promising are inhibitors of TNF-a converting enzyme (TACE) as these may be given orally. Other new anti-inflammatory treatments, including phosphodiesterase-4 inhibitors and p38 mitogen-activated protein (MAP) kinase inhibitors are also effective in inhibiting TNF-a release from inflammatory cells.
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Chemokine inhibitors Many chemokines are involved in COPD and asthma and play a key role in recruitment of inflammatory cells, such as eosinophils, neutrophils, macrophages and lymphocytes.53 Chemokine receptors are attractive targets, as they are seven transmembrane spanning proteins, like adrenergic receptors, and small molecule inhibitors are feasible. CCR2 inhibitors MCP-1 recruits and activates CCR2 on monocytes and T lymphocytes. And blocking MCP-1 with neutralizing antibodies reduces recruitment of both T cells and eosinophils in a murine model of ovalbumin-induced airway inflammation, with a marked reduction in AHR.54 MCP-1 also recruits and activates mast cells, an effect that is mediated via CCR2.55 MCP-1 instilled into the airways induces marked and prolonged AHR in mice, associated with mast cell degranulation. A neutralizing antibody to MCP-1 blocks the development of AHR in response to allergen.55 MCP-1 levels are increased in bronchoalveolar lavage fluid of patients with asthma.56 CCR2 may also play an important role in COPD, as MCP-1 levels are increased in sputum and lungs of patients with COPD.57,58 MCP-1 is a potent chemoattractant of monocytes and may therefore be involved in the recruitment of macrophages in COPD. Indeed the chemoattractant effect of induced sputum from patients with COPD is abrogated by an antibody to CCR2.58 Since macrophages appear to play a critical role in COPD as a source of elastases and neutrophil chemoattractants, blocking CCR2 may be important as a therapeutic strategy in COPD. CCR3 antagonists In asthma, most attention has focused on blockade of CCR3 receptors that are predominantly expressed on eosinophils and mediate the chemotactic effect of eotaxin, RANTES and MCP-4.59 Several small molecule inhibitors of CCR3, including UCB35625, SB-297006 and SB-328437 are effective in inhibiting eosinophil recruitment in allergen models of asthma60,61 and drugs in this class are currently undergoing clinical trials in asthma. Although it was thought that CCR3 were restricted to eosinophils, there is some evidence for their expression on Th2 cells and mast cells, so that these inhibitors may have a more widespread effect than on eosinophils alone, making them potentially more valuable in asthma treatment. CCR4 antagonists CCR4 are expressed on Th2 cells and may be important in he recruitment of Th2 cells to the asthmatic airways in response to macrophage-derived cytokine (MDC).62 CXCR antagonists In COPD the focus of attention has been the blockade of IL-8, which attracts and activates neutrophils via two receptors, the specific low affinity CXCR1 and the high affinity CXCR2 which is shared by other CXC chemokines. A small
molecule inhibitor of CXCR2 has now been developed and may lead to clinical trials in COPD.63 Inhibitory cytokines Although most cytokines have anti-inflammatory effects, others have the potential to inhibit inflammation in asthma and COPD.64 While it may not be feasible or cost-effective to administer these proteins as long-term therapy, it may be possible to develop drugs that increase the release of these endogenous cytokines or activate their receptors and specific signal transduction pathways. IL-1 receptor antagonist IL-1 receptor antagonist (IL-1ra) binds to IL-1 receptors and blocks the action of IL-1b. In experimental animals it reduces AHR and clinical studies are in progress.65 IL-10 IL-10 is a potent anti-inflammatory cytokine that inhibits the synthesis of many inflammatory proteins, including cytokines (TNF-a, GM-CSF, IL-5, chemokines) and inflammatory enzymes (iNOS) that are overexpressed in asthma.66 In sensitized animals IL-10 suppresses the inflammatory response to allergen,67 suggesting that IL-10 might be effective as a treatment in asthma. Indeed, there may be a defect in IL-10 transcription and secretion from macrophages in asthma66,68 and reduced levels of IL-10 are found in sputum of asthmatic and COPD patients.69 IL-10 might also be a therapeutic strategy in COPD, since it inhibits TNF-a, IL-8 and matrix metalloproteinase secretion, and increases tissue inhibitors of metalloproteinases. Recombinant human IL-10 has proved to be effective in controlling inflammatory bowel disease, where similar cytokines are expressed and may be given as a weekly injection.70 In the future, drugs which activate the unique signal transduction pathways activated by the IL-10 receptor, or drugs that increase endogenous production of IL-10 may be developed. In mice, drugs that elevate cyclic AMP increase IL-10 production, but this does not appear to be the case in human cells.71 Interferon-c IFN-c inhibits Th2 cells and should therefore reduce atopic inflammation. In sensitized animals, nebulized IFN-c inhibits eosinophilic inflammation induced by allergen exposure. Administration of IFN-c by nebulization to asthmatic patients did not significantly reduce eosinophilic inflammation, however, possibly due to the difficulty in obtaining a high enough concentration locally in the airways.72 IL-12 IL-12 is the endogenous regulator of Th1 cell development and determines the balance between Th1 and Th2 cells.73 IL-12 administration to rats inhibits allergen-induced inflammation and inhibits sensitization to allergens. Recombinant human IL-12 has been administered to humans and has several toxic effects which are diminished by slow
Future Therapies
escalation of the dose.74 Infusion of human recombinant IL12 has an inhibitory effect on eosinophils in asthmatic patients, but has significant systemic side-effects that preclude its clinical development.
ENZYME INHIBITORS Several enzymes are involved in chronic inflammation and inhibitors of several enzymes are in development for the treatment of airway diseases (Table 62.3). Enzymes may result in the formation of inflammatory mediators, such as eicosanoids, or may have direct inflammatory effects, such as tryptase. Enzymes are also involved in the tissue remodeling that occurs in asthma and COPD and a range of proteinases is implicated in the tissue destruction of emphysema. Tryptase inhibitors Mast cell tryptase has several effects on airways, including increasing responsiveness of airway smooth muscle to constrictors, increasing plasma exudation, potentiating eosinophil recruitment and stimulating fibroblast proliferation. Some of these effects are mediated by activation of the proteinase-activated receptor PAR2. A tryptase inhibitor APC366 is effective in a sheep model of allergen-induced asthma,75 but was only poorly effective in asthmatic patients in a preliminary study.76 More potent tryptase inhibitors and PAR2 antagonists are now in development. It is unlikely that tryptase inhibitors will have a role in COPD as mast cell tryptase is not involved. Neutrophil elastase inhibitors Neutrophil elastase (NE), a neutral serine protease, is a major constituent of lung elastolytic activity. In addition, it potently stimulates mucus secretion and induces IL-8 release from epithelial cells and may therefore perpetuate the inflammatory state. This has led to a search for neutrophil elastase inhibitors. Peptide NE inhibitors, such as ICI 200355, and nonpeptide inhibitors, such as ONO-5046, Table 62.3. Enzyme inhibitors for asthma and COPD
5’-lipoxygenase inhibitors (zileuton, Bay x1005) Tryptase inhibitors (APC 366) Neutrophil elastase inhibitors (ICI 200355, ONO-5046, MR-889, L 658,758) Cathepsin inhibitors (suramin) Matrix metalloproteinase inhibitors (batimastat, marimastat, selective MMP-inhibitors) a1-Antitrypsin (purified, human recombinant, gene transfer) Secretory leukoprotease inhibitor (human recombinant, gene transfer) Elafin
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have been developed for use in COPD. There are few clinical studies with NE inhibitors in COPD. The NE inhibitor MR889 administered for 4 weeks showed no overall effect on plasma elastin-derived peptides or urinary desmosine (markers of elastolytic activity), but these may not be sensitive markers.77 These inhibitors act extracellularly and may not inhibit the enzyme at the site of release when neutrophils adhere to connective tissue. Intracellular NE inhibitors might therefore be more effective, at least in preventing lung destruction. Although NE is likely to be the major mechanism mediating elastolysis in patients with a1antitrypsin (a1-AT) deficiency, it may well not be the major elastolytic enzyme in smoking-related COPD, and it is important to consider other enzymes as targets for inhibition. Cathepsin and proteinase-3 inhibitors NE is not the only proteolytic enzyme secreted by neutrophils. Cathepsin G and proteinase 3 have elastolytic activity and may need to be inhibited together with neutrophil elastase. Cathepsins (cathepsins B, L and S) are also released from macrophages. Suramin, a hexasulfonated naphthylurea that has been used as an antitumor drug, is a potent inhibitor of cathepsin G, proteinase-3 and neutrophil elastase.78 Novel and more specific cathepsin inhibitors are now in development. Matrix metalloproteinase inhibitors Matrix metalloproteinases (MMP) are a group of over 20 closely related endopeptidases that are capable of degrading all of the components of the extracellular matrix of lung parenchyma, including elastin, collagen, proteoglycans, laminin and fibronectin.79 MMPs are produced by neutrophils, alveolar macrophages and airway epithelial cells. Increased levels of collagenase (MMP-1) and gelatinase B (MMP-9) have been detected in bronchoalveolar lavage fluid of patients with emphysema. Lavaged macrophages from patients with emphysema express more MMP-9 and MMP-1 than cells from control subjects, suggesting that these cells, rather than neutrophils, may be the major cellular source.80 Alveolar macrophages also express a unique MMP, macrophage metalloelastase (MMP-12). MMP-12 knock-out mice do not develop emphysema and do not show the expected increases in lung macrophages after long-term exposure to cigarette smoke.81 Tissue inhibitors of metalloproteinases (TIMP) are endogenous inhibitors of these potent enzymes. There are several approaches to inhibiting MMPs.82 One approach is to enhance the secretion of TIMPs and another is to inhibit the induction of MMPs in COPD. MMPs may show increased expression with cigarette smoking through induction in response to inflammatory cytokines, oxidants and other enzymes, such as NE. Nonselective MMP inhibitors have been developed, such as marimastat (BB-2516). Side-effects of such drugs may be a problem in long-term use, however. More selective inhibitors of individual MMPs, such as MMP-9 and MMP-12, are now in development and are likely to be better tolerated in chronic therapy. However, it
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is still not clear whether there is one predominant MMP in COPD or whether a broad spectrum inhibitor will be necessary. a1-Antitrypsin The association of a1-AT deficiency with early onset emphysema suggested that this endogenous inhibitor of NE may be of therapeutic benefit in COPD. Cigarette smoking inactivates a1-AT, resulting in unopposed activity of NE and cathepsins. Extraction of a1-AT from human plasma is very expensive and extracted a1-antitrypsin is only available in a few countries. This treatment has to be given intravenously and has a half-life of only 5 days. This has led to the development of inhaled formulations, but these are inefficient and expensive. Recombinant a1-AT with amino acid substitutions to increase stability may result in a more useful product. Gene therapy is another possibility using an adenovirus vector or liposomes, but there have been major problems in developing efficient delivery systems. There is a particular problem with gene transfer in a1-AT deficiency in that large amounts of protein (1–2 g) need to be synthesized each day. There is no evidence that a1-AT treatment would halt the progression of COPD and emphysema in patients who have normal plasma concentrations. Serpins Other serum protease inhibitors (serpins), such as elafin, may also be important in counteracting elastolytic activity in the lung. Elafin, an elastase-specific inhibitor is found in bronchoalveolar lavage and is synthesized by epithelial cells in response to inflammatory stimuli.83 Serpins may not be able to inhibit NE at the sites of elastin destruction, due to tight adherence of the inflammatory cell to connective tissue. Furthermore, these proteins may become inactivated by the inflammatory process and the action of oxidants, so that they may not be able to adequately counteract elastolytic activity in the lung unless used in conjunction with other therapies. Secretory leukoprotease inhibitor Secretory leukoprotease inhibitor (SLPI) is a 12 kDa serpin that appears to be a major inhibitor of elastase activity in the airways. It is secreted by epithelial cells.84 In vitro recombinant human SLPI is more effective at inhibiting neutrophil mediated proteolysis than a1-AT.85 Recombinant human SLPI given by aerosolization increases antineutrophil elastase activity in epithelial lining fluid for over 12 hours, indicating potential therapeutic use.86
N E W A N T I - I N F L A M M AT O RY D R U G S Inhaled corticosteroids are by far the most effective therapy for asthma, yet are ineffective in COPD. Thus for asthma, one strategy has been to develop safer inhaled corticosteroids or drugs that mimic their effects, whereas in COPD nonsteroidal anti-inflammatory treatments are needed (Table 62.4).
Table 62.4. New anti-inflammatory drugs for asthma and COPD
Phosphodiesterase-4 inhibitors (SB 207499, CP 80633, CDP-840) NF-jB inhibitors (proteasome inhibitors, IjB kinase inhibitors, IjB-a gene transfer) Adhesion molecule inhibitors (anti CD11/CD18, antiICAM-1, E-selectin inhibitors) Interleukin-10 and analogs Tyrosine kinase inhibitors (PPI) p38 MAP kinase inhibitors (SB203580, SB 220025, RWJ 67657)
Novel corticosteroids Systemic side-effects of corticosteroids are largely mediated via binding of glucocorticoid receptors (GR) to DNA and increased gene transcription, whereas their anti-inflammatory effects are due to interaction of GR with coactivator molecules and repression of inflammatory genes. It may be possible to dissociate DNA binding which requires a GR dimer, from coactivator molecule binding that requires only a monomer.87 Several dissociated corticosteroids have now been synthesized and a separation between trans-activation (DNA binding) and trans-repression (coactivator interaction) has been demonstrated in gene reporter systems and in intact cells in vitro.88 Whether this will translate to in vivo differences has not yet been determined and since all corticosteroids have to bind to a single class of GR, a large separation of effects may not be possible. Identification of the major targets for corticosteroid action, such as NF-jB, CBP activation or acetylation of core histones, may be a more promising approach in the future. Inhibition of the inflammatory process It is clear that the inflammatory process differs between asthma and COPD and that different anti-inflammatory treatments may be required. In asthma there is predominance of eosinophil inflammation and many of the novel strategies to control asthma involve inhibition of the eosinophilic inflammatory process at several steps (Fig. 62.3). By contrast, the inflammatory process in COPD is dominated by neutrophils and macrophages, and the inflammatory process appears to be resistant to corticosteroids, indicating that other classes of anti-inflammatory treatment will be needed. Phosphodiesterase inhibitors Phosphodiesterases (PDEs) break down cyclic nucleotides that inhibit cell activation and at least 10 families of enzymes have now been discovered. Theophylline, long used as an asthma treatment, is a weak but nonselective PDE inhibitor. PDE4 is the predominant family of PDEs in inflammatory cells, including mast cells, eosinophils, neutrophils, T lymphocytes, macrophages and structural cells such as sensory nerves and epithelial cells89 (Fig. 62.4).
Future Therapies
ⴚ
T-lymphocyte (Th2 cell)
ⴚ
IL-4, IL-5
ⴚ
Eosinophil recruitment
Chemotaxis Eotaxin, RANTES, MCP-4
CCR3
Eosinophil survival IL-3, IL-5, GM-CSF
ⴚ ⴚ
(Apoptosis)
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Immunomodulators CyA, tacrolimus, rapamycin mycophenolate, brequinar Anti-IL-4, anti-IL-5 Adhesion blockers VLA4 inhibitors, anti-selectins
CCR3 antagonists, met-RANTES Corticosteroids Lidocaine p38 MAPK inhibitors
AIRWAY HYPERRESPONSIVENESS
Fig. 62.3. Inhibition of eosinophilic inflammation. Several strategies are possible to inhibit eosinophil inflammation in tissues, including immunomodulators, inhibitors of driving cytokines (IL-4 and IL-5), inhibition of critical adhesion molecules (VLA4, selectins, ICAM-1), blockade of chemokine receptors on eosinophils (CCR3) and induction of apoptosis.
This has suggested that PDE4 inhibitors would be useful as an anti-inflammatory treatment in asthma and COPD. In animal models of asthma, PDE4 inhibitors reduce eosinophil infiltration and AHR responses to allergen.89 Several PDE4 inhibitors have been tested in asthma, but with disappointing results, as the dose has been limited by side-effects, particularly nausea and vomiting. However, in COPD, a PDE4 inhibitor has shown promising results in terms of improvement in lung function, reduced symptoms and improved quality of life.90 It is likely that this represents an anti-inflammatory effect as the improvement in lung function is relatively slow and is not at the expense of the bronchodilator response to a b2-agonist. PDE4 inhibitors may be better tolerated in COPD because of increased prostaglandin E2 formation which may potentiate their antiinflammatory effect.91 Several steps may be possible to overcome the problem of side-effects. It is possible that vomiting is due to inhibition of a particular subtype of PDE4. At least four human PDE4 genes have been identified and each has several splice variants.92 This raises the possibility that subtype-selective inhibitors may be developed that may preserve the antiinflammatory effect, while having less propensity to sideeffects. PDE4D appears to be of particular importance in inflammatory cells, such as T lymphocytes and eosinophils,
and may be a more specific target93 and subtype-selective PDE4 inhibitors are now in development. PDE7 is a novel subtype of PDE that is expressed in a number of cell types, including T lymphocytes. No selective inhibitors have so far been developed, but antisense oligonucleotides to inhibit PDE7 gene expression demonstrated a marked inhibition of T cell activation, suggesting that PDE7 inhibitors might have anti-inflammatory effects in the treatment of airway diseases. Transcription factor inhibitors Transcription factors, such as NF-jB and AP-1, play an important role in the orchestration of chronic inflammation and many of the inflammatory genes that are expressed in asthma and COPD are regulated by these transcription factors.94 This has prompted a search for specific blockers of these transcription factors.95 NF-jB is naturally inhibited by the inhibitory protein IjB, which is degraded after activation by specific kinases. Inhibitors of IjB kinases or the proteasome, the multifunctional enzyme that degrades IjB, would thus inhibit NF-jB and there is a search for such inhibitors. There are concerns that inhibition of NF-jB may cause side-effects such as increased susceptibility to infections, which has been observed in gene disruption studies when components of NF-jB are inhibited.
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Mast cell Airway smooth muscle cells Eosinophil PDE4 inhibitors
Epithelial cells
T cell
Macrophage
NANC nerves
Cilomilast CDP-840 Roflumilast etc.
Neutrophil Fig. 62.4. Effect of phosphodiesterase 4 (PDE4) inhibitors on the inflammatory process.
Cyclosporin A and tacrolimus inhibit T-lymphocyte function by blocking the transcription factor NF-AT (nuclear factor of activated T cells) by blocking activation of calcineurin. This results in suppression of IL-2, IL-4, IL-5 and GM-CSF and therefore therapeutic potential in asthma. MAP kinase inhibitors There are three major mitogen-activated protein (MAP) kinase pathways and there is increasing recognition that these pathways are involved in chronic inflammation.96 There has been particular interest in the p38 MAP kinase pathway that is blocked by a novel class of drugs, the cytokine suppressant anti-inflammatory drugs (CSAIDs), such as SB203580 and RWJ67657.These drugs inhibit the synthesis of many inflammatory cytokines, chemokines and inflammatory enzymes (Fig. 62.5). Interestingly, they appear to have a preferential inhibitory effect on synthesis of Th2 compared with Th1 cytokines, indicating their potential application in the treatment of atopic diseases.97 Furthermore, p38 MAPK inhibitors have also been shown to decrease eosinophil survival by activating apoptotic pathways.98 P38 MAPK inhibitors are also indicated in COPD as inhibition of this enzyme inhibits the expression of TNF-a and IL-8, as well as MMPs. Whether this new class of anti-inflammatory drugs will be safe in long-term studies remains to be established.
potential target for the development of mast cell stabilizing drugs.99 Syk is also involved in antigen receptor signaling of B and T lymphocytes and in eosinophil survival in response to IL-5 and GM-CSF,100 so that syk inhibitors might have several useful beneficial effects in atopic diseases. Another tyrosine kinase lyn is upstream of syk and an inhibitor of lyn kinase, PP1, has an inhibitory effect on inflammatory and mast cell activation.101 Since lyn and syk are widely distributed in the immune system, there are doubts about the long-term safety of selective inhibitors, however.
LPS IL-1β TNF-α Stress
Irritants
TAK MKK3,MKK6 SB203580 SB220025 RWJ67657 CSAIDs
ⴚ p38α, p38β
AP-1
p38γ, p38δ
ATF-2
TNF-α, GM-CSF, IL-8, CXC chemokines, MMP-9, etc.
Tyrosine kinase inhibitors Syk kinase is a protein tyrosine kinase that plays a pivotal role in signaling of the high affinity IgE receptor (FceRI) in mast cells and in syk-deficient mice mast cell degranulation is inhibited, suggesting that this might be an important
Fig. 62.5. Inhibition of p38 MAP kinase by CSAIDs (cytokine synthesis anti-inflammatory drugs) inhibits the synthesis of multiple inflammatory proteins, including tumor necrosis factor-a (TNF-a), granulocyte– macrophage colony-stimulating factor (GM-CSF), interleukin-8 (IL-8) and matrix metalloproteinase-9 (MMP-9).
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Immunosuppressants T-lymphocytes may play a critical role in initiating and maintaining the inflammatory process in asthma via the release of cytokines that result in eosinophilic inflammation, suggesting that T cell inhibitors may be useful in controlling asthmatic inflammation. The nonspecific immunomodulator cyclosporin A reduces the dose of oral steroids needed to control asthma in patients with severe asthma,102 but its efficacy is very limited. Side-effects, particularly nephrotoxicity, also limit its clinical use. The possibility of using inhaled cyclosporin A is now being explored, since in animal studies the inhaled drug is effective in inhibiting the inflammatory response in experimental asthma.103 Immunomodulators, such as tacrolimus (FK506) and rapamycin, appear to be more potent but are also toxic and may offer no real advantage. Novel immunomodulators that inhibit purine or pyrimidine pathways, such as mycophenolate mofetil, leflunomide and brequinar sodium, may be less toxic and therefore of greater potential value in asthma therapy.104 One problem with these nonspecific immunomodulators is that they inhibit both Th1 and Th2 cells, and therefore do not restore the imbalance between these Th1 and Th2 cells in atopy. They also inhibit suppresser T cells (Tc cells) that may modulate the inflammatory response. Selective inhibition of Th2 cells may be more effective and better tolerated and there is now a search for such drugs. The role of immunomodulators in COPD is even less certain.There is an increase inTc cells in patients with COPD, but the role of these cells is uncertain and the usefulness of immunomodulators in COPD has not yet been assessed. Cell adhesion blockers Infiltration of inflammatory cells into tissues is dependent on adhesion of blood-borne inflammatory cells to endothelial cells prior to migration to the inflammatory site.105 This depends upon specific glycoprotein adhesion molecules, including integrins and selectins, on both leucocytes and on endothelial cells, which may be up-regulated or show increased binding affinity in response to various inflammatory stimuli, such as cytokines or lipid mediators. Drugs which inhibit these adhesion molecules therefore may prevent inflammatory cell infiltration. Thus a monoclonal antibody to ICAM-1 on endothelial cells prevents the eosinophil infiltration into airways and the increase in bronchial reactivity after allergen exposure in sensitized primates.106 The interaction between VLA-4 and VCAM-1 is important for eosinophil inflammation, and humanized antibodies to VLA-4 (a4b1) have been developed.107 Small molecule peptide inhibitors of VLA-4 have subsequently been developed which are effective in inhibiting allergeninduced responses in sensitized sheep.108 Inhibitors of selectins, particularly L-selectin and Eselectin, based on the structure of sialyl-Lewisx inhibit the influx of inflammatory cells in response to inhaled allergen in sensitized sheep.109 These glycoprotein inhibitors, which may inhibit neutrophilic and eosinophilic inflammation, are now in trial in asthma and COPD.110
ANTI-ALLERGIC DRUGS Atopy underlies most asthma and this has prompted a search for anti-inflammatory agents that would selectively target the atopic disease process (Fig. 62.6). Such treatments may then be effective in controlling concomitant allergic diseases. Costimulation inhibitors Costimulatory molecules may play a critical role in augmenting the interaction between antigen presenting cells and CD4+ T lymphocytes. The interaction between B7 and CD28 may determine whether a Th2-type cell response develops, and there is some evidence that B7-2 (CD86) skews towards a Th2 response (Fig. 62.6). Blocking antibodies to B7-2 inhibit the development of specific IgE, pulmonary eosinophilia and AHR in mice, whereas antibodies to B7-1 (CD80) are ineffective.111 A molecule on activated T cell CTL4 appears to act as an endogenous inhibitor of T cell activation and a soluble fusion protein construct CTLA4-Ig is also effective in blocking AHR in a murine model of asthma.112 Anti-CD28, anti-B7-2 and CTLA4-Ig also block the proliferative response of T cells to allergen,113 indicating that these are potential targets for novel therapies that should be effective in all atopic diseases. Th2 cell inhibitors Nonselective T cell suppressants, such as cyclosporin A and tacrolimus, may be relatively ineffective in asthma as they inhibit all types of T cell. CD4+ T cells have been implicated in asthma and a chimeric antibody directed against CD4+
Anti-IL-4 Anti-IL-13 Anti-IgE Anti-CD23
IL-4, IL-13
Allergen
IgE
Antigen-presenting cell
CD23 B7-2 Anti-B7-2
MHCII
CD28
TCR IFN-c IL-12 IL-18
Anti-CD28
ⴚ ⴚ
Th2 cell
IL-4, IL-13 IL-5
Cyclosporin A Tacrolimus Rapamycin Mycophenolate mofetil Anti-CD4 (keliximab)
Fig. 62.6. Inhibition of antigen-presenting cells (APC) and Th2 lymphocytes. Therapies are based on inhibition of co-stimulatory molecules (B7-2, CD28), inhibition of IgE driven APCs, nonselective immunomodulators or cytokines which tip the balance away from Th1 cells towards Th2 cells (IFN-c, IL-12, IL-18).
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(keliximab) which reduces circulating CD4+ cells appears to have some beneficial effect in asthma,114 although longterm safety of such a treatment might be a problem. Furthermore, there is increasing evidence that CD8+ cells (Tc2 cells), through release of IL-5 and other cytokines, might also be involved in atopic diseases, particularly in response to infections with certain viruses.115 There has been a search for selective inhibitors of Th2 cells by identifying features that differentiate Th1 and Th2 cells. The transcription factor GATA-3 appears to be of particular importance in murine and human Th2 cells116 and may be a target for selective immunomodulatory drugs. However, an argument against strategies to control atopic disease by targeting Th2 cells is that chronic stimulation (by exposure to allergen) results in cells that are relatively resistant to immune suppression.117 Anti-IgE Since release of mediators from mast cells in asthma is IgEdependent, an attractive approach is to block the activation of IgE using blocking antibodies that do not result in cell activation. A humanized murine monoclonal antibody directed to the high affinity IgE-receptor (FceRI) binding domain of human IgE (rhuMAb-E25) reduces allergenspecific IgE after intravenous administration.118,119 RhuMAb-E25 reduces early and late responses to inhaled allergen and eosinophil counts in induced sputum.120 While a reduction in early response to allergen, which is due to mast cell activation via bound IgE is predicted, the reduction in the late response and in sputum eosinophils is unexpected, but may be explained by blocking the effect of IgE on low affinity IgE receptors (CD23) on antigen-presenting cells. Anti-IgE in mice inhibits IL-4 and IL-5 secretion and pulmonary eosinophilia by blocking Th2 cell activation in response to allergen, and this is mimicked by an anti-CD23 antibody.121 Clinical studies with rhuMAb-E25 show a steroid-sparing effect in patients with severe asthma,122 indicating that this treatment might be useful in the control of patients with allergic asthma who have problems with side-effects of oral steroids.119
purity may detract from their allergenicity as most natural allergens contain several proteins. Intramuscular injection of rats with plasmid DNA expressing house dust mite allergen results in its long-term expression and prevents the development of IgE responses to inhaled allergen.123 This suggests that allergen gene immunization might be a useful therapeutic strategy in the future. Peptide immunotherapy Small peptide fragments of allergen (epitopes) are able to block allergen-induced T cell responses without inducing anaphylaxis. T cell-derived peptides from cat allergen (fel d1) appear to be effective in blocking allergen responses to cat dander,124 but may induce an isolated late response to allergen by direct T cell activation.125 Vaccination A relative lack of infections may be a factor predisposing to the development of atopy in genetically predisposed individuals, leading to the concept that vaccination to induce protective Th1 responses to prevent sensitization and thus prevent the development of atopic diseases.126 BCG vaccination has been associated with a reduction in atopic diseases in Japan,127 but this has not been confirmed in a Swedish population.128 BCG inoculation in mice 14 days before allergen sensitization reduced the formation of specific IgE in response to allergen and the eosinophilic response and AHR responses to allergen, with an increase in production of IFN-c.129 This has prompted several clinical trials of BCG to prevent the development of atopy. Similar results have been obtained in mice with a single injection of heat-killed Mycobacterium vaccae, another potent inducer of Th1 responses130 and with Listeria. Immunostimulatory DNA sequences, such as unmethylated cytosine-guanosine dinucleotide-containing oligonucleotides (CpG ODN), are also potent inducers of Th1 cytokines and in mice administration of CpG ODN increases the ratio of Th1 to Th2 cells, decreases formation of specific IgE and reduces the eosinophilic response to allergen, an effect which lasts for over 6 weeks.131 These promising animal studies encourage the possibility that vaccination might prevent or cure atopic asthma in the future.
P R E V E N T I V E S T R AT E G I E S The obvious preventive strategy for preventing COPD is stopping smoking. This is covered in Chapter 48. Preventive strategies for asthma are targeted to preventing the Th2 cell preponderance in atopy. Specific allergen vaccination (immunotherapy) Subcutaneous injection of small amounts of purified allergen has been used for many years in the treatment of allergy, but it is not very effective in asthma and has a risk of severe, sometimes fatal, anaphylactic responses. The molecular mechanism of desensitization is unknown. Cloning of several common allergen genes has made it possible to prepare recombinant allergens for injection, although this
GENE THERAPY Since asthma and COPD are polygenic, it is unlikely that gene therapy will be of value in long-term therapy. However, understanding the genes involved in asthma and COPD and in disease severity may identify new molecular targets and may also predict the response to different forms of therapy (pharmacogenetics).132,133 Transfer of anti-inflammatory genes may provide specific anti-inflammatory or inhibitory proteins in a convenient manner and gene transfer has been shown to be feasible in animals using viral vectors.134 Antiinflammatory proteins relevant to asthma and COPD include IL-10 and IjB. Antisense oligonucleotides may
Future Therapies
switch off specific genes, but there are considerable problems in getting these molecules into cells. An inhaled antisense oligonucleotide directed against the adenosine A1receptor has been shown to reduce AHR in a rabbit model of asthma, demonstrating the potential of this approach in treating asthma.128,129,135 Suitable target genes may be IL-4 or IL-5 in asthma and MMP-9 in COPD. Considering the practical problems encountered by gene therapy this approach is unlikely in the foreseeable future, other than for proof of concept studies.
REFERENCES 1. Barnes PJ. New treatments for asthma. Eur. J. Int. Med. 2000; 11:9–20. 2. Barnes PJ. Therapeutic strategies for allergic diseases. Nature 1999; 402:B31–8. 3. Barnes PJ. Strategies for novel COPD therapies. Pulm. Pharmacol. Ther. 1999; 12:67–71. 4. Cochrane GM, Horne R, Chanez P. Compliance in asthma. Respir. Med. 1999; 93:763–9. 5. Barnes PJ. Chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343:269–80. 6. Barnes PJ. Novel approaches and targets for treatment of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:S72–9. 7. Barnes PJ. Mechanisms in COPD: differences from asthma. Chest 2000; 117:10S–14S. 8. Roses AD. Pharmacogenetics and future drug development and delivery. Lancet 2000; 355:1358–61. 9. Barnes PJ. Muscarinic receptor subtypes in airways. Life Sci. 1993; 52:521–8. 10. Alabaster VA. Discovery and development of selective M3 antagonists for clinical use. Life Sci. 1997; 60:1053–60. 11. Disse B, Speck GA, Rominger KL, Witek TJ, Hammer R. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci. 1999; 64:457–64. 12. Takahashi T, Belvisi MG, Patel H et al. Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea-pig and human airways. Am. J. Resp. Crit. Care Med. 1994; 150:1640–5. 13. O’Connor BJ, Towse LJ, Barnes PJ. Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma. Am. J. Respir. Crit. Care Med. 1996; 154:876–80. 14. Maesen FPV, Smeets JJ, Sledsens TJM, Wald FDM, Cornelissen JPG. Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Eur. Respir. J. 1995; 8:1506–13. 15. Littner MR, Ilowite JS, Tashkin DP et al. Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 161:1136–42. 16. Black JL, Barnes PJ. Potassium channels and airway function: new therapeutic approaches. Thorax 1990; 45:213–18. 17. Kidney JC, Fuller RW, Worsdell Y-M, Lavender EA, Chung KF, Barnes PJ. Effect of an oral potassium channel activator BRL 38227 on airway function and responsiveness in asthmatic patients: comparison with oral salbutamol. Thorax 1993; 48:130–4. 18. Olesen SP, Munch E, Moldt P, Orejer J. Selective activation of Ca2-dependent K channels by novel benzimidazolone. Eur. J. Pharmacol. 1994; 251:53–9.
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19. Fox AJ, Barnes PJ, Venkatesan P, Belvisi MG. Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves. J. Clin. Invest. 1997; 99:513–19. 20. Kuo H-P, Rohde JAL, Barnes PJ, Rogers DF. K channel activator inhibition of neurogenic goblet cell secretion in guinea pig trachea. Eur. J. Pharmacol. 1992; 221:385–8. 21. Angus RM, Millar EA, Chalmers GW, Thomson NC. Effect of inhaled atrial natriuretic peptide and a neutral endopeptidase inhibitor on histamine-induced bronchoconstriction. Am. J. Respir. Crit. Care Med. 1995; 151:2003–5. 22. Fluge T, Forssmann WG, Kunkel G et al. Bronchodilation using combined urodilatin-albuterol administration in asthma: a randomized, double-blind, placebo-controlled trial. Eur. J. Med. Res. 1999; 4:411–15. 23. Barnes PJ, Chung KF, Page CP. Inflammatory mediators of asthma: an update. Pharmacol. Rev. 1998; 50:515–96. 24. Drazen JM, Israel E, O’Byrne PM.Treatment of asthma with drugs modifying the leukotriene pathway. N. Engl. J. Med. 1999; 340:197–206. 25. Hill AT, Bayley D, Stockley RA. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am. J. Respir. Crit. Care Med. 1999; 160:893–8. 26. Evans DJ, Barnes PJ, Coulby LJ et al. The effect of a leukotriene B4 antagonist LY293111 on allergen-induced responses in asthma. Thorax 1996; 51:1178–84. 27. Goldie RG, Henry PJ. Endothelins and asthma. Life Sci. 1999; 65:1–15. 28. Benigni A, Remuzzi G. Endothelin antagonists. Lancet 1999; 353:133–8. 29. Repine JE, Bast A, Lankhorst I. Oxidative stress in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1997; 156:341–57. 30. Macnee W. Oxidants/Antioxidants and COPD. Chest 2000; 117:303S–17S. 31. Barnes PJ, Liew FY. Nitric oxide and asthmatic inflammation. Immunol.Today 1995; 16:128–30. 32. Yates DH, Kharitonov SA, Thomas PS, Barnes PJ. Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase. Am. J. Respir. Crit. Care Med. 1996; 154:247–50. 33. Taylor DA, McGrath JL, Orr LM, Barnes PJ, O’Connor BJ. Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5-monophosphate in asthma. Thorax 1998; 53:483–9. 34. Maziak W, Loukides S, Culpitt S, Sullivan P, Kharitonov SA, Barnes PJ. Exhaled nitric oxide in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 157:998–1002. 35. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54:825–57. 36. Egan RW, Umland SP, Cuss FM, Chapman RW. Biology of interleukin-5 and its relevance to allergic disease. Allergy 1996; 51:71–81. 37. Leckie MJ, ten Brincke A, Khan J et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet 2000; 356:2144–8. 38. Gavett SH, O’Hearn DJ, Karp CL et al. Interleukin-4 receptor blockade prevents airway responses induced by antigen challenge in mice. Am. J. Physiol. 1997; 272:L253–61. 39. Borish LC, Nelson HS, Lanz MJ et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebocontrolled trial. Am. J. Respir. Crit. Care Med. 1999; 160:1816–23. 40. Tony HP, Shen BJ, Reusch P, Sebald W. Design of human interleukin-4 antagonists inhibiting interleukin-4-dependent and interleukin-13-dependent responses in T cells and B cells with high efficiency. Eur. J. Biochem. 1994; 225:659–65.
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41. Grunewald SM, Werthmann A, Schnarr B et al. An antagonistic IL-4 mutant prevents type I allergy in the mouse: inhibition of the IL-4/IL-13 receptor system completely abrogates humoral immune response to allergen and development of allergic symptoms in vivo. J. Immunol. 1998; 160:4004–9. 42. Foster PS. STAT6: an intracellular target for the inhibition of allergic disease. Clin. Exp. Allergy 1999; 29:12–16. 43. Losman JA, Chen XP, Hilton D, Rothman P. Cutting edge: SOCS1 is a potent inhibitor of IL-4 signal transduction. J. Immunol. 1999; 162:3770–4. 44. Zhu Z, Homer RJ, Wang Z et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 1999; 103:779–88. 45. Chomarat P, Banchereau J. Interleukin-4 and interleukin-13: their similarities and discrepancies. Int. Rev. Immunol. 1998; 17:1–52. 46. Wills-Karp M, Luyimbazi J, Xu X et al. Interleukin-13: central mediator of allergic asthma. Science 1998; 282:2258–61. 47. Humbert M, Durham SR, Kimmitt P et al. Elevated expression of messenger ribonucleic acid encoding IL-13 in the bronchial mucosa of atopic and nonatopic subjects with asthma. J. Allergy Clin. Immunol. 1997; 99:657–65. 48. Grunig G,Warnock M,Wakil AE et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 1998; 282:2261–3. 49. Shimbara A, Christodoulopoulos P, Soussi-Gounni A et al. IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma. J. Allergy Clin. Immunol. 2000; 105:108–15. 50. Shah A, Church MK, Holgate ST. Tumour necrosis factor a: a potential mediator of asthma. Clin. Exp. Allergy 1995; 25:1038–44. 51. Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-a in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Respir. Crit. Care Med. 1996; 153:530–4. 52. Feldman M, Taylor P, Paleolog E, Brennan FM, Maini RN. Anti-TNF alpha therapy is useful in rheumatoid arthritis and Crohn’s disease: analysis of the mechanism of action predicts utility in other diseases. Transplant. Proc. 1998; 30:4126–7. 53. Luster AD. Chemokines – chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 1998; 338:436–45. 54. Gonzalo JA, Lloyd CM, Kremer L et al. Eosinophil recruitment to the lung in a murine model of allergic inflammation. The role of T cells, chemokines, and adhesion receptors. J. Clin. Invest. 1996; 98:2332–45. 55. Campbell EM, Charo IF, Kunkel SL et al. Monocyte chemoattractant protein-1 mediates cockroach allergen-induced bronchial hyperreactivity in normal but not CCR2/ mice: the role of mast cells. J. Immunol. 1999; 163:2160–7. 56. Holgate ST, Bodey KS, Janezic A, Frew AJ, Kaplan AP, Teran LM. Release of RANTES, MIP-1 alpha, and MCP-1 into asthmatic airways following endobronchial allergen challenge. Am. J. Respir. Crit. Care Med. 1997; 156:1377–83. 57. de Boer WI, Sont JK, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS. Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J. Pathol. 2000; 190:619–26. 58. Traves SL, Culpitt S, de Matos C, Russell REK, Barnes PJ, Donnelly LE. Peripheral blood mononuclear cell chemotaxis to MCP-1, GRO- and IL-8 in COPD. Am. J. Respir. Crit. Care Med. 2000; 163:A987. 59. Heath H, Qin S, Rao P et al. Chemokine receptor usage by human eosinophils. The importance of CCR3 demonstrated using an antagonistic monoclonal antibody. J. Clin. Invest. 1997; 99:178–84. 60. Sabroe I, Peck MJ, Van Keulen BJ et al. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent
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80. Finlay GA, O’Driscoll LR, Russell KJ et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am. J. Respir. Crit. Care Med. 1997; 156:240–7. 81. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage metalloelastase for cigarette smokeinduced emphysema in mice. Science 1997; 277:2002–4. 82. Cawston TE. Metalloproteinase inhibitors and the prevention of connective tissue breakdown. Pharmacol. Ther. 1996; 70: 163–82. 83. Sallenave JM, Shulmann J, Crossley J, Jordana M, Gauldie J. Regulation of secretory leukocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor (ESI/elafin) in human airway epithelial cells by cytokines and neutrophilic enzymes. Am. J. Respir. Cell Mol. Biol. 1994; 11:733–41. 84. Sallenave JM, Si Tahar M, Cox G, Chignard M, Gauldie J. Secretory leukocyte proteinase inhibitor is a major leukocyte elastase inhibitor in human neutrophils. J. Leuk. Biol. 1997; 61:695–702. 85. Llewellyn Jones CG, Lomas DA, Stockley RA. Potential role of recombinant secretory leucoprotease inhibitor in the prevention of neutrophil mediated matrix degradation. Thorax 1994; 49:567–72. 86. McElvaney NG, Doujaiji B, Moan MJ, Burnham MR, Wu MC, Crystal RG. Pharmacokinetics of recombinant secretory leukoprotease inhibitor aerosolized to normals and individuals with cystic fibrosis. Am. Rev. Respir. Dis. 1993; 148:1056–60. 87. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin. Sci. 1998; 94:557–72. 88. Vayssiere BM, Dupont S, Choquart A et al. Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit anti-inflammatory activity in vivo. Mol. Endocrinol. 1997; 11:1245–55. 89. Torphy TJ. Phosphodiesterase isoenzymes. Am. J. Respir. Crit. Care Med. 1998; 157:351–70. 90. Torphy TJ, Barnette MS, Underwood DC et al. Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulm. Pharmacol.Ther. 1999; 12:131–6. 91. Au BT, Teixeira MM, Collins PD, Williams TJ. Effect of PDE4 inhibitors on zymosan-induced IL-8 release from human neutrophils: synergism with prostanoids and salbutamol. Br. J. Pharmacol. 1998; 123:1260–6. 92. Muller T, Engels P, Fozard J. Subtypes of the type 4 cAMP phosphodiesterase: structure, regulation and selective inhibition. Trends Pharmacol. Sci. 1996; 17:294–8. 93. Seybold J, Newton R, Wright L et al. Induction of phosphodiesterases 3B, 4A4, 4D1, 4D2, and 4D3 in Jurkat T cells and in human peripheral blood T-lymphocytes by 8-bromo-cAMP and Gs-coupled receptor agonists. Potential role in b2-adrenoreceptor desensitization. J. Biol. Chem. 1998; 273:20575–88. 94. Barnes PJ, Adcock IM. Transcription factors and asthma. Eur. Respir. J. 1998; 12:221–34. 95. Manning AM. Transcription factors: a new frontier in drug discovery. Drug Disc.Today 1996; 1:151–60. 96. Karin M. Mitogen-activated protein kinase cascades as regulators of stress responses. Ann. N.Y. Acad. Sci. 1998; 851:139–46. 97. Schafer PH, Wadsworth SA, Wang L, Siekierka JJ. p38alpha mitogen-activated protein kinase is activated by CD28-mediated signaling and is required for IL-4 production by human CD4+CD45RO+ T cells and Th2 effector cells. J. Immunol. 1999; 162:7110–19. 98. Kankaanranta H, Giembycz MA, Barnes PJ, Lindsay DA. SB203580, an inhibitor of p38 mitogen-activated protein kinase, enhances constitutive apoptosis of cytokine-deprived human eosinophils. J. Pharmacol. Exp.Ther. 1999; 290:621–8. 99. Costello PS, Turner M, Walters AE et al. Critical role for the tyrosine kinase Syk in signalling through the high affinity IgE receptor of mast cells. Oncogene 1996; 13:2595–605. 100. Yousefi S, Hoessli DC, Blaser K, Mills GB, Simon HU. Requirement of Lyn and Syk tyrosine kinases for the prevention of
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Chapter
Health Economics
63
Sean D. Sullivan and Scott A. Strassels Department of Pharmacy, University of Washington, Seattle, WA, USA
INTRODUCTION
METHODS
Advances in health care appear to be increasingly tied to two major sources of information. The first is the ability to improve health outcomes through new or improved intervention strategies. This primary need to understand clinical efficacy and safety using the best available evidence is the cornerstone of medical practice.The second source of information relates to society’s ability and willingness to pay for intervention strategies. The fields of evidence-based medicine and health economics seek to address these issues through quantitative tools designed to facilitate decisions of resource allocation throughout the various levels of the health care system.1 The purpose of this review is to explore the health economic literature related to asthma and COPD. Until recently, very little was known about the economic consequences of these diseases or of various intervention strategies that conform to evidence-based treatment recommendations. The burden on society from these diseases is large: asthma affects more than 15 million people in the US, leading to more than 500,000 hospitalizations, and over 5000 deaths annually and COPD affects approximately 16 million people, and costs nearly $24 billion (1993 US dollars).2 COPD is the fourth most prevalent cause of death in the US, after cardiovascular disease, cancer, and stroke.3 In addition to the number of people who die each year due to these conditions, affected individuals and caregivers miss work, school and are often unable to take part in their normal daily activities due to their respiratory illness.4 Furthermore, the burden of these diseases on society is expected to increase for the foreseeable future.5 In this review, we first examine the principles of evidencebased medicine and methods of health economics. Second, we explore the health economic burden for asthma and COPD as characterized by cost of illness estimates. Third, we examine health economic studies that focus on interventions that conform to evidence-based treatment guidelines. The intended audience for this review is health-care decision-makers at all levels.
The articles in this review were primarily obtained through a search of the Medline database, using the terms “asthma”, “obstructive lung disease”, and “cost”. Additional studies were identified through the reference lists of identified articles, and by direct inquiries to an extensive number of international investigators in this field. This review includes only English-language studies that reflected original research with explicit descriptions of the methods of economic evaluation. While this review is intended to be comprehensive, it is not a formal quantitative synthesis of the literature.
EVIDENCE-BASED MEDICINE Evidence-based medicine (EBM) is the conscientious, explicit and judicious use of current best evidence, applied to the care of individuals.6 Appropriately used, EBM is a tool to help clinicians and decision-makers choose the best treatment for their patients. The goal of health care is to improve the clinical, economic and humanistic results of treatment. In a setting where decision-making is uncertain, resources are scarce, and when patients and providers may have different priorities, this task may seem daunting. Evidence-based medicine helps quantify the clinical outcomes of health care systematically, and when combined with health economics, we gain important and useful information about the likely clinical and economic results of health care.
T R E AT M E N T G U I D E L I N E S One of the most useful EBM tools is the Clinical Practice Guideline (CPG). Thousands of CPGs have been published by organizations of all sizes, from governmental agencies to international professional medical practice and research groups. In the US, the National Guideline Clearinghouse is a convenient source for nearly 1000 evidence-based CPGs.7
Asthma and Chronic Obstructive Pulmonary Disease
Types of cost included Intangible Indirect Direct Society Point of view
Patient Payor
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Provider
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In order for readers to understand economic evaluations of health care interventions, it is important to consider a few of the main concepts that underlie health economics. Perspective refers to the choice of which costs are included in the analysis.13 Commonly adopted perspectives include government, the payer (in the US, often an insurer), the patient, and society. From a societal perspective, all costs are considered, while the payer’s or provider’s perspective includes only those costs the payer or provider must bear. Perspective is a critically important aspect of a health economic analysis, as the inclusion or omission of costs can significantly affect the results of the analysis. Discounting is used to account for time preference and opportunity costs.14 People tend to prefer to have money and other benefits now rather than later. Due to this time preference, people are often willing to accept less of the benefit in order to get it now. An example of this phenomenon is the lottery. A winner who chooses to take a smaller amount as a lump sum up front rather than waiting for an annuity to mature has expressed their time preference. The concept of opportunity costs is based on the premise that
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H E A LT H E C O N O M I C S : A N O V E RV I E W
the true economic cost of one intervention includes the foregone value of alternative interventions. This implies that resource allocation is a matter of choice and that an intervention should never be evaluated in isolation. Bombardier and Eisenberg15 have suggested a model for the economic evaluation of clinical care that includes three dimensions (see Fig. 63.1). One axis presents the types of costs and benefits associated with health care technology or innovation. These include direct medical expenditures, as well as direct non-medical costs such as transportation expenses and child care expenses related to health care.This dimension also includes indirect costs associated with the loss of workforce participation and loss of productivity, as well as intangible costs which reflect theoretical costs, such as impact of scholastics achievement or career selections that may be associated with the burden of illness. The figure’s second axis reflects the various audiences that will use the information including: patient, payer, health care provider and society as a whole. The third axis in this multidimensional model reflects the types of tools such as cost–benefit analysis and costeffectiveness analysis that provide information on the efficiency. Cost–benefit analysis is the identification and comparison of the costs associated with a new intervention and the benefits derived from its application.16 Costs and benefits are defined in monetary terms and adjusted to net present values. The ratio of monetary benefits to overall costs determines whether the value produced by the new intervention is worth the costs – and the intervention is said to be costbeneficial if the benefits exceed the costs. The main drawback to this method is that it is often difficult to express health outcomes in monetary terms. Cost-effectiveness analysis (CEA) was, to a large extent, designed to overcome the difficulty of expressing benefits in
en
Of the eight asthma-related guidelines (CPGs and other recommendations) archived at the NGC, the most recent CPG was published in 1997 by the National Heart, Lung, and Blood Institute (NHLBI).8 The Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma and Immunology also published an asthma CPG in 1995.8 These CPGs provide similar recommendations, although the NHLBI publication defines asthma severity according to more specific clinical endpoints and provides more specific treatment recommendations. Therefore, we have focused our asthma-related comments on this guideline. There are only a few COPD-related CPGs in the published literature. Of the 16 COPD-related guidelines in the NGC, only one is a CPG, produced in 1997 by the US Department of Veterans Affairs (VA).8 In addition to the VA guideline, however, there are three COPD CPGs of interest, published by the American and British Thoracic Societies (ATS, BTS), and the European Respiratory Society (ERS).9–12 These CPGs overlap substantially in their recommendations. For example, inhaled bronchodilators (IBD) are considered first-line therapy, while the ERS and BTS recommend either IBD or inhaled anticholinergics (IAC). Similarly, the ERS and ATS suggest that long-acting bronchodilators (LABD) may be helpful for patients with night-time or early morning symptoms, while the BTS recommend the limited use of LABD until more information becomes available. The ATS CPG also does not recommend use of inhaled corticosteroids (ICS), while the BTS and ERS CPGs suggest that ICS may be useful for persons who are steroid responders.
Id
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Type of cost analysis Fig. 63.1. Three Dimensions of Economic Evaluation of Clinical Care (Source: Bombardier, ref. 15).
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monetary terms. Cost-effectiveness analysis is a method to assess the comparative impacts of different health care interventions.17 It is based on the premise that for “any given level of resources available . . . (the goal) is to maximize the total aggregate health benefits”.18 One of the key features of CEA is its focus on comparative design. It requires understanding of the clinical effects of interventions and their most likely alternatives as a prerequisite to generating and testing a hypothesis. Clinical effectiveness is measured in terms of outcomes that are relevant to the interested audience, whether it is society, the clinical provider or the patient. For asthma and COPD, there are a number of potential measures of effectiveness. These include measures of symptom burden, lung function, functional status and health-related quality of life.19
ECONOMIC BURDEN OF ASTHMA AND COPD This section will explore the economic burden of asthma and chronic obstructive pulmonary disease (COPD), followed by a detailed review of the comparative health economic literature for these conditions. Asthma The first comprehensive US study of the economics of asthma examined 1985 costs projected to 1990 estimates.20 For 1990, these costs were an estimated 6.2 billion dollars – approximately 1% of all US health expenditures. Subsequent to that publication there have been two additional studies of the US costs of asthma.21,22 Table 63.1 displays 1993 costs projected to 1998 estimates using previously published methods for this type of data projection.20 The 1998 projections reflect a total of 12.6 billion dollars in US costs of asthma. Fifty-eight percent of these costs were direct medical expenditures (DMEs), and 42% were indirect costs. The most notable change in asthma costs during the
1985–1994 period was a decrease in hospitalization costs as a percent of total DMEs. This was due to a notable decrease in length of stay and not to a decrease in the total number of hospitalizations. Also, medication costs have now replaced hospital costs as the largest component of DMEs. The average estimated annual cost per adult (18 years and older) with asthma increased as well during this time period – while costs per child decreased.22 Worldwide, there is considerable interest in the economic impact of asthma – as evidenced by numerous cost-of-illness studies.20, 23–30 These studies are difficult to compare because of differences in definitions of costs, sources of unit costs, differing time periods and exchange rates. Yet, mindful of these difficulties, the Global Initiative for Asthma conducted a review of six asthma cost-of-illness studies (see Table 63.2).31 That review of asthma costs in developed countries suggested an average annual societal burden ranging from $326 to $1315 per afflicted person (1991 US dollars). Approximately 40 to 50% of the total asthma costs were attributed to DMEs. There are also several studies of asthma costs in less developed countries, however, they are limited to small, select samples.31–33 While these studies play an important role in local policy, they are of limited value for purposes of international comparison. There appears to be only one study examining trends in the costs of asthma, conducted in Sweden between 1980 and 1991.34 The results suggest a nearly 37% increase in total asthma costs, with a 41.1% increase in DMEs and 34.2% increase in indirect costs. Special characteristics of the costs of asthma Costs of asthma have also been examined from the perspective of the individual and their family. Most of these reports followed families for an extended period of time, asking them to keep diaries of their asthma-related expenditures. The earliest of these was conducted in the US in 1968.35 It followed 21 families for a period of 1 year and resulted in an annual mean cost of $1245, with poorer families contributing
Table 63.1. Comparison of direct and indirect costs of lung disease, in billions (US $ 1993)
Condition
Total costs
Direct medical costs
Indirect, mortality
Indirect, morbidity
Total indirect
COPD Asthma Influenza Pneumonia Tuberculosis Respiratory cancer
23.9 12.6 14.6 7.8 1.1 25.1
14.7 9.8 1.4 1.7 0.7 5.1
4.5 0.9 0.1 4.6 –– 17.1
4.7 0.9 13.1 1.5 –– 2.9
9.2 2.8 13.2 6.1 0.4 20.0
Source: Division of Epidemiology, National Heart, Lung and Blood Institute, 1996.
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Table 63.2. Summary of randomized health economic studies of pharmacotherapy for persistent asthma
First author, Study year, Ref. method used
Sample size
Perspective
Treatments studied
Length of study
Costs measured
Health outcome measured
Connett 199384
Randomized controlled trial
40 children
Societal
2 groups: Budesonide compared with placebo
26 weeks
Direct and indirect
Lung function (FEV1), symptoms, symptom-free days
Rutten-van Molken 199385
Randomized controlled trial
116 children
Societal
2 groups: Budesonide and salbutamol, salbutamol alone
3 yearsb
Direct and indirect
Lung function (FEV1), symptom-free days, school absences
Rutten-van Molken 199586
Randomized controlled trial
274 adults
Societal
3 groups: Beclomethasone and terbutaline, ipatropium and terbutaline, terbutaline alone
2.5 years
Direct and indirect
Lung function (FEV1, PC20), symptom-free days
O’Byrne 199683
Randomized controlled trial
57 adults
Societal
3 groups: Budesonide 400 lg or Budesonide 800 lg and bronchodilator compared with bronchodilator alone
16 weeks
Direct
Lung function (PEFR), symptom scores, exacerbations, emergency room visits, and willingness to pay
Rutten-van Molken 199888
Randomized controlled trial (open label)
482 adults
Societal
2 groups dry powder formoterol 12 lg or salmeterol 50 lg
28 weeks
Direct
Daytime and night-time symptom scores, episode-free days, quality of life
Lundback 200089
Randomized controlled trial
353 Societal adults and adolescents
2-groups Salmeterol/ fluticasone propionate 50/250 lg combination product BID or budesonide 800 lg BID
24 weeks
Direct
Lung function (PEFR), Successfullytreated episode-free days, symptomfree days
Notes: aStudies greater than 12 weeks. bThe study had a planned 3-year follow-up but only 39 patients reached a follow-up period of 22 months. Source: Adapted from Ref. 172.
Health Economics
Medicaid population and found that asthma costs for African–American children were 24% higher than the costs of white children – primarily due to higher costs from hospitalizations and emergency department visits.49 Indirect costs are seldom included in costs of illness studies for asthma. This is likely due to the lack of standardized approaches for deriving such costs. Recent work in this field is expected to lead to improved understanding and more frequent reporting of these important costs.51 COPD In 1996, 16.2 million people had COPD in the US.52 In 1998, COPD caused approximately 113,000 deaths, and was the fourth most common cause of death.3 According to recent estimates from the National Heart, Lung and Blood Institute, the annual economic burden in the United States of COPD is $23.9 billion.53 This estimate included $14.7 billion in direct expenditures for medical care services, $4.7 billion in indirect morbidity costs and $4.5 billion in costs related to premature mortality. The largest component of the medical costs of COPD is hospitalization.54 Combining disease prevalence and illness burden, COPD and its attendant morbidity results in an estimated $1522 of economic impact on society per person per year or almost three times that for asthma. In a specific study of COPD-related illness costs in the US, Sullivan and colleagues examined the National Medical Expenditure Survey in order to define the contribution of individual cost components to overall illness burden.55 These data indicated that the largest proportion of total medical expenditures was for inpatient hospitalization and emergency room care (72.8%). Outpatient clinic and office visits accounted for 15% of expenditures and prescription drug costs were responsible for 12.2%. Medical expenditures were disproportionately distributed among the sample with 10% of COPD patients accounting for 73% of medical expenditures (Fig. 63.2).
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0% 5% 10% 16% 21% 26% 33% 38% 43% 50% 56% 62% 67% 73% 81% 87% 92% 100%
Population Frequency
a larger proportion of their total family income towards asthma services. A second study of US families, conducted in 1977–1980, resulted in average annual costs of $1087 per child with asthma (n = 25).36 A more recent study from Australia, using similar methods and a much larger sample of children with milder asthma (n = 193), showed a mean annual cost per child of 212 Australian dollars, increasing to 884 Australian dollars for children who had been hospitalized.37 Canadian investigators found that the annual costs per patient in South Central Ontario varied greatly based on disease severity, age, smoking status, drug coverage, health plan and retirement status.38 One study of particular interest characterized asthma costs in lesser developed countries.39 The investigators conducted a mail survey of health care providers in 24 countries throughout Africa and Asia; many of the countries had a limited supply of asthma-related drugs. The results indicated the estimated costs of asthma drugs ranged from 3.8 to 25% of the patient’s monthly income. Another study of eight low and middle income countries found that costs and availability of asthma medications varied widely, representing a potentially important barrier to care.40 Emergency department visits and hospitalizations are key cost components of asthma care. Several studies have attempted to better quantify these costs.41–43 One of these examined the costs of 214 persons with asthma-related ED visits not resulting in hospitalization.41 The ED costs for these individuals ranged from an average of $248 for children 5 years and younger to $457 for adults 18 years and older.42 These costs were similar to those described in another study of more than 3000 adults who had an average ED cost of $234 per visit.43 In this same study, average hospitalization costs for asthma were $3103, however they ranged from approximately $2000 for patients classified as mild upon admission to more than $15,000 per hospitalization for patients defined as most severe.43 There has been at least one population-based study of the cost of asthma for very severe patients.This was based on an analysis of the National Medical Expenditure Survey – a national survey based on a sample of the US population.44 The results suggest that less than 20% of the persons with asthma in the sample were responsible for more than 80% of the total direct costs. Also, perhaps not unexpectedly, persons using more medications had higher costs. Studies from other countries have also described similar findings of cost increases in accordance with disease severity.45–47 High use of short-acting beta-agonists has also been shown to be predictive of high asthma costs.48 There are now two economic studies of children with asthma, one conducted within a single health care organization, the other based on a national population sample; both explore the marginal cost of asthma above other health care costs.49,50 These studies conclude that for children with asthma, there seems to be additional non-asthma-related costs associated with co-morbid upper and lower respiratory conditions. One of these studies examined a low-income,
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Cumulative % Expenditures Fig. 63.2. Distribution of medical care expenditures among respondents with COPD: 1987 National Medical Expenditure Survey, United States.
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An analysis of the Medicare insurance program for the elderly in the United States demonstrated that expenditures for beneficiaries with COPD were nearly 2.5 times higher than per capita total expenditures of those without COPD ($8482 versus $3511).56 As with other serious chronic conditions, the most severely affected individuals incur a substantial share of all costs. Nearly 50% of the total Medicare payments for those with COPD were incurred by approximately 10% of the Medicare beneficiaries with COPD. Hospitalization-related costs – the largest portion of all expenditures for patients with COPD – commonly occur in the latter stages of the disease. The Sullivan et al.55 study estimated that per capita expenditures for inpatient hospitalizations in the COPD cohort were 2.7 times the per capita expenditures of the non-COPD cohort ($5409 versus $2001). A lesson that can be taken from these data suggests that a reduction in the incidence and cost of hospitalization may be a reasonable target for new treatments seeking to lower overall health care costs. Effective interventions that reduce the rate and cost of hospitalizations among those who suffer from COPD will likely be adopted and judged to be cost-effective. Data from the United Kingdom’s Office of National Statistics showed that there were some 203,193 hospital admissions in Northern Ireland, Scotland, Wales and England for COPD in 1994.57 The average length of hospital stay among those admitted for a COPD diagnosis was 9.9 days. The NHS Executive published data in 1996 showing that the medical cost of COPD in the United Kingdom was approximately £846 million or £1,154 (about US$2300) per person per year.58 Of the total estimated economic burden of COPD in the UK, £402 million (47.5%) were for expenditures for pharmaceutical treatments, £207 million (24.5%) for ambulatory oxygen therapy, £151 million (17.8%) for hospital-based care, and the remainder (10.2%) for primary care and community-based services. Expenditures for COPD-related medical care in Sweden were estimated at £115 million in 1991.59 The estimated indirect cost of COPD in Sweden was an additional £152 million. Unlike the United States, the relative indirect cost of COPD in Sweden and the UK exceeded the direct medical care cost. Individuals with COPD frequently receive professional medical care services in their homes. In developed countries, national health insurance plans provide coverage for oxygen therapy, visiting nursing services, rehabilitation, and even mechanical ventilation in the home, although coverage for specific services may vary from country to country.60 The services are considered a direct medical expenditure that is part of the economic burden of this disease. No study has estimated the total social economic cost of providing these services. In 1997, government-sponsored insurance funds in the United States spent $17.7 billion on home health services, about 4% of all public expenditures on health care that year.61 Furthermore, any estimate of direct medical expenditures for home care underrepresents the true cost of home care to
society, because it ignores the economic value of the care provided by family members to those with COPD. The value of the care provided by family members is considered a direct nonmedical expenditure for this condition. In the developing world, it is likely that the economic value of family-provided care exceeds the value of care provided by health delivery systems. Thus, in terms of productivity lost, COPD may be doubly burdensome for low-income countries, since it affects the ability of the affected individual and one or more relatives to work outside the home. Since human capital is often the most important national asset for developing countries, COPD may represent a serious threat to their economies. The data on economic burden of COPD are sparse, particularly outside North America and Europe. While we can learn much from the relatively few studies on economic impact, what is needed are data on the use, cost and relative distribution of medical and nonmedical resources for COPD in countries where the medical and human capital consequences of COPD are significant. Health planners and regulators interested in investing in effective interventions look for these data to help make resource allocation decisions and to prioritize investments relative to other areas of health need.
M A X I M I Z I N G VA L U E I N T H E C A R E O F PERSONS WITH ASTHMA AND COPD Thus far, this review has focused on the economic burden associated with asthma and COPD. Yet, simply identifying the economic burden falls short of understanding how to optimally use resources to improve care. As noted above, there are two basic forms of comparative economic studies, cost–benefit analyses and cost-effectiveness analysis. This next section highlights some of the best examples of guideline-based studies that have met many of the nationally recommended standards for these types of analyses.16,17,62 The review that follows is not exhaustive. For example, the literature on the effectiveness and cost impact of smoking cessation programs is substantial and would exhaust the space limitation. Conversely, there are no published data on the cost-effectiveness of using inhaled corticosteroids in COPD. Thus, it is our aim to highlight those studies that follow reasonable standards for economic evaluation and, where appropriate, to critically evaluate the evidence for cost-effectiveness. This is no small task, as evidential standards in the field of economic evaluation are not yet fully agreed by experts and practitioners.
C O M PA R AT I V E H E A LT H E C O N O M I C STUDIES FOR ASTHMA Asthma is principally diagnosed and managed via clinical assessment. For persons already diagnosed, national guidelines recommend periodic monitoring of pulmonary
Health Economics
function either by spirometry or peak flow measurements.63 To date, however, there have been no health economic evaluations to assess this recommendation. There has been one report of the economic consequences of using pulmonary function tests to screen for asthma.64 Unfortunately, this study of an adult population in the Netherlands examined both asthma and COPD collectively, making it impossible to single out the value of diagnostic testing for asthma or COPD alone. There appear to be no health economic evaluations of the use of other types of diagnostic tests such as X-rays, serologic tests, or skin testing for asthma. Pharmacotherapy Medications are the foundation of asthma care and there are a number of comparative health economic studies of pharmacotherapy. Unfortunately, many of these studies did not meet two of the basic criteria for cost analysis – either they failed to include all costs or they were of too short a duration to be able to assess the impact on such a chronic condition such as asthma.65–73 Table 63.2 provides an overview of some of the key studies that have met many of the design standards of clinical trials. The following sections highlight the most informative of the economic analyses of asthma medications according to the type or classification of drug. Inhaled corticosteroids The National Guidelines for the Diagnosis and Management of Asthma recommend inhaled corticosteroids in addition to as-needed bronchodilator therapy as treatment for persons with persistent asthma – and there is substantial evidence to support this recommendation.63,74 Yet, adding inhaled corticosteroid medications to an existing regimen of inhaled or oral bronchodilator therapy contributes significantly to the overall cost of treating these patients. An important research question is whether inhaled corticosteroids along with as-needed bronchodilators are costeffective compared with as-needed bronchodilator alone for treating persons with mild-to-moderate or moderate-tosevere asthma. Although several observational studies have attempted to examine this issue, this review will focus on prospective randomized controlled clinical trials – because they have better ability to control for important threats to validity.75–82 One of these studies was a 16-week randomized trial of budesonide 400 µg/day, 800 µg/day, and placebo in 57 adults with mild asthma.83 Low-dose budesonide demonstrated better control of morning and nocturnal symptoms, improved PEFR, and was judged to be cost-beneficial compared with placebo. High-dose budesonide did not improve lung function or symptom scores relative to low-dose budesonide. In another study, Connett and colleagues84 examined the cost-effectiveness of inhaled budesonide compared with placebo in a 6-month randomized trial of 40 children aged 1 to 3 years with persistent asthma. The results indicated that budesonide produced a favorable clinical response, increasing symptom-free days when compared with placebo.
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The results also suggested that compared with placebo, budesonide increases overall effectiveness and reduces overall costs by about $9.45 US per symptom-free day gained. Rutten-van Mölken and colleagues85 reported on the costeffectiveness of adding inhaled corticosteroids to an asneeded bronchodilator regimen (ICS + BA) compared with as-needed bronchodilator alone (BA) in a 12-month randomized trial of 116 children with asthma aged 7 to 16 years. The investigators evaluated FEV1 as the primary outcome, and frequency of symptom-free days and school absences as secondary outcome measures. ICS + BA was estimated to cost about $4.75 US per symptom-free day gained relative to use of BA alone. One of the most comprehensive trials to date investigated the costs and effects of adding inhaled anti-inflammatory therapy to inhaled b2-agonist.86 This study was based on 274 adult participants ages 18 to 60 years, with moderately severe asthma or chronic obstructive pulmonary disease as defined by pulmonary function criteria. Each patient was randomized to either inhaled fixed-dose terbutaline plus inhaled placebo, inhaled terbutaline plus 800 µg of inhaled beclomethasone per day, or inhaled terbutaline plus inhaled ipatropium bromide 160 µg per day. Patients were followed for up to 2.5 years.The economic objective of this study was to determine the relative cost per unit of benefit for the three therapeutic arms. The clinical results indicated that adding the inhaled corticosteroid to fixed-dose terbutaline led to a significant improvement in pulmonary function and symptom-free days, whereas addition of the inhaled ipatropium bromide to fixed-dose terbutaline produced no significant clinical benefits over placebo. The incremental cost-effectiveness for inhaled corticosteroid was approximately $5 per symptom-free day gained. The incremental cost-effectiveness of ipatropium bromide was not evaluated because of the lack of clinical benefit relative to placebo.The results from these studies suggest a favorable economic profile of adding inhaled corticosteroids to short-acting b-agonists. There appears to be only one study in the literature that attempts to characterize the relative health economic value between different inhaled steroids, however the unique and nonstandardized approach make it difficult to interpret the results.87 Long-acting b2-agonists Long-acting bronchodilators are a relatively new approach to treating asthma and, to date, there appear to be only two studies evaluating the impact of this type of therapy on the clinical and economic outcomes. One study randomized 145 asthma patients to receive 12 weeks of maintenance therapy with either long-acting formoterol or short-acting albuterol.70 The study results showed no statistically significant differences in symptom-free days between the two treatment groups. The short study period (12 weeks), and retrospective design also limit the value of this study. Because of these results, the authors appropriately did not calculate a cost-effectiveness ratio.
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A more recent study examined the relative economic consequences of treating persons with asthma with twice daily powder formoterol 12 lg, as compared with salmeterol 50 lg.88 Similar to the formoterol versus short-acting albuterol study noted above, the authors concluded that there were no statistically significant differences in symptomfree days between the two treatment groups and because of this, no incremental cost-effectiveness ratio was calculated. Another large RCT examined the costs and effects of using salmeterol/fluticasone propionate combination product (SFC) 50/250 lg twice daily versus budesonide 800 lg twice daily.89 This study was based on 353 adult and adolescent participants (12 years and older) who were symptomatic on current doses of inhaled corticosteroids. The patients were followed for 24 weeks. The results indicated that patients on SFC had significant improvements in several outcomes. The incremental cost-effectiveness for SFC was $1.12 US per symptom-free day gained. This study suggests that this combination therapy may have a favorable economic profile for patients with asthma who are otherwise poorly controlled on moderate doses of inhaled steroids. Inhaled cromolyn sodium There are no published health economic evaluations of inhaled cromolyn sodium that meet current standards of analysis. However, there are two studies that have attempted to define the economic value of this treatment. One study is based on retrospective analysis of 53 patients categorized into two groups: those who received cromolyn sodium for at least 1 year and those who did not receive cromolyn sodium as part of their treatment regimen.90 Another, more recent study of nedocromil sodium was conducted used a retrospective pre–post design to examine this therapy for 553 adults with asthma.91 Unfortunately, these studies are not true cost-effectiveness analyses; rather, they are a variation of a cost comparison of two retrospective cohorts of asthma patients, and as such, they provide little clear knowledge of the economic value of these therapeutic agents. Antileukotriene antagonists There has been one health economic study of the use of zafirlukast for children and adults with mild-to-moderate asthma, however the study did not report on the cost of the study drug, thereby attaching a degree of uncertainty to the value of this treatment strategy.65 There are presently no other published studies that meet current standards to provide an understanding of the economic value of these agents. Other pharmacotherapy There have been a few studies of various other pharmacotherapeutic strategies. One suggested that inhaled anticholinergics may be of benefit in treating children with asthma.92 There also appears to be only one health economic evaluation of asthma pharmacotherapy conducted by a less-developed country. This cost-minimization study,
conducted in India, found the use of oral b-agonists provided no additional clinical benefit and increased costs for persons using inhaled b-agonists as needed.93 Other literature has explored the cost consequences of nebulizers versus MDI with or without spacers in the acute care setting.94–99 Although most of these studies have design limitations, collectively they suggest there is no significant difference in clinical outcomes between nebulizers and MDIs.94,100 These studies also suggest MDIs offer modest cost savings. While there are published studies of various other types of medication delivery devices, they do not meet many of the standards for health economic evaluations.101–103 Asthma patient education, self-management programs and specialty consultation Several publications document the clinical and economic impact of patient-oriented asthma education programs. These educational interventions vary from formal classroom-based medication compliance programs to asthma self-management programs for adults and children/parents. Overall, the economic evaluations of these programs are quite favorable, especially when the programs are aimed at high-risk patients or those with high end healthcare utilization (such as a prior hospitalization).104–115 These studies nearly all take the form of cost–benefit analyses with costs attributed to program costs, and benefits related to changes in emergency department and hospital utilization. One particularly well-designed RCT of an inner-city population was able to demonstrate cost savings from a program of five, 1-hour asthma education sessions targeted at children who had been hospitalized in the past year.114 True cost-effectiveness studies in the field of asthma education and training for self-management are infrequent. Two separate studies of asthma self-management programs in Finland arrived at conflicting conclusions. One study resulted in a cost-effectiveness ratio of 118 Finnish Marks per health day gained.116 A similar study in Finland found no significant health economic value at either 1 or 3 years.117 Another study of asthma self-management in India met a number of the standards for a CEA, however fell short of calculating a cost-effectiveness ratio.118 This study suggested there were health improvements in terms of peak flow measurements and productive days loss, as well as average marginal cost savings of 22%. There have also been studies examining the economic impact of referrals to specialists for persons with moderate to severe asthma.119,120 Retrospective chart reviews found significant reductions in sick office visits, ER visits, hospital days and costs of care.These results must be interpreted with caution in light of flaws in the study design and evaluation methods. Studies of asthma care in EDs and hospitals A number of studies have examined ways in which emergency departments or hospitals might achieve optimal asthma care outcomes at lower costs. Several studies have characterized the use of short stay observation units in the
Health Economics
ED.121–123 Collectively, these studies suggest that use of these units is cost-beneficial. Several other studies have examined the economics of asthma clinical pathways designed to improve and streamline hospital care.124-128 These studies, all nonrandomized and mostly retrospective in design, uniformly focused on length of stay without clearly defining the costs associated with the intervention. While a majority of these studies reported decreased length of stay, the actual cost–benefit of the pathways intervention remains unclear. One wellconducted trial resulted in no significant cost-benefit.128 Studies of disease management programs “Disease management” has become popular during the past decade.129–131 Although there is currently no standard definition for this term, the majority of program descriptions focus on population management, and include some type of multifaceted team approach to improving the delivery of care. There are now a number of health economic studies evaluating asthma-specific disease management programs.132–140 Each of these studies has notable design limitations, particularly in relation to sample selection, controls and economic analyses. Taken together, however, they suggest that a comprehensive approach to asthma management – beyond pharmacotherapy – may have some merit. Further research in the form of prospective randomized clinical trials will help to better elucidate the economic value of this approach to improving asthma outcomes. Other miscellaneous asthma-related health economic studies There are a number of other health economic studies related to asthma care which span the spectrum from examining the value of diagnosis and treatment of gastroesophageal reflux for asthma, to psychosomatic therapy, to use of pharmacists in disease management, and use of physician audit with feedback.141–145 The methods used in these studies do not meet many of the established standards for conducting health economic studies, making the results difficult to interpret.
C O M PA R AT I V E H E A LT H E C O N O M I C E VA L U AT I O N S F O R C O P D Pharmacologic interventions Sclar et al.146 analyzed the medical care expenditures of COPD patients treated with various pharmaceutical interventions. Their study estimated medical expenditures for prescription, physician, laboratory, and hospital services over 15 months in individuals newly diagnosed with COPD. Results were adjusted for age, gender, comorbid diseases, lung function and treatments. The average estimated costs of health care services for an individual over the study period ranged from $596 to $954 in 1994 dollars. Rutten-van Mölken and associates147 investigated the costs and clinical benefits of adding inhaled anti-inflammatory
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therapy to inhaled b2-agonist in persons with asthma and chronic obstructive lung disease. Data from a randomized trial of 274 adult participants aged 18 to 60 years were analyzed.147 Patients were selected for inclusion if they met the age criteria and had diagnosed moderately severe obstructive airway disease defined by pulmonary function criteria. Greater than 70% of patients had asthma and the remainder had COPD. Each was randomized to either fixed-dose inhaled terbutaline plus inhaled placebo, inhaled terbutaline plus 800 µg of inhaled beclomethasone per day, or inhaled terbutaline plus inhaled ipratropium bromide 160 µg per day. Patients were followed for up to 2.5 years. The clinical results indicated that addition of the inhaled corticosteroid to fixed-dose terbutaline led to a significant improvement in pulmonary function (FEV1 and PCO2) and symptom-free days, whereas addition of inhaled ipratropium bromide to fixed-dose terbutaline produced no statistically significant clinical benefits compared with placebo. Analysis of the health economic endpoints showed that the average annual direct medical care cost-savings associated with the use of inhaled corticosteroid were not offset by the increase in costs from the average annual price of the inhaled product. The incremental cost-effectiveness for inhaled corticosteroid was $201 per 10% improvement in FEV1 and $5 for each symptom-free day gained. The incremental cost effectiveness of ipratropium bromide was not evaluated because the trial showed no clinical benefit for ipratropium bromide relative to placebo. More recent data suggest that ipratropium alone or in combination with albuterol can reduce the cost for persons with COPD. Jubran and colleagues148 performed a retrospective, chart-based cost-minimization analysis of theophylline versus ipratropium bromide for patients with COPD. Patients treated with ipratropium had lower costs and a greater number of complication-free months compared with patients taking theophylline. Similarly, in a post hoc analysis of two randomized trials (n = 1067) that patients on a fixed combination of ipratropium and albuterol had improved pulmonary outcomes and reduced exacerbation frequency resulting in lower health care costs when compared with patients on albuterol alone.149 The lower health care costs were a direct result of fewer hospital days (46 versus 103) and fewer patient days of changed or added antibiotics (302 versus 429) in the group randomized to combination therapy compared with those placed on albuterol alone. Even with these important cost and outcome improvements, more than 12% of patients in the study had at least one exacerbation in the first 85 days of drug treatment suggesting that additional economic gains may be available with even more effective therapies. Acute exacerbation of chronic bronchitis (AECB) often requires expensive inpatient care including intensive care stay, ventilation and antibiotic treatments.150 Ciprofloxacin has been studied as a cost-effective alternative to usual care regimens for the treatment of AECB.151 The authors concluded that ciprofloxacin was cost-effective in patients with
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moderate to severe chronic bronchitis who had at least four AECBs in the past year.
COPD found that home care did not appear to improve health outcomes, while the cost impact was mixed.165
Smoking cessation Investing resources in smoking cessation programs is costeffective in terms of medical costs per life year gained. A recent international review of studies found that the median societal cost of various smoking cessation interventions was approximately £17,000 per life year gained.152 The literature on smoking cessation cost-effectiveness studies reports on various interventions such as nicotine transdermal patches, physician and other health professional counseling with and without patches, self-help and group programs and community-based stop-smoking contexts. Similarly, a comprehensive guidance document published in Thorax showed that smoking cessation programs produced cost-effectiveness ratios that ranged from £212 to £873 per life-year gained and were thus a very good health care value for the United Kingdom NHS.153
Lung volume reduction Lung volume reduction surgery (LVRS) has become an available option for treating severely disabling emphysema.166 Considerable debate has centered on the role of LVRS in treating emphysema since evidence from controlled studies is lacking. It has been projected that widespread adoption of this procedure could cost the US health economy more than $6 billion in the first several years of adoption.167 The Health Care Financing Administration (HCFA) has stated that Medicare will no longer provide reimbursement for LVRS until sufficient evidence exists regarding the safety and efficacy of the treatment. A number of studies have estimated costs for LVRS. Elpern and colleagues168 analyzed the hospital costs associated with LVRS in 52 consecutive patients. Total hospital costs ranged from $11,712 to $121,829, and were significantly associated with length of stay, both in the ICU and total length of stay in the hospital. A small number of individuals incurred extraordinary costs because of complications. The mean cost was $30,976 and the median cost was $19,771. Advanced age was a significant factor leading to higher expected total hospital costs. Albert and colleagues169 also evaluated the hospital charges in 23 consecutive patients admitted for LVRS at a single institution. Charges ranged from $20,032 to $75,561 with a median charge of $26,669. The results from this study suggest that the costs of LVRS will fall as complication rates are reduced and average length of stay falls over time as caregivers gain experience with the procedure.
Home oxygen Supplemental home oxygen is usually the most costly component of outpatient therapy for adults with emphysema who require this therapy.154 Studies of the cost-effectiveness of alternative outpatient oxygen delivery methods in the United States and Europe suggest that oxygen concentrator devices may be cost-saving compared with cylinder delivery systems.155,156 Education and pulmonary rehabilitation Education and pulmonary rehabilitation programs have been shown to have beneficial effects in patients with COPD.157 Education programs have been promoted as an economically attractive intervention for individuals with COPD.158,159 A Canadian study found that the incremental cost of pulmonary rehabilitation was $11,597 (CDN) per person. Statistically significant improvements in dyspnea, fatigue, emotional health and mastery were observed.160 An observational study with a small number of subjects found that patients in a pulmonary rehabilitation program utilized fewer health care services compared with those without rehabilitation.161 Because of study design limitations, it is unclear whether these results are generalizable to a larger, more diverse group of patients. The initial costs of the rehabilitation program may be offset if urgent care and emergency room visits or hospitalizations are subsequently reduced. Home-based care Economic studies of home care services have yielded mixed results. One study of a northern Canadian native tribe found that quality of life improved and hospital days per admission fell after a home care program was instituted.162 A randomized, controlled trial in England found that substituting home care for inpatient hospital care produced no greater health outcomes while increasing costs.163,164 A recent evidencebased review of home care for several conditions including
Transplantation Lung transplantation is a costly but often effective therapy for severe emphysema. Ramsey and colleagues170 examined the hospitalization costs associated with lung transplantation. Studies of lifetime expenditures for lung transplantation have ranged from $110,000, to well over $200,000.171 Unlike LVRS, the costs associated with lung transplantation remain elevated for months to years after surgery due to the high cost of complications and immunosuppression regimens.
CONCLUSIONS The health economic literature for asthma and COPD has evolved considerably during the past decade. Both cost-ofillness studies and comparative health economic evaluations have begun to define the boundaries by which current and new intervention strategies will provide value to patients, providers and communities. The literature suggests that the use of inhaled corticosteroids for mild to moderate persistent asthma is relatively cost-effective. There also appears to be some cost-benefit to asthma education directed at selfmanagement for selected subgroups of patients. Disease
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management programs may, with further study, provide a comprehensive intervention strategy that adds value to current clinical care of persons with asthma. There are, however, a number of problems that need to be addressed before studies of this type can be effectively used to determine optimal clinical strategies. First among the barriers is the lack of standardized outcomes for use in health economic analysis of both asthma and COPD. For asthma, the symptom-free day is beginning to emerge as a standard measure. Researchers in the field of COPD have not, as yet, benefited from national or international discussions aimed at standardizing outcome measures for this condition.The federal government and pharmaceutical industry have yet to fully embrace the concept of health economic evaluations as a critical component in the quest to improve the diagnosis and management of asthma and COPD.There is evidence, at least for asthma, that more economic evaluations will be forthcoming. Yet, until better economic analyses are made available, the allocation of resources for asthma and COPD will continue to primarily rely on expert opinion rather than evidence-based literature.
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122. Marks MK, Lovejoy FH Jr, Rutherford PA, Baskin MN. Impact of a short stay unit on asthma patients admitted to a tertiary pediatric hospital. Qual. Manage. Health Care 1997; 6:14–22. 123. Rydman RJ, Isola ML, Roberts RR et al. Emergency department observation unit versus hospital inpatient care for a chronic asthmatic population. Med. Care 1998; 36:599–609. 124. Doan T, Grammer LC,Yarnold PR, Greenberger PA, Patterson R. An intervention program to reduce the hospitalization cost of asthma patients requiring intubation. Ann. Allergy Asthma Immunol. 1996; 76:513–18. 125. McDowell KM, Chatburn RL, Myers TR, O’Riordan MA, Kercsmar CM. A cost-saving algorithm for children hospitalized for status asthmaticus. Arch. Pediatr. Adolesc. Med. 1998; 152:977–84. 126. Bailey R, Weingarten S, Lewis M, Mohsenifar Z. Impact of clinical pathways and practice guidelines on the management of acute exacerbations of bronchial asthma. Chest 1998; 113:28–33. 127. Kelly SX, Anderson CL, Pestian JP et al. Improved outcomes for hospitalized asthmatic children using a clinical pathway. Ann. Allergy Asthma Immunol. 2000; 84:509–16. 128. Kwan-Gett TS, Lozano P, Mullin K, Marcuse EK. One-year experience with an inpatient asthma clinical pathway. Arch. Pediatr. Adoles. Med. 1997; 151:684–90. 129. Hunter DJ, Fairfield F. Disease management. Br. Med. J. 1997; 315:50–3. 130. Harris JM. Disease management: new wine in new bottles? Ann. Intern. Med. 1996; 124:838–42. 131. Epstein RS, Sherwood LM. From outcomes research to disease management: a guide for the perplexed. Ann. Intern. Med. 1996; 124:832–7. 132. Integrated care for asthma: a clinical, social, and economic evaluation. Grampian Asthma Study of Integrated Care. Br. Med. J. 1994; 308:559–64. 133. Kelly CS, Morrow AL, Shults J, Nakas N, Strope GL, Adelman RD. Outcomes evaluation of a comprehensive intervention program for asthmatic children enrolled in Medicaid. Pediatrics 2000; 105:1029–35. 134. Gilmet GP, Zeitz HJ, Lewandowski JJ. Pediatric asthma outcomes after implementation of a disease management model: the Asthmatter of Fact Program. Dis. Manage. 2000; 3:11–19. 135. Levenson T, Grammer LC, Yarnold PR, Patterson R. Costeffective management of malignant potentially fatal asthma. Allergy Asthma Proc. 1997; 18:73–8. 136. Jowers JR, Schwartz AL, Tinkelman DG et al. Disease management program improves asthma outcomes. Am. J. Manage. Care 2000; 6:585–92. 137. Greineder DK, Loane KC, Parks P. A randomized controlled trial of a pediatric asthma outreach program. J.Allergy Clin. Immunol. 1999; 103:436–40. 138. Watanabe T, Ohta M, Murata M, Yamamoto T. Decrease in emergency room or urgent care visits due to management of bronchial asthma inpatients and outpatients with pharmaceutical services. J. Clin. Phar.Ther. 1998; 23:303–9. 139. Curtin K, Hayes BD, Holland CL, Katz LA. Computer-generated intervention for asthma population care management. Effective Clin. Pract. 1998; 1:43–6. 140. Rossiter LF, Whitehurse-Cook MY, Small RE et al. The impact of disease management on outcomes and costs of care: a study of low-income asthma patients. Inquiry 2000; 37:188–202. 141. O’Connor JF, Singer ME, Richter JE. The cost-effectiveness of strategies to assess gastroesophageal reflux as an exacerbating factor in asthma. Am. J. Gastroenterol. 1999; 94:1472–80. 142. Deter HC. Cost–benefit analysis of psychosomatic therapy in asthma. J. Psychosom. Res. 1986; 30:173–82. 143. Munroe WP, Kunz K, Dalmady-Israel C, Potter L, Schonfeld WH. Economic evaluation of pharmacist involvement in disease
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management in a community pharmacy setting. Clin. Ther. 1997; 19:113–23. Knoell DL, Pierson JF, Marsh CB, Allen JN, Pathak DS. Measurement of outcomes in adults receiving pharmaceutical care in a comprehensive asthma outpatient clinic. Pharmacotherapy 1998; 18:1365–74. McCowen C, Neville RG, Crombie IK, Clark RA, Warner FC. The facilitator effect: results from a four-year follow-up of children with asthma. Br. J. Gen. Pract. 1997; 47:156–60. Sclar DA, Leff RF, Skaer TL, Robison LM, Nemic NL. Ipratropium bromide in the management of chronic obstructive pulmonary disease: Effect on health service expenditures. Clin. Ther. 1994; 16:595–601. Rutten-van Mölken MP,Van Doorslaer EK, Jansen MC, Kerstjens HA, Rutten FF. Costs and effects of inhaled corticosteroids and bronchodilators in asthma and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1995; 151:975–82. Jubran A, Gross N, Ramsdell J et al. Comparative cost-effectiveness analysis of theophylline and ipratropium bromide in chronic obstructive pulmonary disease. A three-center study. Chest 1993; 103:78–84. Friedman M, Serby CW, Menjoge SS, Wilson D, Hilleman DE, Witek TJ. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest 1999; 115:635–41. Connors AF, Dawson NV, Thomas C et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. Am. J. Respir. Crit. Care Med. 1996; 154:959–67. Grossman R, Mukherjee J, Vaughan D et al. A 1-year communitybased health economic study of ciprofloxacin vs usual antibiotic treatment in acute exacerbation of chronic bronchitis. Chest 1998; 113:131–41. Tengs TO, Adams ME, Pilskin JS et al. Five hundred life saving interventions and their cost-effectiveness. Risk Analysis 1995; 15:369–90. Parrott S, Godfrey C, Raw M, West R, McNeill A. Guidance for commissioners on the cost effectiveness of smoking cessation interventions. Thorax 1998; 53(Suppl. 5):S1–38. Petty TL, O’Donohue WJ Jr. Further recommendations for prescribing, reimbursement, technology development, and research in long-term oxygen therapy. Summary of the Fourth Oxygen Consensus Conference, Washington, DC, 15–16 October 1993. Am. J. Respir. Crit. Care Med. 1994; 150:875–7. Pelletier-Fleury N, Lanoe JL, Fleury B, Fardeau M. The cost of treating COPD patients with long-term oxygen therapy in a French population. Chest 1996; 110:411–16. Heaney LG, McAllister D, MacMahon J. Cost minimization analysis of provision of oxygen at home: are the Drug Tariff guidelines cost effective? Br. Med. J. 1999; 319:19–23. Ries AL, Kaplan RM, Limberg TM, Prewitt LM. Effects of pulmonary rehabilitation on physiologic and psychological and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann. Intern. Med. 1995; 122:823–32. Folgering H, Rooyakkers J, Herwaarden C. Education and cost/benefit ratios in pulmonary patients. Monaldi Arch. Chest Dis. 1994; 49:166–8. Tougaard L, Krone T, Sorknaes A et al. Economic benefits of teaching patients with chronic obstructive pulmonary disease about their illness. Lancet 1992; 339:1517–20. Goldstein RS, Gort EH, Guyatt GH, Feeny D. Economic analysis of respiratory rehabilitation. Chest 1997; 112:370–9. Ries AL. Position paper of the American Association of Cardiovascular and Pulmonary Rehabilitation: scientific basis of pulmonary rehabilitation. J.Cardiopulm.Rehab. 1990; 10:418–41. Miles-Tapping C. Home care for chronic obstructive pulmonary disease: impact of the Iqaluit program. Arctic Med. Res. 1994; 53:163–75. Shepperd S, Harwood D, Jenkinson C, Gray A,Vessey M, Morgan
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P. Randomised controlled trial comparing hospital at home care with inpatient hospital care. I: three-month follow up of health outcomes. Br. Med. J. 1998; 316:1786–91. Shepperd S, Harwood D, Gray A, Vessey M, Morgan P. Randomised controlled trial comparing hospital at home care with inpatient hospital care. II: cost minimisation analysis. Br. Med. J. 1998; 316:1791–6. Soderstrom L, Tousignant P, Kaufman T. The health and cost effects of substituting home care for inpatient acute care: a review of the evidence. Can. Med. Assoc. J. 1999; 160:1151–5. Huizenga HF, Ramsey SD, Albert RA. Estimated growth of lung volume reduction surgery among Medicare enrollees: 1994–1996. Chest 1998; 114:1583–7. Gentry C. Second Opinion. Why Medicare covers a new lung surgery for just a few patients. Wall Street J. June 29, 1998.
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168. Elpern EH, Behner KG, Klontz B et al. Lung volume reduction surgery. An analysis of hospital costs. Chest 1998; 113:896–9. 169. Albert RK, Lewis S, Wood D, Benditt JO. Economic aspects of lung volume reduction surgery. Chest 1996; 110:1068–71. 170. Ramsey SD, Patrick DL, Albert RK et al.The cost-effectiveness of lung transplantation: a pilot study. Chest 1995; 108:1594–601. 171. Molken MP,Van Doorslaer EK, Rutten FF. Economic appraisal of asthma and COPD care: a literature review 1980–1991. Soc. Sci. Med. 1992; 35:161–75. 172. Sullivan SD, Weiss KB. Pharmacoeconomics of asthma treatments. In: Barnes PJ, Rodger IW, Thomson NC (eds), Asthma: Basic Mechanisms and Clinical Management, 3rd edn, pp. 903–16. San Diego: Academic Press, 1998.
Management of Chronic Asthma in Adults
Chapter
64
Ann J. Woolcock Institute of Respiratory Medicine, Royal Prince Alfred Hospital, University of Sydney, Australia
INTRODUCTION This chapter discusses the long-term management of asthma in adults with reference to the management of exacerbations where needed. There is no universally agreed method of management because the causes and natural history of the different syndromes that constitute asthma are poorly understood and there are few long-term, controlled trials of different forms of treatment. This has led to a variety of treatment practices and patients often receive confusing information from doctors, nurses, pharmacists and asthma-educators. Conflicting information about drugs and their actions exists in the literature. Furthermore, drugs that are widely used in one country appear to be ineffective in another1 and within Europe widely differing prescribing practices occur.2 To try to address this confusion, management plans for asthma started to appear about 10 years ago.3–6 This then led to international and global plans.7–9 The purpose of these plans is to provide a basis for a unified approach to management and, eventually, to allow self-management by the patient. In the absence of data about long-term outcomes in groups with or without treatment designed to achieve control, these management plans have been written as “consensus” documents. Most of them are extremely detailed and not easily used by busy doctors.10,11 The answers to specific questions frequently asked by doctors, such as when to use which drug, the appropriate doses and criteria for altering the doses, are only partially addressed by plans. Another problem with guidelines is that “asthma” is sometimes used to mean both the disease and the episodes of airway narrowing which leads to confusion. The recent plan published from South Africa12 is simple and addresses the needs of that country. Each country needs to publish its own asthma management guidelines and update them regularly. Some of these problems are addressed in the Asthma Management Plan described below. It is based on that published by the National Asthma Campaign in Australia13 and stresses achieving control of the disease using both pharmacological and nonpharmacological measures. The details
are for management of patients with severe, persistent asthma but the principles are the same for all patients with asthma. The commonly used drugs are described and the factors that trigger and aggravate the disease are discussed. The management of patients with a poor response to conventional treatment and the likely changes in treatment that will occur in coming years are discussed at the end of the chapter.
C L A S S I F I C AT I O N O F A S T H M A F O R PURPOSES OF MANAGEMENT Persistent asthma The airways narrow too much and too easily in response to a wide variety of provoking stimuli. It varies from mild to life-threatening in severity. Airway hyperresponsiveness (AHR)14 and airway inflammation are present.15,16 Episodic asthma (often seasonal) The airways narrow too much and too easily in response to specific stimuli, such as pollen allergens and viral infections. Between episodes, airway function and airway responsiveness are normal. Episodic asthma is more common in children than adults, but occurs in some patients who are allergic to pollens and grain dusts during the season of exposure. Histological changes have been reported between episodes of symptoms in patients with episodic asthma.17
AIMS OF MANAGEMENT Concept of control In 2001, the approach to management is changing somewhat, rather than talking about reducing the severity of disease, the emphasis is now on gaining and maintaining control. Definitions of degrees of control are emerging – “optimal” control, “good” control, “partnership” control. Table 64.1 shows the criteria for optimal control.
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Table 64.1. Criteria for optimal control
Few or no daytime symptoms (including exercise) No night-time symptoms No use of rescue short-acting beta agonist (SABA) Waking PEF above 85% of recent best Lung function (PEF or FEV1) close to predicted value and maintained with time Less than two exacerbations a year No side-effects of drugs Normal airway responsiveness
Time to achieve control The first four of these aspects of control can be achieved within about 6 months or less depending on the initial severity, but to determine that the last four aspects have been achieved takes at least 2 years of treatment. An important message that seems to escape most patients and doctors is that the disease can be completely controlled in almost all patients if the management plan is adhered to. Furthermore, there is some evidence that the earlier after diagnosis that treatment is introduced, the easier it is to achieve.18 It must be stressed that although these aims are logical and based on common sense, there are no long-term trials to determine the best ways of achieving them or of comparing optimal control with the variable degrees of control that most patients achieve at the present time. Partnership in care Increasingly the degree of control to be aimed at is discussed between the patient and the doctor and the degree of control agreed.19 Prevention It is generally agreed that the aims of asthma management are largely related to prevention (as in occupational asthma), yet prevention of the disease is hardly ever mentioned in articles and book chapters relating to management, even though it is now well established that in childhood it is those who become atopic (especially the host dust mite)20,21 who are at risk. Since most adults have had some asthma in childhood, prevention by avoidance of risk factors and adoption of protective factors in childhood are more important, because it is too late to prevent asthma becoming persistent once it is established in adults.
ASTHMA MANAGEMENT PLAN Table 64.2 shows a three step management plan. The plan stresses the assessment of the asthma (when the patient is not having an attack) and indicates ways to obtain control.
Table 64.2. Summary of asthma management
Assessment Best achievable lung function (PEF and spirometric function) Severity of disease when not treated Nature of disease Intervention Precise drug use Action plan for exacerbations Address lifestyle and aggravating factors Commitment Educate the patient and family Review regularly
ASSESSMENT Find best lung function The best achievable values for peak expiratory flow (PEF) and spirometric function are needed as a guide to the longterm control of asthma. It is important to know if residual airflow limitation exists after maximal steroid therapy has been given. If the patient has not achieved a PEF value close to the predicted value (obtained from the tables for age, sex, height and race) in a week of monitoring (Fig. 64.1), it is possible that the best lung function has not been reached. In such a patient, a trial of oral steroids with PEF monitoring should be undertaken. Usually 5 days of prednisone or prednisolone 0.8 mg/kg/day is enough, but if improvement is still occurring after 5 days the medication can be continued for up to 10 days. The prednisone is then stopped and inhaled corticosteroids are continued. The best PEF value obtained is noted and 85% of this value becomes the “target” waking value – the amount of steroids given is aimed at reaching this value. At the same time the “best” spirometric value (FVC and FEV1) should be recorded at a visit while the patient is on prednisone. These values serve as reference values for long-term management. Assess severity This is done from the history of day- and night-time symptoms, bronchodilator use and the minimum waking peak expiratory flow (amPEF) over 2 weeks, expressed as a percentage of the recent best as shown in Fig. 64.1. When the amPEF is close to predicted and 90% of the recent best and the patient has episodic symptoms, the patient can be regarded as having episodic asthma. This can be confirmed by a provocation test with histamine or methacholine. If it is normal, the patient can be regarded as having episodic disease and be treated with beta agonists on demand. If there is AHR present then the patient should be regarded as having persistent disease – this can be mild, moderate or severe, depending on the score.
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Morning PEF
as a percentage of the recent best (or even predicted) value, is a good indicator of the severity of the airway abnormality in most patients.24 Values above 95% are normal, while values below 70% indicate severe disease as shown inTable 64.3 and Fig. 64.2. For initial assessment, two weeks of readings, recorded both on waking and in the evenings is enough to provide an accurate reflection of the situation – unless the patient is having, or has just had, a severe exacerbation.
Evening PEF
Highest PEF (670)
800
PEF (L/min)
700 600 500 Lowest morning PEF (570) 400 300
0
7 Days
14
Minimum morning PEF (% recent best) 570/670 85% Fig. 64.1. A simple index of PEF variation. The lowest waking peak expiratory flow over 2 weeks is expressed as a percentage of the recent best.24
At present there is no “gold standard” against which to assess severity. Table 64.3, derived from that published by Reddel et al.22 shows a scoring system that has proved useful. The total score ranges from 1 to 8, 0–2 for night symptoms, 0–2 for short-acting bronchodilator use over a period of a week, 0–2 for variability of PEF rates and 0–2 for exacerbations over the last 12 months. A total score can be calculated and those with a score of more than 4 usually have persistent asthma. While those with a score of less than 3 usually have mild persistent asthma or episodic asthma. Symptoms are wheeze, chest tightness, breathlessness and cough, alone or in combination.The frequency of symptoms is important and, in particular, waking at night regularly with wheezing or coughing is a symptom of severe disease.23 The amount of short-acting beta-agonist (SABA) use helps in the assessment of severity, but only when the patient has been advised to use it for symptoms only, not when it is prescribed on a regular basis. Measurement of amPEF is important for determining the severity of asthma and for continuing management. The minimum value for amPEF over a 14-day period, expressed
Assess type of asthma It is increasingly recognized that asthma is not one disease, even in adults. Thus, there is clearly asthma associated with atopy, asthma in which atopy plays no role and occupational asthma in which the airways narrow in response to a specific substance to which the patient becomes “sensitized” at the workplace. The pathological changes appear to be the same as those seen in other forms of asthma.25 More details are given in Chapter 38. Aspirin-sensitive asthma and asthma associated with allergic bronchopulmonary aspergillosis and asthma associated with Churg–Strauss syndrome are forms of disease that need to be recognized when the patient is first investigated.
I N T E RV E N T I O N In patients with persistent disease, drug therapy is used to obtain control.To lower the score outlined in Table 64.3, the aim is to reduce severity by treating the airway inflammation with inhaled corticosteroids and in many instances with long-acting beta-agonists. However, addressing lifestyle problems and reducing exposure to known aggravating factors are also important to achieving control. Precise drug use: Long-term drugs for control (first line) Inhaled corticosteroids (ICS) There is no doubt that in adults with persistent asthma ICS are the only drugs that can truly be called “first line” and are to be used in all patients. They are effective because they have a number of actions (see Chapter 52). Biopsy studies show that they restore the bronchial epithelium that is commonly friable and easily shed.26 Their effects on cells and structures deeper in the airway wall in
Table 64.3. Score for severity and titrating ICS dose
Night waking SABA Lowest am PEF % recent best Exacerbations (12 mo) Max total 8 SABA, short-acting beta-agonist.
Score 0
Score 1
Score 2
None None 85% None
Once/2 weeks 1–3 /week 70–85% One
Once/2 weeks 4/week 70% One
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790 800 680 700 700
600
(89%)
PEF (L/min)
500 440 (65%) 400 300
200
100 a
b
c
0 0
4
8
12
16
20
24
28
32
Weeks from commencement of budesonide Morning pre-bronchodilator PEF Evening pre-bronchodilator PEF "Post-bronchodilator" PEF
(a) Poor asthma control (b) Stable asthma (c) Exacerbation
Fig. 64.2. PEF recordings from a patient over a 32-week period. Initially the patient had controlled asthma (lowest amPEF 65% of recent best). Following commencement of inhaled budesonide treatment, asthma control improved (lowest amPEF 89% of recent best). This patient also experienced a severe asthma exacerbation.61
persistent adult asthma is largely unknown, although it appears that they have some effect on the collagen deposited beneath the basement membrane.27
side-effects (so special attention to pharyngeal cleaning is needed) and the hazard that, for some reason, the patient does not return for dose reduction.
Clinical effects Although when given accurately, they do not inhibit the early or late responses to allergen challenges, when given to patients with symptoms they have good effects within several days. In most patients, particularly those who have not taken the drugs previously, there is a dose-related effect in improving the severity of the disease. In a recent study,22 we were able to show that there is a different time course for different measurements. The order of improvement is night symptoms, clinic FEV1, amPEF, daytime symptoms, amount of rescue SABA and finally AHR, which was still improving at 72 weeks (Fig. 64.3). The outstanding improvement observed in this trial, while the dose of budesonide was being reduced, can be accounted for by the high starting dose (at least 1.6 mg/day) together with the fact that patients had electronic monitoring and were compliant with their treatment with ICS. The hardest part of treating patients with chronic adult asthma is persuading them to continue treatment once control of symptoms has been achieved. In our experience starting with a high dose for 8 weeks and then reducing the dose once good (although not optimal) control is achieved, is usually successful. The only hazards of this high-dose approach are local throat
Down titration Down titration is the most important part of treatment of chronic adult asthma. Control can be achieved relatively easily with high doses of ICS, but there will be
No night symptoms 100%
FEV1
amPEF
No SABA use
% Improvement
AHR
No night symptoms FEV1 amPEF No SABA use AHR 2
4
6 Months
24
Fig. 64.3. Rate of improvement in measures of asthma control with ICS treatment, based on a clinical trial starting with high dose budesonide.22
Management of Chronic Asthma in Adults
side-effects (most easily demonstrated is bruising) if it continues indefinitely. For reduction we used a score similar to the one shown in Table 64.3. If the score was stable or reduced after 8 weeks a trial of reduction of budesonide by 400 lg (1/4 the initial dose) was undertaken for another 8 weeks. If the score was worse, the dose remained unchanged or increased. The aim is to find the least dose of ICS that keeps the minimum amPEF above 85% of the recent best and no symptoms. Most patients understand this and record their amPEF and SABA use for 1–2 weeks before seeing their doctor. Electronic spirometers with simple questions make this extremely easy but they are expensive outside the clinical trials setting. Do steroids become less effective when they are used intermittently? There is no good answer to this, but in the many trials when salmeterol was first introduced it was compared with doubling the dose of the ICS, which had little effect on indices such as amPEF.There has been no good explanation for this. Thus there is some evidence that both starting early28 and reaching a reasonable level of control early in treatment are important. It should be remembered that many people over the age of 40 years have irreversible lung function so that PEF never gets close to predicted, but other aspects of good control are achievable. In spite of many studies that show that the doses of ICS can be reduced in many patients (some patients apparently go into remission), clinical experience suggests that relapse occurs in many patients when they are stopped.29 Maintenance on a low dose is usual, but this may well change with time. Side-effects of inhaled corticosteroids are: • Pharyngeal effects Some adult patients taking ICS experience dysphonia, the cause of which is unclear, and a smaller number develop thrush.30 These problems can be prevented by the use of a spacer device31,32 by reducing the number of inhalations (using high-strength aerosols) and by gargling after use. In some patients antifungal agents are needed to control the local symptoms. There remain a small group of patients where excessive “throat clearing” remains a problem. • Systemic effects Systemic effects are dependent upon the dose. They are not apparent in doses below 1.0 mg/day of the commonly used drugs and are much less than those observed with doses or oral steroids needed to maintain the same degree of control. Biochemical evidence of adrenal suppression rarely occurs on doses of less than 1.5 mg daily. When it is present, it is probably not medically important, but indicates that sufficient drug is being absorbed to have a systemic effect. Potential clinical effects are bruising, osteoporosis, development of cataracts and of these bruising is the most common. The evidence that osteoporosis33 and cataracts34 occur in the absence of courses of oral steroids or when the doses are kept below 1.0 mg/day is not convincing. The side-effects seen over many years with oral steroids cause steroid
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phobia and many patients, doctors and pharmacists maintain elements of this phobia, which is probably unjustified. Nevertheless, the long-term effects of these drugs have not been documented and it is prudent to continue to reduce the daily dose to the minimum that is needed to maintain the degree of control agreed between the doctor and the patient over time. Dose and administration Even though a precise dose of ICS is indicated for each asthmatic, it is not possible to outline the exact dose for a given patient, which depends on the severity of disease, the potency and the fomulation (aerosol or powder) of the drug, as well as the delivery device used. In general, it makes sense to start with high doses and to reduce the dose as soon as the severity improves. Nebulized forms (available as budesonide) may be needed initially in those with poor lung function, but the role of this form of the drug in adults is not established. Attention should be paid to teaching each patient the action of ICS on the airways, how to use them and what to expect. This takes time but it is one of the most crucial elements of asthma management. Long-acting b-agonists (LABA) These drugs are proving to be different in some respects from SABA (Chapter 49).They appear to increase the effectiveness of ICS,35 thus allowing the dose needed to achieve the early phases of control to be reduced. However, when they are stopped, the degree of control lessens. To gain optimal control, that represents true improvement in airway function, probably depends on the continuing use of ICS. Long-acting drugs are given in low dose and act to control the asthma rather than as relievers of acute episodes or airway narrowing, although formoterol acts more rapidly than salmeterol, and may have a place as a reliever medication. Their mechanism of action is similar to all beta-agonists, however their long action appears to be an important factor in asthma control. Used alone they have no place in the long-term treatment of asthma.36,37 Long-acting b-agonists act for 12 hours38–40 and, in the case of salmeterol, appear to have actions other than just bronchodilation.41 Their overall place in the management of patients with asthma is becoming defined. The greatest advantage of these drugs is in preventing night-time symptoms and in improving the quality of sleep. So far, sideeffects do not appear to be a problem. Tachyphylaxis to bronchodilatation has not been demonstrated but, after the first few days of continuing treatment, there is a reduction in the duration of the effects of salmeterol against stimuli such as exercise.42–44 The combination of LABA with ICS seems to be so successful that salmeterol is now available combined in the one device with various doses of fluticasone (seretide) (and the same will soon be available for formoterol with budesonide). These combinations are referred to as “controllers”. The combined drugs need to be used with care and methods of down titration are not yet well established. During exacerbations, the doses can be increased or ICS added.
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Theophylline This drug has many actions (see Chapter 51). The mechanism by which theophylline bronchodilates is unknown. However, it appears to increase intracellular cyclic AMP by a mechanism different from the b-agonists. However, it has been shown to have a beneficial effect when added to ICS45 and is cheaper than LABA. Compared with adding a LABA to ICS it is less effective and causes more side-effects.46 Precise drug use: preventers (second line) Sodium cromoglycate and nedocromil sodium Sodium cromoglycate (SCG) has been available for nearly 30 years. It prevents airway narrowing induced by allergens, exercise, SO2 and other irritants and can be given immediately before the provocation (Chapter 61). It may have a small effect on airway inflammation, but mainly to prevent the inflammation from worsening during the allergen season. It is used mostly in children. Nedocromil sodium (NS) is slightly more potent and was developed for use in adults. It can also prevent provocation by allergens, SO2, and exercise. In long-term therapy these drugs have almost no effect on the control of asthma. A recent review suggests they are little better than placebo.47 These drugs have virtually no side-effects.The dry powder form of SCG sometimes causes minor irritation and some patients complain that NS has an unpleasant taste from metered-dose aerosols, although SCG is also available as 20-mg spincaps and 20 mg nebulizer solution. They can be used immediately prior to exposure to known triggers to prevent attacks. Anti-leukotrienes and 5-LO inhibitors Montelukast, zafurlukast and pranlukast are available as leukotriene receptor antagonists and zyleutin as a 5-LO inhibitor (in the USA only).The last drug is more difficult to use as liver function tests must be monitored. At the present time, montelukast is the most widely used drug. It was developed in the USA and is marketed for its advantages of once daily oral format and of not being a steroid.These drugs have been shown to decrease exercise-induced attacks especially by increasing the recovery time after the bronchoconstriction. They also have a small effect to improve symptoms and lung function during 4 to 6 weeks of therapy. They have not been shown to achieve the degree of control of asthma as in Table 64.2 and Fig. 64.2. It is said to have a place in patients with aspirin-sensitive asthma, but so far this has not been well documented. Many clinicians have anecdotal patients who do extremely well on the drug, but at the present time there is no way of determining which patients will respond. Adults who have not achieved good control with high-dose ICS plus LABA, should be tried on the drug. Its chief limitation in most countries is its cost. It is much more expensive than ICS and has a much lesser effect than ICS.48 They are claimed to have anti-inflammatory effects, but these are hard to show in vivo in humans, except for a decrease in circulating eosinophils.49 Certainly leukotrienes have potent effects on the airways, but how much of the abnormality present in most asthmatics is caused by these
mediators alone remains unknown. These are interesting drugs because they increase our knowledge about asthma. They have no well-documented side-effects except for reports of Churg–Strauss syndrome which may have resulted from reduction of oral steroids. Drugs for treating exacerbations Short-acting beta-agonists (SABA) Salbutamol and terbutaline have become the mainstay of SABA treatment in most countries. They are most effective when inhaled, although oral and intravenous forms are also available. For reasons that are not understood, only the inhaled forms of beta-agonists protect against provoked attacks, such as exercise (Table 64.4). As aerosols they protect against provoking stimuli for about 2 hours. Tachyphylaxis to their bronchodilating effects has not been found in patients with asthma (Chapter 49). They are less effective at reversing the late than the early allergic response. Throughout the last 10 years the question about their effect on the severity of asthma when they are used regularly has been raised because of the controversy over fenoterol.50,51 A yearlong study in New Zealand showed that four times a day use of fenoterol was associated with worsening control of asthma in 40 out of 64 subjects who completed a trial. It may be that the effects demonstrated for fenoterol do not apply to all b-agonists. However, it is clear that when used alone b-agonists do not improve the overall severity of asthma. Nevertheless, many people with episodic or mild disease use it to control symptoms and their asthma remains well controlled. Sales of salbutamol have been increasing worldwide in the last 20 years and there is little objective evidence that this drug has caused any problem. Side-effects Tremor and slight tachycardia occur acutely and are well known.These effects usually decrease with time and are rarely a problem unless the drugs are used to excess. Attempts have been made to show tachyphylaxis to the bronchodilating effects of salbutamol in asthmatic airways,52 but this has not been found although it may occur in nonasthmatic people. Dose and administration These drugs are usually given in the inhaled form with doses varying from 100–200 lg. Metereddose inhalers, nebulizing solutions and dry powder forms are available, in addition to tablets and syrups. Table 64.4. Indications for use of short b-agonist aerosols
Accute severe attacks – these drugs may be life saving For diagnosis – does lung function improve within minutes? For assessment of severity – amount required plus PEF variability For symptoms which are causing distress or anxiety Before exercise to prevent airway narrowing
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Theophylline Theophylline is used infrequently as a bronchodilator acutely in asthma, but gives symptomatic relief to those with severe airway narrowing. There is a well-recognized group of subjects, usually dependent on long-term or frequent short-term courses of oral steroids, who use theophylline to control their symptoms. It is used less and less for symptoms in asthma. Side-effects In doses sufficient to cause bronchodilatation it cause nausea, headache and hyperactivity in children. The drug can cause fatal neurological and cardiovascular events. The increasing awareness of the side-effects of this drug has led to its decreasing use in some countries. However, sideeffects can be avoided by using the drug in lower doses as an adjunct to other therapy. Dose and administration When used as a bronchodilator, particularly in treating severe attacks, doses are adjusted to keep the serum levels within the “therapeutic” range, while avoiding toxicity. The slow release forms are most effective in reducing large fluctuations in serum levels. In patients with severe disease, especially those requiring low doses of oral prednisone in addition to ICS, they appear to have a steroidsparing effect and can be used in lower doses.The effort and expense of monitoring serum levels is not required for lowdose treatment. Anti-cholinergics The drugs ipratropium bromide and oxitropium are used to block the cholinergic receptors (Chapter 50).They are effective bronchodilators and are useful in patients with chronic obstructive pulmonary disease.They have a slower onset than the b-agonists.They are used in conjunction with SABA in the treatment of acute attacks, particularly in children. At present they have little role in the long-term management of asthma. Systemic steroids Mechanism of action Corticosteroids, when administered systemically, have similar actions to those described for topical steroids although their effect on the small airways is unknown. They take 4–6 hours to have an effect and will act on all the cells with steroid receptors.They may have less effect on cells in the airway lumen and on the epithelium than ICS. Clinical effects In the management plan, oral steroids are used as a trial to find the best lung function in patients whose PEF remains lower than predicted and to treat severe exacerbations. In children it has been shown that a single dose (30 or 60 mg) of prednisone, as well as nebulized bronchodilator, reduces the need for hospital admission53 and this probably also happens in adults, although data showing this rapid effect have not been published for adults. Side effects The side-effects of systemic steroids are well documented and include bruising, osterporosis, cataracts, hypertension, diabetes and cushingoid features. Changing the patient to ICS potentially reduces these effects. It takes
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many months to change patients to the inhaled form and care must be taken to implement all the other steps in the management plan at the same time. Dose and administration For finding the best lung function, it is usual to use 0.8–1.0 mg/kg body weight per day in divided doses. Trial and error will determine the symptoms and the amPEF values that herald an exacerbation and the dose of oral steroid needed to abort a severe attack. Usually 25 mg in divided doses for 1–2 days is sufficient. It is not necessary to reduce the dose slowly when it has been used for less than a week, unless experience shows that sudden withdrawal is associated with worsening asthma.The ICS should not be stopped while the patient is on oral steroids. Some patients, usually those who have been on oral steroids before the advent of the inhaled forms, require daily use of oral steroids to control symptoms. However, over a period of many months, sometimes years, it is usually possible to withdraw all oral steroids and replace them with the newer potent inhaled forms. Some physicians use alternate day steroids, but this often results in a higher “overall” steroid dose than the use of “pulses” of highdose therapy, even if these are necessary at monthly intervals. Drugs for reducing the dose of systemic steroids Some patients are relatively steroid-unresponsive and a few controlled on high doses of oral drugs are used to help to reduce the dose. • Macrolide antibiotics There has been increasing interest in chronic infection with Chlamydia as a cause of severe chronic asthma.54,55 There are some reports of improvement, but a trial in Australia failed to show a response. • Gold salts These drugs, sometimes used for the treatment of arthritis, are used in some countries for treatment of patients with severe asthma.56 There has been no trial published of the effects on patients already enrolled in a management plan that maximizes the use of inhaled steroids and other measures aimed at reducing severity. • Methotrexate This drug is used commonly in the USA in patients who need high doses of oral steroids to control their asthma.57,58 It has anti-inflammatory actions and in some subjects can be used to reduce the dose of prednisone without causing too many side-effects itself. Discontinuing the methotrexate usually leads to a relapse. As with gold, there has been no trial in patients who have first been treated with a strict management plan, which includes high doses of ICS, such as that described above. Overall its inconsistent effectiveness and its side-effects lead to the conclusion that it probably has little place outside perhaps for the occasional patient who responds well and does not develop side-effects. • Cyclosporin A There is one controlled trial of cyclosporin (5 mg/kg/day) in steroid-dependent asthmatics (Alexander et al. personal communication). Overall, the small improvements achieved seemed to be outweighed by the side-effects and cost. Anecdotal use has not shown it to be a big advance.
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Action plan (for exacerbations) Besides the precise use of drugs, a written action plan (sometimes called an asthma management plan) is necessary for all patients whose asthma is not under control or who are known to have exacerbations, even if they have infrequent attacks. The general aim is to abort a severe attack by increasing the dose of inhaled steroids or starting high-dose oral steroids once symptoms or PEF begin to deteriorate. There is no place for low doses of oral steroids in aborting attacks. A flow chart for writing an action plan is shown in Fig. 64.4, based on that used in New Zealand.59 The plan should be written, the patient should be able to recognize an impending attack, know which drugs to take and how to call for help. It is increasingly realized that moderate and severe exacerbations occur from only a few causes – viral infections (and these are hard to avoid), failure to take the correct dose of ICS on a regular basis, exposure to a high dose of a provoking or aggravating agent and occasionally drugs such as aspirin in someone with aspirinsensitive asthma. Treatment of exacerbations If, in spite of the written plan or because the plan was not used, the patient has a severe attack, the guidelines outlined by the British Thoracic Society60 should be followed. The patient should be monitored with an oximeter and PEF measurements and oxygen given. The drugs needed are oral or intravenous corticosteroids in adequate doses, nebulized bronchodilating drugs and, if the response is poor, parenteral bronchodilators, usually intravenous salbutamol. Intravenous aminophylline is rarely used now but many patients respond well to it. For less severe exacerbations, SABAs are increased and high-dose oral prednisone administered for several days. In the case of viral infections there may be little response until the infection resolves.61
Best recent peak flow
Address lifestyle and aggravating factors Lifestyle Often the problem of poor control arises because of the chaotic lifestyle of the patient including working mothers, shift work and busy lives in which there is no routine. There are no good controlled trials of “healthy living” in adults with asthma, but there is some anecdotal evidence that regular exercise, especially swimming makes most asthmatics feel better. Studies have shown the effectiveness of exercise in improving overall well-being.62 The acute symptoms induced by exercise can be prevented with a SABA or SCG aerosol prior to the exercise.63 The role of diet is controversial. Some people are truly allergic to some foods, but this is more common in children. The role of fish, fresh fruit and vegetables (for anti-oxidants) and low salt has all been raised and may be important, but there are no data to show that altering diet influences the course of asthma.64 Another important lifestyle problem is obesity and many women with severe asthma are overweight and some people believe that obesity is a risk factor for asthma.65 Other measures Acupuncture, hypnosis, meditation, Chinese herbal medicine and many other “alternative” remedies are used frequently by patients with asthma. These measures are almost never successful in reducing the basic severity of the disease, but often the patient feels better and patients should be encouraged to explore these treatments, provided that the other measures outlined in the management plan are followed exactly. Allergen desensitization In many countries, particularly in those where many asthmatics are treated by allergists, patients are given courses of
Date
Asthma under control
PEF above
Waking at night Getting a cold Needing more reliever
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Increase ICS or start LABA
Getting worse Reliever only lasting 2–3 hours
PEF below
Start prednisone and contact doctor
Very severe attack Reliever not working
PEF below
Continue regular treatment
Dial XXX or call emergency doctor
Fig. 64.4. Adult self-management plan for exacerbations. This is customized for each patient, and shows suggested changes to treatment based on changes in symptoms and/or amPEF. The XXX telephone number needs to be appropriate for each country (adapted from The Asthma and Respiratory Foundation of New Zealand (Inc)).59
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desensitization for asthma. There are many placebocontrolled studies and a Cochrane report66 showing some benefits (fewer symptoms and medication use) against placebo. It has not been trialed against conventional best practice drug therapy. In practices of pulmonologists, particularly in England and Australia, desensitization is not used because the drugs are so effective, while desensitization is expensive, time-consuming and risks side-effects. Furthermore, there are no trails against the use of conventional drug therapy. Desensitization is of proven benefit for some allergic situations, such as venom allergy and seasonal allergic rhinitis so that it has great potential for the future when it may be possible to change the response of T cells to the important allergens associated with asthma. Aggravating factors • Physical factors These include exercise, strong smells and cold, factors that are usually identified by the patient. Changes in the weather (especially thunderstorms)67,68 are a cause of acute attacks both in England and Australia. Introducing the management plan and achieving control can minimize the effect of most physical factors. In the long term, exercise-induced asthma symptoms will disappear as part of the overall control. Until the control is present, appropriate use of SABA before exercise is most effective. • Allergens Although recently there has been some doubt about the role of allergens as aggravating factors, all allergic asthmatics know that certain situations will make them wheeze. In relation to house dust mites (HDM), research in this area has been hampered by effective methods to reduce mite levels. Recently approaches based on a combination of barriers and washing of bedding have been effective in reducing HDM exposure and clinical evaluation of the effectiveness is awaited. Allergen exposure in the first years of life may be particularly important in causing severe disease in children. These, together with the fact that asthma rarely completely reverses once it becomes persistent, mean that the most rational approach to asthma management is prevention. Allergen avoidance is important for families with a history of allergic disease. The allergens that appear to be important throughout the world are house dust mites, molds, pollens and animal proteins. Large amounts of these allergens can be found in house dust, particularly from carpets. House dust mites, both alive and dead, present the biggest problem. Present evidence suggests that most mattresses and pillows, apart from areas with very low humidity, harbor mites. It seems likely that allergens are constantly inhaled and this can lead to continuing inflammation of the airways. The most sensible solution for patients is to live in an allergen-free environment as much as possible. However, there is currently no groundswell of public opinion for building allergen-free houses.
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Recommendations for reducing allergen levels in houses There are few data about methods of reducing allergens in houses. It is known that mites thrive in conditions of humidity and access to food – human skin scales. Based on this knowledge, most asthma plans suggest the following: • The humidity in the house should be minimized by good ventilation. • All bedding (mattress, pillows and quilt) need to be in allergen-proof covers or washed in hot water. All bedding including sheepskins should be washed regularly at 60°C. • Wall to wall carpet is to be removed if possible as it is a source of allergen in houses, but there is no controlled trial of carpet removal. • It should be explained to the patient that no vacuum cleaner removes more than a small percentage of mites (which have legs designed to stick to carpet fibers) from the carpet. Furthermore, antimite surface sprays have not been shown to help. • The role of cats is controversial. They should be removed completely unless in the house from birth of the child. Cats kept outside remain an important source of allergen. • Clothes have the highest source of allergen and spread it widely. • Recently there has been evidence that feather pillows have reduced levels of mites.69,70 This may be because feathers are hydrophobic or on the other hand synthetic pillows may be predisposed to a high HDM level (see Chapter 47). It should be routine to ask for symptoms of rhinitis (nasal obstruction or sneezing), about snoring and interrupted sleep, and about gastric reflux (heart burn). These problems, when treated, help the overall well-being of patients, though they may have only a small effect on achieving control of asthma.
COMMITMENT Education Analysis of trials of education show that education alone does not improve the degree of control of asthma,71 but when combined with good treatment, education programs are beneficial (Chapter 69). However, unless the patient, the family, and in the case of children, the teacher most involved, understand the nature of asthma, the aims of treatment and the management plan, it will not be possible to achieve optimal control of the disease. This is especially important in those with a score of more than 6 (as shown in Table 64.3). Studies of the role of education when a strict management plan is used show good improvement.72 Education takes time, which may not be available to all doctors. This means that an education program should be developed in association with hospitals where asthma is treated. Each doctor needs a kit that includes pictures of airways, drugs and a number of peak flow meters. The latter
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can be lent to the patient until it is decided whether one is needed permanently. Fig. 64.5 shows a diagram that can be used to illustrate asthma and its treatment. Review regularly Asthma is a chronic disease, which carries a number of long-term risks including symptoms, altered lifestyle, the development of permanently abnormal lung function, the side-effects of drugs and premature death. In those with moderate or severe persistent asthma (a score of 6 or more), it almost never remits and this means continuing care. Regular visits to the doctor, at which the diaries are reviewed, are essential. At these visits a new score (hopefully less) is calculated, treatment changed, the action plan updated, drugs prescribed and education continued. Fig. 64.6 shows the progress of the management plan for a patient over a 72-week period. Some patients improve more rapidly than this while others take much longer. In time, patients can take more responsibility, but in the first year of treatment, regular appointments, regardless of symptoms, must be made. Every patient with persistent asthma should have one doctor who is committed to her/his care for life.
T R E AT M E N T O F T H E PAT I E N T W I T H SEVERE PERSISTENT ASTHMA In some patients, all these measures fail to achieve reasonable control. This is usually because of failure to achieve control early in treatment, which in turn is because insufficient ICS are either prescribed or taken. However, sometimes the severity and chronicity of the disease make asthma difficult to treat. In this group long-term commitment is needed and each step in the management plan should be
Long-term control ICS LABA Theophylline (low dose)
implemented carefully. In addition, it is helpful to ask the following questions: • Does the patient have asthma? Sometimes a diagnosis is assumed in a patient who is hyperventilating, simulating symptoms or who has bronchiectasis or cystic fibrosis. A biopsy is usually diagnostic and can give helpful information. • Is the patient complying with drugs? Some patients deliberately avoid the drugs, others forget, others take them incorrectly. This may be difficult to determine, but often explains the lack of improvement. An additional family member plus an asthma educator can be helpful in getting the patient to reveal the amount of medication taken. Objective studies of compliance show that the majority of patients fail to take their medications as prescribed.73 • Have the relevant allergens and aggravators been removed/treated? In particular, does the patient snore or have severe reflux? Treating the rhinitis usually allows the patient to sleep better and treatment of severe snoring may help. • Does the patient respond to high doses of prednisone using objective measures? If so, then adequate doses of inhaled plus oral steroids are needed. If not, the diagnosis should be questioned. The patient may have chronic fixed airway obstruction or steroid-resistant asthma. • Would a trial of gold salts, cyclosporin, or methotrexate help? A trial with one of these drugs is indicated if the management plan has been implemented and drugs complied with for at least a year. In addition, it should be demonstrated that steroid therapy is effective but needed in amounts that cause excessive side-effects before these potentially toxic agonists are used. In most practices these conditions are rarely met.
Reliever SABA Anticholinergic Theophylline (high dose) OCS
Asthma Triggers, e.g. exercise allergens viruses
Normal Protective factors Avoid risk factors Vaccines (future)
Attack
Preventers SCG/NS Anti-leukotrienes
Fig. 64.5. A cross-section diagram of the mechanisms thought to be present in causing persistent asthma and “attacks” of airway narrowing. The role of different classes of drugs in treating the disease, and in reversing and preventing attacks is shown. This diagram is useful for patient education. The actions of the drugs are discussed in the text.
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700
600
PEF (L/min)
500
400
300 Morning pre-BD PEF Evening pre-BD PEF Post-BD PEF Prescribed budesonide dose (mg/day)
200
BUD 3200 2400
100
1600 800
0 0
8
16
24
32
40
48
56
64
72
Weeks of budesonide treatment Fig. 64.6. The PEF recordings from a 52-year-old patient over 72 weeks showing instability at first and then good control. The prescribed dose of budesonide is shown.
• Is the environment a causal factor? If the patient knows that in a different house, region or country, asthma control is improved then a trial of living in a new environment is indicated. • Does the patient have abnormal illness behavior? Some patients need to be sick and respond to asthma management only if they develop another illness. A variety of psychological problems occur in patients with severe persistent asthma and the help of a psychiatrist can be of great benefit.
L I K E LY F U T U R E C H A N G E S T O MANAGEMENT Asthma continues to be managed without the benefit of a systematic approach and without the results of long-term trials of treatment, in which the effect of specific management plans on the outcome of the disease is defined. Until such trials are done, it is unlikely that dramatic progress will be made. The following list outlines some of the likely changes in the overall approach to the management of asthma, based on results of recent studies and on the increasing use of management plans. Future therapies are reviewed in Chapter 62. • Most adult asthma actually starts in childhood so good treatment at the first sign of the disease will become more important.
• Inhaled corticosteroids will be used more precisely.These drugs are expensive and in doses above 1 mg per day they have side-effects. In addition many patients do not respond to increasing doses, thus the precise use of dose, starting high and then reducing, will become the norm. Furthermore, newer ICS, which are metabolized in the lung, will become available. • Increasing use of long-acting b-agonists. These drugs, used in conjunction with inhaled corticosteroids may have a role in “aborting” the disease is used soon after symptoms begin. • Less and less emphasis will be placed on the use of shortacting beta-agonists, except in episodic (intermittent) disease. • Methods of delivering the drugs to the airways will improve. It seems unlikely that full control can be achieved with oral drugs because the epithelium is the main target of treatment. • Management should be discussed between the patient and doctor so that the degree of control to be aimed at and with which drugs are agreed. This is already happening and will continue as consumer groups insist on a greater say in their management. • More emphasis on lifestyle. The roles of diet, exercise (especially swimming) and relaxation, will be much more widely accepted. • As the cost of drugs increases, patients, doctors and governments will need to be assured that the drugs being used have definitely been shown to achieve control and
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that there is less use of drugs whose main advantage is ease of use. Thus the introduction of protocols, which allow doctors to determine the exact number and doses of drugs needed to obtain predetermined outcomes, seems inevitable.
S U M M A RY The control of asthma takes months to years to achieve and, in the absence of viral infection, exacerbations are largely due to poor compliance. Most patients who have moderate or severe disease need to monitor amPEF while taking inhaled corticosteroids, especially at times when they are changing doses up or down or are experiencing more symptoms. To gain optimal control and then to maintain it indefinitely by titrating treatment down once control is achieved and increasing it in some cases during exacerbations. Achieving this aim is often more an “art” than a “science” since it involves, in most patients, convincing them to continue to take inhaled corticosteroids (ICS).
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nists in primary human lung fibroblasts and vascular smooth muscle cells. J. Biol. Chem. 1999; 274:1005–10. White M, Shapiro G, Taylor J et al. The salmeterol xinafoate/ fluticasone propionate dry powder combination product via diskus inhaler improves asthma control compared to the individual products in patients previously treated with inhaled corticosteroids. Am. J. Respir. Crit. Care Med. 1999:159:A635. Reese PR, Mahajan P, Woodring A. Salmeterol/Fluticasone proprionate combination product improves quality of life in asthma patients. Eur. Resp. J. 1998; 12(Suppl. 28):35S (Abstr.). Arvidsson P, Larsson S, Lofdahl C-G, Melander B, Wahlander L, Svedmyr N. Formoterol, a new long-acting bronchodilator for inhalation. Eur. Respir. J. 1989; 2:325–30. Ullman A, Svedmyr N. Salmeterol, a new long activating inhaled B2 adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients. Thorax 1988; 43:674–8. Johnson M. Salmeterol (review). Med. Res. Rev. 1995; 15:225–57. Twentyman OP, Finnerty JP, Harris A, Palmer J, Holgate ST. Protection against allergen-induced asthma by salmeterol. Lancet 1990; 336:1338–42. Ramage L, Lipworth BJ, Ingram CG, Cree IA, Dhillon DP. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir. Med. 1994; 88:363–8. Simons FE, Gerstner TV, Cheang MS. Tolerance to the bronchoprotective effect of salmeterol in adolescents with exerciseinduced asthma using concurrent inhaled corticosteroid treatment. Pediatrics 1997; 104:547–53. Villaran C, O’Neill SJ, Helbling A et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. Montelukast/Salmeterol Exercise Study Group. J. Allergy Clin. Immunol. 1999; 104:547–53. Barnes PJ, Pauwels RA. Theophylline in the management of asthma: time for reappraisal? Eur. Respir. J. 1994; 7:579–91. Wilson AJ, Gibson PG, Coughlan J. Long acting beta-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev 2000; (2):CD001281. Tasche MJA, Uijen JHJM, Bernsen RMD, de Jongste JC, van der Wouden JC. Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma: a systematic review. Thorax 2000; 55:913–20. Malmstrom K, Rodriguez-Gomez G, Guerra J et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Montelukast/Beclomethasone Study Group. Ann. Intern. Med. 1999; 130: 487–95. Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group. Arch. Intern. Med. 1998; 158: 1213–20. Sears MR. Prescribing fenoterol and severity of asthma. N. Z. Med. J. 1990; 103:21–2. Wong CS, Pavord ID, Williams J, Britton JR, Tattersfield AE. Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma. Lancet 1990; 3367:1396–9. Drazen JM, Israel E, Boushey HA et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. N. Engl. J. Med. 1996; 335:841–7. Harris JB, Weinberger MM, Nassif E, Smith G, Milavetz G, Stillerman A. Early intervention with short courses of prednisone to prevent progression of asthma in ambulatory patients
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incompletely responsive to bronchodilators. J. Pediatr. 1987; 110:627–33. Hahn DL, McDonald R. Can acute Chlamydia pneumoniae respiratory tract infection initiate chronic asthma? Ann. Allergy Asthma Immunol. 1998; 81: 339–44. Kraft M, Cassell GH, Henson JE et al. Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma. Am. J. Respir. Crit. Care Med. 1998; 158: 998–1001. Klaustermeyer WB, Noritake DT, Dwong FK. Chrysotherapy in the treatment of corticosteroid-dependent asthma. J. Allergy Clin. Immunol. 1987; 79:720–5. Shiner RJ, Nunn AJ, Fan Chung K, Geddes DM. Randomised, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma. Lancet 1990; 336:137–40. Mullarkey MF, Lammert JK, Blumenstein BA. Long-term methotrexate treatment in corticosteroid-dependent asthma. Ann. Intern. Med. 1990; 112:577–81. D’Souza W, Burgess C, Ayson M, Crane J, Pearce N, Beasley R. Trial of a “credit card” asthma self-management plan in a highrisk group of patients with asthma. J. Allergy Clin. Immunol. 1996; 97:1085–92. British Thoracic Society. The British Guidelines on Asthma Management 1995 Review and Position Statement. Thorax 1997; 52:S1–21. Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A. Differences between asthma exacerbations and poor asthma control. Lancet 1999; 353: 364–9 (erratum: Lancet 1999; 353:758). Svenonius E, Kautto R, Abborelius MJ. Improvement after training of children with exercise-induced asthma. Acta Pediatr. Scand. 1983; 72:23–30. Anderson SD. Exercise-induced asthma: stimulus, mechanism and management. In: Barnes PJ, Rodgers IW, Thomson NC (eds). Asthma: Basic Mechanisms and Clinical Management, pp. 503–22. London: Academic Press, 1988. Monteleone CA, Sherman AR. Nutrition and asthma. Arch. Intern. Med. 1997; 157:23–34. Camargo CA, Weiss ST, Zhang S, Willett WC, Speizer FE. Prospective study of body mass index, weight change and risk of adult-onset asthma in women. Arch. Intern. Med. 1999; 159: 2582–8. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2000(2):CD001186. Newson R, Strachan D, Archibald E, Emberlin J, Hardaker P, Collier C. Acute asthma epidemics, weather and pollen in England, 1987–1994. Eur. Resp. J. 1998; 11:694–701. Girgis ST, Marks GB, Downs SH, Kolbe A, Car GN, Paton R. Thunderstorm-associated asthma in an inland town in southeastern Australia. Who is at risk? Eur. Respir. J. 2000; 16:3–8. Rains N, Sibers R, Crane J, Fitzharris P. House dust mite allergen (Derp1) accumulation on new synthetic and feather pillows. Clin. Exper. Allergy 1999; 29:182–5. Kemp TJ, Siebers RW, Fishwick D, O’Grady GB, Fitzharris P, Crane J. House dust mite allergen in pillows. Br. Med. J. 1996; 313:916. Gibson PG, Coughlan J, Wilson AJ et al. Self-management education and regular practitioner review for adults with asthma. Cochrane Database Syst Rev 2000(2): CD001117. Gibson PG, Coughlan J, Wilson AJ, Abramson M, Hensley MJ, Walter EH. Self-management education and regular practitioner review for adults with asthma (Cochrane Review). In: The Cochrane Library. Oxford; 1999. Cochrane GM. Therapeutic compliance in asthma; its magnitude and implications. Eur. Respir. J. 1992; 5:122–4.
Acute Exacerbations of Asthma
Chapter
65
Chakradhar Kotaru Division of Pulmonary/Critical Care, University of Colorado – Health Sciences Center, Denver, CO, USA
E.R. McFadden Airway Disease Center and the Division of Pulmonary and Critical Care Medicine, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
All chronic inflammatory diseases are subject to episodic deterioration and asthma is no exception.While intermittent exacerbations of obstruction can vary widely in severity in this disease, most can be controlled by escalation of the patient’s chronic therapy. However, if an attack is intense enough, occurs in the absence of adequate pulmonary reserve, or at a time when host defenses are impaired, the patient may suffocate. Fortunately, death from asthma is rare and the majority of the acute episodes clear without harm. This chapter focuses on the pathobiological events associated with severe decompensations and their resolution.
DEFINITION Status asthmaticus is a term used to describe a prolonged episode of symptomatic airway obstruction that is poorly responsive to treatment. Unfortunately, there is no consensus as to how long an attack has to last to be so classified or to the form of the failed therapy. The term “status asthmaticus” will be avoided and any episode that fails to respond to aggressive outpatient or emergency room therapy and so requires hospitalization will be considered “severe”. Attempts to define “severity” by arbitrary decrements in pulmonary mechanics, as has been done in a number of guidelines,1,2 will not be used. Although intuitively appealing, such approaches have not proven very functional because the initial degree of obstruction simply does not predict the subsequent response to therapy.3,4
EPIDEMIOLOGY Acute bronchial asthma is a common problem with immense medical and economic impacts. It is estimated that this disease affects as many as 12 to 14 million people in the
United States, with costs in excess of $6 billion per year.5 Most of the morbidity and all of the mortality tends to be associated with acute exacerbations, and dealing with these events accounts for the majority of expenditure in money and health-care resources. Asthma attacks result in almost 2 million visits to emergency departments each year6 and approximately 500,000 admissions to hospitals annually for control, with an average stay of 5 days. Five to 10% of the asthmatic population is at risk for an episode of refractory obstruction and, of those who require intubation, 10% to 20% will die.7,8 In the past 30 years, asthma-related case-fatality rates in industrialized countries have varied from 1.5 to 8.5 per 100,000 persons.9 Rates in the USA have been consistently at the lower end of this range, but have cyclically changed. In the last two decades the death rate has increased from 1.3 to 2.0 per 100,000.10 While this represents a large percentage increase, the actual number of patients dying is still small (5500 to 6000/yearly) and most have nothing to fear.11
R I S K FA C T O R S F O R A D V E R S E OUTCOMES Physiological and historical factors The identification of patients at high risk for a fatal or near fatal attack of asthma is a challenging problem. Based on retrospective analysis of asthma deaths and near deaths, a number of risk factors, such as marked circadian variation in lung function, psychological abnormalities, the use of three or more medications, recurrent hospitalizations, frequent emergency room visits, and previous occurrences of lifethreatening asthma attacks have been postulated as being predictive.12–21 Regrettably, all but the last are too nonspecific to be of much value. Many patients require multiple medications to control their illness, have large nocturnal
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fluctuations in lung function, or have a psychological overlay to their disease, but never experience respiratory failure. Similarly, it is common practice, particularly in urban hospitals, for patients with asthma to use the emergency department as a primary source of care. Finally, admission to the hospital in some environments can be a function of the experience and persistence of the treating physician and not necessarily a marker of the severity of a given attack. In an analysis of 1591 consecutive visits to the authors’ emergency department for the care of asthma over 3 years, 29% of the patients were taking three or more bronchodilators, 25% had one or more admissions to hospital per year, 19% had two or three visits to the emergency department per year, and 6% had one or more admissions to intensive care units. During this time, no deaths were recorded. A review of the studies in which data on recurrent hospitalizations or life-threatening exacerbations are available is quite revealing. There are eight such papers in the English language involving more than 900 patients that contain such information.7,13–16,22–24 On average, only 36% of the participants had a previous hospital admission for the treatment of their disease in the year preceding their fatal or nearfatal episode and just 6% had a history of a previous lifethreatening attack as measured by the need for ventilatory assistance or admission to an intensive care unit. Thus, the seminal events are uncommon to rare. Obviously, however, when present in the history, they demand particular attention. Another point worth emphasizing is that asthmatics who have respiratory failure with one episode tend to develop it with subsequent ones. If this pattern is unrecognized, it puts the person in a high-risk category. How then does one detect a patient in potential danger, particularly when it is a first-time event? The answer lies in the recognition of the patterns of asthma decompensation. With the rare exception of sudden asphyxiant asthma, death from this disease is an evolutionary process in which the patient’s risk increases in direct proportion to the severity and frequency of the episodes of obstruction, and inversely with the extent of recovery. The typical pattern is an oscillatory one manifested by recurrence and partial remission until gas exchange cannot be sustained.25,26 Because the clinical–physiological correlates of asthma are imprecise,27 symptoms and signs alone are poor markers of impending fatality, because those that are associated with nonfatal asthma are qualitatively similar to those in lethal situations. Such manifestations and their management translations, in and of themselves (namely office and emergency department visits and hospitalizations, etc.), show only a qualitative loss of disease control, but an escalating pattern of symptoms portends future problems if it is not interrupted. To avoid disaster, when symptoms are frequent and recovery short, daily measurements of some aspects of pulmonary mechanics such as PEFR are critical, and treatment adjustments should be based on the patient’s needs, as objectively determined, rather than the physician’s or patient’s subjective impressions. In emergent situations, asthmatics at risk for fatal out-
comes are those with a pretreatment SaO2 of less than 90%; normal or high values for PaCO2 after receiving appropriate therapy; persistent metabolic acidosis; or severe obstruction that does not improve by 30% to 40%, or worsens, with sympathomimetics.7,23,24,28–30 The existence of any of these elements requires continued assessment in an environment capable of providing ventilatory assistance. When dealing with an individual with a previous lifethreatening attack, prudence dictates that all subsequent exacerbations should be viewed as potentially lethal. Hence, every effort should be directed toward prophylaxis. Here too, long-term objective monitoring of lung function is essential, particularly in the year after the near-fatal episode, for subsequent death rates are high.25 Failures of assessment There is now little doubt that one of the major contributing causes to poor outcomes in acute asthma is a failure of either the patient, the caregiver or the treating physician to recognize the seriousness of the episode.31 An analysis of asthma deaths in Great Britain in the 1970s and 1980s demonstrated a deficiency in supervision or management in 98% of fatalities.31 Apologists often claim that there may be little one can do to prevent such unfortunate events from occurring because most deaths are sudden events at home or work,32 however, a more critical review of the literature on asthma deaths demonstrates this to be untrue. The duration of the final episode was 12 hours or more13,31,33 and approximately one-half of individuals are admitted to the hospital.13,31,33,34 Thus, there is more than enough time to assess and treat. Adverse responses to medication It is well-established that severe episodes of asthma and even deaths can follow the ingestion of aspirin in sensitive patients35,36 or the use of b-adrenergic blockers.37,38 Aspirin is not unique in this regard and there are major crossreactions between nonsteroidal anti-inflammatory agents of all types. The sensitivity to such drugs can be exquisite and 10–20 mg of aspirin can produce severe reactions. Similarly, even select b-blockers, given as eye drops twice daily to treat glaucoma, can cause major attacks. Several studies have suggested that the regularly scheduled use of b2-adrenergic agonists can worsen asthma12 and even lead to death.39,40 A large national trial has disproved the first point41 and the second flies in the face of a large body of conflicting information. For example, the amount of inhaled albuterol believed to cause death in the Canadian case study (1.4 canisters/month) actually corresponds to only 3 days of a standard oral dose. Few experienced clinicians could accept such a conclusion. Equally importantly, the findings on b-agonists and death in the Canadian investigation do not concur with studies from multiple other sites around the world42 in which no such relationship was found. Genetic markers With the development of techniques to decipher genetic coding, a number of candidate genes for asthma have been
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identified (i.e. genes regulating cytokines, transcription factors, receptors, lipid mediator generation and immune recognition). Although polymorphisms in the promoter or coding region of the candidates have been identified, their importance in clinical asthma remains undefined. Recent attempts to investigate the potential role of polymorphisms in the interleukin 4 (IL-4) gene have suggested that codons in this complex, such as the IL4C-589T allele may be a risk factor for life-threatening disease43 and that the IL4RAa576R allele may contribute to low lung function.44 The possibility of the existence of genetically dysfunctional b2-adrenergic receptors has also been investigated.45 Amino acid substitutions from Arg→Gly at position 16, from Gln→Glu at position 27 and from Thr→Ile at position 164 are known to influence receptor function in vivo and it has been suggested that they would be adversely contributing to asthma morbidity.46 Asthmatics who took albuterol on a regular basis and who were homozygous for arginine at codon 16 had a mild deterioration in peak flow (PEF) (~30 L decrement) over the study. When this same population took the medication on an as needed basis, the PEF effect disappeared. It should be noted, however, that there was no change in FEV1 under any circumstances. A corollary study from the same data found that the Arg/Arg allele may confer a risk for more severe asthma attacks.47 Even though the effect was very small, studies such as these will undoubtedly help clarify some of the more murky areas of asthma pathophysiology.
PAT H O G E N E S I S As indicated above, the mechanisms by which acute episodes of asthma are initiated and sustained, for the most part, are unknown. Asthma is frequently thought of as an “allergic” phenomenon and mediator release and its pathophysiologic sequences surely follow exposure to antigens in sensitized patients. However, acute attacks can occur with “nonimmunologic” stimuli, such as exercise, cold air, irritant vapors (chemical smells, perfumes, laundry detergent, etc.), air pollutants (SO2, NOx, O3 and particulates), pharmacologic agents (aspirin, other nonsteroidal antiinflammatory drugs, beta-adrenergic blockers and sulfites), emotional upsets, viral respiratory tract infections, and highand low-molecular-weight occupational sensitizers. With these precipitants, the involvement of inflammatory cell mediators has been difficult to demonstrate, and the role, if any, that they play is far from clear. Irrespective of the biochemical paths involved, current wisdom holds that the airflow limitation derives from a combination of smooth muscle contraction, mucosal edema and a diminution of clearance of luminal secretions and debris. Most asthma attacks are short-lived, suggesting that the first two components predominate and resolve spontaneously with removal of the offending agent. This pattern is readily demonstrated in the laboratory with exposures to agents with widely diverse mechanisms of action such as
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antigens, exercise, aspirin and beta-blockers. Generally, the more intense the stimulus, the longer it takes to recover, but even in these circumstances the patient rapidly responds to a bronchodilator. Of all the potential inciting events for acute episodes of asthma, only three, viral respiratory infections, antigens and the oxidizing air pollutants (O3 and NOx), carry with them the ability to sensitize the tracheobronchial tree to other stimuli; hence, exposure to these triggers can beget other attacks.26,48–50 Antigens are also unique in that a single contact can result in repetitive attacks hours or days later.48 None of the other precipitants carry this risk. The reason why patients develop persistent symptoms that bring them to medical attention is not yet established. Intuitively, one tends to think in terms of overwhelming exposures to allergens or environmental irritants, but such events are relatively rare and are easily documented (e.g. thermal inversions, high atmospheric particulate levels, industrial accidents, etc.).Typically, contact with the participating stimulus is not particularly egregious, but is often superimposed upon a background of heightened airway responsiveness manifested by low-grade symptoms. Interviews with patients in emergency departments indicate that upper respiratory tract infections, discontinuation of medications or prolonged contact with allergens are frequent antecedent events. It is, therefore, likely that patients have ongoing active inflammatory processes upon which a second stimulus is superimposed. In patients dying from acute attacks, there is exudation of plasma proteins into the airway walls and lumens, with mucosal and submucosal edema, as well as infiltration of the eosinophils, neutrophils, plasma cells and lymphocytes.51 In addition, there is hypertrophy of the bronchial smooth muscle, hyperplasia of the mucosal and submucosal vessels, denudation of the epithelium, and thickening of the subepithelial collagen layer. If the pathological process becomes severe enough, the airways become blocked with thick, tenacious secretions, gas exchange becomes compromised, and the patient suffocates. A major advance of the last decade has been the observation that asthma is a chronic inflammatory disease and that seemingly asymptomatic patients have some of the above pathological changes in their airways, although to a lesser degree.52 The cellular and molecular mechanisms underlying the above events are incompletely understood, but they likely derive from an interaction among the resident and infiltrating inflammatory cells that results in the elaboration of a variety of mediators and cytokines.53–55 Cells likely to be important in the development of acute symptoms are the mast cell and the bronchial epithelial cells. The mediators released from mast cells, such as histamine; bradykinin; the leukotrienes C, D, and E; platelet-activating factor; and the prostaglandins (PG) E2, F2 alpha, and D2, produce an intense, immediate inflammatory reaction. In addition to their ability to evoke prolonged contraction of airway smooth muscle and mucosal edema, the leukotrienes may also increase mucous production and impair mucociliary transport. The chemotactic factors elaborated (eosinophil
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and neutrophil chemotactic factors of anaphylaxis and leukotriene-B4) bring eosinophils, platelets and polymorphonuclear leucocytes to the site of the reaction. The airway epithelium amplifies bronchoconstriction by elaborating endothelin-1 and promoting vasodilatation through the release of nitric oxide, PGE2, and the 15-hydroxyeicosotetraenoic acid products of arachidonic acid metabolism.They also generate cytokines such as granulocyte–macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-8, RANTES and eotaxin.
lessness and chest congestion with small improvements in lung function when appropriate therapy is given.56 The use of accessory muscles and pulsus paradoxus also tend to remit first followed thereafter by dyspnea. Typically, most patients consider their attacks over clinically when their FEV1 equals or exceeds 50% of normal and their residual volume falls to 200% of normal.27 It is important to appreciate that the signs of rhonchi and wheezing take much longer to resolve and do not bear a constant relationship to the patient’s symptoms. In fact, in one study in which more than 90% of patients considered themselves asymptomatic, 40% were still wheezing when examined.27
C L I N I C A L M A N I F E S TAT I O N S Most people with acute asthma present with a constellation of symptoms consisting of cough, dyspnea and wheezing. These typically occur simultaneously, but isolated symptoms also occur. In one large study involving 205 patients, 10% did not mention breathlessness.22 All, however, had cough and wheeze. Other variants such as only cough or dyspnea have been described.27 The physical signs associated with acute airway obstruction are tachycardia, tachypnea, wheeze, hyperinflation of the thorax, accessory muscle use, pulsus paradoxus and diaphoresis. The first three are the signs traditionally noted and followed. Unfortunately, however, they do not correlate with the intensity of an attack, offer any prognostic value, or add to care.22,27,56 Composite data from large series27,57 demonstrate that about 50% of patients aged 14 to 45 years have heart rates between 90 and 120 beats per minute and that only 10% to 12% exceed this value. The pulses of the remainder are normal. Respiratory rates lie between 20 and 30 breaths per minute in more than 50% of patients and there are more than 30 breaths per minute in fewer than 20%. Wheeze is present in virtually all patients and is a poor indicator of functional impairment.56 Sweating, the use of accessory muscles, and the presence of large swings in blood pressure during respiration all indicate substantial airway narrowing.56,58,59 Although not formally studied, dyspnea sufficient to interfere with speech is often included in this category. This last sign, however, can be misleading and the authors have observed tragic outcomes when it was relied upon as the sole index of severity. In large series, statistically, about 25% of patients have a paradoxical pulse greater than 15 mm Hg22,27 and 30 to 35% use accessory muscles when first examined.22,27,57 The prevalence of a paradoxical pulse and accessory muscle use increases with deep inspirations because this maneuver accentuates the underlying pathophysiology. The absence of accessory muscle use and/or a paradoxical pulse, should not be viewed sanguinely. These findings are not present when respirations are slow and shallow. Cyanosis, altered consciousness, gasping respirations, and a silent chest in a dyspneic asthmatic all indicate grave illness.These events occur in less than 1% of cases. Serial studies of the pattern of recovery demonstrate that acutely ill patients rapidly lose their complaints of breath-
P H Y S I O L O G I C M A N I F E S TAT I O N S Although bronchial asthma is considered primarily a disease of airways, virtually all aspects of pulmonary function are compromised during acute attacks. The sine qua non is a reversible increase in airway resistance that results in decreased forced expiratory volumes and flow rates, premature airway closure, hyperinflation of the lungs and hemithoraces, increased work of breathing, changes in elastic recoil, and frequency-dependent behavior of the lung.56,60–65 In addition, there is abnormal distribution of both ventilation and perfusion and altered arterial blood gas levels.60,63,66–72 In very symptomatic patients, there can be electrocardiographic evidence of pulmonary hypertension, right ventricular strain, and compromised left ventricular filling.64,70,71 When a patient presents for therapy, his or her forced vital capacity tends to be 50% or less of normal. The FEV1 averages 35% or less of predicted, and the peak flow and the flows in the mid-vital-capacity range are reduced to 20% or less of expected.27 Often, there is substantial air trapping. In acutely ill patients, residual volume (RV) frequently approaches 400% of normal and functional residual capacity doubles. The typical pattern of blood gas abnormalities seen in acute asthma is a combination of hypoxemia, hyperventilation, and respiratory alkalosis.60,67,70,71 Generally, the more severe the obstruction, the lower the arterial oxygen tension (PaO2), but values less than 50 mm Hg are unusual at sea level. Patients generally hyperventilate irrespective of the degree of obstruction, and the PaCO2 ranges between 30 and 35 mm Hg. Carbon dioxide retention tends to occur less than 10% of the time and is rarely seen until the FEV1 falls to around 15 to 20% of predicted. Normocarbia is associated with severe obstruction (FEV1 <25% of predicted) and should be viewed as impending respiratory failure and treated as such. The vast majority of patients have a respiratory alkalosis with normal arterial saturation because of the shape of the oxyhemoglobin association–disassociation curve. In extremely severe obstruction, metabolic acidosis may be seen.60,64 It can also be induced with the aggressive administration of sympathomimetics.73,74
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The mechanism underlying the blood gas abnormalities is misdistribution of inspired air.The majority of the incoming air goes to a small number of alveolar units, while the blood supply is distributed to the remaining poorly ventilated areas. Alveolar hypoventilation can develop from overwhelming obstruction or from an abnormality in ventilatory control mechanisms. Some patients have blunted hypoxic or hypercapnic drives and are unable to increase their minute ventilations appropriately as their bronchi narrow.75 These situations are rather rare, but pose a great risk for developing respiratory failure during an acute exacerbation. It is important to note that the ventilation/perfusion (V˙ A/Q˙ ) mismatching and resulting hypoxemia can last for weeks after a single episode66 because of persistent peripheral airway obstruction.61
ASSESSMENT The management of an acute asthmatic episode begins with an assessment of its severity. Objective measures are necessary to confirm the presence of obstruction, evaluate its magnitude and determine the adequacy of gas exchange. All too often, this aspect of care is ignored and asthmatic patients are treated solely based on clinical impressions. The reasons for this behavior are curious, given that it would clearly be viewed as unacceptable to treat other potentially life-threatening conditions such as myocardial infarction, hypertensive crises, or diabetic ketoacidosis, for example, without gathering objective data on the severity of the condition. Rapid evaluation of the patient is critical and it is quite helpful to have an algorithm to ensure that none of the important elements are missed.29 It is also critical to continually assess the patient’s progress during treatment. One would think that the diagnosis of acute asthma could be made with ease and for the most part, this is true. However, as pointed out earlier, not all of the patients present with all of the typical signs and symptoms and there are a number of mimicking conditions. A good general rule is to consider all patients with acute severe dyspnea and wheeze as having asthma until proven otherwise. With such an approach, one will make mistakes, but they are apt to be infrequent and in our current state of knowledge, it is best to err on the side of caution. A review of the hospital admissions for asthma from our emergency department for the last several years indicates that approximately 1% did not have the disease and their symptoms were due to conditions such as glottic dysfunction, noncardiogenic and cardiogenic pulmonary edema and pulmonary emboli. On physical examination, it is often recommended to record pulse, respiratory rate, level of consciousness, ability to speak, the presence of a paradoxical pulse, use of accessory muscles and whether a patient can speak. The prevalence of each of these and their advantages and disadvantages have been listed earlier in this work. Auscultation of the chest is mandatory to note the presence or absence of rhonchi and the quality of the patient’s aeration. Quantitation of the
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latter is desirable, but often not obtainable because of intraand inter-observer variability. Conceptually, the signs and symptoms of acute asthma that we monitor are only surrogate representations of the severity of the patient’s obstruction and how well he/she is oxygenating. The best means of making these determinations are by using indices derived from a forced exhalation, such as peak expiratory flow rate (PEFR) and FEV1, coupled with measures of arterial oxygen saturation (SaO2) from pulse oximetry. Peak flows are easily obtained and sufficiently accurate for monitoring purposes, so they tend to be used more frequently. About 55% of patients have values below 40% of normal when first seen and, in 20%, PEFR ranges between 40 and 60%.27,57,76 Given that arterial desaturation (i.e. SaO2 <90%) and CO2 retention (i.e. PCO2 >45 at sea level) occur concurrently in asthma and only develop with severe obstruction, pulse oximetry serves well. The only exception to this rule is when supplemental O2 is being given; then CO2 can rise without a decrease in SaO2.77 Consequently, arterial blood gases can be used selectively for the most part. In our Emergency Department protocol, they are drawn in all patients with a presenting SaO2 less than 90% and in anyone with unremitting or worsening obstruction after adequate treatment. As alluded to in a previous section, failure to adequately assess acutely ill patients is a common problem. In a New Zealand investigation,78 the records of 150 consecutive patients with acute asthma seen in the emergency units of three major hospitals were examined. In 11% of cases, the patient’s current medication was not included in the record, and in approximately 50%, no global assessment of the severity of obstruction was recorded. In 26% of cases, there were no objective measures of the intensity of the attack. Only 17% of the patients had an arterial blood gas drawn and in only 25% was a notation made regarding the presence of cyanosis. Similar results were obtained from an analysis of 3358 emergency room visits of children in Toronto.79 The presence of dyspnea was recorded in only 68% of the patients, 65% had an assessment of accessory muscle use, and in just 37% was the presence or absence of cyanosis noted. Pulmonary function tests were obtained in 2% and arterial blood gases in 1%. Hence, despite extensive literature on the management of patients with acute bronchial asthma, it appears that little of what is written influences medical practice.
RESPONSE TO THERAPY Acute episodes of bronchial asthma are one of the most common respiratory emergencies seen in the practice of medicine, and it is essential that the physician recognizes which episodes of airway obstruction are life-threatening and which patients demand what level of care. These distinctions can be made readily by assessing selected clinical parameters in combination with measures of expiratory flow and gas exchange. The presence of a paradoxical pulse, use
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of accessory muscles, and marked hyperinflation of the thorax signify severe airway obstruction, and failure of these signs to remit promptly after aggressive therapy mandates objective monitoring of the patient with measurements of arterial blood gases. There is a rough correlation between the severity of the obstruction with which the patient presents and the time it takes to resolve it. Those individuals with the most impairment typically require the most extensive therapy for resolution. If the PEFR or FEV1 is equal to or less than 20% of predicted on presentation and does not double within an hour of receiving the preceding therapy, the patient is likely to require extensive treatment including glucocorticoids before the obstruction dissipates. This group represents approximately 20% of all the patients who present for acute care. As a general rule, if the clinical signs of a paradoxical pulse and accessory muscle use are diminishing, and/or if PEFR is increasing, there is no need to change medications or doses; the patient need only be followed. However, if the PEFR falls by more than 20% of its previous value or if the magnitude of the pulsus paradoxicus is increasing, serial measures of arterial blood gases are required, as well as a reconsideration of the therapeutic modalities being employed. If the patient has hypocarbia, one can afford to continue the current approaches a while longer. On the other hand, if the PaCO2 is within the normal range or is elevated, the patient should be monitored in an intensive care setting, and therapy should be intensified to reverse or arrest the patient’s respiratory failure. The key to the management of acute severe asthma is to stabilize the patient as rapidly as possible, ensure adequate oxygenation, and reverse bronchial narrowing. These goals are readily achieved with an intensification of standard modalities, meticulous monitoring of the patient’s condition, and persistent avoidance of therapeutic mishaps. It is worthwhile remembering that no matter how anxious a patient appears, any attempt to alleviate it pharmacologically is apt to result in disaster. The emotional response to tachycardia, tachypnea, diaphoresis and dyspnea, as well as the signs and symptoms themselves dissipate rapidly as the bronchi open and air trapping improves.27 Even in patients treated with nonselective adrenergic agonists such as epinephrine, heart rates actually fell as obstruction dissipated. b-Agonists The most effective treatment for acute episodes of asthma requires a systematic approach based on the aggressive use of sympathomimetic agents and serial monitoring of key indices of improvement mentioned above. Reliance on empirism and subjective assessment is no longer acceptable. Multiple inhalations of short-acting sympathomimetics, such as albuterol, are the cornerstone of most regimens. These drugs provide three to four times more relief than does intravenous aminophylline.80 Anticholinergic drugs are not first-line therapy because of their long lag time to onset (approximately 30 to 40 min) and their relatively modest bronchodilator properties.81 In emergency situations, b2-
agonists can be given every 20 minutes by handheld nebulizer for two to three doses. The optimum cumulative dose of albuterol appears to lie between 5 and 10 mg.3,4 It does not matter how the adrenergic agonists are inhaled. Treatment with albuterol administered by jet nebulizer, metered dose inhaler, or dry powder inhaler all provide equal resolution in acute situations.82 Aminophylline or ipratropium can be added to the regimen after the first hour in an attempt to speed resolution. Recent studies in a large series of patients demonstrate that b2-agonists alone terminate attacks in approximately two-thirds of patients, and that another 5 to 10% benefit from a methylxanthine or ipratropium in combination with a sympathomimetic.29,81 The remainder has a poor acute response to all forms of therapy. Intravenous adrenergic agonists do not offer any advantages over the inhaled route. Theophylline The use of theophylline as first-line therapy has been superseded by the b2-agonist agents. Recently, it has been suggested that aminophylline will dispense the need for admission,83 but the data are not very compelling and theophyllines are at best second-line approaches. A number of studies have attempted to examine the usefulness of anticholinergics in the setting of acute asthma, but the issue remains controversial with almost equal numbers of positive84–86 and and negative trials.87,88 It is important to note that even in the trials with positive results, the advantages appear small and the clinical significance unclear. In our experience,81 the addition of ipratropium does not provide any therapeutic benefit to the effects of beta-agonists in any measured outcome. Glucocorticoids Glucocorticoids are potent anti-inflammatory agents that interfere with the transcription of nuclear factors that regulate cytokine production, impede the synthesis of proinflammatory mediators, prevent the migration and activation of inflammatory cells and induce apoptosis of eosinophils.89 They are also thought to up-regulate beta-adrenergic receptor therapy resulting in improved bronchodilatation90 and diminish capillary permeability.91 Glucocorticoids are not bronchodilators and the correct dose to use in acute situations is a matter of debate. The available data indicate that very high doses do not offer any advantage over more conventional amounts.92 In the United States, a usual starting dose is 40 to 60 mg of methylprednisolone intravenously every 6 hours. Since intravenous and oral administration produce the same effects, prednisone, 60 mg every 24 hours can be substituted. Clinical impressions suggest that smaller quantities may work as effectively, but there are no confirmatory data. In the United Kingdom and elsewhere, acute asthma both in and out of hospital is frequently treated with doses of prednisolone ranging from 30 to 40 mg given once daily.92 It should be emphasized that the effects of steroids in acute asthma are not immediate and may not be seen for 6 hours or more after the initial
Acute Exacerbations of Asthma
administration.93 Consequently, it is mandatory to continue vigorous bronchodilator therapy during this interval. Irrespective of the regimen chosen, it is important to appreciate that rapid tapering of glucocorticoids frequently results in recurrent obstruction. Most authorities recommend reducing the dose by one-half every third to fifth day after an acute episode. Oxygen As indicated, profound hypoxemia is rare in acute asthma and in most cases adequate tissue oxygenation can be achieved easily with low concentrations of supplemental oxygen.29 While treatment guidelines often recommend use of high flow oxygen in such settings,94,95 this may not be without detriment. Recent data show that acutely ill asthmatics given 100% oxygen show worsening carbon dioxide retention.81 This is particularly troubling in patients with severe obstruction. Consequently, in our current state of knowledge, it would be prudent to exercise caution in the administration of uncontrolled oxygen in acute asthma.
V E N T I L AT O RY A S S I S TA N C E Unrelenting severe airway obstruction with hyperinflation and positive end expiratory pressures results in a mechanically disadvantaged diaphragm at end expiration and imposes tremendous workloads on the respiratory muscles to maintain gas exchange. When these demands cannot be met or when ventilatory drive is suppressed, hypercapnic respiratory failure with hypoxemia and a respiratory acidosis follows. In addition, when the functional residual capacity approaches total lung capacity, cardiac filling and emptying may become seriously compromised further aggravating tissue hypoxia and promoting a metabolic acidosis. Severely ill asthmatics with respiratory arrest or impending respiratory failure need ventilatory assistance with endotracheal intubation to ensure adequate gas exchange (Chapter 58). However, mechanical ventilation in these patients is fraught with problems and requires someone experienced with airway and ventilator management. Manipulation of the upper airway can induce laryngospasm or worsen bronchospasm. The institution of positive pressure ventilation in an already hyperinflated thorax can compromise venous return and precipitate cardiac arrest. A brief trial of disconnection from the ventilator is usually diagnostic of excessive PEEP when blood pressure recovers.96 Failure of hypotension to respond to bolus administration of fluids and limitation of ventilation frequency should prompt a search for another cause, such as pneumothorax or myocardial dysfunction. Since the airways are heterogeneously narrowed in asthma, the less involved parts of the lungs when exposed to high inflation pressures undergo regional overdistension. This may result in not only lung rupture, but also direct alveolar damage.97,98 Therefore strategies aimed at limiting inflating pressures are essential to avoid complications of mechanical ventilation.
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Controlled hypoventilation or permissive hypercapnia is one method that has been tried.99,100 It is accomplished using low tidal volumes and a slow respiratory rate allowing a long expiratory time to help deflate the overdistended lung. Care needs to be taken to avoid the cerebral vasodilator properties of CO2 such as cerebral edema and buffer therapy may be needed to maintain systemic pH. Near normal endotracheal intubation is not a benign procedure in severe asthma and death rates in intensive care units from complications of mechanical ventilation has been reported to be as high as 40%. In addition, use of neuromuscular blockade in combination with large doses of corticosteroids can contribute to the development of myopathy.101,102 Noninvasive ventilatory assistance by a facemask has been used in patients able to protect their airway with hypercapnic respiratory failure.103–106 However, rigorous data confirming any benefit in the acute asthmatic is lacking. In an uncontrolled study, Meduri and colleagues107 report their experience in 17 patients in status asthmaticus and respiratory failure. Noninvasive positive pressure ventilation in such a setting appeared to help resolve hypercapnia and hypoxemia, and obviated the need for endotracheal intubation in all but two instances. Although these results are promising, more work is needed in a larger group of patients before firm conclusions can be drawn.
E X P E C TAT I O N S O F S U RV I VA L The difficulty in accurately assessing the prognosis of an acutely ill asthmatic is in part due to a lack of well-accepted definition of severity. To some, hypercapnia defines a severe attack,7 while to others it is the need for endotracheal intubation and mechanical ventilation.23 The former occurs 10–20 times more frequently than the need for ventilatory assistance and does not necessarily imply an ominous prognosis.62,70,74,108 In the two studies that involved patients with severe asthma,67,108 the prevalence of hypercapnia varied from 27–62% but the need for ventilatory assistance ranged between 8 and 30%. It is impossible to ascertain how the decision to intubate was reached, but all too often, it seems to have been reached by subjective rather than objective criteria.16 The long-term prognosis of a near fatal attack is poor. About 17% of such patients ultimately die of their illness, 10% in the first year after the index event.16,24,35,109 In a longterm follow-up of patients who were intubated for respiratory failure,7 60% of those discharged were rehospitalized at least once, and 19% twice. Nineteen patients needed mechanical ventilation for a second time and 17 died.
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49. Holtzman MJ, Cunningham JH, Sheller JR, Irsigler GB, Nadel JA, Boushey HA. Effect of ozone on bronchial reactivity in atopic and nonatopic subjects. Am. Rev. Respir. Dis. 1979; 120:1059–67. 50. Stevenson DD, Simon RA. Sulfites and asthma. J. Allergy Clin. Immunol. 1984; 74:469–72. 51. Messer J, Peters GA, Bennet WA. Cause of death and pathological findings in 304 cases of bronchial asthma. Dis. Chest 1960; 38:616–23. 52. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am. J. Respir. Crit. Care Med. 1996; 154:1505–10. 53. Barnes PJ, Adcock IM. Transcription factors and asthma. Eur. Respir. J. 1998; 12:221–34. 54. Holgate ST. The cellular and mediator basis of asthma in relation to natural history. Lancet 1997; 350(Suppl 2): SII5–9. 55. American Thoracic Society. Progress of the interface of inflammation and asthma. Am.J.Respir.Crit.Care Med. 1995; 152: 221–34. 56. Fischl MA, Pitchenik A, Gardner LB. An index predicting relapse and need for hospitalization in patients with acute bronchial asthma. N. Engl. J. Med. 1981; 305:783–9. 57. Centor RM, Yarbrough B, Wood JP. Inability to predict relapse in acute asthma. N. Engl. J. Med. 1984; 310: 577–80. 58. Fanta CH, Rossing TH, McFadden ER Jr. Emergency room of treatment of asthma. Relationships among therapeutic combinations, severity of obstruction and time course of response. Am. J. Med. 1982; 72:416–22. 59. Rose CC, Murphy JG, Schwartz JS. Performance of an index predicting the response of patients with acute bronchial asthma to intensive emergency department treatment. N. Engl. J. Med. 1984; 310:573–7. 60. Brenner BE, Abraham E, Simon RR. Position and diaphoresis in acute asthma. Am. J. Med. 1983; 74: 1005–9. 61. Gold WM, Kaufman HS, Nadel JA. Elastic recoil of the lungs in chronic asthmatic patients before and after therapy. J. Appl. Physiol. 1967; 23:433–8. 62. McFadden ER Jr, Lyons HA. Arterial-blood gas tension in asthma. N. Engl. J. Med. 1968; 278:1027–32. 63. Woolcock AJ, Read J. Lung volumes in exacerbations of asthma. Am. J. Med. 1966; 41:259–73. 64. British Thoracic Society. Guidelines on the management of asthma. Thorax 1993; 48:S21–4. 65. Permutt S. Physiologic changes in the acute asthmatic attack. In Austen KF, Lichtenstein LM (eds), Asthma: Physiology, Immunopharmacology, and Treatment, pp. 1072–82, 1973. 66. McFadden ER Jr, Lyons HA. Serial studies of factors influencing airway dynamics during recovery from acute asthma attacks. J. Appl. Physiol. 1969; 27:452–9. 67. Rees HA, Millar JS, Donald KW. A study of the clinical course and arterial blood gas tensions of patients in status asthmaticus. Q. J. Med. 1968; 37:541–61. 68. Bentivoglio LG, Beerel F, Byron AC. Regional pulmonary function studies with xenon-133 in patients with bronchial asthma. J. Clin. Invest. 1963; 42:15–27. 69. McFadden ER Jr, Lyons HA. Airway resistance and uneven ventilation in bronchial asthma. J. Appl. Physiol. 1968; 25:452–9. 70. Tai E, Read J. Blood-gas tensions in bronchial asthma. Lancet 1967; 1:644–6. 71. Weng TR, Langer HM, Featherby EA, Levison H. Arterial blood gas tensions and acid-base balance in symptomatic and asymptomatic asthma in childhood. Am. Rev. Respir. Dis. 1970; 101:274–82. 72. Rebuck AS, Pengelly LD. Development of pulsus paradoxus in the presence of airways obstruction. N. Engl. J. Med. 1973; 288:66–9. 73. Appel D, Rubenstein R, Schrager K, Williams MH Jr. Lactic acidosis in severe asthma. Am. J. Med. 1983; 75:580–4. 74. Miyamoto T, Mizuno K, Furuya K. Arterial blood gases in bronchial asthma. J. Allergy 1970; 45:248–54.
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100. Feihl F, Perret C. Permissive hypercapnia. How permissive should we be? Am. J. Respir. Crit. Care Med. 1994; 150:1722–37. 101. Douglass JA, Tuxen DV, Horne M et al. Myopathy in severe asthma. Am. Rev. Respir. Dis. 1992; 146:517–19. 102. Picado C, Montserrat J, Agusti-Vidal A. Muscle atrophy in severe exacerbation of asthma requiring mechanical ventilation. Respiration 1988; 53:201–3. 103. Brochard L, Isabey D, Piquet J et al. Reversal of acute exacerbations of chronic obstructive lung disease by inspiratory assistance with a face mask. N. Engl. J. Med. 1990; 323:1523–30. 104. Nava S, Compagnoni ML. Noninvasive mechanical ventilation in hypercapnic respiratory failure: evidence-based medicine. Monaldi Arch. Chest Dis. 2000; 55:345–7. 105. Celikel T, Sungur M, Ceyhan B, Karakurt S. Comparison of non-
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invasive positive pressure ventilation with standard medical therapy in hypercapnic acute respiratory failure. Chest 1998; 114:1636–42. Meduri GU. Noninvasive positive-pressure ventilation in patients with acute respiratory failure. Clin. Chest Med. 1996; 17:513–53. Meduri GU, Cook TR, Turner RE, Cohen M, Leeper KV. Noninvasive positive pressure ventilation in status asthmaticus. Chest 1996; 110:767–74. Braman SS, Kaemmerlen JT. Intensive care of status asthmaticus. A 10-year experience. JAMA 1990; 264:366–8. Boulet LP, Deschesnes F, Turcotte H, Gignac F. Near-fatal asthma: clinical and physiologic features, perception of bronchoconstriction, and psychologic profile. J. Allergy Clin. Immunol. 1991; 88:838–46.
Childhood Asthma
Chapter
66
Simon Godfrey Institute of Pulmonology, Hadassah University Hospital and The Hebrew University-Hadassah Medical School, Jerusalem, Israel
INTRODUCTION Asthma is by far the most common chronic respiratory disease of children in developed countries and affects between about 10 and 30% of all school-age children. Differences in the incidence of asthma in children from different countries can be seen from the International Study of Asthma and Allergies in Childhood (ISAAC) which gives the point prevalence of asthma in 13–14-year-old children.1 The highest incidence is some 30–35% in the UK, Australia and New Zealand and the lowest incidence is 2–5% in Russia, China and Greece. In a total population survey from one area of all Israeli boys aged 17 years2 and approximately 85% of girls, we found a lifetime incidence of asthma 9.6% in the boys and 6.0% in girls and a point incidence of asthma at age 17 of 5.9% in boys and 3.7% in girls. In the United States it has been estimated that there are now about 15 million asthmatics of whom some 4 million are children.3 The incidence of asthma at all ages has been steadily increasing at roughly 6–8% per annum.4,5 Mortality from asthma, although low especially in young people, was also rising until recently when it has tended to level off at about 3–5 per million in children and 6–15 per million in young adults.3,6 This, taken with the rising incidence of asthma in the childhood population over this period, suggests that the risk of dying from asthma for an asthmatic child may actually have been falling. The cost of treating children with asthma places a very considerable burden on the health resources in developed countries due to the cost of medications, hospitalizations and the time spent by parents and other carers in looking after the asthmatic child. In a survey of the cost of chronic illnesses in over 300,000 children in the Washington State Medicaid health care program, asthma accounted for 12.5% of the total annual health expenditure on children and, apart from prematurity-related diseases, was many times more costly to the program than all other chronic diseases of childhood.7 Although the cost of caring for the individual asthmatic child was not particularly great, the number of asthmatics was much greater than the number with other diseases and hence the total cost was much higher.
About 80% of asthmatic children begin to have symptoms before the age of 4–5 years and only about 10% begin wheezing in later childhood.8–10 Asthma is more common in boys than girls, but there does not appear to be any difference in the severity of asthma between the sexes. There is often a personal or family background of asthma or atopic diseases in asthmatic children and troublesome infantile eczema tends to be associated with more troublesome asthma later on.11 The odds ratio (OR, no increased risk OR = 1.0) for a child having asthma was found to be 2.6 if one first degree relative had asthma and 5.2 if two first degree relatives had asthma.12 The younger asthmatic child is often very troubled by cough, especially at night, rather than frank wheezing and so the diagnosis is often given as “bronchitis” or “spastic bronchitis”, rather than asthma. There is grave doubt as to whether children even suffer from “chronic bronchitis” in the adult sense.13 In children with chronic cough but no other lung disease, lung function tests and bronchial provocation challenges by exercise will often produce a typical asthmatic picture in those with true “cough variant asthma”.14 In a study of children from Australia and New Zealand, no less than 41% of those who reported nocturnal cough were found to have bronchial hyperreactivity to histamine.14–16 On the other hand, there are other causes of cough and respiratory symptoms in the young child and these must be distinguished by appropriate clinical and laboratory investigations.
C L A S S I F I C AT I O N O F A S T H M A S E V E R I T Y In order to treat asthma, it is helpful to be able to define the severity of the condition and various national and international guidelines for the management of asthma have been developed which include recommendations for children. There are two main types of guidelines – those such as the National Institutes of Health Global Initiative for Asthma (GINA) guidelines17 classify asthma severity based on symptoms and those like the British Thoracic Society (BTS) guidelines18 classify asthma severity based on the medication needed to control symptoms. In fact, neither system is really
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of much use in real life because most patients are (or should be) somewhat symptomatic on their current therapy and cannot simply be placed on a BTS or GINA guideline step. The overall severity of asthma may be described in terms of the amount of disturbance the disease causes the child and family and the following is a general classification of childhood loosely based on the GINA and BTS guidelines. • Mild asthma: Discrete attacks for no more than 1–2 days occurring no more often than once per month with symptom-free intervals or very brief attacks occurring no more than twice per week. Attacks respond readily to b2-agonist therapy and do not cause the child to miss more than the occasional day of schooling. This group corresponds approximately to GINA steps 1–2, BTS step 1. • Moderate asthma: Attacks more often than twice weekly with occasional more prolonged exacerbations and some nocturnal symptoms. These children require daily medication to prevent symptoms and additional reliever medication on an as-needed basis. They may well miss occasional days of schooling without adequate treatment. This group corresponds approximately to GINA steps 2–3, BTS step 2–3. • Severe asthma: Continuous or virtually continuous symptoms by day and some nocturnal disturbance with occasional prolonged severe exacerbations. They require daily medication for prevention and relief of symptoms which only respond adequately to moderate to high doses of corticosteroids. Such children often miss some schooling and are normally unable to keep pace with their peers without adequate treatment. This group corresponds approximately to GINA steps 3–4, BTS step 3–5. Mild and moderate asthma may well be seasonal with complete or virtually complete freedom from symptoms once the relevant season is over. Severe asthma is rarely seasonal although the severity of symptoms (and need for treatment) may fluctuate from time to time. There are two other forms of asthma, which do not fit readily into the above classification and are seen from time to time in children. • Exercise-induced asthma (EIA): Exercise is a potent stimulus for a short attack of bronchospasm and occurs in most asthmatics if they exercise hard enough. Some children, mostly fit, young adolescents have little or no clinical asthma on a day-to-day basis but may be severely handicapped by EIA when they take part in sports. • Sudden life-threatening asthma: A few asthmatics suffer from infrequent but devastatingly severe attacks of asthma. Often the onset of an attack is unpredictable although this form of asthma may occur in the child with a marked specific allergy such as from eating nuts. They represent a very high-risk group and their management is problematic.
Whatever the overall pattern of asthma in the child, the severity of the individual attacks of asthma varies from time to time. It is important to note that there is no direct link between the overall severity of the asthma as defined above and the severity of the individual attacks. In mild attacks the child should only be mildly distressed, able to talk normally, and respond well to an inhaled b2-agonist. In a moderate to severe attack, the child would be distressed, with some difficulty in talking, oxygen saturation may be a little reduced and the response to a b2-agonist is modest. In a severe and potentially life-threatening attack, there will be severe distress, difficulty in talking, oxygen desaturation and possibly clinical cyanosis and the intensity of wheezing may actually be diminished.
CONTRIBUTING AND TRIGGERING FA C T O R S I N C H I L D H O O D A S T H M A Bronchial hyperreactivity As with adults, the basis of asthma in children is bronchial hyperreactivity which means that the intrathoracic airways of the asthmatic child narrow to a far greater degree than those of a normal child in response to various known and unknown stimuli. Provided proper statistical techniques are used to define normality, then the very large majority of asthmatic children are hyperreactive to methacholine or histamine and to a lesser extent to exercise.19 The bronchial hyperreactivity in children with asthma differs in an important respect from the bronchial hyperreactivity that can be demonstrated in some children with other types of pediatric chronic obstructive lung diseases (PCOPD), such as cystic fibrosis or primary ciliary dyskinesia. While nonspecific bronchial hyperreactivity to methacholine is present in children with PCOPD, often to the level found in asthma, hyperreactivity to physical exercise or inhaled adenosine-5monophosphate is highly specific and only present in asthmatic children.20 Genetic background A number of studies have shown that there is a relatively high incidence of atopy and bronchial hyperreactivity amongst the totally healthy relatives of asthmatic children and wheezy infants21,22 and a much higher concordance for asthma and bronchial hyperreactivity in identical twins (57–71%) as compared with fraternal twins (0–19%).23 However, concordance is not perfect in identical twins, suggesting that environmental trigger factors may be needed to act on the genetic predisposition to develop asthma.24,25 Allergy There is no doubt that inflammation related to allergic processes is of fundamental importance in asthma, especially in childhood asthma. The problem is to determine the importance of specific allergies in the initiation and persistence of the asthma. Positive skin tests to one or more common allergens are found in about 93% of patients,26 but
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Smoking and pollution While there is no evidence that environmental pollution can cause a child to become asthmatic without a familial or genetic predisposition it is now certain that pollution, especially by tobacco smoke, can increase the incidence of lower respiratory tract disease and provoke attacks of asthma. This increase in incidence of asthma and lower respiratory tract illnesses in children exposed to environmental tobacco smoke in the home or in day-care centers has now been demonstrated in several studies.27–30 However, some caution is warranted concerning more general pollution since the recent European air pollution study (PEACE) failed to show any correlation between pollution levels and the incidence of childhood asthma.31 Infection One of the most common provoking factors for asthma attacks in young children is viral infections. The mechanism by which viruses induce asthma attacks is unknown, although the respiratory syncytial virus (RSV) can induce immunological changes in the host.32 In a study of children attending the emergency room for an acute attack of asthma, evidence of viral infection especially with RSV was significantly more common in those under 2 years of age, while in older children evidence of rhinovirus infection and allergy to common inhalants was more likely.33 On the other hand, it has been hypothesized, based on the lower rate of childhood asthma in less privileged societies, that viral infections in infancy might actually be protective against developing asthma by enhancing Th1 lymphocyte production at the expense of Th2 cells. The relationship between viral infection and asthma has recently been the subject of a comprehensive review by Stein et al.,34 who suggest that depending upon the virus and the host response, infection could be either protective or enhancing for asthma. There is no evidence that bacterial infections can initiate an asthma attack, but some children may develop secondary bacterial infections. We performed bronchoalveolar lavage in children with asthma who presented with persistent or recurrent infiltrates in their lungs and found that in about half there was a high neutrophil count in the lavage fluid and a pathogenic organism was cultured.35 Exercise Physical exercise is a powerful inducer of an attack of asthma and exercise-induced asthma (EIA) is common in children who are naturally far more active physically than adults. The severity of EIA is modified by the climate of the air being breathed and is substantially reduced if the air is warm and humid. It is also influenced by the type of exercise and is far less common after intermittent exercise such as occurs in most team games, as compared with continuous running for 6 to 8 minutes. Swimming rarely causes EIA,
probably because the air that the child breathes is relatively humid. Emotional factors There is general agreement that emotional factors can provoke or even ameliorate the asthma, but there is no evidence that they can cause asthma to arise de novo. It has been found that a variety of emotional disorders in the family are associated with severe asthma, but cause and effect are difficult to separate since studies of wheezy infants and their families suggest that if the infant has anxiety-provoking symptoms then a high proportion of families develop dysfunctional behavioral patterns.36 Meijer et al.37 have shown that more structured and interdependent family relationships were associated with better asthma control independent of asthma severity. Greater perceptual accuracy on the part of the child in detecting respiratory symptoms has been shown, as expected, to be associated with better control of asthma and less morbidity.38
N AT U R A L H I S T O RY O F C H I L D H O O D ASTHMA For a long time it was generally believed that a large proportion of children grow out of their asthma, although objective evidence in support of this concept is quite scarce. From a detailed long-term follow-up of a population of asthmatic children with perennial asthma attending a hospital clinic in London, Balfour-Lynn39 showed that about half of those requiring nonsteroidal prophylaxis became symptom-free before puberty and almost all of the others during puberty. An interesting observation in this long-term followup study as illustrated in Fig. 66.1 was that puberty was delayed by about 15 months in asthmatics of both sexes and
Girls
Boys
16
14 Age (years)
it is interesting that the incidence of positive skin tests increases in older children, just at the time that their asthma is tending to improve.
12
10
8
Steroid
No steroid
Steroid
No steroid
Fig. 66.1. Age of onset of puberty in asthmatic boys and girls classified according to whether or not they received regular inhaled corticosteroid therapy as their main treatment. The horizontal dashed lines represent the mean 2 s.d. of the age of onset of puberty in healthy British children. Redrawn from the data of Balfour-Lynn.39
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this was quite independent of the treatment they were receiving.40 There are only a few community-based studies that have followed asthmatic children until they reached 30–40 years of age41–43 and the results are summarized in Table 66.1. These studies suggest that of children who were already asthmatic by the age of 7–12 years, about 65% will be totally symptom-free or only have minimal symptoms as 30–40-year-old adults. Two of the studies suggest that about 20% of children never lose their asthma and continue with the disease throughout adult life. It seems likely that another 15% or so of asthmatic children lose their asthma for a while, but relapse before reaching the age of 30–40 years. However, it should be emphasized that all these studies were begun some 25–50 years ago when the management of childhood asthma was less effective and before inhaled corticosteroids were available. More recently it has been suggested that the early introduction of effective antiinflammatory treatment improves the prognosis of childhood asthma.44 It remains to be seen what effect this has on whether or not the child grows out of his asthma and remains symptom-free during adult life.
DIFFERENTIAL DIAGNOSIS OF ASTHMA IN CHILDREN The diagnosis of asthma in children is based on the typical history and clinical findings backed in some cases by laboratory investigations. There are however a number of other conditions which can produce symptoms similar to those of asthma, especially in the infant and young child which need to be considered in the differential diagnosis. In the upper airways, trachea and main bronchi noisy breathing may be due to adenoid hypertrophy, laryngo-tracheo-bronchitis (croup) and congenital airway anomalies such as tracheomalacia, bronchomalacia or compression by vascular rings. Gastro-esophageal reflux is very common in otherwise perfectly healthy young infants and some infants not only reflux, but also aspirate gastric contents into the lungs producing recurrent episodes of airway obstruction with generalized wheezing. Foreign body aspiration can occasionally mimic asthma and unilateral wheezing should always be treated with suspicion.
Diseases of the smaller airways can be particularly difficult to differentiate from asthma in children. Acute viral bronchiolitis is very common in early infancy, occurring in epidemics in the winter and is mostly due to infection with the respiratory syncytial virus (RSV). The infant presents with respiratory distress, wheezing and hyperinflation which usually subsides spontaneously over a week or so. About 40% of these infants have repeated episodes of wheezing which tend to become less severe and less frequent with time and cease after 2–3 years of age unless the child develops classical asthma. The differentiation from asthma may be very difficult and indeed some believe that this is a form of true asthma. Bronchiolitis obliterans is an uncommon form of pediatric chronic obstructive pulmonary disease with fixed airways obstruction and persistent wheezing which mostly follows severe viral pneumonia, often due to adenoviral infection. These children are almost always misdiagnosed as asthmatics until it becomes obvious that their airways obstruction is totally resistant to treatment. Primary ciliary dyskinesia – the “immotile cilia syndrome” affects a small proportion of children who suffer repeated respiratory infections, otitis media and sinusitis but may present with a relatively mild form of chronic obstructive pulmonary disease that is often mistaken for asthma or cystic fibrosis. Cystic fibrosis (CF) is an autosomal recessive disorder which in most patients causes severe and progressive lung disease and pancreatic insufficiency. Infants with CF frequently present with a picture of chronic obstructive pulmonary disease which is easily mistaken for bronchiolitis or asthma.
T H E W H E E Z Y I N FA N T The wheezy infant presents one of the most common and greatest diagnostic and management problems in pediatrics. In countries with well-defined seasons, there is an epidemic of bronchiolitis in infants each winter which is usually due to infection with the respiratory syncytial virus (RSV). The infection results in wheeze, cough and shortness of breath lasting for a few days and closely resembles an asthma attack clinically, except that the airways obstruction is normally unresponsive to medications effective in children with
Table 66.1. Prognosis of childhood asthma
Blair41 Jenkins et al.42 Oswald et al.43 Strachan and Gerritsen89 Average
No.
Age of children
Age of adults
% symptomfree
% with symptoms
% never remitted
244 741 249 539
<12 <7 <8 <8
30–40 29–32 35 34–35
52 75 65 58 65
27 25 35 21 35
21
21
Childhood Asthma
asthma. There have been a number of studies which have attempted to determine the relationship between wheezing in infancy and later asthma in childhood. In a prospective cohort study Martinez et al.45 found that approximately 40% of infants who wheezed for the first time under the age of 3 years never wheezed again up to the second evaluation at age 6 years. There was some evidence to suggest that the children who wheezed before the age of 3 years and stopped wheezing were different from those who continued to wheeze (Table 66.2). Very similar conclusions can be drawn from other studies which have shown that there are differences in the prognosis of infants who wheezed due to viral infections, compared with those who began to wheeze later or had an atopic personal or family background.46 In a longterm controlled study undertaken some years ago by Pullan and Hey47 in infants with proven RSV bronchiolitis, 38% of the RSV group of infants had repeated episodes of mild wheezing compared with 15% of the controls. By the age of 10 years only 6.2% of the RSV group and 4.5% of the control group were wheezing. However, this issue is still unresolved because in a recent study by Sijurs et al.48 there was a significant increase in asthma after bronchiolitis while the meta-analysis of Kneyber at al.49 failed to find evidence supporting RSV infection as a cause of later asthma. Clinically and physiologically, the bronchiolitic infant resembles the child with asthma but most objective studies have failed to show any real improvement in lung function in infants due to the administration of selective b2-agonist bronchodilators.50–52 Oral corticosteroids have not been shown to influence the course of acute viral bronchiolitis in infants.53,54 Recently, Richter et al.55 failed to show any benefit in either lung function or the incidence of later wheezing in infants treated with nebulized budesonide for 6 weeks after acute bronchiolitis. Thus it appears that the airways obstruction in the wheezy infant is usually resistant to drugs normally effective in childhood asthma, although there are exceptions and every clinician is aware of the very dramatic response that can be seen in even very young infants.
Table 66.2. Factors associated with different patterns of wheezing in infants and young children
Vmax FRC<1 year Mother smokes Mother with asthma IgE Skin tests
Wheezed only <3 year
Wheezed <3 year and continued
Reduced Yes No Normal Negative
Normal No Yes Elevated Positive
From the data of Martinez et al.99
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C L I N I C A L I N V E S T I G AT I O N O F T H E A S T H M AT I C C H I L D History taking As with all medicine, history taking forms the basis of the investigation of childhood asthma. Since the history must usually be taken from a third party (normally the parents) history taking may be more problematic either because the parents are unaware of important details, or because they interpret their observations consciously or unconsciously and present an “edited” version. Attention should be paid to the degree of disability that the asthma is causing to both the child and the family including the amount of schooling that is being missed and the number of days of invalidism during which the child cannot undertake normal activities.The vast majority of children with asthma are atopic and react to a number of allergens on skin testing. Parents are often convinced (sometimes by their doctors) that this means that the asthma is due to exposure to these allergens and avoidance is all that is required. It is important to take a careful allergic history to determine which substances (if any) will regularly and invariably provoke an attack when the child is exposed to them. A most important aspect of history taking concerns the previous treatments that the child has received, especially how they were taken, for how long and with what effect. If the child is receiving drugs by inhalation it is most important to enquire about the type of inhaler being used, the manner in which it is being used and whether or not the child is willing and able to cooperate with the treatment. The physician must always be on guard so as not to miss one of the alternative diagnoses discussed above in the child initially thought to have asthma. In such cases, the physician often finds it frustrating because of the inability to get a clear history of asthma from the parents – it just does not “sound right” – and this should alert to the possibility that one is dealing with something else. Physical examination Physical examination is not particularly helpful in most children with asthma since the presence or absence of wheezing on any particular occasion is no guide to the overall severity of the disease. One of the most useful signs of chronicity is given by the height and weight of the child which should be recorded at every visit. These should be plotted on a centile chart in order to standardize for age and sex. Asthma is a disease which slows growth and delays puberty quite apart from the effect of any drugs,40 with eventual catch-up growth. Experience suggests that inadequate treatment may exaggerate this phenomenon and, of course, injudicial use of systemic corticosteroids may slow the growth in height and increase weight. Signs which might indicate an alternative diagnosis should be sought, especially in a child whose illness does not fit with the usual pattern of asthma. An integral part of the physical examination of the child with asthma who uses any type of device for inhaling medications is to observe exactly how the device is being used either by the child or the parents if they usually administer the medication.
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Asthma and Chronic Obstructive Pulmonary Disease
Special investigations Tests of lung function Tests of lung function are undoubtedly a most useful guide to management and simple lung function tests should be carried out on every child at every attendance at the clinic provided that the child is able to undertake the test reliably. The most useful tests are almost always the simplest and most children over about 6 years can undertake spirometry. Very occasionally it is useful to have a more detailed evaluation of lung function if there is some doubt about the validity of the results of peak flow, FEV1 or flow-volume measurements. Whole body plethysmography and measurements of forced expiratory flow are also possible in infants, but at present these are confined to highly specialized centers.56,57 Tests of bronchial reactivity Testing bronchial reactivity can be of major importance in making the diagnosis and evaluating the severity of the asthma. If the diagnosis is clinically obvious and the response to treatment is as expected, tests of bronchial reactivity are probably superfluous for clinical management. They are most useful when the diagnosis is uncertain or when the severity of the asthma is in doubt.There are various ways of measuring nonspecific (i.e. nonallergic) bronchial reactivity in children of which the simplest is by physical exercise. A positive response to exercise (a greater than 13% fall in FEV1 after 6 minutes of strenuous exercise) can be expected in only about 63% of asthmatic children, but the specificity of this test is 94%. Bronchial provocation by inhalation has now been widely performed in children and the simplest method for those old enough to cooperate with spirometry is the tidal breathing method described by Cockcroft et al.58 The optimal dose of methacholine or histamine for distinguishing the asthmatic from the normal response is a cumulative dose of 6.6 lmol (equivalent to a methacholine step concentration of 3.2 mg/ml). This test has a sensitivity of 92% and a specificity of 89%.19 In children too young to perform lung function tests, the provoking agent can be delivered to an open face mask rather than to a mouth piece. We have shown that the end point of the challenge can be judged by the appearance of wheezing heard with a stethoscope, mild desaturation determined by pulse oximetry, tachycardia or tachypnea.59–61 This end point, which we termed the provocation concentration for wheezing (PCW) correlates very well with the PC20 in those children old enough to perform both types of test and is about half of one doubling concentration greater than that causing a 20% fall in FEV1. Children with asthma generally respond abnormally to both exercise and methacholine challenges, while those with other types of chronic lung disease often respond abnormally to methacholine but not to exercise or adenosine 5-monophosphate inhalation.20 Other investigations Other investigations may be required when the diagnosis is in doubt or when there is the possibility of a more complicated
picture.These will include simple radiology where appropriate as when there is a suspicion of pneumonia or atelectasis (“middle lobe syndrome”). Computerized tomography is rarely indicated in the asthmatic child and is mainly needed to determine whether a persistent middle lobe atelectasis has become bronchiectasis. One particular problem that is sometimes encountered in children with even quite mild asthma, especially in warm, dry climates, is bronchocentric granulomatosis or the mucoid impaction syndrome.62,63 This is probably just a more extreme variant of the common middle lobe syndrome, but it results in major plugging of relatively large airways with very tenacious bronchial casts which behave like foreign bodies. Hematological and biochemical investigations are sometimes helpful, especially when the diagnosis is in doubt since almost all asthmatic children are atopic and should have an elevation of total IgE and eosinophilia (unless receiving systemic corticosteroids). Skin testing or the measurement of specific IgE levels is of limited value in most children with asthma, but a total lack of response should cast doubt on the diagnosis since only a small minority of asthmatic children fail to respond to common inhalant allergens. A sweat test is mandatory if cystic fibrosis is suspected and if there is any doubt, then genotyping for the known CF genes should be performed. In those patients in whom recurrent infections suggest the possibility of immunodeficiency as an alternative diagnosis, appropriate immunological investigations should be performed. Bronchoscopy is indicated when there is doubt about the diagnosis and there is a suspicion that the problem may be foreign body aspiration. Persistent or recurrent atelectasis, usually of the right middle lobe, is an indication for bronchoscopy to determine the anatomy and the presence or absence of a pathogenic organism. Bronchoscopy has no place in the routine management of the child with asthma and should only be used when there are clear clinical indications. A brush biopsy from the nasal mucosa is indicated in children where primary ciliary dyskinesia is considered as a possible alternative diagnosis. Ambulatory follow-up of the asthmatic child Asthma diaries can be used for the follow-up of symptoms in the child with asthma on a day-to-day basis, but as with adults they are of doubtful reliability over more than a short period due to accidental or deliberate faking.64–69 In an imaginative recent study, Rich et al.70 provided a group of 20 young asthmatics with video cameras with which to record details of their everyday life and how they managed their asthma. All were thought to be well educated about asthma management and yet the video recordings showed gross discrepancies about what the patient said concerning their environments and treatment even though they knew that the videos were to be reviewed. Diurnal peak expiratory flow (PEF) recording in the home is now commonly recommended for asthmatics because of its practicability and the generally accepted belief that it improves management.71 However, studies have cast doubt on the reliability and value of PEF measurements as an index of asthma severity. We
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undertook a study of home monitoring of PEF in 28 children and young adults with asthma of different severity who recorded their symptoms, drug consumption and PEF twice daily for a mean of 82 days over a 12-week period.72 We found that PEF measured twice daily at home correlated well with clinical indices of asthma and rescue bronchodilator consumption in those with more severe disease, but poorly in those with mild asthma making such measurements of limited value. From this study it was concluded that PEF monitoring adds little to daily recording of symptoms and bronchodilator use in young patients with severe asthma and is too insensitive to register meaningful changes in those with milder asthma. Measurement of PEF at home is of course very dependent upon the cooperation of the child or parents and is extremely vulnerable to deliberate or accidental faking. It should probably be restricted to children with specific management problems and should not be used as a guide to treatment on a routine basis.
T R E AT M E N T O F C H R O N I C C H I L D H O O D ASTHMA The treatment of chronic asthma in children should logically be based on the minimum needed to reduce the amount of disturbance it caused to the everyday life of the child and the family to an acceptable level. This principle has now been enshrined in the various national and international guidelines for the management of asthma in children and adults.17,18,73–76 The amount of disturbance to the everyday life of the child and the family can be evaluated as follows: • The frequency of daytime attacks lasting more than 24 hours and needing extra medication • The presence of completely symptom-free intervals lasting more than 4 weeks without medication • The frequency of waking at night because of asthma symptoms – although the parents may not be aware of this • The amount of absence from school or other child care facility because of asthma • The ability of the child to keep up with peers in normal physical activity • The frequency of hospital admissions or attendances at the Accident and Emergency Department • The frequency of any life-threatening episodes of acute asthma requiring intensive care. The principles of managing asthma in children are largely similar to those used for adults except for some differences in recommended doses of medications and the particular attention needed to the way in which inhaled medications are administered in children.The guidelines describe four or five steps of escalating treatment (the number depending upon which side of the Atlantic they were composed) with
the recommendation that the patient be started on the step most appropriate to the severity of the asthma. Most now recommend starting treatment on a step higher than would appear to be necessary and stepping down once control has been obtained. Follow-up is essential to determine whether the current step is appropriate and whether treatment should be increased to the next step if inadequate, or reduced if it appears to be set too high. A simplified version of the five steps in the British Thoracic Society guidelines for the pharmacological management of childhood asthma is shown in Fig. 66.2. These guidelines apply to children above about 2 years of age because management of the wheezy infant is far less certain and indeed controversial. Whatever step is decided upon it may be necessary to begin with a short 5-day course of oral corticosteroid, such as prednisolone or betamethasone (which tastes better) at the start of treatment if the child is significantly obstructed at the time. A major factor in the management of asthma in children is the ability of the child to take medications, especially inhaled medications, and the ability of the parents to administer them to their child. It is quite useless to prescribe a metered-dose inhaler without a spacer for most young children and quite unrealistic to expect parents to administer medications through a nebulizer to a screaming infant who is terrified by the noise of the compressor. The choice of inhalation device must be tailored to each child and its efficient use ensured by education of the child and family (and sometimes even the doctor). Routes of drug delivery for children The route of drug delivery in asthma is important at all ages, but especially in children where the ability or willingness to
Short-acting β2-agonist as required
Short-acting β2-agonist as required plus lowdose ICS or SCG or SRT or SDAM-CS
Short-acting β2-agonist as required plus low-dose ICS plus longacting β2agonist or SRT or high-dose ICS or SDAM-CS
Short-acting β2-agonist as required plus highdose ICS plus long-acting β2-agonist or SRT or SDAM-CS plus anticholinergic?
Short-acting β2-agonist as required plus high-dose ICS plus long-acting β2-agonist or SRT plus SDAM-CS plus anticholinergic?
1
2
3
4
5
Mild
Mild/Mod
Mod/Sev
Severe
Very severe
Fig. 66.2. Guideline steps for the management of chronic asthma in children as described in the text. Beneath each step is shown the asthma severity for which the step would be appropriate. ICS, inhaled corticosteroids; SCG, sodium cromoglycate; SRT, slow release theophylline; SDAM-CS, single dose alternate morning oral corticosteroids; mod, moderate; sev, severe. (From Godfrey S. Childhood Asthma, In: Clark TJH, Godfrey S, Lee TH, Thomson NC (eds) Asthma, London: Arnold 2000 reproduced with permission.)
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comply with the treatment may assume greater significance. For younger children the oral route would normally be preferred and can be used for b2-agonists, methylxanthines, corticosteroids and anti-leukotrienes (not yet recommended for children under 6 years of age), but not for cromones. However, a young child may well refuse to swallow the medication, even if it has a good taste and will almost certainly refuse to take one with a bad taste such as prednisolone. The inhaled route is now available for all the most important anti-asthmatic medications with the exception of the methylxanthines and anti-leukotrienes and is the preferred route both for adults and children. Metered-dose inhaler Pressure activated metered-dose inhalers (pMDI) are currently the cheapest and most widely available devices for inhaling sympathomimetics, anticholinergics and corticosteroids. These pMDIs are very convenient for delivering drugs by inhalation but the technique used by the patient must be perfect. Most children over the age of about 6 or 7 years can be taught to use a pMDI effectively. The age range and applicability of pMDIs can be increased considerably by the use of a spacer between the pMDI and the mouth. The best type for children (and probably adults) is one with both inspiratory and expiratory valves and a volume small enough to make it easily portable. Infants and very young children can be given drugs from pMDIs if a suitable soft face mask is attached to the spacer and held firmly over the mouth and nose. The physician who prescribes the inhaler must take responsibility for ensuring that the child and the parents are properly instructed in its use. Dry powder inhalers An alternative is the dry powder inhaler (DPI) with a powder reservoir which is available for the commonly used b2-agonists, anticholinergics and corticosteroids. These DPIs require much less skill on the part of the patient than the pMDI and are more convenient than the combination of a pMDI and spacer. A survey in our department has shown that some 3-year-olds, over half the 4-year-olds and virtually every 5-year-old could use the Turbuhaler DPI device effectively. Wet nebulizers The delivery of medications by wet nebulization is particularly useful in children since it requires a minimum of cooperation and can be used at all ages. Sympathomimetics, anticholinergics and inhaled corticosteroids are available for nebulization. It is important to use an efficient nebulizer which delivers the recommended dose over about 5–7 minutes, because if it takes longer the child may well refuse to cooperate. Since most of the drug is delivered in the first few minutes it is important that the child use the nebulizer continuously and not take it off to run about and then return in an intermittent fashion.
Special considerations of the pharmacological management of asthma in children Although the management guidelines for children closely follow those for adults there are some areas where they may differ due to the preferences of pediatricians. Some would still prefer to use a cromone, such as sodium cromoglycate at BTS step 2 in the guidelines, rather than commencing low-dose inhaled corticosteroids and others may prefer to use a leukotriene antagonist at this step – at least for children over 6 years of age. Pediatricians are naturally reluctant to use oral corticosteroids in children other than for short “rescue” courses, but occasionally this may be unavoidable. In children needing daily oral corticosteroids for prophylaxis, giving the drug as a single dose every other morning is unlikely to be associated with significant growth suppression. This type of treatment is most likely to be needed in the younger child in whom the parents find it completely impossible to administer corticosteroids effectively by inhalation. The need for long-term oral corticosteroids to manage very severe asthma (BTS step 5) in children is extremely uncommon and should always call into question whether or not the family are compliant with the treatment and indeed whether or not the child has asthma. Wheezy infants The management of the acutely wheezy infant less than about 2 years of age is very problematic. There is little, if any, evidence that infants with acute viral bronchiolitis respond to medications used for asthma including oral corticosteroids.53,54 Treatment is essentially supportive ensuring that the infant is well-hydrated, fed and oxygenated while awaiting spontaneous recovery which usually occurs over a few days. There is some evidence to support the administration of a nonselective adrenergic drug which reduces edema and is vasoconstrictive.77 The management of the infant with recurrent wheezing less than about 2 years of age is even more problematic. There is no doubt that a small proportion of such infants do indeed have asthma and respond well to the same medications as do older children. For such infants the guidelines are applicable with particular attention to the technique of administration of inhaled medications. However, many infants with recurrent wheezing are not true asthmatics and their disease is probably the result of temporary damage to the small airways following acute viral bronchiolitis. Given that at present the differential diagnosis of nonasthmatic post-bronchiolitic wheezing from infantile asthma is impossible, the most logical approach in any chronically wheezy infant is to treat as if it were asthma. If there is a good clinical response, then the treatment should be continued as appropriate but if not, serious consideration should be given to withdrawal of any oral or inhaled corticosteroids that are being used. Most would inevitably continue to receive b2-agonists, but at least these are not likely to be harmful. It is always important to consider alternative diagnoses in the infant who does not respond to treatment.
Childhood Asthma
Corticosteroids in the treatment of asthma in children Despite the obvious efficacy of corticosteroids in the management of childhood asthma, side-effects, especially growth retardation, are a concern to many parents and physicians. Even normal doses of inhaled corticosteroids can reduce lower leg growth measured by knemometry in a dosedependent fashion in the short-term, but this is much less than that seen with oral corticosteroids.78,79 These shortterm studies were undertaken in children with very mild asthma, so that any positive effect on growth resulting from the beneficial effect of the inhaled corticosteroid on the asthma would not have been seen. There have been a number of long-term studies of growth in children treated with inhaled corticosteroids which have shown no adverse effect on growth. Thus in a study of asthmatic children who were followed until they had passed through puberty BalfourLynn40 showed that the final height of asthmatics (Fig. 66.3) was on average just what was predicted by the height centile at entry when there was no evidence of growth retardation. A matched controled retrospective study of adults who had been asthmatics as children also showed no effect on growth of either the asthma or corticosteroid therapy.80 Likewise a meta-analysis of the effect of oral and inhaled corticosteroids on growth in 810 children81 found a small degree of growth impairment with oral therapy, but none with inhaled therapy even with higher doses, longer use or worse asthma. A number of studies in children have shown that inhaled corticosteroids even in reasonable doses can reduce adrenal function although this is less likely with the more modern
112
Adult height/predicted centile height (%)
108
707
drugs compared with the older inhaled corticosteroids.82,83 However, clinically evident adrenal insufficiency has not been a problem in children taking reasonable doses of inhaled corticosteroids provided they have not also been receiving oral corticosteroids. Nevertheless, it is wise to keep the dose of inhaled corticosteroid to the lowest that controls symptoms adequately.
T R E AT M E N T O F A C U T E S E V E R E A S T H M A IN CHILDREN Any child with asthma of whatever grade can occasionally have an attack of acute, severe asthma which may or may not be so severe as to be life-threatening. In the survey from Australia,84 it was noted that about one-third of children who died from asthma were judged to have been mild asthmatics prior to the terminal illness. In general, the approach to the management of an acute exacerbation in a child differs little, if at all, from the management of acute exacerbations of asthma in adults with appropriate attention, of course, to the doses of medications. The correct management of acute exacerbations of asthma depends upon: • For ambulatory patients Correct interpretations of warning symptoms at home Correct treatment at home Recognition when hospital treatment is needed • For children coming to hospital Correct evaluation in Accident and Emergency Department Correct treatment in Accident and Emergency Department Recognition when transfer to intensive care is needed Correct timing of discharge from hospital • For all children Correct follow-up and modification of treatment
104
NONPHARMACOLOGICAL MANAGEMENT OF CHILDHOOD ASTHMA 100
96
92
Steroids
No steroids
Fig. 66.3. Final post-puberty height as percentage of that predicted from the height centile at the onset of asthma in boys and girls classified according to whether or not they received regular inhaled corticosteroid therapy as their main treatment. Redrawn from the data of Balfour-Lynn.40
Allergic management Almost all children with asthma are atopic and skin testing reveals a positive response to multiple allergens in about 95% of patients. Despite the undoubted theoretical importance of allergy in childhood asthma, the evidence that hyposensitization is of value to the large majority of asthmatics is very controversial. In a study by Adkinson et al.85 asthmatic children requiring daily medication for control of symptoms were treated by hyposensitization and allergen avoidance in a controlled trial for 2 years, but failed to show any clinical benefit or reduction in bronchial hyperreactivity. Moreover, there was a 34% incidence of adverse systemic reactions to the injections in the treated group compared
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with 7% in the control group. Even effective mite avoidance cannot be guaranteed to improve asthma in mite-sensitive children. Frederick et al86 used mite-impermeable bed coverings to reduce mite exposure for 3 months in asthmatic children and although this reduced the amount of Der-p-1 allergen retrievable from the bedding, there was no clinical effect and no change in bronchial hyperreactivity to histamine. Even so, it seems reasonable when careful historytaking, coupled with proper skin testing to confirm an important allergic component in provoking or prolonging the asthma, to make a sensible attempt to avoid contact with the allergen. Because of the supposed importance of food allergens, many children have quite absurd exclusion diets inflicted upon them, which make their lives and those of their parents almost intolerable. Fortunately most children have the good sense to ignore the diet whenever possible. Environmental factors and smoking Air pollution can aggravate asthma and this is sometimes taken to indicate that the family should move to another area. With adequate medications it should rarely if ever be necessary for such a drastic course and almost every child can be managed adequately in his own home. Of course the asthmatic patient should never smoke and children must be taught this at an early age. Smoking by other members of the family in the home must also be strongly discouraged. Gastroesophageal reflux There is no doubt that some children with asthma also have gastroesophageal reflux and this may even be the real cause of symptoms in the very young infant. In older asthmatic children and adults, it is far from clear which comes first, the asthma or the reflux and there is also uncertainty as to the efficacy of anti-reflux treatment in reducing asthma severity in such patients.87,88 Psychological management Children with troublesome asthma sometimes have overt emotional problems and this has been taken as evidence that asthma is a “psychological” disease. While there is no evidence that emotional factors on their own can induce a normal child to become asthmatic, there is equally no doubt that they can adversely influence the disease in the genuinely asthmatic child. This is often manifest as inability or failure to comply with management plans due to the inappropriate response of the child, or more usually, of the family. Various methods have been tried for the psychological treatment of childhood asthma, but education of the child and the family about asthma management is probably the single most useful approach. Other treatments There is no evidence that any type of “breathing exercises” or physical training can improve or cure asthma. Physical exercise is a powerful trigger factor for asthma and many active young asthmatics find this to be very troublesome if they are not given adequate medication to protect them
from exercise-induced asthma. Although physical exercise is good for asthmatic children and is to be encouraged, there is little evidence to suggest that it has a significant influence on the course of the disease. The various forms of complementary or alternative medicine, such as acupuncture and homeopathy have not been shown to be effective in treating asthma in controlled clinical trials and cannot be recommended.
LIVING WITH CHILDHOOD ASTHMA The successful management of asthma depends to a very large degree on providing the child and the family with a good understanding of the nature of asthma and its treatment. The physician must take time to explain this to the child and the parents in terms that they can understand and the message must be reinforced at subsequent visits. There are a number of important points that should be made during the discussion: • There is no cure for asthma, but there is excellent treatment which can allow virtually all asthmatics to lead normal lives.The majority of children become completely symptom-free or almost so during or by the end of childhood. There is some evidence that good treatment encourages this tendency to grow out of asthma. • Asthma is rarely fatal but in those cases where it is, there has almost always been inadequate treatment or failure to comply with medical advice. • Far more patients die because they do not get corticosteroid therapy than the reverse. In conventional doses, corticosteroids are not harmful to children (or adults) and they form the mainstay of the treatment of chronic asthma at all ages. It is most important that the child and the family be provided with a written treatment plan which is consistent with the needs of the child and their ability to comply with the recommendations. The simpler the regimen, the more likely is compliance and successful control of asthma.
S C H O O L I N G A N D T H E A S T H M AT I C CHILD With proper management, asthma should cause little or no interference with schooling in the large majority of asthmatic children. They should be able to take part in all normal activities, including games and competitive sports. Teachers and other carers should be able to deal with asthmatic children, since at least 10–15% of the class are likely to have asthma. This means that they should know which children have asthma, something about the nature of the disease and its treatment. In particular they should
Childhood Asthma
appreciate that exercise can be difficult for the asthmatic child who may need to take a b2-agonist before games. They should also be able to recognize deteriorating asthma in a pupil and inform the parents and know how to administer inhaled medications for an acute attack. It is self-evident that teachers and other role models should not smoke and should strongly discourage smoking by children, especially asthmatics.
CONCLUSIONS Asthma is a common condition in children and although most are mildly affected the quality of life of many children can be seriously disturbed unless adequate treatment is provided. This involves making the correct diagnosis, excluding other diagnoses, evaluating the severity of the asthma and prescribing appropriate treatment, taking into account the ability of the child and family to comply with the management plan. Guidelines for the management of asthma in children are similar to those for adults with emphasis on anti-inflammatory treatment for the child with chronic asthma. Corticosteroids used sensibly and in reasonable doses do not adversely affect growth in asthmatic children who require them. About two-thirds of children with asthma can be expected to ‘grow out’ of their disease completely and there is some evidence that the early introduction of effective treatment improves the prognosis.
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11. Aberg N, Engstrom I. Natural history of allergic diseases in childhood. Acta Paediatr. Scand. 1990; 79:206–11. 12. Dold S, Wjst M, vonMutius E, Reitmeir P, Stiepel E. Genetic risk for asthma, allergic rhinitis, and atopic dermatitis. Arch. Dis. Child. 1992; 67:1018–22. 13. Taussig LM, Smith SM, Blumenfeld R. Chronic bronchitis in childhood: What is it? Pediatrics 1981; 67:1–5. 14. Koh YY, Jeong JH, Park Y, Kim CK. Development of wheezing in patients with cough variant asthma during an increase in airway responsiveness. Eur. Respir. J. 1999; 14:302–8. 15. Asher MI, Pattemore PK, Harrison AC et al. International comparison of the prevalence of asthma symptoms and bronchial hyperresponsiveness. Am. Rev. Respir. Dis. 1988; 138:524–9. 16. Koh YY, Chae SA, Main KU. Cough variant asthma is associated with a higher wheezing threshold than classic asthma. Clin. Exp. Allergy 1993; 23:696–701. 17. National Institutes of Health. Expert Panel Report 2. Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 97–4051. Bethesda, Maryland: National Institutes of Health, National Heart, Lung, and Blood Institute, 1997. 18. The British Thoracic Society and others. The British guidelines on asthma management 1995 review and position statement. Thorax 1997; 52(Suppl. 1):S1–21. 19. Godfrey S, Springer C, Bar-Yishay E, Avital A. Cut-off points defining normal and asthmatic bronchial reactivity to exercise and inhalation challenges in children and young adults. Eur. Respir. J. 1999; 14:659–68. 20. Avital A, Springer C, Bar-Yishay E, Godfrey S. Adenosine, methacholine, and exercise challenges in children with asthma or paediatric chronic obstructive pulmonary disease. Thorax 1995; 50:511–16. 21. Konig P, Godfrey S. Exercise-induced bronchial lability and atopic status of families of infants with wheezy bronchitis. Arch. Dis. Child. 1973; 48:942–6. 22. Konig P, Godfrey S. Prevalence of exercise-induced bronchial lability in families of children with asthma. Arch. Dis. Child. 1973; 48:513–18. 23. Konig P, Godfrey S. Exercise-induced bronchial lability in monozygotic (identical) and dizygotic (nonidentical) twins. J. Allergy Clin. Immunol. 1974; 54:280–7. 24. Nieminen MM, Kaprio J, Koskenvuo M. A population-based study of bronchial asthma in adult twin pairs. Chest 1991; 100:70–5. 25. Lichtenstein P, Svartengren M. Genes, environment, and sex: factors of importance in atopic diseases in 7–9-year-old Swedish twins. Allergy 1997; 52:1079–86. 26. Russell G, Jones SP. Selection of skin tests in childhood asthma. Br. J. Dis. Chest 1976; 70:104–6. 27. Murray AB, Morrison BJ. The effect of cigarette smoke from the mother on bronchial responsiveness and severity of symptoms in children with asthma. J.Allergy Clin. Immunol. 1986; 77:575–81. 28. Martinez FD, Cline M, Burrows B. Increased incidence of asthma in children of smoking mothers. Pediatrics 1992; 89:21–6. 29. Chilmonczyk BA, Salmun LA, Megathlin KN et al. Association between exposure to environmental tobacco smoke and excerbation of asthma in children. N. Engl. J. Med. 1993; 328:1665–9. 30. Holberg CJ, Wright AL, Martinez FD, Morgan WJ, Taussig LM. Child day care, smoking by caregivers, and lower respiratory tract illness in the first 3 years of life. Pediatrics 1993; 91:885–92. 31. Viegi G. Air pollution epidemiology and the European Respiratory Society: the PEACE project. Eur. Respir. Rev. 1998; 52:1–3. 32. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B, Bjorksten B. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics 1995; 95:500–5. 33. Duff AL, Pomeranz ES, Gelber LE et al. Risk factors for acute wheezing in infants and children: viruses, passive smoke, and IgE antibodies to inhalant allergies. Pediatrics 1993; 92:535–40.
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34. Stein RT, Holberg CJ, Morgan WJ et al. Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood. Thorax 1997; 52:946–52. 35. Springer C, Avital A, Noviski N et al. Role of infection in the middle lobe syndrome in asthma. Arch. Dis. Child. 1992; 67:592–4. 36. Gustafsson PA, Bjorksten B, Kjellman NI. Family dysfunction in asthma: a prospective study of illness development. J. Pediatr. 1994; 125:493–8. 37. Meijer AM, Griffioen RW, van NJ, Oppenheimer L. Intractable or uncontrolled asthma: psychosocial factors. J. Asthma 1995; 32:265–74. 38. Fritz GK, McQuaid EL, Spirito A, Klein RB. Symptom perception in pediatric asthma: relationship to functional morbidity and psychological factors. J. Am. Acad. Child. Adolesc. Psychiatry 1996; 35:1033–41. 39. Balfour-Lynn L. Childhood asthma and puberty. Arch. Dis. Child. 1985; 60:231–5. 40. Balfour-Lynn L. Growth and childhood asthma. Arch. Dis. Child. 1986; 61:1049–55. 41. Blair H. Natural history of childhood asthma. 20-year follow up. Arch. Dis. Child. 1977; 52:613–19. 42. Jenkins MA, Hopper JL, Bowes G, Carlin JB, Flander LB, Giles GG. Factors in childhood as predictors of asthma in adult life. Br. Med. J. 1994; 309:90–4. 43. Oswald H, Phelan PD, Lanigan A, Hibbert M, Bowes G, Olinsky A. Outcome of childhood asthma in mid-adult life. Br. Med. J. 1994; 309:95–6. 44. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir. Med. 1994; 88:373–81. 45. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ, and the Group Health Medical Associates. Asthma and wheezing in the first six years of life. N. Engl. J. Med. 1995; 332:133–8. 46. Sporik R, Holgate ST, Cogswell JJ. Natural history of asthma in childhood – a birth cohort study. Arch Dis Child 1991; 66:1050–3. 47. Pullan CR, Hey EN.Wheezing, asthma and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy. Br. Med. J. 1982; 284:1665–9. 48. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am. J. Respir. Crit. Care Med. 2000; 161:1501–7. 49. Kneyber MCJ, Steyerberg EW, de Groot R, Moll HA. Long-term effects of respiratory syncytial virus (RSV) bronchiolitis in infants and young children: a quantitative review. Acta Paediatr. 2000; 89:654–60. 50. Sly PD, Lanteri CJ, Raven JM. Do wheezy infants recovering from bronchiolitis respond to inhaled salbutamol? Pediatr. Pulmonol. 1991; 10:36–9. 51. Tepper RS, Rosenberg D, Eigen H, Reister T. Bronchodilator responsiveness in infants with bronchiolitis. Pediatr. Pulmonol. 1994; 17:81–5. 52. Henderson AJW, Arnott J, Young S, Warshawski T, Landau LI, LeSouef PN. The effect of inhaled adrenaline on lung function of recurrently wheezy infants less than 18 months old. Pediatr. Pulmonol. 1995; 20:9–15. 53. Webb MSC, Henry RL, Milner AD. Oral corticosteroids for wheezing attacks under 18 months. Arch. Dis. Child. 1986; 61:15–19. 54. Springer C, Bar-Yishay E, Uwayyed K,Avital A,Vilozni D, Godfrey S. Corticosteroids do not affect the clinical or physiological status of infants with bronchiolitis. Pediatr. Pulmonol. 1990; 9:181–5. 55. Richter H, Seddon P. Early nebulized budesonide in the treatment of bronchiolitis and the prevention of postbronchiolitic wheezing. J. Pediatr. 1998; 132:849–53.
56. Taussig LM, Landau LI, Godfrey S, Arad I. Determinants of forced expiratory flows in newborn infants. J. Appl. Physiol. 1982; 53:1220–7. 57. Beardsmore CS, Godfrey S, Shani N, Maayan C, Bar-Yishay E. Airway resistance measurements throughout the respiratory cycle in infants. Respiration 1986; 49:81–93. 58. Cockcroft DW, Killian DM, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin. Allergy 1977; 7:235–43. 59. Avital A, Bar-Yishay E, Springer C, Godfrey S. Bronchial provocation tests in young children using tracheal auscultation. J. Pediatr. 1988; 112:591–4. 60. Noviski N, Cohen L, Springer C, Bar-Yishay E, Avital A, Godfrey S. Bronchial provocation determined by breath sounds compared with lung function. Arch. Dis. Child. 1991; 66:952–5. 61. Springer C, Godfrey S, Picard E et al. Efficacy and safety of methacholine bronchial challenge performed by auscultation in young asthmatic children. Am. J. Respir. Crit. Care Med. 2000; 163:857–60. 62. Katzenstein AL, Liebow AA, Friedman PJ. Bronchocentric granulomatosis, mucoid impaction and hypersensitivity reactions to fungi. Am. Rev. Respir. Dis. 1975; 111:497–537. 63. Christensen WN, Hutchins GM. Hypereosinophilic mucoid impaction of bronchi in two children under two years of age. Pediatr. Pulmonol. 1985; 1:278–83. 64. Spector SL, Kinsman R, Mawhinney H et al. Compliance of patients with asthma with an experimental aerosolized medication: implications for controlled clinical trials. J. Allergy Clin. Immunol. 1986; 77:65–70. 65. Coutts JAP, Gibson NA, Paton JY. Measuring compliance with inhaled medication in asthma. Arch. Dis. Child. 1992; 67:332–3. 66. Rand CS, Wise RA. Measuring adherence to asthma medication regimens. Am. J. Respir. Crit. Care Med. 1994; 149:S69–76. 67. Verschelden P, Cartier A, L’Archeveque J, Trudeau C, Malo JL. Compliance with and accuracy of daily self-assessment of peak expiratory flows (PEF) in asthmatic subjects over a three month period. Eur. Respir. J. 1996; 9:880–5. 68. Chowienczyk PJ, Parkin DH, Lawson CP, Cochrane GM. Do asthmatic patients correctly record home spirometry measurements? Br. Med. J. 1994; 309:1618. 69. Cote J, Cartier A, Malo JL, Rouleau M, Boulet LP. Compliance with peak expiratory flow monitoring in home management of asthma. Chest 1998; 113:968–72. 70. Rich M, Lamola S, Amory C, Schneider L. Asthma in life context: Video Intervention/Prevention Assessment (VIA). Pediatrics 2000; 105:469–77. 71. National Heart, Lung and Blood Institute, National Institute of Health. Guidelines for the Diagnosis and Management of Asthma. Publication No. 91-3042. Bethesda, MD:NIH, 1991. 72. Uwyyed K, Springer C, Avital A, Bar-Yishay E, Godfrey S. Home recording of PEF in young asthmatics: does it contribute to management? Eur. Respir. J. 1996; 9:872–9. 73. Warner JO, Gotz M, Landau LI et al. Management of asthma: A consensus statement. Arch. Dis. Child. 1989; 64:1065–79. 74. Asthma: a follow-up statement from an international paediatric asthma consensus group. Arch. Dis. Child. 1992; 67:240–8. 75. Guidelines on the management of asthma. Thorax 1993; 48(Suppl.):S1–24. 76. Warner JO, Naspitz CK, Cropp GJA. Third international pediatric concensus statement on the management of childhood asthma. Pediatr. Pulmonol. 1998; 25:1–17. 77. Kristjansson S, Carlsen KCL, Wennergren G, Strannegard IL, Carlsen KH. Nebulised recemic adrenaline in the treatment of acute bronchiolitis in infants and toddlers. Arch. Dis. Child. 1993; 69:650–4. 78. Wolthers OD, Pedersen S. Short term linear growth in asthmatic children during treatment with prednisolone. Br. Med. J. 1990; 301:145–8.
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79. Wolthers OD, Pedersen S. Growth of asthmatic children during treatment with budesonide: a double blind trial. Br. Med. J. 1991; 303:163–5. 80. Silverstein MD,Yunginger JW, Reed CE et al. Attained adult height after childhood asthma: effect of glucocorticoid therapy. J. Allergy Clin. Immunol. 1997; 99:466–74. 81. Allen DB, Mullen M, Mullen B. A meta-analysis of the effect of oral and inhaled corticosteroids on growth. J. Allergy Clin. Immunol. 1994; 93:967–76. 82. Phillip M, Aviram M, Leiberman E et al. Integrated plasma cortisol concentration in children with asthma receiving long-term inhaled corticosteroids. Pediatr. Pulmonol. 1992; 12:84–9. 83. Pedersen S, Fuglsang G. Urine cortisol excretion in children treated with high doses of inhaled corticosteroids: a comparison of budesonide and beclomethasone. Eur. Respir. J. 1988; 1:433–5. 84. Robertson CF, Rubinfeld AR, Bowes G. Pediatric asthma deaths in Victoria: The mild are at risk. Pediatr. Pulmonol. 1992; 13:95–100.
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85. Adkinson NF, Eggleston PA, Eney D et al. A controlled trial of immunotherapy for asthma in allergic children. N. Engl. J. Med. 1997; 336:324–31. 86. Frederick JM, Warner JO, Jessop WJ, Enander I, Warner JA. Effect of a bed covering system in children with asthma and house dust mite hypersensitivity. Eur. Respir. J. 1997; 10:361–6. 87. Cucchiara S, Santamaria F, Minella R et al. Simultaneous prolonged recordings of proximal and distal intraesophageal pH in children with gastroesophageal reflux disease and respiratory symptoms. Am. J. Gastroenterol. 1995; 90:1791–6. 88. Vincent D, Cohen-Jonathan AM, Leport J et al. Gastrooesophageal reflux prevalence and relationship with bronchial reactivity in asthma. Eur. Respir. J. 1997; 10:2255–9. 89. Strachan D, Gerritsen J. Long-term outcome of early childhood wheezing: population data. Eur. Respir. J. 1996; 9(Suppl. 21):42S–7S.
Treatment for Stable COPD
Chapter
67
Stephen I. Rennard University of Nebraska Medical Center, Omaha, NE, USA
INTRODUCTION
D I A G N O S I S A N D S TA G I N G
COPD is, for most individuals, a relentlessly progressive disorder, a feature which is recognized in the definition of COPD included in the GOLD Guidelines. COPD is defined as a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.1 “Stable” COPD, therefore, is an incorrect term which is generally applied to individuals who are in their usual state of deteriorating health that is, not experiencing an acute exacerbation. While the current therapies available to treat so-called “stable” COPD only partially meet therapeutic goals, these therapies can often offer considerable benefit. It is likely that many patients with COPD, however, are inappropriately undertreated. A number of professional societies, including the American Thoracic Society2 and the European Respiratory Society,3 have prepared guidelines for the diagnosis and management of COPD. More recently, as a result of collaboration between the World Health Organization and the National Heart Lung and Blood Institute, USA, the Global Initiative for Chronic Obstructive Lung Disease (GOLD Guidelines) have been prepared.1 The guidelines reflect changes in the diagnostic approach and management strategy for COPD. This chapter will outline the current therapeutic strategy for the management of COPD patients who are “stable,” that is in their usual state of health. The medications used to treat patients with COPD are, in many cases, identical to those used to treat patients with asthma. The strategy for the use of these medicines, however, differs importantly between COPD and asthma. Effective patient management, therefore, requires that the clinician make an appropriate diagnosis, accurately stage the severity of disease in an individual patient and clearly define therapeutic goals. The pharmacology relating to individual classes of drugs is provided in detail in accompanying chapters as is information relating to nonpharmacological treatments. This chapter describes the overall strategy for the use of these treatments in various stages of COPD.
Airflow limitation is a characteristic feature of both asthma and COPD. In asthma, the airflow limitation is generally reversible either spontaneously or with treatment. In COPD, in contrast, there may be some degree of reversibility, but expiratory airflow limitation, to some extent, is always present (see Chapter 43). Some definitions of COPD have specifically excluded patients with airflow reversibility.3 This has led to considerable confusion as bronchodilators are first-line therapy for patients with COPD (see below). The distinction between COPD and asthma has often been a difficult one for several reasons. Some patients with COPD may have a considerable degree of reversibility. These individuals may be considered as having both COPD and asthma. Such a distinction is more than semantic as a therapeutic plan for both asthma and COPD needs to be established and maintained. Such individuals, moreover, may not be rare.While not confirmed in all studies,4 patients with asthma, as a group, have been suggested to have an accelerated rate of loss of lung function5,6 which implies that a significant number may develop clinical COPD. The therapeutic goals for the stable COPD patient are varied (Table 67.1). As COPD progresses, the relative importance of the various therapeutic goals changes. Appropriate management of the COPD patient, therefore, requires an accurate assessment of disease stage. Current staging of COPD depends on quantitative assessment of expiratory airflow to grade disease severity. Since airflow limitation can Table 67.1. Therapeutic goals in COPD
Prevent disease progression Relieve symptoms Improve health status (quality of life) Prevent exacerbations Prolong life Anticipate end of life issues
Asthma and Chronic Obstructive Pulmonary Disease
result from several distinct physiologic processes (see Chapter 5), this parameter represents an integration of several distinct processes. In addition, many of the features of COPD are very weakly related to the FEV1 (see below). An accurate staging of the COPD patient, however, can serve as an initial guide to therapeutic intervention and can help the clinician determine appropriate therapeutic goals. The GOLD staging system The GOLD Guidelines are the most recent attempt to develop generally applicable guidelines for COPD.1 The objectives of GOLD are to increase awareness of COPD among health care professionals, health care authorities and the general public, to stimulate research and to improve the diagnosis, management and prevention of COPD. In order to accomplish these latter goals, the GOLD Initiative revisited the definition, diagnosis and staging of COPD with the intent of establishing a means for global acquisition of basic epidemiologic information for clinical outcomes data and for recommendations for clinical care. A global approach was felt to be urgently needed as understanding the heterogeneous biological and clinical features of COPD has been greatly confounded by marked differences in disease definition and classification. The staging system for COPD established in the GOLD Guidelines represents a significant change from prior classifications. These changes were based on the recognition that COPD is a progressive disorder and that clinically detectable abnormalities often develop several decades before patients complain of symptoms.7 Recognition that patients often complain of symptoms only after considerable disability has developed supports an aggressive proactive strategy for early detection and diagnosis. GOLD staging • Stage 0: Persistent cough and sputum. Although often discounted by smokers, these symptoms are abnormal and require an appropriate diagnosis. Individuals with persistent cough and sputum may have airway inflammation due to inhaled toxins as the underlying cause. While inflammation of the large airways may be present without airflow limitation, such individuals may also have inflammation of the smaller airways and alveolar structures. Cough and sputum, therefore, may indicate the presence of pathology at sites which can lead to airflow limitation. In addition, in contrast to earlier studies which suggested that cough and sputum do not lead to airflow limitation,7 more recent studies in larger numbers of subjects suggest that cough and sputum production per se are risk factors for the development of fixed airflow limitation.8 Cough and sputum production are required to define stage 0 and may be present in any other stage. • Stage 1. While population differences are well recognized, expiratory airflow is generally considered to be normal if greater than 80% predicted. An individual starting at 100%, therefore, can lose up to one-fifth of their expiratory airflow and remain within the normal
range. Early in the development of COPD, however, lung volumes frequently increase due to loss of lung elastic recoil.9 As a result, the vital capacity is relatively well preserved.This makes the ratio of FEV1/FVC, termed the Tiffeneau Index, a more sensitive measure of early COPD. Stage 1, therefore, recognizes the earliest physiologic abnormalities as a reduction in the FEV1/FVC ratio, while the FEV1 remains within the normal range (that is greater than 80% predicted). • Stage 2. This stage includes patients with reductions in expiratory airflow beyond the normal range, but generally excludes those likely to have respiratory failure. All individuals have a reduction in FEV1/FVC ratio and FEV1 is between 30 and 80% predicted. Within this range, individuals with FEV1 greater than 50% predicted, staged 2A, are less likely to complain of symptomatic dyspnea. Individuals between 30 and 50% are those more likely to have symptoms of dyspnea and are staged 2B. • Stage 3. This includes individuals who have an FEV1 less than 30% predicted or who have an FEV1 less than 50% predicted and evidence of current or previous respiratory failure or of right-sided heart failure. Severe COPD is intended to indicate patients who are likely to require a high degree of support, may have increasingly frequent hospitalizations and may require support in an intensive care unit setting. Severe patients are appropriate for very aggressive therapeutic interventions. The care of these patients is a major determinant of overall health care expenditures for COPD. The staging system presented in the GOLD Guidelines differs from prior staging systems in a number of important ways (Fig. 67.1). The ATS staging system was designed to help guide referral for specialist evaluation, particularly in
Cough Sputum* 100
Severity
75
*At risk FEV1
714
Mild
50
Moderate Severe 25
0 GOLD (2001)
ATS (1995)
ERS (1995)
Fig. 67.1. Comparison of staging systems. The GOLD Guidelines1 represent the most current staging for COPD. These guidelines differ from earlier guidelines proposed by the American Thoracic Society2 and the European Respiratory Society3 providing greater emphasis on early recognition and staging, as well as stratifying more severe patients likely to require high levels of intervention. See text for details.
Treatment for Stable COPD
the United States. In the ATS staging system,2 stage 1 included all subjects with lung function greater than or equal to 50% predicted. The rationale for this staging was that individuals greater than 50% rarely have respiratory failure and rarely require oxygen therapy. Often these individuals are relatively asymptomatic, and it was felt that stage 1 patients would most often require relatively little therapy other than reduction of risk factors. The GOLD Guidelines, in contrast, emphasize early diagnosis and early physiologic staging. While many patients in the early stages of COPD may not present to the physician with complaints, often these individuals may be experiencing alterations in their lifestyle, suggesting that therapeutic interventions designed to improve performance and reduce symptoms might be appropriate. This approach is supported by data from the NHANES study suggesting that nearly two-thirds of adults in the United States with airflow limitation have never been diagnosed.10 More than half of these individuals, moreover, report some symptoms, suggesting a significant burden results from undiagnosed disease. The European Respiratory Society (ERS) Guidelines also recognize the importance of early diagnosis of COPD.3 The use of the Tiffeneau Index (FEV1/FVC ratio) was recommended as an early sensitive indicator that airflow limitation is present. The ERS Guideline, however, utilized predicted values in order to determine abnormalities in the Tiffeneau Index. While a statistically rigorous definition of normality has an intellectual appeal, the so-called “normal” values frequently used depend on body size and shape and, therefore, are not necessarily applicable to all ethnic populations. Because of problems with validating normal values and in order to simplify the calculations required, the GOLD Guidelines utilize a value of 0.7 to establish an abnormal Tiffeneau Index, recognizing that there is some arbitrariness in the selection of this cutoff. The ERS Guidelines also differ from the GOLD Guidelines in categorizing everyone with an FEV1 less than 50% predicted as having severe disease. While this identifies individuals who are likely to be symptomatic and, therefore, likely to require symptombased therapeutic interventions, it does not distinguish individuals who are likely to require hospitalization and who are at risk for respiratory failure. The GOLD Guidelines, by refining the staging of COPD, provides a better basis to guide the clinician in selecting therapy for the COPD patient. Limitations in current COPD staging It is widely recognized that many features of COPD correlate very poorly with the FEV1.11,12 Several investigators have suggested multidimensional staging systems for COPD which could independently stage features in addition to FEV1.13,14 A recent analysis13 suggests that as many as six dimensions may be relatively independent clinical features in COPD (Table 67.2). While theoretically appealing, such complex staging systems are not, at present, either widely adopted or recognized as practicable. Nevertheless, the clinician must recognize that the GOLD staging, while useful
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Table 67.2. Potential independent dimensions for assessment of COPD patients
Lung function (FEV1) Cough and sputum Dyspnea Health status Bronchodilator reversibility Body mass index
as a guide to therapy (Fig. 67.2), is not a complete clinical description. GOLD staging, therefore, must be supplemented with careful clinical assessment. The following therapeutic strategies are based on this approach.
THERAPEUTIC GOAL: PREVENT DISEASE PROGRESSION The risk factors which contribute to the development of COPD are discussed in detail in Chapter 36. Exogenous risk factors for the development of COPD include cigarette smoking, air pollution, viral and bacterial infections, nutritional deficiencies and diseases which can affect lung development. Airways hyperreactivity is also a risk factor which may depend on an interaction of exposures and genetic factors. It is likely that a number of genetic factors will influence the development of COPD.The best characterized of these is severe deficiency of alpha-1 protease inhibitor. Cigarette smoking The major means to prevent disease progression in COPD is to eliminate relevant risk factors. Far and away the most important risk factor is cigarette smoking.7,10 Addressing cigarette smoking, therefore, is the most important measure to prevent disease progression. The problem of smoking is best addressed within the context of a comprehensive program designed to prevent smoking initiation and to encourage and facilitate smoking cessation (Chapter 48).15 Other approaches, for example harm reduction strategies, may play a role but cannot at present be advocated due to lack of supporting data.16 While social and community-based approaches to the problem of smoking are essential, it is equally important that the clinician recognize and appropriately treat the medical aspects of cigarette smoking. The vast majority of smokers are addicted, and nicotine is the major addicting component in cigarette smoke. Smoking, therefore, is most correctly regarded as a chronic disease which is characterized by frequent remissions (quit attempts that succeed for varying lengths of time) and relapses. In this context, COPD can be regarded as one of the many secondary consequences of the primary disease: smoking. Several therapeutic strategies are effective in helping smokers quit (Chapter 48). Behavioral interventions, which
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Therapy at Each Stage of COPD Patients must be taught how and when to use their treatments and treatments being prescribed for other conditions should be reviewed. Beta-blocking agents (including eye drop formulations) should be avoided. Stage
Characteristics
ALL
Recommended treatment • Avoidance of risk factor(s) • Influenza vaccination
0 At risk
• Chronic symptoms (cough, sputum) • Exposure to risk factor(s) • Normal spirometry
I Mild COPD
• FEV1/FVC <70% • FEV1 <80% predicted • With or without symptoms
• Short-acting bronchodilator when needed
II Moderate COPD
IIA: • FEV1 /FVC <70% • 50% 0 FEV1 <60% predicted • With or without symptoms
• Regular treatment with one or more bronchodilators
IIB: • FEV1 /FVC <70% • 30% 0 FEV1 <50% predicted • With or without symptoms
• Regular treatment with one or more bronchodilators
• FEV1 /FVC <70% • FEV1 <30% predicted or presence of respiratory failure or right heart failure
• Regular treatment with one or more bronchodilators • Inhaled glucocorticosteroids if significant symptoms and lung function response or if repeated exacerbations • Treatment of complications • Rehabilitation • Long-term oxygen therapy if respiratory failure • Consider surgical treatments
III Severe COPD
• Inhaled glucocorticosteroids if significant symptoms and lung function response
• Rehabilitation
• Rehabilitation
• Inhaled glucocorticosteroids if significant symptoms and lung function response or if repeated exacerbations
Fig. 67.2. COPD treatment suggestions based on the GOLD staging system. Reproduced from the GOLD Committee Report (www.goldcopd.com). Individual patient management should be guided by clinical response. See text for details.
can be as brief as a few minutes of personalized practical advice, can increase quit rates several-fold above the spontaneous quit rate.15 Increasing the intensity, duration and number of sessions can increase behaviorally based quit attempts.17 Pharmacologic treatment can approximately double quit rates achieved with behavioral interventions alone. To date, two strategies for pharmacologic treatment to aid smoking cessation have been approved: nicotine replacement therapy and bupropion therapy (see Chapter 48 for details in the use of these medications). The Agency for Health Care Quality in the United States currently recommends that every smoker making a serious quit attempt should be offered pharmacologic treatment in order to maximize the chances that the quit attempt will be successful.15 Smoking should be addressed in every COPD patient on a regular basis. Nonsmoking patients who have developed COPD must be counseled not to begin as they have already demonstrated their unusual susceptibility. Former smokers should be regularly interviewed and counseled in order to anticipate and prevent relapse. Relapse, for example, is common at times of stress and is often associated with concurrent use of alcohol.18 Finally, COPD patients who
continue to smoke should be counseled and encouraged to make quit attempts which can then be properly supported. A defeatist attitude toward smoking cessation in COPD patients is clearly unwarranted. Smoking cessation can be achieved in COPD patients as documented in several studies.19,20 When COPD patients quit, moreover, it is likely that benefits ensue. In one study, symptoms of cough and sputum production were greatly reduced among smokers who quit.21 The frequently reported complaint that smoking cessation is associated with an increase in cough, therefore, does not appear to be supported among the majority of smokers. The Lung Health Study,19 moreover, in a large randomized prospective trial, clearly demonstrated that when smokers with mild COPD quit, the accelerated rate of loss of lung function which characterizes these individuals normalizes (Fig. 67.3). In the first year after quitting, lung function improves slightly among quitters. After a year of stability, lung function decline resumes, but the rate of decline resembles much more closely that of nonsmokers, rather than that of smokers with mild COPD. This study, therefore, clearly demonstrates that progressive lung function loss can be slowed in COPD by smoking cessation.
Treatment for Stable COPD
counsel C O P D patients regarding these risks, specific therapeutic interventions to mitigate the risks associated with air pollution have not been assessed (Chapter 41). As episodes of worsening pollution, particularly those associated with particulates, are associated with increased exacerbation rates and increased mortality,^' the availability of such interventions would address an important unmet need.
2.9 ^ ^ ^ ^ o S u s t a i n e d quitters
^ -1 2.8 >"
Cr ^^^^^^~~~--~-^
LLI
0
2.7 ^~*^Continuing smokers
1 1 2.6 g 00
O
°-
2.5
Screen 2
1
2
3
1
4
717
5 1
Follow-up, years Fig. 67.3. Benefits of smoking cessation. Individuals with mild COPD who quit smoking initially improve lung function then decline at a rate similar to that estimated for nonsmokers. In contrast, continuing smokers decline at an accelerated rate (reproduced from Ref. 19 with permission).
Whether such benefits would accrue in more severe disease where the pathophysiologic processes may be different remains to be determined. Nevertheless, smoking cessation must be considered a therapeutic goal of prime importance for all patients with C O P D . P h a r m a c o l o g i c interventions in continuing smokers Current concepts suggest that smoke-induced inflammation leads to tissue damage and structural alterations causing airflow limitation in smokers. Agents which modify these pathophysiologic processes are plausible candidates for reducing lung function loss. Unfortunately, no therapeutic intervention based on these concepts has yet been found to alter lung function loss in C O P D . T h e Lung Health Study,'' in addition to evaluating smoking cessation, also evaluated the anticholinergic bronchodilator ipratropium based on the concept that airways reactivity is a risk factor for the development of C O P D . While ipratropium had a bronchodilator effect and, therefore, acutely improved airflow, it was completely without effect in altering the progressive loss of lung function. Several studies have assessed the effect of inhaled glucocorticoids based on the rationale that, as antiinflammatory agents, they may mitigate inflammationinduced lung damage and lung function loss.^^"^'' None of the studies was able to show a statistically significant effect on lung function loss. Pollution Indoor and outdoor air pollution, as well as exposures to dust and fumes in the workplace are recognized risk factors for the development of COPD.^^"^* While it is reasonable to
Infections Infections in childhood have been suggested to contribute to C O P D pathogenesis.^"'^' To date, no specific antiviral strategies have been assessed to alter C O P D natural history. Colonization of the airways with bacteria and acute infections with viruses in adulthood, however, are believed to contribute both to acute exacerbations and, possibly, to progressive lung function loss (Chapter 68).* It is reasonable, therefore, to advocate vaccination for influenza and for pneumococcus. Whether these will affect progressive lung function loss, however, is not known. Alpha-1 protease inhibitor Severe congenital deficiency of alpha-1 protease inhibitor ( a l P I , formerly termed alpha-1 antitrypsin) is a major risk factor for the development of C O P D (Chapter 29). Deficient individuals are at increased risk for developing emphysema at an early age, particularly if they smoke. Deficient individuals can also develop airways reactivity and chronic bronchitis.^^ Purified a l P I is available for intravenous infusion. Definitive, controlled, randomized trials with a l P I have not yet been done. Two registry studies, however, suggest that alpha-1 antitrypsin replacement may slow lung function loss.^^'^'' One smaller prospective controlled trial also showed a trend in favor of replacement based on C T scan.^^ Replacement is now recommended by the Canadian Thoracic Society.^* As only a subset of a l P I deficient patients will develop C O P D , current recommendations are that therapy be offered only to individuals with evidence of compromise of lung function. Therapy is not recommended for continuing smokers as cigarette smoke can inactivate alpha-1 protease inhibitor. The currently available product is purified from pooled human plasma. The product is relatively expensive and, while it is tested for HIV and hepatitis, has the potential for transmission of disease. Therapy requires intravenous infusions generally given at weekly intervals. Interestingly, replacement therapy may also be associated with a reduction in infectious episodes in deficient individuals.^'
T H E R A P E U T I C G O A L : RELIEF OF SYMPTOMS Dyspnea The primary strategy to improve symptomatic dyspnea in C O P D patients is based on the concept that symptoms are secondary to compromised lung function. Improvement in lung function, therefore, is the proximate goal, with
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improvement in symptoms the desired consequence. To this end, bronchodilators represent the first-line symptom-based pharmacologic intervention in COPD. The connection between bronchodilation and dyspnea relief, however, is likely indirect. There are several factors which contribute to dyspnea (Chapter 5).38,39 It is likely, however, that in COPD the major determinant of dyspnea is increased inspiratory work.40,41 This work depends in part on airway caliber, and bronchodilators by improving airflow might have some benefit. A more important determinant of inspiratory work, however, is likely dynamic hyperinflation which develops in many COPD patients with increasing respiratory rate.42,43 This likely accounts for the marked increase in dyspnea on exertion experienced by COPD patients who may be relatively asymptomatic at rest. This also likely accounts for why many COPD patients have greatly restricted activity levels, i.e. inactivity has been adopted to reduce the risk of dyspnea. Bronchodilators may reduce the dynamic hyperinflation44 and thus contribute to reduced dyspnea by a mechanism not directly reflected by the measurement of airflow, e.g. FEV1, at rest.45 The strategic use of bronchodilators in COPD differs fundamentally from the strategy with which they are used in asthma. In asthma, the basic strategy is to prevent episodes of bronchoconstriction with the use of anti-inflammatory agents. Bronchodilators are used only when this approach fails. Dyspneic COPD patients, in contrast, will always have significantly impaired lung function. Bronchodilators, even if they are of limited effectiveness, by virtue of improving lung function, have the potential for reducing dyspnea. For this reason, bronchodilators are first-line therapy in the treatment of symptomatic dyspnea in COPD patients, and they are most often used on a regular basis. Paradoxically, therefore, bronchodilators are of higher priority in COPD than in asthma, even though COPD patients will, in general, have a more modest response to bronchodilators. Bronchodilators Choice of drug and formulation Several classes of bronchodilators are available and, within each class, there are several agents and formulations available.The pharmacology of these agents is discussed in detail in Chapters 49, 50, and 51. The magnitude of the bronchodilator response achieved in most COPD patients is relatively modest and is generally in the range of 100 to 300 ml improvement in the FEV1. This response is similar to the improvement in airflow achieved in normal individuals given bronchodilators and may represent inhibition of “normal” airway tone. The modest improvement achieved, however, is relatively more important the more severe the airflow limitation. That is, a 300 ml improvement for an individual with a 4 liter FEV1 represents a 7.5% improvement. This would generally not be regarded as a positive response. The same improvement, however, for an individual with a 1 liter FEV1 would represent a 30% improvement and would be a very gratifying clinical response. A number of definitions have been used to
characterize responders to bronchodilators among COPD patients. Despite the definition used, however, the number of patients showing a response increases as the disease becomes more severe, likely because the modest improvements are more meaningful when they are added to a relatively more severe baseline lung function.46 Bronchodilator response among most COPD patients is distributed as a single normal distribution.47 The response of a given patient, moreover, is, to some degree, variable.46 This means that it is not strictly correct to classify patients as bronchodilator-responsive or nonresponsive. Patients who have a marked bronchodilator response and who normalize their lung function should be considered as likely having asthma. Patients who have a very modest response, however, may still derive considerable clinical benefit from bronchodilators, and bronchodilator therapy should not be denied based on pulmonary function testing in a laboratory setting. Current guidelines do not recommend any specific bronchodilator as being superior as an initial therapeutic choice. Clinical studies suggest that response to individual drugs can be highly variable. In the set of clinical trials of over 800 COPD patients tested with the beta-agonist albuterol and the anticholinergic ipratropium, 25% responded (with at least a 200 ml or 12% improvement in FEV1) only to albuterol, 25% responded only to ipratropium, 30% responded to both and 25% responded to neither.48,49 The choice of an agent, therefore, should depend on a number of factors including local availability and cost, the ability to provide adequate support required for training in the use of devices and, importantly, on individual patient response both with regard to efficacy and side-effects (see Table 67.3). The GOLD Guidelines recommend that, when possible, bronchodilators be administered via an inhaled route. This offers an increase in the therapeutic index, thus maximizing benefit compared with side-effects. Inhaled medications, however, may not be appropriate for some individuals. Oral agents, however, are generally more convenient and, in some populations, have a higher degree of acceptability. Such agents should be considered by the clinician for selected patients. When utilizing bronchodilators, the most appropriate strategy is for the clinician to accurately diagnose and stage each patient, initiate therapy and then to gauge response. Spirometric assessment of airflow will provide objective measures to complement clinical assessments of the individual patient. More sophisticated physiologic assessment, such as exercise testing or lung volume measurement is not recommended as a routine, although the inspiratory capacity has been suggested as an easily performed surrogate for hyperinflation.45 For patients in whom the clinical response is suboptimal, several issues should be addressed. First, for individuals using inhalation devices, assurance that the device is being used correctly is essential. Several studies suggest that with metered dose and dry powder inhalers, patient compliance with proper technique is poor and deteriorates significantly with time.50–53 Continual patient education in the use of these devices, therefore, is required.
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Treatment for Stable COPD
Table 67.3. Considerations for choosing bronchodilators
Cost Availability Individual patient response Benefit Side-effects Route Inhaled Better therapeutic index Education required (particularly if multiple medications and devices are used) Oral Convenience Acceptability Compliance Duration of action Combination of agents in different classes Therapy should be assessed empirically using quantitative measures of airflow and clinical response. Reassessment should occur regularly and therapy adjusted (usually increased as disease progresses).
Wet nebulizers are not believed to have any benefits over hand-held devices for most patients.^'''^^ These devices require maintenance and cleaning and do not offer the convenience of portability. Nevertheless, many patients prefer them,^*'^' and they may be particularly beneficial for subjects with altered mental status, in those whose inspiratory flow rate is too low to permit effective inhalation, or in individuals who are unable to use hand-held devices.^* If the medication is being taken correctly and clinical response is unsatisfactory, it is recommended that bronchodilators of several classes be combined. Combinations of anticholinergic and short-acting beta-agonist bronchodilators can be taken as separate inhalers, or these medications can be administered together in the same device.^'"*' The combination device results in better bronchodilation and a slightly prolonged duration of effect.*^ While administration as a combination decreases the ability to regulate the dose of individual components, combination inhalers have achieved a high degree of patient acceptance, likely due both to their increased convenience and to the improved efficacy which likely accompanies both improved compliance and dual pharmacological benefits. A variety of other combinations have also been assessed (see Ref. 63 for a detailed review). Ipratropium has been successfully combined with the long-acting bronchodilator salmeterol.*'' Interestingly, with this combination, the benefits of a single combined inhalation persisted for the entire 12 hours of monitoring, despite the fact that ipratropium, which is generally believed to have
a 4- to 6-hour duration of action, was not re-administered. Finally, both anticholinergics and beta-agonists can be combined with theophylline.*^'** Because beta-agonists and theophylline both may increase cyclic A M P through differing mechanisms, there is the possibility for synergistic interaction between these bronchodilators. Most C O P D patients will have progressive disease. It is likely, therefore, that as disease worsens, bronchodilator therapy will have to be intensified. This suggests that most C O P D patients will, eventually, be treated with combination bronchodilator therapy. It also suggests that empirical clinical trials assessing the therapeutic benefit of bronchodilators should be repeated in an organized fashion on a regular basis as disease progression occurs (see Table 67.3). Frequency of use Short-acting bronchodilators can be used on an as-needed basis for episodic dyspnea in C O P D patients. This "rescue" use, however, is more appropriate for the treatment of asthmatic patients who experience episodes of severe bronchospasm. Patients with C O P D are always airflow-limited, and episodic dyspnea is more likely related to episodes of increased exertion. Episodic treatment after the fact with a short-acting bronchodilator, therefore, is less likely to be of benefit than is regular maintenance therapy with bronchodilators. Short-acting bronchodilators, even when taken on a regular basis, result in lung function which will be increasing and decreasing throughout the day. In practice, regular use of short-acting agents was not better than P R N use.*' For this reason, there may be significant advantages in the use of long-acting bronchodilators in patients with C O P D . Not only are these agents more convenient, they avoid periods of bronchodilatation interspersed with relatively poor airflow (Fig. 67.4). Long-acting bronchodilators are recommended for regular use in the G O L D Guidelines.
•••••• Placebo - • — Salmeterol ' - • - Ipratropium
1
-0.1
2
3
4
5
6
7
8
9
10
11
12
13
Time (hours)
Fig. 67.4. Comparison of bronchodilator response to a shortacting bronchodilator (ipratropium) given every 5 hours with a longacting bronchodilator (salmeterol) given every 12 hours. While the maximal bronchodilator effects are similar, the long-acting agent provides more consistent bronchodilation throughout the day (reproduced from Ref. 48 with permission).
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Asthma and Chronic Obstructive Pulmonary Disease
Glucocorticoids Glucocorticoids are not bronchodilators. Nevertheless, they may result in a modest improvement in lung function and can, therefore be considered for patients who do not have an adequate response to aggressive combined bronchodilator treatment. The recommendation made in former guidelines suggesting a 2-week trial with oral glucocorticoids to determine responsiveness,2 was not supported in a clinical trial.24 Oral challenge is no longer recommended. If glucocorticoids are to be given on a trial basis to improve lung function in COPD, inhaled medication is the preferred modality. A clinical trial of 3 to 6 months may be required and care must be taken to assure adequate compliance before the trial is deemed unsuccessful.24 The response to glucocorticoids, in terms of FEV1 improvement, however, is likely to be modest. The large trials assessing the effect of glucocorticoids on COPD natural history noted an improvement compared with placebo of about 50 ml.22,24 After that initial improvement, as noted above, there is no detectable effect on the progressive loss of lung function which characterizes COPD. Caution should be taken in initiating inhaled glucocorticoid therapy. Not only do these agents have systemic effects in COPD,22 but discontinuation of the medications may be associated with precipitation of COPD exacerbation.68 Pulmonary rehabilitation Pulmonary rehabilitation can also help control symptoms of dyspnea (Chapter 59). It is likely that rehabilitation can help control symptoms of dyspnea by several mechanisms2,69,70 First, regular conditioning may decrease the psychological anxiety which may amplify the subjective perception of the symptoms. Second, improved training may decrease oxygen requirements and, therefore, the increased ventilatory requirements associated with exercise. Finally, it is likely that many patients experience dyspnea primarily because of dynamic hyperinflation which, in turn, depends on respiratory rate. A rehabilitation program may train subjects to exercise without such marked hyperinflation. Whatever the mechanisms, rehabilitation can contribute greatly to improved symptom control and functionality in COPD patients.1,71,72 It is reasonable that an aggressive rehabilitation program be combined with aggressive bronchodilator therapy. Optimizing lung function will make it possible for a COPD patient to exercise to a higher level. It is likely, therefore, that optimal benefits from both bronchodilator therapy and pulmonary rehabilitation require appropriate concurrent use of these therapeutic modalities. While rehabilitation is widely recognized as an important therapeutic intervention for subjects with severe COPD, exercise training is likely important for individuals with milder disease as well.69 As noted above, many COPD patients deal with symptoms of mild dyspnea on exertion during the early phases of their disease by decreasing their level of activity. This “strategy”, however, likely contributes
to the severe deconditioning which characterizes COPD patients and to their functional compromise. Maintaining a high level of exercise activity in mildly affected patients, therefore, should be an important therapeutic goal. Appropriate use of bronchodilators in order to optimize lung function and thus permit regular sustained activity at a high level can, therefore, be appropriate in patients with relatively mild disease. Long-acting bronchodilators may be particularly important in order to permit a sustained high level of activity throughout the day. As many patients may be “asymptomatic”, the clinician should specifically inquire about changes in activity levels which may be very insidious over time.73 Narcotics As COPD progresses, symptoms of dyspnea can become severe despite maximal functional support. Opiates, likely through a central action, can decrease the subjective perception of dyspnea. These drugs carry significant hazard as they can also significantly depress ventilation and lead to CO2 retention. They may also suppress cough and may lead to retained secretions. Any subjective effect on dyspnea is not accompanied by an improvement in exercise tolerance.74–77 Their routine use is specifically listed as contraindicated in the GOLD Guidelines due to the limited benefits and adverse effects.1 The full text of the GOLD Panel Report is available at www.goldcopd.com.The use of opiate narcotics, however, in end-stage COPD may be considered as a potential palliative measure for individuals suffering from severe dyspnea. In this context, the use is analogous to the use of these medications in the control of severe pain for patients with other terminal illnesses, recognizing that the predictable adverse effects of the medications may be acceptable in order to relieve suffering. If used for this purpose, systemic administration is generally recommended, since administration via inhalation has been demonstrated to have no significant advantages.75,78,79 Surgery Two surgical options have been suggested for COPD patients: lung volume reduction and lung transplantation (Chapter 60). • Lung volume reduction surgery removes areas of relatively nonfunctioning lung in individuals with severe emphysema and hyperinflation and can restore the ability of the chest and diaphragm to function as a bellows, thus improving function.80–82 The therapy is currently regarded as experimental as it is unclear which patients are appropriate for this intervention. This surgery should be distinguished from bullectomy, in which isolated nonfunctional bullae are resected. Recent attention to pneumoreductive surgery has reemphasized the advantages of bullectomy as well, and the availability of CT scanning to define the presence of such lesions has created surgical options for an increasingly large number of COPD patients.83
Treatment for Stable COPD
• Transplantation can be offered to COPD patients when appropriate. As COPD is, however, a disease which generally progresses with age and as many patients are or have been smokers who have concurrent co-morbidities, most patients with COPD are not appropriate candidates for pulmonary transplantation at the present time. For selected individuals, such as those with alpha-1 protease inhibitor deficiency, this may represent an important therapeutic option, although whether transplantation improves survival for COPD patients in general, is unclear at present.84,85 Mucolytics Cough and sputum production are often major complaints disturbing patients with COPD. As noted above, these symptoms correlate poorly with FEV1 and may be present in individuals with normal lung function, where they can serve as an indicator of disease risk. Management of cough and sputum, however, represent important clinical goals for the COPD patient. Despite the very long history of drugs designed to treat cough and sputum,86 no therapeutic interventions are currently available which have been demonstrated to have Level of Evidence A benefits for control of cough and sputum. A number of muco-active agents are in use in various countries and, while often popular, they are not universally available. Among these are ambroxol, bromhexine, iodinated glycerol and potassium iodide, agents believed to work by modifying the secretion of ions and water by the airway epithelium.87–89 One study suggested some symptom improvement with iodinated glycerol, but the medication was removed from the market in the United States because of toxicity concerns.90 Clinical trials with ambroxol have resulted in mixed results.91,92 A number of other “mucolytics”, many with free-SH groups, have been assessed, but have provided controversial results (Chapter 61). These agents are believed to function either as antioxidants or, potentially, as disrupters of mucus structure, i.e. as true mucolytics.93,94 Clear clinical benefits, however, have been difficult to demonstrate.95 Several studies have suggested a benefit for N-acetylcysteine, particularly in decreasing exacerbation frequency,96–98 and this has been further supported by meta-analyses.99,100 The GOLD Guidelines suggest that the benefits of N-acetylcysteine may be due to the anti-oxidant effect and rate the benefits of the medication as Level B. The guidelines, however, do not recommend use of these agents in any specific group of COPD patients until further studies are conducted. If available, an empiric trial of a muco-active agent can certainly be conducted. It seems likely that the heterogeneous collection of conditions included in COPD will include some who may respond favorably to these agents. Research in the area of muco-regulation is currently very active and several drugs which act primarily on cough and sputum, by targeting airway nerves, neuropeptides, ion transporters and cell differentiation are currently under evaluation (Chapter 62).
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Anti-tussives A number of preparations are able to suppress cough likely through a central mechanism.101 Opiates are particularly potent in this regard. Regular use of these medications, however, is contraindicated in the GOLD Guidelines due to concerns that suppression of cough can lead to retention of secretions and increased risk for infection. Treatment of weakness COPD patients are frequently bothered by symptoms in addition to cough, sputum and breathlessness.Weakness is a major feature of COPD. This may, in part, be due to the deconditioning which characterizes COPD patients. In addition, weakness may result from alterations in skeletal muscle which are secondary to the disease process itself.102,103 In this context, skeletal muscle apoptosis has been noted in COPD patients.104 Weakness in COPD patients, moreover, is a better correlate of exercise performances than is FEV1.12,105 Therapeutic agents which increase muscle mass are available, but have not yet demonstrated clinical benefit in COPD patients.106 While no specific therapeutic interventions have yet been demonstrated to have a beneficial effect by increasing strength in COPD patients, several clinical recommendations follow. First, drugs which could contribute to weakness, particularly systemic glucocorticoids, should be avoided. Second, adequate nutrition should be maintained, particularly at times of intercurrent illness when catabolism may be high and lean muscle mass may be at hazard. Antidepressants COPD patients are frequently depressed. Whether depression is a consequence of the chronic illness or represents a manifestation of the disease process is undetermined. It is interesting, however, that endogenous depression can increase the risk of an individual to become a smoker and to remain a persistent smoker. Such individuals, of course, would be at risk for developing COPD. As the disease progresses, they may manifest their underlying depression. As depression can sometimes be exacerbated by cigarettesmoking cessation, smoking cessation attempts may also unmask underlying depression in these individuals. Close clinical observation should be maintained. If depression develops, an accurate diagnosis and treatment with an appropriate antidepression regimen should be initiated.This may be essential not only in optimizing patient function, but also in preventing smoking relapse. Depression may have other, indirect effects complicating the management of COPD.107 Depressed patients are less likely to be compliant with medications, particularly those such as inhalers which require attention to detail to assure proper use. Depressed patients, moreover, are less likely to comply with an exercise program. Mortality is higher among depressed patients.108 Treatment of depression, therefore, may improve compliance with other aspects of disease management. Conversely, a successfully implemented exercise program can greatly reduce depression.107
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MANAGEMENT ISSUES Health status With the availability of standardized instruments to assess health status (sometimes termed “quality of life”), it has become clear that COPD patients experience symptomatology in a number of quantifiable domains.109,110 While groups of COPD patients show a reasonable relationship between FEV1 and health status, for individual patients, the relationship is very weak.11 It is reasonable, therefore, for health status to be regarded as a separate therapeutic goal in COPD. Several bronchodilators including ipratropium,47,48 salmeterol48,111 and formoterol112 have shown improvements in health-related quality of life for those using these instruments. To date, no drug has regulatory approval for this specific indication, however. Improvement in quality of life, however, should not be regarded as a surrogate for physiologic improvement. Health status measures reflect a variety of inputs, and it is likely that information gained from the use of these measures can help the clinician more effectively develop a strategy to utilize medications. Health status instruments are probably not helpful for clinical management of an individual patient. Recognizing that a number of domains can improve and that they may improve independently, however, can encourage the clinician to continue therapy when spirometric improvements are modest, but a patient relates to individual benefit. As noted above, several studies have been conducted to assess the effect of inhaled glucocorticoids on loss of lung function in COPD.22–24 None of the studies demonstrated a statistically significant effect on lung function decline. One of the studies, the ISOLDE Study,24 however, demonstrated an effect on the rate of decline in health status measured with the St. George’s Respiratory Questionnaire.113 While all COPD patients experience decline in health status, patients treated with placebo experienced a decline of four units, believed to be the smallest clinically meaningful change over a period of about 15 months. Patients treated with inhaled glucocorticoids experienced this same decline, but it took 24 months. Inhaled glucocorticoids, therefore, appeared to slow the inexorable decline in health status without affecting the relentless decline in lung function. This effect of glucocorticoids has been suggested to be due to an effect on exacerbations.24,113 In this context, exacerbations of COPD are associated with worsened health status which can be documented by the St. George’s Respiratory Questionnaire114 (Chapter 68). A study of shorter duration also indicated that inhaled glucocorticoids can decrease exacerbation frequency and/or intensity in patients with COPD.115 This may be responsible for the effect of inhaled glucocorticoids on health status. Prevention of exacerbations As noted above, inhaled glucocorticoids may reduce exacerbation frequency in COPD.24,115 A number of other interventions may have a similar effect. Several bronchodilators, including the short-acting anticholinergic ipratropium,116
the long-acting anticholinergic tiotropium117 and the longacting beta-agonist bronchodilator salmeterol,48 have all been reported to reduce exacerbation frequency in COPD (Chapter 68). The mechanism by which bronchodilators might affect exacerbation frequency remains undetermined. As noted above, therapy with the anti-oxidant N-acetylcysteine has been demonstrated in several large studies96–98 to reduce exacerbations, and this benefit has been supported by meta-analyses.99,100 The immunostimulator OM-65 also has been shown to have an effect in reducing the severity of exacerbations.118 Prevention of exacerbations represents a therapeutic goal distinct from improvement in lung function, although it may be connected to quality of life as noted above. This has important clinical implications. If therapy is initiated in order to prevent exacerbations, it will, generally speaking, be impossible for the clinician to gauge whether therapy in an individual patient has been beneficial. That is, patients are likely to experience a small number of exacerbations on an irregular basis.Whether exacerbation frequency is decreased in response to therapy, therefore, may be extraordinarily difficult to gauge in an individual patient. For this reason, when therapies are initiated in COPD patients, clear therapeutic intent should be defined by the clinician. Initiation of bronchodilator therapy to improve symptoms should be reassessed and therapy modified based on functional and clinical (symptomatic) response. Initiation of therapy for exacerbation prevention, in contrast, is likely to be continued for life, barring the onset of adverse side-effects. Prolongation of life It is frequently stated that oxygen therapy is the only treatment in COPD which has clearly been demonstrated to prolong life. The incorrect implication of this oft-quoted (and correct) statement is that other treatments for COPD do not prolong life. Several studies demonstrate the life-prolonging effect of oxygen. The first, the MRC trial, compared no oxygen with nocturnal oxygen in hypoxic COPD patients with evidence of right-heart failure.119 Oxygen supplementation at night significantly prolonged life. A study conducted under the auspices of the NIH in the United States compared continuous oxygen therapy (actually administered about 19 hours per day on average) and found superior survival compared with oxygen administered at night only.120 These two studies, which have been supported by several subsequent studies, have led to our current practice of oxygen administration (Chapter 55). Several subsequent studies have also evaluated survival in hypoxic COPD patients.121–123 These studies, interestingly, show a progressive improvement in the survival of hypoxic COPD patients. While there are a number of potential reasons to explain this historic trend of improving survival, including changes in diagnosis (with enrollment of milder patients with a better prognosis), with better concurrent care of non-COPD comorbidities or with more effective utilization of oxygen therapy with current devices, it is also
Treatment for Stable COPD
possible, even likely, that some improvement in survival is due to current management of COPD compared with that available 20 years ago.124 It is unlikely, moreover, that bronchodilator therapy can be compared with placebo with the outcome being survival. Even if approvable by an ethics board, few patients are likely to opt for potential randomization to a placebo when an effective therapy exists that could improve their symptoms, particularly for a study requiring several years with the endpoint being mortality! Thus, while survival data for therapeutic modalities other than oxygen do not currently exist, the practitioner can be encouraged that aggressive treatment of COPD patients is likely to be both beneficial symptomatically and may improve survival as well. End-of-life issues COPD is a relentlessly progressive disease. Patients, therefore, will deteriorate and, as the disease progresses, will be increasingly likely to experience episodes of respiratory failure. These episodes may require implementation of invasive and heroic measures such as mechanical ventilation (Chapter 58). In communities where such treatments are available, they can frequently be life-saving, at least over the short term. Prognosis for COPD patients, however, is limited once respiratory failure has ensued. In one study, patients hospitalized with a PCO2 of greater than 50 experienced a 2-year mortality of 49%. Thus, while many individuals will survive for extended periods following episodes of respiratory failure, many will not (Chapter 68).Whether heroic measures should be initiated and to what degree such measures should be extended are issues which should be discussed with COPD patients in advance. Obviously, such decisions are always subject to reconsideration. Nevertheless, careful attention toward preparing advance directives can frequently expedite the delivery of appropriate care as COPD progresses.
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88. Ziment I. Inorganic and organic iodides. In: Braga PC, Allegra L (eds) Drugs in Bronchial Mucology, pp. 251–60. New York: Raven Press, 1989. 89. Disse BG. The pharmacology of ambroxol – review and new results. Eur. J. Respir. Dis. Suppl. 1987; 153:255–62. 90. Petty TL. The national mucolytic study. Results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis. Chest 1990; 97:75–83. 91. Guyatt GH, Townsend M, Kazim F, Newhouse MT. A controlled trial of ambroxol in chronic bronchitis. Chest 1987; 92:618–20. 92. Olivieri D, Zavattini G, Tomasini G et al. Ambroxol for the prevention of chronic bronchitis exacerbations: long-term multicenter trial. Protective effect of ambroxol against winter semester exacerbations: a double-blind study versus placebo. Respiration 1987; 51:42–51. 93. Dechant K, Noble S. Erdosteine (new drug profile). Drugs 1996; 52:875–81. 94. Marchioni CF, Polu JM, Taytard A, Hanard G, Noseda G, Mancini C. Evaluation of efficacy and safety of erdosteine in patients affected by chronic bronchitis during an infective exacerbation phase and receiving amoxycillin as basic treatment (ECOBES, European Chronic Obstructive Bronchitis Erdosteine Study). Int. J. Clin. Pharm.Ther. 1995; 33:612–18. 95. Braga PC, Allegra L (eds) Drugs in Bronchial Mucology, New York: Raven Press, 1989. 96. Hansen NCG, Skriver A, Brorsen-Riis L et al. Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis. Resp. Med. 1994; 88:531–5. 97. Babolini G, Blasi A, Cornia G et al. for the Multicenter Study Group. Long-term oral acetylcysteine in chronic bronchitis, a double-blind controlled study. Eur. J. Respir. Dis. 1980; 61:93–108. 98. Boman G, Backer U, Larsson S, Melander B, Wahlander L. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. Eur. J. Respir. Dis. 1983; 64:405–15. 99. Grandjean EM, Berthet P, Ruffmann R, Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials. Clin.Ther. 2000; 22:209–21. 100. Stey C, Steurer J, Bachmann S, Medici TC, Tramer MR. The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Eur. Respir. J. 2000; 16:253–62. 101. Irwin RS, Curley FJ, Pratter MR. The effects of drugs on cough. Eur. J. Respir. Dis. Suppl. 1987; 153:173–81. 102. Engelen MP, Schols AM, Lamers RJ, Wouters EF. Different patterns of chronic tissue wasting among patients with chronic obstructive pulmonary disease. Clin. Nutr. 1999; 18:275–80. 103. Casaburi R. Skeletal muscle function in COPD. Chest 2000; 117:267S–71S. 104. Agusti AGN, Sauleda J, Batle S et al. Skeletal muscle apoptosis in COPD. Eur. Resp. J. 2000; 16:575S. 105. Nici L. Mechanisms and measures of exercise intolerance in chronic obstructive pulmonary disease. Clin. Chest Med. 2000; 21:693–704. 106. Casaburi R. Rationale for anabolic therapy to facilitate rehabilitation in chronic obstructive pulmonary disease. Baillières Clin. Endocrinol. Metab. 1998; 12:407–18. 107. Borson S, Claypoole K, McDonald GJ. Depression and chronic obstructive pulmonary disease: treatment trials. Semin. Clin. Neuropsych. 1998; 3:115–30. 108. Fried TR, Pollack DM, Tinetti ME. Factors associated with sixmonth mortality in recipients of community-based long-term care. J. Am. Geriatr. Soc. 1998; 46:193–7. 109. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A selfcomplete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am. Rev. Respir. Dis. 1992; 145:1321–7.
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110. Guyatt GH, Berman LB, Townsend M, Pugley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax 1987; 42:773–8. 111. Jones PW, Bosh TK. Quality of life changes in COPD patients treated with salmeterol. Am. J. Respir. Crit. Care Med. 1997; 155:1283–9. 112. Appleton S, Smith B, Veale A, Bara A. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 2000; 2. 113. Spencer S, Calverley PM, Sherwood Burge P, Jones PW. Health status deterioration in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 163:122–8. 114. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 157:1418–22. 115. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimiou J. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998; 351:773–80. 116. Friedman M, Serby CW, Menjoge SS, Wilson JD, Hilleman DE, Witek JJ Jr. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest 1999; 115:635–41. 117. Jones PW, Koch P, Menjoge SS, Witek TJ. The impact of COPD exacerbations (EXAC) on health related quality of life (HRQL) is attenuated by tiotropium (TIO). Am. J. Respir. Crit. Care Med. 2001; 163:A771.
118. Collet JP, Shapiro P, Ernst P, Renzi T, Ducruet T, Robinson A. Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. The PARI_IS Study steering committee and research group. Prevention of acute respiratory infection by an immunostimulant. Am. J. Respir. Crit. Care Med. 1997; 156:1719–24. 119. Stuart-Harris C, Bishop JM, Clark TJH et al. Medical Research Council Work Group. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1:681–6. 120. Kvale PA, Cugell DW, Anthonisen NR et al. for the Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. Ann. Intern. Med. 1980; 93:391–8. 121. Cooper JA. Kinetics of pulmonary inflammatory mediator production during development of cyclophosphamide-induced pulmonary injury. (In press). 122. Strom K. Survival of patients with chronic obstructive pulmonary disease receiving long-term domiciliary oxygen therapy. Am. Rev. Respir. Dis. 1993; 147:585–91. 123. Carrera M, Sauleda J, Bauza F et al. The results of the operation of a monitoring unit for home oxygen therapy. Arch. Bronconeumol. 1999; 35:33–8. 124. Rennard S, Carrera M, Agusti AGN. Management of chronic obstructive pulmonary disease: are we going anywhere? Eur. Respir. J. 2000; 16:1035–6.
Acute Exacerbations of COPD
Chapter
68
J.A. Wedzicha St Bartholomew’s and Royal London School of Medicine and Dentistry, London, UK
EPIDEMIOLOGY OF COPD E X A C E R B AT I O N S There has been considerable recent interest into the causes and mechanisms of exacerbations of COPD, as COPD exacerbations are an important cause of the considerable morbidity and mortality found in COPD.1 COPD exacerbations increase with increasing severity of COPD. Some patients are prone to frequent exacerbations that are an important cause of hospital admission and readmission and these frequent exacerbations may have considerable impact on quality of life and activities of daily living.2 COPD exacerbations are also associated with considerable physiological deterioration and increased airway inflammatory changes3 that are caused by a variety of factors such as viruses, bacteria and possibly common pollutants (Fig. 68.1). COPD exacerbations are more common in the winter months and there may be important interactions between cold temperatures and exacerbations caused by viruses or pollutants.4 Earlier descriptions of COPD exacerbations have concentrated mainly on studies of hospital admission, though most COPD exacerbations are treated in the community and not associated with hospital admission. A cohort of moderate to severe COPD patients was followed in East London, UK (East London COPD Study) with daily diary cards and peak flow readings. The patients were asked to report
Pollutants
exacerbations as soon as possible after symptomatic onset.2 The diagnosis of COPD exacerbation was based on criteria modified from those described by Anthonisen and colleagues,5 that require two symptoms for diagnosis, one of which must be a major symptom of increased dyspnea, sputum volume or sputum purulence. Minor exacerbation symptoms included cough, wheeze, sore throat, nasal discharge or fever (Table 68.1). The study found that about 50% of exacerbations were unreported to the research team, despite the considerable encouragement provided and only diagnosed from diary cards, though there were no differences in major symptoms or physiological parameters between reported and unreported exacerbations.2 Patients with COPD are accustomed to frequent symptom changes and thus may tend to underreport exacerbations to physicians. These patients have high levels of anxiety and depression and may accept their situation.6,7 The tendency of patients to underreport exacerbations may explain the higher total rate of exacerbations at 2.7 per patient per year, which is higher than previously reported by Anthonisen and co-workers5 at 1.1 per patient per year. However, in the latter study, exacerbations were unreported and diagnosed from patients’ recall of symptoms.
Table 68.1. Diagnosis of exacerbation
Major symptoms
Dyspnea Increase in sputum volume Sputum purulence
Minor symptoms
Cough Wheeze Sore throat Common cold symptoms (nasal congestion/discharge)
Temperature
Exacerbations
Respiratory viruses Fig. 68.1. Etiology of COPD exacerbations.
Bacteria
Definition requires 2 symptoms, one of which at least must be a major symptom. Symptoms must be present for 2 consecutive days. Adapted from Refs 2 and 3.
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Using the median number of exacerbations as a cut-off point, COPD patients in the East London Study were classified as frequent and infrequent exacerbators. Quality of life scores measured using a validated disease-specific scale – the St George’s Respiratory Questionnaire (SGRQ) – were significantly worse in all of its three component scores (symptoms, activities and impacts) in the frequent, compared with the infrequent exacerbators. This suggests that exacerbation frequency is an important determinant of health status in COPD and is thus one of the important outcome measures in COPD. Factors predictive of frequent exacerbations included daily cough and sputum and frequent exacerbations in the previous year. A previous study of acute infective exacerbations of chronic bronchitis found that one of the factors predicting exacerbation was also the number in the previous year,8 though this study was limited to exacerbations presenting with purulent sputum and no physiological data were available during the study. In a further prospective analysis of 504 exacerbations, where daily monitoring was performed, there was some deterioration in symptoms, though no significant peak flow changes.9 Falls in peak flow and FEV1 at exacerbation were generally small and not useful in predicting exacerbations, but larger falls in peak flow were associated with symptoms of dyspnea, presence of colds and related to longer recovery time from exacerbations. Symptoms of dyspnea, common colds, sore throat and cough increased significantly during the prodromal phase and this suggests that respiratory viruses may have early effects at exacerbations. The median time to recovery of peak flow was 6 days and 7 days for symptoms, but at 35 days peak flow had returned to normal in only 75% of exacerbations, while at 91 days, 7.1% of exacerbations had not returned to baseline lung function. Recovery was longer in the presence of increased dyspnea or symptoms of a common cold at exacerbation. The changes observed in lung function at exacerbation were smaller than those observed at asthmatic exacerbations, though the average duration of an asthmatic exacerbation was longer at 9.6 days.10,11 The reasons for the incomplete recovery of symptoms and lung function are not clear, but may involve inadequate treatment or persistence of the causative agent. The incomplete physiological recovery after an exacerbation could contribute to the decline in lung function with time in patients with COPD. However to date there is no evidence that patients with incomplete recovery of their exacerbation have a greater decline in lung function and further studies on the natural history of COPD exacerbations are required. The association of the symptoms of increased dyspnea and of the common cold at exacerbation with a prolonged recovery suggests that viral infections may lead to more prolonged exacerbations. As colds are associated with longer exacerbations, COPD patients who develop a cold may be prone to more severe exacerbations and should be considered for therapy early at onset of symptoms.
A I R WAY I N F L A M M AT I O N AT E X A C E R B AT I O N Although it has been assumed that exacerbations are associated with increased airway inflammation, there has been little information available on the nature of inflammatory markers especially when studied close to an exacerbation, as performing bronchial biopsies at exacerbation is difficult in patients with moderate to severe COPD. The relation of any airway inflammatory changes to symptoms and physiological changes at exacerbations of COPD is also an important factor to consider. In one study, where biopsies were performed at exacerbation in patients with chronic bronchitis, increased airway eosinophilia was found, though the patients studied had only mild COPD.12 With exacerbation, there were more modest increases observed in neutrophils, T-lymphocytes (CD3) and tumor necrosis factor-a (TNF-a) positive cells, while there were no changes in CD4 or CD8 T cells, macrophages or mast cells. However the technique of sputum induction allows study of these patients at exacerbation and it has been shown that it is a safe and well-tolerated technique in COPD patients.13 Levels of inflammatory cytokines have been shown to be elevated in induced sputum in COPD patients when stable, though changes at exacerbation had not been previously studied.14 In a prospectively followed cohort of patients from the East London COPD Study, inflammatory markers in induced sputum were related to symptoms and physiological parameters both at baseline and at exacerbation.3 There was a relation between exacerbation frequency and sputum cytokines, in that there was increased sputum IL-6 and IL-8 found in patients at baseline when stable with frequent exacerbations, compared with those with infrequent exacerbations (Fig. 68.2), although there was no relation between cytokines and baseline lung function. Sputum cell counts were not increased at baseline in patients with more frequent exacerbations suggesting that the increased cytokine production comes from the bronchial epithelium in COPD. As discussed below, exacerbations are triggered by viral infections, especially by rhinovirus that is the cause of the common cold. Rhinovirus has been shown to increase cytokine production in an epithelial cell line15 and thus repeated viral infection may lead to up-regulation of cytokine airway expression. At exacerbation, increases were found in induced sputum interleukin (IL)-6 levels and the levels of IL-6 were higher when exacerbations were associated with symptoms of the common cold (Fig. 68.3). Experimental rhinovirus infection has been shown to increase sputum IL-6 in normal subjects and asthmatics.16–18 However, rises in cell counts and IL-8 were more variable with exacerbation and not reaching statistical significance, suggesting marked heterogeneity in the degree of the inflammatory response at exacerbation. The exacerbation IL-8 levels were related to sputum neutrophil and total cell counts, indicating that neutrophil recruitment is the major source of airway IL-8 at exacerbation. Lower
Acute Exacerbations of COPD
(a)
IL-6 pg/ml
300
200
100
0
n⫽
21 ⭐2
23 ⭓3
No. of exacerbations in previous year
IL-8 pg/ml
(b)
20 000
10 000
0
n⫽
21 ⭐2
23 ⭓3
No. of exacerbations in previous year Fig. 68.2. (a) Induced sputum levels of IL-6 in patients who are categorized as frequent exacerbators (more than three exacerbations in the previous year) and those who are infrequent exacerbators (less than two exacerbations in previous year). Data is expressed as medians (IQR) (reproduced from Bhowmik et al.3). (b) Induced sputum levels of IL-8 in patients with frequent exacerbations and infrequent exacerbations. Data are expressed as medians (IQR) (reproduced with permission from Bhwomik et al.3).
1000
IL-6 pg/ml
800 600 400 200 0
n⫽
18 No cold
19 Cold
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airway IL-8 has been shown to increase with experimental rhinovirus infection in normal and asthmatic patients in some studies,17 but not in others.18 However, COPD patients already have up-regulated airway IL-8 levels when stable due to their high sputum neutrophil load14 and further increases in IL-8 would be unlikely. COPD exacerbations are associated with a less pronounced airway inflammatory response than asthmatic exacerbations,19 and this may explain the relatively reduced response to steroids seen at exacerbation in COPD patients, relative to asthma.20–26 In the study performed by Bhowmik and colleagues,3 there was no increase seen in the eosinophil count at exacerbation, even though the patients in that study were sampled early at exacerbation with onset of symptoms. Compared with the study by Saetta and colleagues,12 where patients had mild COPD, the patients had more severe and irreversible airflow obstruction with an FEV1 at 39% predicted. Thus it is possible that the inflammatory response at exacerbation is different in nature in patients with moderate to severe COPD than in patients with milder COPD. Patients were followed with daily diary cards in the study by Bhowmik and colleagues3 and thus the inflammatory response could be related to exacerbation recovery. There was no relation between the degree of inflammatory cell response with exacerbation and duration of symptoms and lung function changes. Induced sputum markers taken 3 to 6 weeks after exacerbation showed no relation to exacerbation changes. Thus levels of induced sputum markers at exacerbation do not predict the subsequent course of the exacerbation and will not be useful in the prediction of exacerbation severity.
ETIOLOGY COPD exacerbations have been associated with a number of etiological factors, including infection and pollution episodes (Table 68.2). COPD exacerbations are frequently triggered by upper respiratory tract infections and these are more common in the winter months, when there are more respiratory viral infections in the community. Patients may also be more prone to exacerbations in the winter months, as lung function in COPD patients shows small but significant falls with reduction in outdoor temperature during the winter months.4 COPD patients have been found to have increased hospital admissions, suggesting increased exacerbation when increasing environmental pollution occurs. During the December 1991 pollution episode in the UK, COPD mortality was increased together with an increase in hospital admission in elderly COPD patients.27 However, common pollutants especially oxides of nitrogen and particulates may interact with viral infection to precipitate exacerbation rather than acting alone.28
Presence of common cold symptoms Fig. 68.3. Induced sputum IL-6 levels in the absence and presence of a natural cold. Data are expressed as medians (IQR) (reproduced with permission from Bhwomik et al.3).
Viral infections Viral infections are an important trigger for COPD exacerbations. Studies in childhood asthma have shown that
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Table 68.2. Causes of COPD exacerbations
Viruses
Rhinovirus (common cold) Influenza Parainfluenza Coronavirus Adenovirus RSV Chlamydia pneumoniae
Bacteria
Haemophilus influenzae Streptococcus penumoniae Branhamella cattarhalis Staphylococcus aureus Pseudomonas aeruginosa
Common pollutants
Nitrogen dioxide Particulates Sulfur dioxide Ozone
viruses, especially rhinovirus (the cause of the common cold) can be detected by polymerase chain reaction from a large number of these exacerbations.29 Rhinovirus has not hitherto been considered to be of much significance during exacerbations of COPD. In a study of 44 chronic bronchitics over 2 years, Stott and colleagues30 found rhinovirus in 13 (14.9%) of 87 exacerbations of chronic bronchitis. In a more detailed study of 25 chronic bronchitics with 116 exacerbations over 4 years, Gump et al.31 found that only 3.4% of exacerbations could be attributed to rhinoviruses. In a more recent study of 35 episodes of COPD exacerbation using serological methods and nasal samples for viral culture, little evidence was found for a rhinovirus etiology of COPD exacerbation.32 Two recent studies showed that at least one-third of COPD exacerbations was associated with viral infections, and that the majority of these were due to rhinovirus.33,34 Viral exacerbations were associated with symptomatic colds and prolonged recovery.9 However Seemungal and colleagues34 showed that rhinovirus can be recovered from induced sputum more frequently than from nasal aspirates at exacerbation, suggesting that wild-type rhinovirus can infect the lower airway and contribute to inflammatory changes at exacerbation. They also found that exacerbations associated with the presence of rhinovirus in induced sputum had larger increases in airway IL-6 levels,34 suggesting that viruses increase the severity of airway inflammation at exacerbation. This finding is in agreement with the data that respiratory viruses produce longer and more severe exacerbations and have a major impact on health care utilization.9,33 Other viruses may trigger COPD exacerbation, though coronavirus was associated with only a small proportion of asthmatic exacerbations and is unlikely to play a major role in COPD.29,35
Bacterial colonization Airway bacterial colonization has been found in approximately 30% of COPD patients, and this colonization has been shown to be related to the degree of airflow obstruction and current cigarette smoking status.36 Although bacteria such as Haemophilus influenzae and Streptococcus pneumoniae have been associated with COPD exacerbation, some studies have shown increasing bacterial counts during exacerbation, while others have not confirmed these findings.37,38 Soler and colleagues39 showed that the presence of potentially pathogenic organisms in bronchoalveolar lavage from COPD patients at bronchoscopy was associated with a greater degree of neutrophilia and higher TNF-a levels. Hill and colleagues40 in a larger study showed that the airway bacterial load was related to inflammatory markers. They also found that the bacterial species was related to the degree of inflammation, with Pseudomonas aeruginosa colonization showing greater myeloperoxidase activity (an indirect measure of neutrophil activation). Thus bacterial colonization in COPD may be an important determinant of airway inflammation and thus further long-term studies are required as to whether bacterial colonization predisposes to decline in lung function, characteristic of COPD. There is no evidence that patients with frequent exacerbations have increased sputum bacterial colonization to explain the higher cytokine levels observed in the frequent exacerbator patient group.3 However, it is also possible that there may be interactions between viral and bacterial infection at COPD exacerbation. Other organisms such as Chlamydia pneumoniae, that have been associated with asthmatic exacerbation, may also play a role in COPD exacerbation.
PAT H O P H Y S I O L O G I C A L C H A N G E S Relatively little information is available on pathological changes in the airway during COPD exacerbation. In patients with moderate and severe COPD, the mechanical performance of the respiratory muscles is reduced. The airflow obstruction leads to hyperinflation, with the respiratory muscles acting at a mechanical disadvantage and generating reduced inspiratory pressures. The load on the respiratory muscles is also increased in patients with airflow obstruction by the presence of intrinsic positive endexpiratory pressure (PEEP). With an exacerbation of COPD, the increase in airflow obstruction will further increase the load on the respiratory muscles and increase the work of breathing, precipitating respiratory failure in more severe cases. The minute ventilation may be normal, but the respiratory pattern will be irregular with increased frequency and decreased tidal volume. The resultant hypercapnia and acidosis will then reduce inspiratory muscle function, contributing to further deterioration of the respiratory failure. Hypoxemia in COPD usually occurs due to a combination of ventilation-perfusion mismatch and hypoventilation,
Acute Exacerbations of COPD
although arterio-venous shunting can also contribute in the acute setting.This causes increase in pulmonary artery pressure, which can lead to salt and water retention and the development of edema. The degree of the ventilation perfusion abnormalities increases during acute exacerbations and then resolves over the following few weeks. Acidosis is an important prognostic factor in survival from respiratory failure during a COPD exacerbation and thus early correction of acidosis is an essential goal of therapy.
T R E AT M E N T Inhaled bronchodilator therapy Beta-2-agonists and anti-cholinergic agents are the inhaled bronchodilators most frequently used in the treatment of acute exacerbations of COPD. In patients with stable COPD, symptomatic benefit can be obtained with bronchodilator therapy in COPD, even without significant changes in spirometry. This is probably due to a reduction in dynamic hyperinflation that is characteristic of COPD and hence leads to a decrease in the sensation of dyspnea especially during exertion.41 In stable COPD, greater bronchodilatation has been demonstrated with anti-cholinergic agents than with b2-agonists, which may be due to the excessive cholinergic neuronal bronchoconstrictor tone.42 However, studies investigating bronchodilator responses in acute exacerbations of COPD have shown no differences between agents used and no significant additive effect of the combination therapy, even though the combination of an anticholinergic and bronchodilator has benefits in the stable state.43,44 This difference in effect between the acute and stable states may be due to the fact that the larger doses of drug delivered in the acute setting produce maximal bronchodilatation, whereas the smaller doses administered in the stable condition may be having a submaximal effect. Methylxanthines, such as theophylline, are sometimes used in the management of acute exacerbations of COPD. There is some evidence that theophyllines are useful in COPD, though the main limiting factor is the frequency of toxic side-effects. The therapeutic action of theophylline is thought to be due to its inhibition of phosphodiesterase which breaks down cyclic AMP, an intracellular messenger, thus facilitating bronchodilatation. However, studies of intravenous aminophylline therapy in acute exacerbations of COPD have shown no significant beneficial effect over and above conventional therapy.45 There are some reports of beneficial effects of methylxanthines upon diaphragmatic and cardiac function, though these mechanisms require further study in patients with COPD exacerbations. Corticosteroids Only about 10 to 15% of patients with stable COPD show a spirometric response to oral corticosteroids46 and, unlike the situation in asthma, steroids have little effect on airway inflammatory markers in patients with COPD.47,48 Although corticosteroids have traditionally been used in the management
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of acute exacerbations of COPD, there is only recently evidence of their beneficial role in the acute situation.20–26 A number of early studies have investigated the effects of corticosteroid therapy on COPD exacerbation. In an early controlled trial in patients with COPD exacerbations and acute respiratory failure, Albert and co-workers20 found that there were larger improvements in pre- and postbronchodilator FEV1 when patients were treated for the first 3 days of the hospital admission with intravenous methylprednislone than those treated with placebo. Another trial found that a single dose of methylprednisolone given within 30 minutes of arrival in the accident and emergency department produced no improvement after 5 hours in spirometry, and also had no effect on hospital admission, though another study reduced readmission.21,22 A retrospective study of patients treated with steroids at exacerbation compared with those not treated showed that the steroid group had a reduced chance of relapse after therapy.23 Thompson and colleagues24 gave a 9-day course of prednisolone or placebo in a randomized manner to out-patients presenting with acute exacerbations of COPD. Unlike the previous studies, these patients were either recruited from out-patients or from a group that were pre-enrolled and selfreported the exacerbation to the study team. In this study, patients with exacerbations associated with acidosis or pneumonia were excluded, so exacerbations of moderate severity were generally included. Patients in the steroidtreated group showed a more rapid improvement in PaO2, alveolar-arterial oxygen gradient, FEV1, peak expiratory flow rate and a trend towards a more rapid improvement in dyspnea. In a recent cohort study by Seemungal and colleagues,9 the effect of therapy with prednisolone on COPD exacerbations diagnosed and treated in the community was studied. Exacerbations treated with steroids were more severe and associated with larger falls in peak flow rate. The treated exacerbations also had a longer recovery time to baseline for symptoms and peak flow rate. However, the rate of peak flow rate recovery was faster in the prednisolone-treated group, though not the rate of symptom score recovery. An interesting finding in this study was that steroids significantly prolonged the median time from the day of onset of the initial exacerbation to the next exacerbation from 60 days in the group not treated with prednisolone, to 84 days in the patients treated with prednisolone. In contrast, antibiotic therapy had no effect on the time to the next exacerbation. If short course oral steroid therapy at exacerbation does prolong the time to the next exacerbation, then this could be an important way to reduce exacerbation frequency in COPD patients, which is an important determinant of health status.2 Davies and colleagues25 studied patients admitted to hospital with COPD exacerbations who were randomized to prednisolone or placebo. In the prednisolone group, the FEV1 rose faster until day 5, when a plateau was observed in the steroid-treated group. Changes in the pre-bronchodilator and post-bronchodilator FEV1 were similar suggesting that
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this is not just an effect on bronchomotor tone, but involves faster resolution of airway inflammatory changes or airway wall edema with exacerbation. Length of hospital stay analysis showed that patients treated with prednisolone had a significantly shorter length of stay. Six weeks later, there were no differences in spirometry between the patient groups and health status was similar to that measured at 5 days after admission. Thus the benefits of steroid therapy at exacerbation are most obvious in the early course of the exacerbation. A similar proportion of the patients, approximately 32% in both study groups required further treatment for exacerbations within 6 weeks of follow-up, emphasizing the high exacerbation frequency in these patients. Niewoehner and colleagues26 performed a randomized controlled trial of either a 2-week or 8-week prednisolone course at exacerbation compared with placebo, in addition to other exacerbation therapy. The primary end point was a first treatment failure, including death, need for intubation, readmission or intensification of therapy. There was no difference in the results using the 2- or 8-week treatment protocol. The rates of treatment failure were higher in the placebo group at 30 days, compared with the combined 2- and 8-week prednisolone groups. As in the study by Davies and colleagues, the FEV1 improved faster in the prednisolonetreated group, though there were no differences by 2 weeks. In contrast, Niewoehner and colleagues performed a detailed evaluation of steroid complications and found considerable evidence of hyperglycemia in the steroid-treated patients. Thus steroids should be used at COPD exacerbation in short courses of no more than 2 weeks duration to avoid risk of complications.
taken in providing supplemental oxygen to patients with COPD, particularly during acute exacerbations, when respiratory drive and muscle strength can be impaired leading to significant increases in carbon dioxide tension at relatively modest oxygen flow rates. However, in the vast majority of cases, the administration of supplemental oxygen increases arterial oxygen tension sufficiently without clinically significant rises in carbon dioxide. It is suggested that supplemental oxygen is delivered at an initial flow rate of 1–2 L/minute via nasal cannulae or 24–28% inspired oxygen via Venturi mask, with repeat blood gas analysis after 30–45 minutes of oxygen therapy. Hypercapnia during COPD exacerbations may be managed initially with the use of respiratory stimulants. The most commonly used is doxapram, which acts centrally to increase respiratory drive and respiratory muscle activity. The effect is probably only appreciable for 24 to 48 hours, the main factor limiting its use being side-effects which can lead to agitation and are often not tolerated by the patient. There are only a few studies of the clinical efficacy of doxapram and short-term investigations suggest that improvements in acidosis and arterial carbon dioxide tension can be attained.51 A small study comparing doxapram with noninvasive ventilation (NIPPV) in acute exacerbations of COPD, suggested that NIPPV was superior with regard to correction of blood gases during the initial treatment phase.52 Increases in pulmonary artery pressure during acute exacerbations of COPD can result in rightsided cardiac dysfunction and development of peripheral edema. Diuretic therapy may thus be necessary if there is edema or a rise in jugular venous pressure.
Antibiotics Acute exacerbations of COPD often present with increased sputum purulence and volume and antibiotics have traditionally been used as first-line therapy in such exacerbations. However, viral infections may be the triggers in a significant proportion of acute infective exacerbations in COPD and antibiotics used for the consequences of secondary infection. A study investigating the benefit of antibiotics in over 300 acute exacerbations demonstrated a greater treatment success rate in patients treated with antibiotics, especially if their initial presentation was with the symptoms of increased dyspnea, sputum volume and purulence.5 Patients with mild COPD obtained less benefit from antibiotic therapy. A randomized placebo-controlled study investigating the value of antibiotics in patients with mild obstructive lung disease in the community concluded that antibiotic therapy did not accelerate recovery or reduce the number of relapses.49 A meta-analysis of trials of antibiotic therapy in COPD identified only nine studies of significant duration and concluded that antibiotic therapy offered a small but significant benefit in outcome in acute exacerbations.50
Ventilatory support Noninvasive ventilation The introduction of noninvasive positive pressure ventilation (NIPPV) using nasal or face masks, has had a major impact on the management of acute exacerbations and has enabled acidosis to be corrected at an early stage. Studies have shown that NIPPV can produce improvements in pH relatively rapidly, at 1 hour after instituting ventilation.53,54 This will allow time for other conventional therapy to work, such as oxygen therapy, bronchodilators, steroids and antibiotics and thus reverse the progression of respiratory failure and reduce mortality. With NIPPV, there are improvements in minute ventilation, reductions in respiratory rate and in transdiaphragmatic activity. Thus NIPPV can improve gas exchange and allows respiratory muscle rest in respiratory failure. With the use of NIPPV patient comfort is improved. There is also no requirement for sedation with preservation of speech and swallowing. The technique can be applied in a general ward, though a high dependency area is preferable and intensive care is unnecessary. Patient cooperation is important in application of NIPPV. The main advantage of the use of NIPPV is avoidance of tracheal intubation and the ability to offer ventilatory support to patients with respiratory failure due to severe
Management of respiratory failure Hypoxemia occurs with more severe exacerbations and usually requires hospital admission. Caution should always be
Acute Exacerbations of COPD
COPD, who would be considered unsuitable for intubation. A lower incidence of nosocomial penumonia has also been reported with the use of NIPPV compared with conventional intubation and ventilation. Following a number of uncontrolled studies, randomized controlled trials have shown benefit of NIPPV in acute COPD exacerbations. A UK study showed that with the use of NIPPV in exacerbations of respiratory failure, earlier correction of pH can be achieved, together with reduction in breathlessness over the initial 3 days of ventilation, compared with a control standard therapy group.53 A study from the USA showed a significant reduction in intubation rates with NIPPV from 67% in a group receiving conventional therapy to 9% in the NIPPV group.55 A third study showed convincingly that in patients with exacerbations of respiratory failure, the use of NIPPV with pressure support ventilation, reduces the need for intubation and mortality was significantly reduced from 29% in the conventionally treated group to 9% in the NIPPV group.54 Complications, which were specifically associated with the use of mechanical ventilation, were also reduced. The difference in mortality disappeared after adjustment for intubation, suggesting that the benefits with NIPPV are due to fewer patients requiring intubation.This was also the first study to show that hospital length of stay can be reduced with use of NIPPV. A recent study showed that NIPPV can be applied on general wards, though patients with more severe acidosis had a worse outcome.56 These studies have treated patients where the pH was below 7.35, rather than just below 7.26, when the prognosis of COPD worsens. A number of these patients may have improved without NIPPV, though it seems that the major effect of NIPPV is the earlier correction of acidosis and thus avoidance of tracheal intubation, with all its associated complications. Studies have shown that NIPPV can be successfully implemented in up to 80% of cases.57,58 NIPPV is less successful in patients who have worse blood gases at baseline before ventilation, are underweight, have a higher incidence of pneumonia, have a greater level of neurological deterioration and where compliance with the ventilation is poor.57 Moretti and colleagues59 have recently shown that “late treatment failure” (after an initial 48 hours of therapy with NIPPV) is up to 20% and that patients with late failure were more likely to have severe functional and clinical disease with more complications at the time of admission. Identification of patients with a potentially poor outcome is important as delay in intubation can have serious consequences for the patient. Indications for invasive ventilation If NIPPV fails, or is unavailable in the hospital, invasive ventilation may be required in the presence of increasing acidosis (Chapter 58). It may be considered in any patient when the pH falls below 7.26. Decisions to ventilate these patients may be difficult, though with improved modes of invasive ventilatory support and better weaning techniques, the outlook for the COPD patient is better.
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Patients will be suitable for tracheal intubation if this is the first presentation of COPD exacerbation or respiratory failure, or there is a treatable cause of respiratory failure, such as pneumonia. Information will be required on the past history and quality of life, especially the ability to perform daily activities. Patients with severe disabling and progressive COPD may be less suitable, but it is important that adequate and appropriate therapy has been used in these patients, with documented disease progression. The patient’s wishes and those of any close relatives should be considered in any decision to institute or withhold lifesupporting therapy. Supported discharge Many hospital admissions are related to exacerbations of COPD and thus reductions of admissions, especially during the winter months when they are most frequent, is particularly desirable. Over the last few years, a number of different models of supported discharge have been developed and some evaluated.60–62 Patients have been discharged early with an appropriate package of care organized, including domiciliary visits made to these patients after discharge by trained respiratory nurses. Cotton and colleagues61 randomized patients either to discharge on the next day or to usual management and found that there were no differences in mortality or readmission rates between the two groups. There was a reduction in hospital stay from a mean of 6.1 days to 3.2 days. In another larger study by Skwarska and colleagues,62 patients were randomized either to discharge on the day of assessment or to conventional management. Again there were no differences in readmission rates, no differences in visits to primary care physicians, and health status measured 8 weeks after discharge was similar in the two groups. The authors also demonstrated that there were significant cost savings of around 50% for the home support group, compared with the admitted group. However, other considerations need to be taken into account in organizing an assisted discharge service, in that resources have to be released for the nurses to follow the patients and the benefits may be seasonal, as COPD admissions are a particular problem in the winter months. Further work is required on the different models of supported discharge available and the cost-effectiveness of these programs. Prevention of COPD exacerbation There has been relatively little attention paid to aspects of prevention of exacerbations in patients with COPD. As respiratory tract infections are common factors in causing exacerbation, influenza and pneumococcal vaccinations are recommended for all patients with significant COPD. A study that reviewed the outcome of influenza vaccination in a cohort of elderly patients with chronic lung disease found that influenza vaccination is associated with significant health benefits with fewer outpatient visits, fewer hospitalizations and a reduced mortality.63 Long-term antibiotic therapy has been used in patients with very frequent exacerbations,
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though there is little evidence of effectiveness. Recently there has been a report of the effects of an immunostimulatory agent in patients with COPD exacerbations, with reduction in severe complications and hospital admissions in the actively treated group.64 Further studies on the effects of these agents in the prevention of COPD exacerbation are required. In the recent ISOLDE study of long-term inhaled steroids in patients with moderate to severe COPD, a small reduction in exacerbation frequency was demonstrated. However, the overall exacerbation frequency was relatively low in that study and this was probably due to a retrospective assessment of exacerbation.65 Another earlier study suggested that the severity of exacerbations may be reduced with inhaled steroid therapy.66 An observational study showed that exacerbations were increased following withdrawal of inhaled steroids, though this study was not placebocontrolled.67 Two recent studies have also shown that small reductions in exacerbations can be achieved with bronchodilator therapy, though both studies involved relatively short periods of therapy at 12 weeks.68,69 Mahler and colleagues68 found that the time to the first exacerbation was longer with therapy with the long-acting beta-agonist, salmeterol, though the overall number of exacerbations during the study was relatively small. Van Noord and colleagues69 in a similar study suggested that the combination of salmeterol and ipratropium was most effective in reduction of exacerbation. Longer-term studies of the effects of bronchodilators on COPD exacerbation are now required.
PAT I E N T E D U C AT I O N There is a need for increased patient education about detecting and treating exacerbations early in the natural history (Chapter 69). More specific written treatment plans for COPD patients at risk may be useful, as are produced for asthmatics, though such an approach requires formal testing. Following an exacerbation, the COPD patient’s condition should be reviewed and attention given to risk factors and compliance with therapy. Strategies to reduce exacerbation frequency need to be urgently developed.We will then be in a better position to reduce significantly the morbidity associated with COPD exacerbation and improve the health-related quality of life of our patients in this disabling condition.
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4. Donaldson GC, Seemungal T, Jeffries DJ, Wedzicha JA. Effect of environmental temperature on symptoms, lung function and mortality in COPD patients. Eur. Respir. J. 1999; 13:844–9. 5. Anthonisen NR, Manfreda J,Warren CPW, Hershfield ES, Harding GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann. Intern. Med. 1987; 106:196–200. 6. Okubadejo AA, Jones PW, Wedzicha JA. Quality of life in patients with COPD and severe hypoxaemia. Thorax 1996; 51: 44–7. 7. Okubadejo AA, O’Shea L, Jones PW, Wedzicha JA. Home assessment of activities of daily living in patients with severe chronic obstructive pulmonary disease on long term oxygen therapy. Eur. Respir. J. 1997; 10:1572–5. 8. Ball P, Harris JM, Lowson D,Tillotson G,Wilson R. Acute infective exacerbations of chronic bronchitis. Q. J. Med. 1995; 88:61–8. 9. Seemungal TAR, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 161:1608–13. 10. Reddel HS, Ware S, Marks G, Salome C, Jenkins C, Woolcock A. Differences between asthma exacerbations and poor asthma control. Lancet 1999; 353:364–9. 11. Tattersfield AE, Postma DS, Barnes PJ et al. Exacerbations of asthma. Am. J. Respir. Crit. Care Med. 1999; 160: 594–9. 12. Saetta M, Di Stefano A, Maestrelli P et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am. J. Respir. Crit. Care Med. 1994; 150:1646–52. 13. Bhowmik A, Seemungal TAR, Sapsford RJ, Devalia JL, Wedzicha JA. Comparison of spontaneous and induced sputum for investigation of airway inflammation in chronic obstructive pulmonary disease. Thorax 1998; 53:953–6. 14. Keatings VM, Collins PD, Scott DM et al. Differences in interleukin-8 and tumor necrosis factor in induced sputum from patients with chronic obstructive pulmonary disease and asthma. Am. J. Respir. Crit. Care Med. 1996; 153:530–4. 15. Subauste MC, Jacoby DB, Richards SM, Proud D. Infection of a human respiratory epithelial cell line with rhinovirus. J. Clin. Invest. 1995; 96:549–57. 16. Fraenkel DJ, Bardin PG, Sanderson G et al. Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects. Am. J. Respir. Crit. Care Med. 1995; 151:879–86. 17. Grunberg K, Smits HH, Timmers MC et al. Experimental rhinovirus 16 infection: effects on cell differentials and soluble markers in sputum of asthmatic subjects. Am. J. Respir. Crit. Care Med. 1997; 156:609–16. 18. Fleming HE, Little EF, Schnurr D et al. Rhinovirus-16 colds in healthy and asthmatic subjects. Am. J. Respir. Crit. Care Med. 1999; 160:100–8. 19. Pizzicini MMM, Pizzichini E, Clelland L et al. Sputum in severe exacerbations of asthma: kinetics of inflammatory indices after prednisone treatment. Am. J. Respir. Crit. Care Med. 1997; 155: 1501–8. 20. Albert RK, Martin TR, Lewis SW. Controlled clinical trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency. Ann. Intern. Med. 1980; 92:753–8. 21. Emerman CL, Connors AF, Lukens TW, May ME, Effron D. A randomised controlled trial of methylprednisolone in the emergency treatment of acute exacerbations of chronic obstructive pulmonary disease. Chest 1989; 95:563–7. 22. Bullard MJ, Liaw SJ, Tsai YH, Min HP. Early corticosteroid use in acute exacerbations of chronic airflow limitation. Am. J. Emerg. Med. 1996; 14:139–43. 23. Murata GH, Gorby MS, Chick TW, Halperin AK. Intravenous and oral corticosteroids for the prevention of relapse after treatment of decompensated COPD. Chest 1990; 98:845–9. 24. Thompson WH, Nielson CP, Carvalho P et al. Controlled trial of oral prednisolone in outpatients with acute COPD exacerbation. Am. J. Respir. Crit. Care Med. 1996;154:407–12.
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25. Davies L, Angus RM, Calverley PMA. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet 1999; 354:456–60. 26. Niewoehner DE, Erbland ML, Deupree RH et al. Effect of systemic glucocorticoids on exacerbations of chronic obstuctive pulmonary disease. N. Engl. J. Med. 1999; 340:1941–7. 27. Anderson HR, Limb ES, Bland JM, Ponce de Leon A, Strachan DP, Bower JS. Health effects of an air pollution episode in London, December 1991. Thorax 1995; 50:1188–93. 28. Linaker CH, Coggon D, Holgate ST et al. Personal exposure to nitrogen dioxide and risk of airflow obstruction in asthmatic children with upper respiratory infection. Thorax 2000; 55:930–3. 29. Johnston SL, Pattemore PK, Sanderson G et al. Community study of the role of viral infections in exacerbations of asthma in 9–11year-old children. Br. Med. J. 1995; 310:1225–9. 30. Stott EJ, Grist NR, Eadie MB. Rhinovirus infections in chronic bronchitis: isolation of eight possible new rhinovirus serotypes. J. Med. Microbiol. 1968; 1: 109–17. 31. Gump DW, Phillips CA, Forsyth BR. Role of infection in chronic bronchitis. Am. Rev. Respir. Dis. 1976; 113:465–73. 32. Philit F, Etienne J, Calvet A et al. Infectious agents associated with exacerbations of chronic obstructive pulmonary disease and attacks of asthma. Rev. Mal. Respir. 1992; 9:191–6. 33. Greenberg SB, Allen M,Wilson J, Atmar RL. Respiratory viral infections in adults with and without chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 162: 167–73. 34. Seemungal TAR, Harper-Owen R, Bhowmik A, Jeffries DJ, Wedzicha JA. Detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease. Eur. Respir. J. 2000; 16:677–83. 35. Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. Br. Med. J. 1993; 307:982–6. 36. Zalacain R, Sobradillo V, Amilibia J et al. Predisposing factors to bacterial colonization in chronic obstructive pulmonary disease. Eur. Respir. J. 1999; 13:343–8. 37. Monso E, Rosell A, Bonet G et al. Risk factors for lower airway bacterial colonization in chronic bronchitis. Eur. Respir. J. 1999; 13:338–42. 38. Wilson R. Bacterial infection and chronic obstructive pulmonary disease. Eur. Respir. J. 1999; 13:233–5. 39. Soler N, Ewig S, Torres A, Filella X, Gonzalez J, Zaubet A. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease. Eur. Respir. J. 1999; 14:1015–22. 40. Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA. Association between airway bacterial load and markers of airway inflammation in patients with chronic bronchitis. Am. J. Med. 2000; 109:288–95. 41. Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1996; 153:967–75. 42. Braun SR, McKenzie WN, Copeland C, Knight L, Ellersieck M. A comparison of the effect of ipratropium and albuterol in the treatment of chronic obstructive airway disease. Arch. Intern. Med. 1989; 149:544–7. 43. Combivent Inhalation Aerosol Study Group. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. Chest 1994; 105:1411–19. 44. Rebuck AS, Chapman KR, Abboud R et al. Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am. J. Med. 1987; 82:59–64. 45. Rice KL, Leatherman JW, Duane PG et al. Aminophylline for acute exacerbations of chronic obstructive pulmonary disease. A controlled trial. Ann. Intern. Med. 1987; 107:305–9.
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46. Callahan CM, Cittus RS, Katz BP. Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease: a meta-analysis. Ann. Intern. Med. 1991; 114:216–23. 47. Keatings VM, Jatakanon A,Worsdell Y, Barnes PJ. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am. J. Respir. Crit. Care Med. 1997; 155:542–8. 48. Culpitt SV, Maziak W, Loukidis S et al. Effects of high-dose inhaled steroids on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1635–9. 49. Sachs APE, Koeter GH, Groenier KH, Van der Waaij D, Schiphuis J, Meyboom-de Jong B. Changes in symptoms, peak expiratory flow and sputum flora during treatment with antibiotics of exacerbations in patients with chronic obstructive pulmonary disease in general practice. Thorax 1995; 50:758–63. 50. Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations. A meta-analysis. JAMA 1995; 273:957–60. 51. Moser KM, Luchsinger PC, Adamson JS et al. Respiratory stimulation with intravenous doxapram in respiratory failure. N. Engl. J. Med. 1973; 288:427–31. 52. Angus RM, Ahmed AA, Fenwick LJ, Peacock AJ. Comparison of the acute effects on gas exchange of nasal ventilation and doxapram in exacerbations of chronic obstructive pulmonary disease. Thorax 1996; 51:1048–50. 53. Bott J, Carroll MP, Conway JH et al. Randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease. Lancet 1993; 341: 1555–7. 54. Brochard L, Mancebo J, Wysocki M et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N. Engl. J. Med. 1995; 333: 817–22. 55. Kramer N, Meyer TJ, Meharg J, Cece RD, Hill NS. Randomized prospective trial of noninvasive positive pressure ventilation in acute respiratory failure. Am. J. Respir. Crit. Care Med. 1995; 151:1799–806. 56. Plant PK, Owen JL, Elliott MW. A multicentre randomised controlled trial of the early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards. Lancet 2000; 355:1931–5. 57. Ambrosino N, Foglio K, Rubini F, Clini E, Nava S, Vitacca M. Non-invasive mechanical ventilation in acute respiratory failure due to chronic obstructive pulmonary disease: correlates for success. Thorax 1995; 50:755–7. 58. Brown JS, Meecham Jones DJ, Mikelsons C, Paul EA,Wedzicha JA. Outcome of nasal intermittent positive pressure ventilation when used for acute-on-chronic respiratory failure on a general respiratory ward. J. R. Coll. Phys. Lond. 1998; 32: 219–24. 59. Morretti M, Cilione C, Tampieri A et al. Incidence and causes of non-invasive mechanical ventilation failure after initial success. Thorax 2000; 55:819–25. 60. Gravil JH, Al-Rawas OA, Cotton MM et al. Home treatment of exacerbations of COPD by an acute respiratory assessment service. Lancet 1998; 351:1853–5. 61. Cotton MM, Bucknall CE, Dagg KD et al. Early discharge for patients with exacerbations of COPD: a randomised controlled trial. Thorax 2000; 55:902–6. 62. Skwarska E, Cohen G, Skwarski KM et al. A randomised controlled trial of supported discharge in patients with exacerbations of COPD. Thorax 2000; 55:907–12. 63. Nichol KL, Baken L, Nelson A. Relation between influenza vaccination and out-patient visits, hospitalisation and mortality in elderly patients with chronic lung disease. Ann. Intern. Med. 1999; 130:397–403. 64. Collet JP, Shapiro S, Ernst P et al. Effect of an immunostimulating agent on acute exacerbations and hospitalization in COPD patients. Am. J. Respir. Crit. Care Med. 1997; 156:1719–24. 65. Burge PS, Calverley PMA, Jones PW et al. Randomised, double
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blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br. Med. J. 2000; 320: 1297–303. 66. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimiou J. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998; 351:773–80. 67. Jarad N, Wedzicha JA, Burge PS, Calverley PMA. An observational study of inhaled corticosteroid withdrawal in patients with
stable chronic obstructive pulmonary disease. Respir. Med. 1999; 93:161–6. 68. Mahler DA, Donohue JF, Barbee RA et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999; 115: 957–965. 69. van Noord JA, de Munck DRAJ, Bantje ThA et al. Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur. Respir. J. 2000; 15: 878–85.
Education and Self-Management
Chapter
69
Martyn R. Partridge The Faculty of Medicine, Imperial College, London, UK
Globally, the number of people with asthma is the same as the total population of the Russian Federation. A similar number have COPD. For some of these 300 million people, we have therapies that can dramatically influence their diseases. Others have persisting and regular symptoms. All have to live with a long-term condition. How can we help them benefit most from all that is available? This chapter is concerned with patient education and selfmanagement and will compare and contrast the similarities and differences between these interventions in asthma and COPD and highlight the areas meriting further research.
W H AT I S PAT I E N T E D U C AT I O N ? The term patient education has an unpleasant inference suggesting some inadequacy on the patient’s behalf which needs rectifying. It seems preferable to make the concept more positive and to list the constituent parts. Van den Borne1 has defined patient education as “a systematic learning experience in which a combination of methods is generally used, such as the provision of information and advice and behavior modification techniques, which influence the way the patient experiences their illness and/or their knowledge and health behavior, aimed at improving or maintaining health or learning to cope with a condition, usually a chronic one”. For the health care professional an essential prerequisite to patient education is an understanding of how the patient feels about their long-term condition and its management.
H O W D O E S I T F E E L T O H AV E C O P D ? COPD is largely a smoking-related disease. In many countries the prevalence of smoking is low amongst health care professionals, especially amongst doctors. Personal experience of the condition is therefore likely to be uncommon. Surveys of the views, opinions and concerns of those with COPD are less numerous than are those amongst people
with asthma, and the population affected less diverse – being mainly a disease of the fifth, sixth and seventh decades, with more men than women being affected. Those with COPD frequently suffer feelings of guilt about having caused the disease by smoking, and they experience great sadness when they see others around them smoking and proceeding along their path. They frequently report lack of support on social issues, financial issues and from health care professionals. Professionals imbued with a culture of curing and obsessed with the writing of prescriptions may not actually say “There is nothing I can do for you”, but they convey such negativity by body language or attitude. The late Trevor Clay, a nurse who died from lung disease associated with an inherited condition wrote “There is no cure, no magic, but there is always something that can be done!” He also wrote “Having a long-term condition is not about dying – that only takes a few minutes or less – but I’ve been struggling to breathe for over 20 years and I’ve been living a lot and suffering as little as possible”.2 Others may find it less easy to be positive. Anxiety, frustration and depression are frequently experienced by sufferers and they may become socially isolated.3 Psychiatric disorders may reach a prevalence of 50% in those with COPD,4 and Dudley et al.5 observed those with severe COPD to be in “emotional strait jackets” – no longer able to become angry, depressed or even happy, as any significant emotional changes triggered distressing symptoms.The mind/body interaction can thus become a vicious cycle with symptoms leading to anxiety, and emotional distress aggravating the symptoms. Psychological impairment may also follow from derangement of blood gases leading to diminished levels of alertness, irritability, restlessness, headaches and confusion and loved ones may be unaware of the reasons for these factors in their partners. Psychological and personality profiles of those with severe COPD may also influence survival. One study of males with severe COPD showed a significant difference in personality and psychological profile between those who died and those who were alive at the end of 4 years of follow-up, irrespective of the degree of impairment of pulmonary function or oxygenation.6
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In those at the severe end of the spectrum of COPD, a common therapeutic intervention is the use of supplementary oxygen. When this is recommended to be used long term, it could impact significantly upon the patient’s life and may enhance feelings of social isolation.7 In another survey of those on long-term oxygen from oxygen concentrators, the results were more positive. Eighty-three percent of those surveyed reported marked improvement in general wellbeing on oxygen, 82% reported improvement in breathing and 62% mobility, and 52% reported improvement in sleep pattern. A third thought that the concentrator was too noisy. Sadly, a third continued to smoke.8
H O W D O E S I T F E E L T O H AV E A S T H M A ? The ages of those suffering from asthma is more diverse than those suffering from COPD. Furthermore, whilst chronic disability and daily symptoms are common in asthma, the symptoms may be more variable. Such variability can induce additional stresses, and uncertainty invokes an unpleasant emotion with fears of holidays, celebrations or important work events being interrupted by unexpected exacerbations. Denial of the diagnosis or its implication is common9 and feelings of stigma frequent, but there is no easy comparison to suggest whether it is higher or lower than in COPD. Fears and concerns regarding the medication are common, although steroid phobia amongst patients and parents may be perceived by health professionals to be more common than it really is. Dissatisfaction with dependency on long-term medication may be one of the most common reactions and patients frequently stop medication just to confirm continued need.What is unclear is why there is such a large difference between the goals for asthma management as outlined in guidelines, and control as discovered by surveys of patients. One recent survey conducted 400 interviews with current asthma patients in seven countries. Over one-third of children and half of the adults reported daytime symptoms at least once a week. Sleep disruption every night was reported by 6.7% of children and 5.3% of adults. A total of 36% of children and 27.9% of adults required an unscheduled urgent care visit in the past 12 months. One or more emergency room visits due to asthma were reported for 18% of children and 11% of adults in the past year.10 In another large UK study, 44% of respondents reported at least one activity was “totally or very limited” by their asthma and 20% reported three or more activities to be so limited.11 How far such morbidity reflects inadequacies of currently available therapies, inadequacies of the health care system, or patients not utilizing that which is available is not entirely clear. Only half of those surveyed in the UK11 had had their peak flow measured by a doctor or nurse in the past year, and 45% of respondents said they had neither had, nor wanted, regular asthma review. Without such review there is a danger that adaptation leads to acceptance of ongoing morbidity. Even with review, there is a danger that the patient may not “offer” symptoms for fear that it
may lead to further prescriptions, and the doctor may falsely conclude that all is well. For these reasons it has been recommended that at each consultation every patient with asthma is asked three questions:12 In the last week or month • Have you had difficulty sleeping because of your asthma symptoms (including cough)? • Have you had your asthma symptoms during the day (cough, wheeze, chest tightness or breathlessness)? • Has there been any limitation of activities (time off work or school or inability to undertake hobbies) because of asthma. Has your asthma interfered with your usual activities (e.g. housework, work/school, etc.)?
COMPLIANCE IN ASTHMA AND COPD The term noncompliance is used to describe a situation where, for whatever reason, the patient does not take treatment or other actions in a manner as previously discussed with their health professional. Recent trends have been to replace the word compliance with “adherence” or “concordance”, but this seems unnecessary if it is emphasized from the outset that the term is not being used in any way in a pejorative sense. Noncompliance may involve noncompliance with lifestyle advice (e.g. continued smoking), failure to attend for follow-up, failure to undertake recommended monitoring, or failure to take therapy. The size of the problem is likely to be large and underestimated. Noncompliance with medication is either inferred from the presence of poorly controlled disease or confirmed by monitoring drug taking, which may involve measurement of drug levels in urine, plasma or saliva, or by prescription monitoring. More modern methods involve the fitting of microprocessors to the lids of bottles or inhaler devices.13–15 Such methods are inappropriate at a clinical level and it is preferable to accept that noncompliance is common, and instead make efforts to consider the factors involved and work with the patient to tackle the underlying causes. It is likely that the size of the problem is of similar magnitude in asthma as in COPD, and these two diseases probably do not differ from other long-term conditions such as hypertension or arthritis. Some of the causes may however be diseasespecific and possibilities are listed in Table 69.1. Perhaps the most essential is to understand the importance of good communication between patient and health care professional. In one UK study,16 only 22% of those with asthma reported having had a good discussion with their doctor, and in another study a median dissatisfaction rate of 38% with medical communication was reported.17 The effect of this upon compliance may be considerable. In one study, 50 adults with moderate to severe asthma were studied and compliance with inhaled steroid therapy electronically monitored. Mean adherence was 63%. Factors
Education and Self-Management
Table 69.1. Factors which may be involved in non-compliance with the taking of medication in asthma and COPD
Factors associated with medication Use of the word “drug” Difficulties with inhaler devices Regimens involving multiple medications Awkward four times daily dosing regimens Side-effects Cost of medication Difficulty getting to the doctor (for a prescription) or the pharmacy (for it to be dispensed) Perceived lack of effectiveness of medication Non-medication factors Denial of diagnosis Fears of side-effects Unexpressed/unanswered concerns Dissatisfaction with health care professionals Misunderstanding or lack of instruction Anger, stigma or depression Underestimation of severity Forgetfulness or complacency Cultural issues
associated with poor adherence included less than 12 years of formal education, and a low household income, but poor patient/clinician communication was independently associated with poor adherence. Those with at least 70% adherence scored the patient/clinician communication significantly better than those with less than 70% adherence.18 Key elements of good communication are shown in Table 69.2 and the “building blocks” necessary to achieve an ideal situation are shown in Fig. 69.1.
W H AT A R E T H E C O N S T I T U E N T PA R T S N E C E S S A RY F O R S U C C E S S F U L E D U C AT I O N A N D S E L F - M A N A G E M E N T IN COPD; WHO SHOULD PROVIDE IT AND WHERE? Clear, evidence-based advice regarding education and selfmanagement is far harder to offer to those with COPD than it is for asthma. In both disease groups there is a problem in that published reports often give too little information about the intervention offered and do not describe the selfmanagement advice given. In studies involving COPD this is further compounded by a difficulty in separating the educational components from the support and the physical exercise components of pulmonary rehabilitation programmes. Nevertheless it is likely that education and self-management programmes for COPD should cover the ground outlined in Table 69.3. Self-management involves both alterations in lifestyle and alterations in treatment, and it is immediately
739
Table 69.2. General guidelines on ways to improve communication with patients and their families
Be attentive Elicit underlying concerns Offer reassuring messages that alleviate fears Immediately address any concerns that are mentioned Use interactive dialogue (open-ended questions, analogies) Tailor the therapeutic regimen to lifestyle Provide a written management plan Use appropriate nonverbal engagement Use praise when patient has undertaken correct management strategies Elicit goals; share goals Help the patient plan longer-term care and selfmanagement (Adapted from Partridge and Hill30)
apparent that the balance between these two is different for COPD than it is for asthma (as shown in Table 69.4). One study of such interventions allocated 56 subjects with COPD to either usual care or to receiving a booklet (outlining advice presumed to be similar to that in Table 69.3), an action plan and a reserve supply of steroids and antibiotics. After 6 months there were no differences in quality of life scores or pulmonary function, but those given the self-treatment advice were significantly more likely to have started steroids or antibiotics in response to deteriorating symptoms.19 Numbers were too small to look at effects upon hospitalization rates and larger studies would need to include cost-effectiveness evaluation. Some pre-test/posttest nonrandomized studies have suggested that “education” may reduce hospitalization rates,20 but more research is clearly needed. If benefits are shown it will then be important to discern which components of an intervention, rehabilitation or self-management is responsible. Most reports of educational and self-management activities in COPD have involved respiratory nurse specialists, physiotherapists or respiratory therapists. Most studies have been out-patient based. Where outreach home-based programmes have been assessed, they have shown no significant reductions in hospitalization rates, but there may be some health-related quality of life gains.21
PAT I E N T E D U C AT I O N A N D S E L F MANAGEMENT IN ASTHMA In contrast to the situation in COPD, studies of this area involving those with asthma are numerous and the results in adults and older children almost always positive, especially involving those who have attended hospital-based programs.22–24 The key constituents of such interventions are shown in Table 69.4.
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Asthma and Chronic Obstructive Pulmonary Disease
Government and public set appropriate scene Access to independent information Effective consultation training Regular and convenient follow-up HCPs observe guidelines Medicines freely available Easy-to-use medication Patient happy with medication Patient has received action plan Patient feels in control Patient and HCP share understanding of condition and common goal
Optimal airway control
Fears and concerns dealt with Patient accepts diagnosis
Fig. 69.1. It is often useful to think of the barriers that prevent good health outcomes. In the case of asthma and COPD, several “building blocks” which recognize the patient as a whole person have to be in place before we can surmount the wall and achieve optimal airway control.
Table 69.3. Self-management advice for those with COPD
Lifestyle changes
Treatment changes
1. Stop smoking (and avoid smoky environments) 2. Use nicotine replacement therapies as appropriate as advised 3. Use effective breathing methods 4. Use effective coughing methods 5. Undertake your exercise programme as advised during your pulmonary rehabilitation course 6. Eat a balanced diet: include plenty of fresh fruit and vegetables and drink plenty of fluids to help keep mucus thin. Avoid gas-forming foods such as broccoli, cabbage, onions, beans and sauerkraut. If eating makes you breathless, use supplementary oxygen whilst chewing, or liquidize solids 7. Adjust daily activities of living. Sit down to do personal tasks such as washing or shaving or doing household tasks such as washing up or preparing meals. Use a stool in the shower and use a hairdryer to dry feet or back.
1. Continue regular bronchodilators – usually a combination of anticholinergic agents and beta-agonists 2. At times of worsening symptoms increase dose, frequency and possibly route of administration e.g. spacer or nebulizer 3. If sputum changes color, consider starting reserve course of antibiotics 4. If much more breathless, and lessening response to bronchodilators, consider a course of steroid tablets according to doctor’s advice 5. Use oxygen as advised – either long-term or supplementary during exertion – know when to increase this and be aware of the importance of early morning confusion or headaches which might suggest CO2 retention.
Education and Self-Management
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Table 69.4. Self-management advice for those with asthma
Lifestyle changes
Treatment changes
1. Allergen avoidance 2. Avoiding smoking and smokey environments 3. Avoid exercising outdoors, especially on the outskirts of cities, at times of high pollution levels 4. Eat a balanced diet.
1. If you have no symptoms and your peak flow is better than 80–85% of your best peak flow, continue your regular preventative treatment, or talk to your doctor or nurse about taking less treatment 2. If you get a cold, or have your asthma symptoms during the day or at night, or if your peak flow is less than 80–85% of your best peak flow, increase your preventer treatment according to your written personal action plan 3. If you are increasingly breathless, and your reliever therapy is less effective and your peak flow is less than 60–70% of your usual best peak flow, start steroid tablets according to your written personal action plan and contact your doctor 4. If you are too breathless to speak, or your peak flow is less than 40–50% of your usual best peak flow, continue to use your reliever, take eight of the 5 mg prednisolone tablets, and call your doctor or an ambulance urgently.
A Cochrane review of the subject of self-management education for adults with asthma was undertaken by Gibson and colleagues in 1999 and compared self-management education with usual care in 22 studies.25 Self-management education was associated with reduction in hospitalization rates, emergency room visits, unscheduled visits to the doctor, days off work or school, and night-time asthma. Selfmanagement programs that involved a written action plan showed greater reduction in hospitalization rates than those that did not, and people who managed their asthma by selfadjustment of their asthma treatment using an individualized written plan had better lung function than those whose medications were adjusted by a doctor. Fewer studies have been undertaken of the value of selfmanagement in children, but good randomized controlled trials involving self-management interventions in those who have been hospitalized, have shown significant reduction in readmission rates.26,27 Studies of the costeffectiveness of the teaching of self-management skills in those with asthma have shown significantly beneficial cost–benefit ratios.28,29
S U M M A RY • Living with a long-term illness can be difficult. • Health care professionals need an understanding of how their patients feel, and good communication is essential if we are to understand fully what our patients want of us, and how best we can provide optimal care. • It is important to offer the information the patient wants, rather than what we perceive they need.
• Personalized self-management advice which helps them to adjust their lifestyle or treatment to keep themselves well, is necessary. Current evidence is that this is of significant value in those with asthma but more marginal value in COPD, although larger studies looking at a wider variety of outcomes are needed.
REFERENCES 1. van den Borne HW. The patient: from receiver of information to informed decision maker. Patient Edu. Couns. 1998; 34:89–102. 2. Clay T. How to keep the customer satisfied. Thorax 1994; 49:279–80. 3. Dudley DL, Glaser EM, Jorgenson BN, Logan DL. Psychological concomitants to rehabilitation in chronic obstructive pulmonary disease. Part I: Psychosocial and psychological considerations. Chest 1980; 77:413–20. 4. Rutter BM. Some psychological concomitants of chronic bronchitis. Psych. Med. 1977; 7:459–64. 5. Dudley DL, Wermuth C, Hague W. Psychological aspects of care in chronic obstructive pulmonary disease. Heart Lung 1973; 2:289–303. 6. Ashutosh K, Haldipur C, Boucher ML. Clinical and personality profiles and survival in patients with COPD. Chest 1997; 111:95–8. 7. Ring L, Danielson E. Patients experiences of long term oxygen therapy. J. Adv. Nur. 1997; 26:337–44. 8. Dilworth JP, Higgs CMB, Jones PA, White RJ. Acceptability of oxygen concentrators: the patient’s view. Br. J. Gen. Pract. 1990; 40:415–17. 9. Adams S, Pill R, Jones A. Medication, chronic illness and identity. The perspective of people with asthma. Soc. Sci. Med. 1997; 45:189–201.
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10. Rabe KF, Vermeire PA, Soriano JB, Maier WC. Clinical management of asthma in 1999: The asthma insights and reality in Europe (AIRE) study. Eur. Respir. J. 2000; 16:802–7. 11. Price D, Wolfe S. Delivery of asthma care: patients use of and views on healthcare services as determined from a nationwide interview survey. Asthma J. 2000; 5:141–4. 12. Clinical Effectiveness and Evaluation Unit. Measuring Clinical Outcome in Asthma. A Patient-Focused Approach. London: Royal College of Physicians of London, 1999. 13. Cranmer JA, Mattson RH, Prevey MC, Scheyer RD, Ovelette VL. How often is medication taken as prescribed. JAMA 1989; 261:3273–7. 14. Rand CS, Wise RA, Nide S et al. Metered dose inhaler adherence in a clinical trial. Am. Rev. Respir. Dis. 1992; 146:1559–64. 15. Cochrane GM. Compliance in asthma: A European perspective. Eur. Respir. Rev. 1995; 5:116–19. 16. Partridge MR. Asthma: lessons from patient education. Patient Edu. Couns. 1995; 26:81–6. 17. Ley P. Communicating with Patients. London: Croon Helm, 1988. 18. Apter AT, Reising ST, Affleck G, Barrows C, ZuWallack RL. Adherence with twice daily dosing of inhaled steroids: socioeconomic and health belief difference. Am. J. Respir. Crit. Care Med. 1998; 157:1810–17. 19. Watson PB,Town GI, Holbrook N, Dwan C,Toop LJ, Drennan CJ. Evaluation of a self-management plan for chronic obstructive pulmonary disease. Eur. Respir. J. 1997; 10:1267–71. 20. Howard JE, Davies JL, Roghmann KJ. Respiratory teaching of patients: how effective is it? J. Adv. Nurs. 1987; 12:207–14. 21. Smith B, Appleton S, Adams R, Southcott A, Ruffin R. Home care by outreach nursing for COPD (Cochrane Review). In: The Cochrane Library, Issue 4, Oxford:Update Software, 2000.
22. Ignacio-Garcia JM, Gonalez-Santos P. Asthma self-management education program by home monitoring of peak expiratory flow. Am. J. Respir. Crit. Care Med.1995; 151:353–9. 23. Lahdensuo A, Haahtela T, Herrala J et al. Randomised comparison of self management. Br. Med. J. 1996;312: 748–52. 24. Adams RJ, Smith BJ, Ruffin RC. Factors associated with hospital admissions and repeat emergency department visits for adults with asthma. Thorax 2000; 55:566–73. 25. Gibson PG, Coughlan J, Abramson M. The effects of selfmanagement education and regular practitioner review in adults with asthma (Cochrane Review). In: The Cochrane Library, Issue I, Oxford: Update Software, 1999. 26. Madge P, McColl J, Paton J. Impact of a nurse led home management training programme in children admitted to hospital with acute asthma: a randomised controlled study. Thorax 1997; 52: 223–8. 27. Wesseldine L, McCarthy P, Silverman M. A structured discharge procedure for children admitted to hospital with acute asthma: a randomised controlled trial of nursing practice. Arch. Dis. Child. 1999; 80:110–14. 28. Lahdensuo A, Haahtela T, Herrala J. Randomised comparison of cost-effectiveness of guided self-management and traditional treatments of asthma in Finland. Br. Med. J. 1998; 316:1138–9. 29. Clark NM, Feldman CH, Evans D, Levison MJ, Wasilewski Y, Mellins RB. The impact of health education and cost of health care use by low income children with asthma. J. Allergy Clin. Immunol. 1986; 78: 108–15. 30. Partridge MR, Hill SR. Enhancing care for people with asthma: The role of communication, education, training and selfmanagement. Eur. Respir. J. 2000; 16:333–48.
Subject Index
Note: Abbreviations in subentries CT computed tomography FEV1 forced expiratory volume in 1 second FVC forced vital capacity GM-CSF granulocyte macrophage colonystimulating factor IL interleukin MMPs - matrix metalloproteinases NSAIDs non-steroidal antiinflammatory drugs TGF transforming growth factor TNF tumor necrosis factor Page numbers in bold refer to major discussions. Page numbers in italics refer to pages on which figures &/or tables appear. Since the major subjects of this book are asthma and COPD, entries have been kept to an absolute minimum under these keywords. Readers are advised to seek more specific index entries. A accessory muscles, acute asthma 692 ACE inhibitors see angiotensinconverting enzyme (ACE) inhibitors acetylation, histones see histone acetylation acetylcholine (ACh) release by airway epithelial cells 326 increased by b-blockers (asthma) 328 parasympathetic nerves 323 thromboxane A2 action 223 response reduced by histamine 224 N-acetylcysteine 636, 636, 721 antioxidant effects 636, 636, 644 asthma exacerbation induced 440 COPD exacerbation prevention 722 as mucolytic drug 636, 636 acid anhydrides 395 acidosis, COPD exacerbation 730
lactic 424, 620 management 732, 733 acinus 62 acrolein 72 activator protein-1 (AP-1) see AP-1 transcription factor activities of daily living disturbance 481 scales/questionnaires 483 activity limitations, definition 481 acupuncture, asthma 638 acute bronchitis, COPD exacerbation 728 see also acute exacerbations of chronic bronchitis acute exacerbations of asthma 5–6 adverse response to drugs 690 aggravating factors 683 bacterial infection association 573 children, management 707 clinical features 692 drugs associated/causing 439, 440, 690 see also beta (b)-blockers epidemiology 689 histamine release 293 life-threatening 689, 690 aspirin-induced 441 in children 700 long-term prognosis after 695 management 681–682, 693 action plan/guidelines 682 response to therapy 693–695 self-management 682 ventilatory assistance 695 pathogenesis 691–692 pathology 691 physiologic manifestations 692–693 risk factors for adverse outcomes 689–691 survival expectations 695 viral-induced 146, 408, 408 see also viral infections see also acute severe asthma acute exacerbations of chronic bronchitis 728, 730 antibiotic therapy trials 575–576, 576 ciprofloxacin, cost-effectiveness 665–666
classification 574 diagnosis 574–575 role of bacterial infection 575–578 serological studies 575 Winnipeg Criteria 574 acute exacerbations of COPD 5–6, 727–736 airway inflammation 728–729 classification scheme 574, 581–582, 582 clinical features 728 COPD exacerbation 734 cytokine changes 373 diagnosis 727, 727 epidemiology 727–728 epithelial cell loss 199 etiology 727, 727, 729–730, 730 glucocorticoids effect 722 infections associated 414, 415 infections triggering 577–578, 728 see also viral infections management of infections 579, 732 minor 727 mortality 733 pathogens associated 577, 577–578 pathology 63 pathophysiology 730–731 pharmaco-economic considerations 582–583 predictive factors 728 prevention 579, 722, 733–734 risk stratification 581–582, 582 superoxide anion production and 249 treatment 731–734 antibiotics 579–580, 732 anticholinergics 531, 731 bronchodilators 531, 731 corticosteroids 731–732 guidelines 581–582, 582 respiratory failure management 732 supported hospital discharge 733 see also acute exacerbations of chronic bronchitis acute-on-chronic inflammation 262, 316, 344 acute severe asthma 689 adrenaline 334 anticholinergic bronchodilators 530 childhood, treatment 707
744
Index
acute severe asthma—cont renin–angiotensin system activation 336 systemic corticosteroids 559 theophylline 540 see also acute exacerbations of asthma; asthma severity acute viral bronchiolitis see bronchiolitis, acute viral adenosine 294–296 antagonist 295 bronchoconstriction induced by 295 bronchospasm induced by 295 effect on airways 294, 295 mast cell degranulation 295 receptor antagonists A2b antagonist 296, 536 theophylline 536 receptors 295 release 294 role in airway disease 295–296 role in allergic response 296 synthesis and metabolism 294–295 adenosine monophosphate (AMP) 295 response in asthma vs COPD 425 adenoviral DNA, incorporation into airway cells 362 adenovirus infections, COPD exacerbation 415 adenylyl cyclase 521 adhesion molecules see cell adhesion molecules adolescents, smoking 12, 14, 25 adrenaline (epinephrine) 329, 334–335 acute severe asthma 334 circadian variations 334 concentrations during exercise 334, 335, 337 source and release 334 adrenergic nerves 329–330 tracheobronchial blood flow regulation 178 a-adrenergic receptor 330 b2-adrenergic receptor agonists see betaagonists b-adrenergic receptor antagonists see beta (b-)blockers b2-adrenergic receptors see betaadrenoceptors adrenomedullin 336 in asthma 353 adult-onset asthma 4 adult respiratory distress syndrome (ARDS) 135 aeroallergens 21–22 see also allergen(s) aerobic training, COPD 622 afferent nerves 323, 324–326, 325 in airway disease 326, 333 airway hyperesthesia 326 C fibers see C nerve fibers inflammation involvement 333 rapidly adapting receptors (RARs) 325, 435
slowly adapting receptors (SARs) 324–325 age asthma/COPD prevalence 8, 8, 15 asthma severity relationship 22 age of onset allergen-induced asthma 387 asthma 20 childhood asthma 699 chronic persistent 20–21 airflow limitation blood neutrophil count relationship 249 COPD 361 reversibility 3, 3–4, 5, 7, 449 assessment after smoking cessation 364 definition 5 site during forced expiration 47–48 during tidal breathing 48, 48, 60 see also airway obstruction airflow obstruction see airway obstruction airflow resistance acute asthma 692 alveolar disease impact 49 in COPD, during exercise 423 sites increased resistance 46–47, 48, 60, 61–62 increased resistance in COPD 46, 48 normal 57 see also airflow limitation air pollutants COPD exacerbation trigger 729 current exposures 431–432 gases 4, 431 mechanisms of damage by 435–436 reactive oxygen species formation 244–245 types 431–432 air pollution acute health effects 432, 434–435 asthma 434 COPD 434–435 assessment of health effects 432–433 methods 432–433 asthma association 434 childhood asthma 701 exercise-induced asthma 422–423 chronic health effects 433–434 COPD etiology and pathogenesis 362, 370, 434, 717 exacerbation trigger 6, 729 episodes 431, 434 historical aspects 431 individual responses and factors affecting 433, 433 mechanisms of effects 435–436 reduction childhood asthma management 708
COPD management 717 risk of death 435 air quality, standards 431, 432 air travel, hypoxemia 593–594 airway(s) adenosine effects 294, 295 anatomy (normal) 57–58, 62 area–transmural pressure curves 43–44 bacterial colonization see bacterial colonization blood flow see tracheobronchial circulation branching and cross-sectional area 57 caliber see airway caliber central collapsibility enhancement 44 normal anatomy 57 resistance, COPD 46 challenge, growth factor response in animals 287 complement effect 301 development (in utero) 24 distending forces 44 endothelin effects 298–300, 299 epithelial cells see epithelial cells, airway growth 20, 20 in utero 24 histamine effect 291, 292 hyperesthesia, afferent nerve sensitivity increased 326 infections see infections, respiratory tract injury see epithelial cells, airway innervation see airway nerves intraluminal area (A) 43 intraluminal contents, COPD 364 large, narrowing in asthma 47 lumen 195, 195 eosinophil entry vs apoptosis 199, 201 plasma entry 196–197 see also plasma exudation microcirculation leucocyte migration 205 plasma protein release 197, 198 mucosa see mucosa, airway mucus see mucus narrowing see airway narrowing neuropeptides 330–331 nitric oxide synthase distribution 308, 308 perimeter–lung coupling 44 peripheral 58 site of obstruction in asthma 59, 63 smooth muscle remodeling 73 pH, in asthma 349 plasma exudation see plasma exudation platelet activating factor (PAF) effect 296, 297 response to allergens 385, 385 see also allergen(s) serotonin effect 293, 293
Index
surface tension changes, asthma 59 tachykinins effects 331–332, 332 tone regulation, childhood respiratory illness and adult COPD 26 transmural pressure (Ptm) 43 airway caliber airway–transmural pressure curves 43–44 autonomic control 323, 527, 527–528 see also airway nerves edema effect on 179 factors determining 43–44 hormonal control 336–337 reduction 43 by smooth muscle shortening 59–60 vasoactive peptide control 334–336 airway function 43–48 airway–transmural pressure curves 43–44 alveolar disease contribution 53–54 gender differences 24 response to bronchodilators/ bronchoconstrictors 44–46 site of airflow limitation during forced expiration 47–48 site of increased airflow resistance (tidal breathing) 46–47, 48, 60 airway function tests 43 asthma differentiation from COPD 48 see also lung function tests airway hyperresponsiveness (AHR) allergen-induced 385 time course 385 see also under allergen(s) allergen-induced in mice eosinophils role 81–82 IgE and mast cells role 80–81 ovalbumin effect 79–80 animal models of chronic bronchitis 83–84 assessment in asthma/COPD diagnosis 450 asthma 7, 45–46, 344, 344 mechanisms/factors causing 344 triggers 344 causes 45, 45, 344 chromosome 5q linkage 32 chronic sulfur dioxide exposure in animals 83–84 COPD 26 challenge tests 45 development 15–16, 362 exercise effect 424–425 mortality prediction 14 corticosteroid effects 552 IL-5 inhibitor action 644 loss of plateau of maximal narrowing 45 ovalbumin sensitization of mice 80 prevalence, atopy relationship 387, 388 prevention/reduction (by) antibodies to adhesion molecules 206
antisense oligonucleotides 652–653 BW755C (lipoxygenase inhibitor) 222 glucocorticoids 318–319 indomethacin 222, 223, 223 role of IgE and mast cells 80–81 seasonal and diurnal changes 385 smoking and 45 spasmogens causing 329 terminology 383 see also bronchial hyperresponsiveness airway inflammation adhesion molecules involved see cell adhesion molecules adhesive mechanisms/steps 205, 206 allergic, asthma 13 see also allergen-induced asthma antigen-induced, animal models 207 assessment tests 451, 457–464 carbon monoxide see carbon monoxide exhaled hydrocarbons 460–461 asthma 13, 59, 63, 68, 343–344, 349–352 distribution 133 sites 47 chronic, control by Th2 cytokines 126 chronic bronchitis 371 chronic sulfur dioxide exposure in animals 83 COPD 4, 61, 68, 131, 277 CD8 T cells 127 cell types involved 127 distribution 133 macrophage role 105, 277 COPD exacerbations 728–729 cytokines role 262 see also cytokine(s) eosinophilic 115–117 in asthma 4 in COPD subset 13–14 therapy 117 see also eosinophil(s) exhaled breath see exhaled breath condensate lung function decline affected by 26 lymphocyte homing and chemokine regulation 124–125, 125 measurement in COPD 364–365 nerve interactions 323, 324 neuropeptides 331 neutrophilic in COPD 4 see also neutrophil(s) pathogenesis, by reactive oxygen species 243, 243 pathology 262 remodeling mechanism 67–68 see also airway remodeling smoking-induced changes 62 TNF-a polymorphism 36 airway narrowing 350 asthma 46–47, 48, 59 COPD 46, 48, 64 cysteinyl leukotrienes mediating 228
745
methacholine inhalation 44 site 47–48, 48, 60, 61–62 airway nerves 323–324 Ad fibers 325 adrenergic 329–330 afferent (sensory) see afferent nerves airway remodeling 73–74 asthma pathogenesis 351 cholinergic 326–329 see also cholinergic nerves cotransmission and neuropeptides role 323–324, 324 inflammatory cell interactions 323, 324 interactions between pathways 323 myelinated 324, 325 NANC see nonadrenergic, noncholinergic (NANC) nerves neurotransmitters 323, 324, 324 unmyelinated 325 airway obstruction 43 animal models of chronic bronchitis 83–84 asthma, site 60, 63, 63–64 blood eosinophilia as risk factor 248 chronic irreversible 5 chronic sulfur dioxide exposure in animals 83–84 COPD neutrophil role 131 site 61–62, 64 TNF-a polymorphism 320 mucosal thickness 179 recurrent, children 20 severe, acute asthma 692, 694 in smokers 15 spectrum of diseases involving 3, 3–4 see also airflow resistance; airway narrowing; bronchoconstriction airway pathology 57–66 asthma 58–60, 63, 63–64, 126, 343 acute exacerbations 691 airway wall thickening 59 bronchoscopy, 59 59 distinguishing features 59 mucosal folding pattern change 59 postmortem studies 58, 58–59 smooth muscle shortening 59 structural features 59 structure/function relationship 59–60, 60 surface tension changes and 59 T cells role 126 COPD 61–63, 64, 364 acute exacerbations 63, 63 chronic bronchitis 61 emphysema 62, 62–63 site 61–62 remodeling see airway remodeling airway plugs asthma 60, 63, 63, 72, 343 COPD 159 airway reactivity see airway responsiveness airway remodeling 5, 67–78, 283
746
Index
airway remodeling—cont COPD pathogenesis 372 cytokines role 267–268 definition 67 effect of matrix remodeling 71–72 diffuse matrix deposition 72 subepithelial basement membrane deposition 71–72 epithelial cells role 150 events leading to 68, 69 growth factors involved 283, 284 interleukin-1 role 285 matrix metalloproteinases involved 280 mechanisms 67–71, 372 effects of altered matrix on 71 epithelial damage, inflammation and repair 67–70 extracellular matrix 70 fibronectin role 372 growth factors role 70–71, 285, 372 inflammatory mediator role 70–71 mediators involved 68–69, 69 proteolytic enzyme role 71 mucous metaplasia see mucous metaplasia natural history and clinical importance 67 new therapeutic targets 74 platelet-derived growth factor role 285 processes 67 smooth muscle see airway smooth muscle (ASM), remodeling TGF-b effect/role 287, 372 therapy effect 74 TIMP-1 level elevation 280 TNF-a actions 284 vascular and neural changes 73–74 airway resistance see airflow resistance airway responsiveness 14, 44–46 asthma development prediction 14 bronchoconstrictor response 45–46 bronchodilator response 44–45 to carbachol, genetics 31–32 COPD etiology 14, 362–363 increased by IL-10 25 intermediate phenotype 14 lung function loss relationship 362–363, 363 see also airway hyperresponsiveness (AHR) airway smooth muscle (ASM) 43, 165–176 activation, cell adhesion molecules role 207 adrenaline effect 334 adrenergic control 329, 330 anatomy (normal) 57 in asthma 169, 350 autonomic control 323, 323 bradykinin effects 239 calcium homeostasis 166–168 calcium metabolism, modulators 167, 167
calcium signaling regulation see calcium signaling cell adhesion molecule expression 172 chemokines released 172 cholinergic control 326, 327 complement action 301 contractile agonist receptors 165 calcium sensitivity increase 167–168 density changes 167 contractility increase 167, 168 contraction airway caliber reduction 59–60 airway hyperresponsiveness 45, 45 stabilizing forces 44 by tachykinins 331 thromboxane A2 causing 223 velocity 43 cytokines released 172 signaling pathways regulating 173 distribution 57–58 DNA synthesis 171 effects of viruses on 410–411 epithelial cell damage effect 146 factors affecting in asthma/COPD 169 function 165 factors affecting 44 histamine effect 292 hyperplasia 73 asthma 350 cytokines influencing 267 IL-6 inducing 172 hypertrophy 350 as immunomodulatory cell 171–173 kinin effects on 239 nitric oxide synthase 172–173 PGE2 production 173 proliferation 169–173 contractile agonist-induced 170 endothelin-1 299 growth factors role 267–268 histamine role 291 mitogens 73, 169, 280 phosphatidylinositol 3–kinase pathway 170–171 phospholipase C activation 169, 170 regulation 169 reactive oxygen species effects 369 receptors in leucocyte activation 172–173 relaxation b2-adrenoceptor agonists 521, 521 prostaglandin E2 action 223, 224 theophylline effect 537–538 remodeling 73 patterns 73 reduced by drugs 74 spasm 73 stiffening 43 theophylline effects 537–538 TNF-a-stimulated 172 airway wall
blood supply 177 compliance, asthma/COPD 44 increased blood volume around 43–44 thickening 43–44 asthma 59, 139 bronchoconstrictor response 45 albuterol 690 acute asthma management 694 airway blood flow decrease 180, 180 comparative studies, COPD 665 ipratropium vs 665, 718 long-acting b2-agonists, comparisons in asthma 663, 664 vasodilator effect 180, 180 aldehydes, exhaled, marker of lipid peroxidation 248 allergen(s) 383–393 age-related changes in response 22 airway hyperresponsiveness due to see airway hyperresponsiveness (AHR) animal danders 384 asthma due to 23, 383, 387 allergen exposure/severity relationship 493–494 exacerbation 683 mouse model 79 sensitization to indoor allergens 496 see also allergen-induced asthma asthma-like symptoms in adults 21 avoidance see allergen avoidance binding to IgE 34 cat 384 distribution/aerodynamic properties 489–490 Fel d 1 489, 652 peptide immunotherapy 652 cockroach 492 desensitization 652 chronic asthma management 682–683 dog 384 Can f 1 489, 489, 490, 492, 492 distribution/aerodynamic properties 489–490, 490, 491 exercise-induced asthma and 422–423 exposure avoidance see allergen avoidance exposure effect on response to treatment 494–495 exposure in early infancy 496, 497 evidence against role in asthma 21–22 fungal spores 384 goblet cell metaplasia induced by 158 grass pollen, reduction measures 494 house dust mite see house dust mites/allergens increased exposure, increased atopy/asthma prevalence 384 ingested 387 inhaled 4, 385–387
Index
types 384 inhaled, airway response mechanisms 386–387 patterns 385 pharmacology and drug action 385–386 injected 387 injection therapy 386 insect 384–385 molds 493 mouse model of asthma 79–82 mucus secretion induced by 156 occupational 385 particle size distribution 489, 490 perennial, chronic persistent asthma 23 pet 384, 496–497 see also cat, dog (above) pollen 384 sensitization asthma development 21–22 changes with time/age 22 mouse model of asthma 79–82 types 384–385 vaccination (desensitization) 652, 707–708 allergen avoidance 22, 489–507 asthma chronic 683 secondary prevention 497 treatment 493–494 atopy pet ownership and sensitization 496–497 primary prevention 496 see also Atopy children 707–708 clinical trials 495–496 high-altitude studies 495 mite allergen avoidance 495–496, 501–507 occupational asthma model 495 pet allergen avoidance 496 cockroach allergens 492 distribution/aerodynamic properties relevance to 489–490, 490 epidemiological studies 494 house dust mite allergens see house dust mites/allergens household measures 683 molds 493 outdoor allergens 493 grass pollen exposure reduction 494 pet allergen avoidance 491, 491–492, 492, 493 pet removal 683 potential benefits 497 recommendations for homes 683 allergen-induced asthma 13 age of onset 387 clinical features 387–388 cycloxygenase products involved 222 diagnosis 388 etiology 387 historical aspects 383
management 388 anti-allergic drugs 651, 651–652 cromones 633 homeopathy 638 IL-4 inhibition 644–645 IL-13 inhibition 645 interferon-c 646 leukotriene receptor antagonist 230, 644 recombinant IL-12 646–647 perennial, development/maintenance 387, 387 preventative strategies 652 Th2 cell activation 257 allergen-induced bronchoconstriction, reduction by prostaglandin E2 224 allergic bronchopulmonary aspergillosis (ABPA) 388–389 allergic bronchopulmonary mycoses 388–389 diagnosis and treatment 389 allergic reactions adenosine role 296 ingested/injected allergens 387 see also allergy allergic rhinitis 5, 383 antihistamine treatment 567 asthma in early life and 23 experimental rhinovirus infection 408 genetic linkage studies 32 increased VCAM-1 and ICAM-1 205 prevalence 9 historical 383–384 allergy 13–14 childhood asthma 700–701 management 707–708 genetics 31 historical aspects 383–384 hyposensitization 707–708 intermediate phenotype between asthma/COPD 13–14 origin of term 383 tests for 450 see also skin-prick tests all-trans-retinoic acid 320 almitrine pulmonary hypertension treatment 188–189 side effects 189 ALOX-5 gene 354 alpha-1 protease inhibitor (a1-antitrypsin) 275 deficiency 275, 279 carbon monoxide diffusing capacity 450 COPD/emphysema association 36, 215, 277, 279, 319–320, 363, 717 lung transplantation 721 mutations 319–320 neutrophil elastase inhibitor 277, 647 paracinar emphysema, CT 472–473, 473 Pi Z phenotype 279, 319–320
747
smokers/nonsmokers 363 functions 275, 277 inactivation 276, 370 replacement, COPD progression prevention 717 alpha2-macroglobulin see a2-macroglobulin alpha-adrenoceptors 330 Alternaria 21, 22 allergens 384 alternative therapies see complementary/ alternative medicine; smoking cessation altrakincept (soluble IL-4 receptors) 644 aluminium smelter workers 401, 402 alveolar disease, contribution to airway function 53–54 alveolar epithelium COPD 367 see also epithelial cells, airway alveolar function tests 48–51 carbon monoxide transfer 49, 51 pulmonary gas exchange 49, 50, 51 alveolar hypoventilation, acute asthma 693 alveolar macrophages see macrophage(s), alveolar alveolar septal cells, apoptosis 186 alveolar space, reactive oxygen species in 248–249 alveoli structure in COPD 364 volume 49 alveolitis, T cell 124 amantadine 416, 635 ambroxol 721 American Cancer Society 433 AmericanThoracic Society (ATS) 7, 414 COPD staging system 714, 714–715 pulmonary rehabilitation 427 amino acids, reactive oxygen/nitrogen species interaction 244 aminoguanidine 644 aminopeptidase M 238 aminophenylethyladenosine (APNEA) 295 aminophylline 535 clinical use in asthma 540–541 routes of administration 540 side-effects 541 amoxicillin–clavulanic acid, COPD exacerbation treatment 580 amphetamines, in early inhalers 441 anaphylactoid reactions 440 aspirin-intolerant asthma 441 ‘anatomical shunts,’ VA/Q ratios 49 angiogenesis airway remodeling 73 mediators/agents stimulating 74 substance P stimulating 332 angiotensin-converting enzyme (ACE) 238, 335 kinin degradation 238 tachykinin degradation 332
748
Index
angiotensin-converting enzyme (ACE) inhibitors 145 cough 439 for pulmonary hypertension 606 angiotensin II 335–336 receptor antagonists 336, 606 animal models 79–88 antigen-induced airway inflammation 207 apoptotic lung cell death 186 asthma, neutrophil influx 132 bronchoconstriction due to cycloxygenase metabolites 222 chronic bronchitis see chronic bronchitis comparisons and characteristic traits 85 COPD pathogenesis 278–279 neutrophil role 132 gene targeting 278–279 growth factors 287–288 mouse models of asthma 79–82 basophil role 94 complement factor 4 defect 301 mast cell role 94 see also airway hyperresponsiveness (AHR) anti-allergic drugs 651, 651–652 costimulation inhibitors 651, 651 antibiotics 573–585 acute exacerbations of chronic bronchitis 575–576, 576 amoxicillin–clavulanic acid 580 asthma treatment 573 azithromycin 580 bronchoconstriction due to 440 cephalosporins 580 Chlamydia pneumoniae infection 573 ciprofloxacin 583 clarithromycin 580 COPD exacerbations 579, 579–580 guidelines for use 414 prevention 579, 733–734 treatment 575–576, 576, 732 COPD treatment 573–583 fluoroquinolones 580 infective exacerbation treatment 415 macrolide, chronic asthma 681 Mycoplasma pneumoniae infection 573 oral penicillins 580 pharmacokinetic considerations 579–580 resistance 579 tetracyclines 580 trimethoprim–sulfamethoxazole 580 vicious circle hypothesis 578, 578 anti-CD4 antibody, asthma 601 anticholinergic agents, naturally occurring 527 see also atropine anticholinergic bronchodilators 527–534 asthma 329 acute severe 530 children 530
exacerbation treatment 681 stable 329, 530, 530 autonomic control of airway caliber 527, 527–528 b-blocker-induced asthma prevention 328 classification 528 clinical efficacy 529–532 clinical recommendations 532–533 combinations with other bronchodilators 532, 719 COPD 44 acute exacerbations 531, 731 bronchodilators with 719 mechanism of action 328 response 44 stable 531, 531 dose response 529 ipratropium bromide see ipratropium bromide new agents 642–643 paradoxical bronchoconstriction 532 pediatric airways disease 530 pharmacology/pharmacokinetics 528–529 protection against bronchospastic stimuli 529 rationale for use 527–528 scopolamine 528, 529 side-effects 532 sleep quality 532 structures 529 tiotropium 528, 529, 643 see also ipratropium bromide antidepressants, COPD management 721 anti-exudative effects 198 antigen presentation 262 cytokines release and 262, 265 macrophage 265, 345 antigen-presenting cell (APCs) 103 dendritic cells 345 lung 123 professional 103 antigen recognition 119 antihistamines 567 anti-IgE antibodies/therapy in asthma 117, 345, 386, 601, 652 effect on allergen-induced airway response 386 anti-inflammatory agents anti-leukotrienes see anti-leukotrienes cromones 633–634 cytokine suppressant antiinflammatory drugs (CSAIDs) 650, 650 future therapies 648, 648–651 MAP kinase inhibitors 650, 650 NSAIDs see NSAID-induced asthma phosphodiesterase (PDE) inhibitors 648–649 targets for COPD 642 theophylline see theophylline transcription factor inhibitors 649–650
anti-inflammatory mechanisms, in asthma 352–353 inflammatory mechanism imbalance 352, 353 anti-leukotrienes 565, 565–567 anti-inflammatory effects 567 aspirin-induced asthma 566 chronic asthma management 680 comparative studies 664 corticosteroids, add-on therapy 554 cysteinyl-leukotriene antagonists 565, 566, 643–644 effects in asthma 566 exercise-induced asthma 566 5-lipoxygenase inhibitors 566, 571 new agents 643–644 role in COPD 567 safety 567 antimicrobial resistance 579 see also antibiotics antioxidants 369, 635–636, 644 N-acetylcysteine 636, 644 dietary 635–636 gene expression 250–251 glutathione 635, 636 management of chronic asthma 682 in smokers 460 antisense oligonucleotides 652–653 a1-antitrypsin see alpha-1 protease inhibitor anti-tussives, COPD management 721 antiviral drugs 416 influenza treatment 635 AP-1 transcription factor 318 activation 318 by reactive oxygen species 246, 250 in asthma 348 in corticosteroid mechanism of action 548, 549 functions and genes regulated 318 inhibition by glucocorticoids 319, 548 apoptosis 199 alveolar septal cells 186 corticosteroid effects 112 molecular mechanisms 550 endothelial cells 185, 186, 371 eosinophils see eosinophil(s) of inflammatory infiltrate 135 inhibition, theophylline 537 lung structural cells 186 skeletal muscle 373 arachidonic acid leukotriene synthesis 227, 228 metabolism 221, 227 arachidonic acid products 221, 221 asthma pathogenesis 221–222 bronchoconstriction in animals 222 exercise-induced bronchoconstriction 224, 224 released by eosinophils 115 arrhythmias, b2-adrenoceptor agonists 524 arterial blood gases
Index
abnormalities in acute asthma 692–693 alveolar–arterial 49, 50, 51 exchange 49, 49, 50, 51 asbestosis 284, 401 ASM see airway smooth muscle (ASM) aspergillosis, allergic bronchopulmonary (ABPA) 388–389 Aspergillus antigens 384 animal model of growth factor action 287 Aspergillus fumigatus 388–389 aspirin, desensitization 441 aspirin-induced asthma 440, 690 clinical features 441 cysteinyl leukotrienes release 224, 441 prevention, leukotriene receptor antagonist 230 response to lysine aspirin 441 treatment 441–442 assessment of asthma 676–677 acute exacerbations 693 failure, acute asthma fatality 690 types 677 assist-control ventilation 611 astemizole 567 asthma acute severe see acute severe asthma adult-onset 4 characteristics 4, 4 children see children as chronic disease 3, 7, 344 chronic persistent see chronic persistent asthma COPD differentiation 4–5, 4–5, 44 airway function tests 48 carbon monoxide transfer coefficient (KCO) 51, 52 extrapulmonary manifestations of COPD 53 gas exchange and PCO2 levels 49 COPD overlap 5, 16, 19 intermediate phenotype with COPD 13–15 COPD similarities/differences 3, 3–4, 4 definitions 3, 7, 447 limitations 6 deterioration, prediction from nitric oxide level 311 development, prediction from airway responsiveness 14 forms in infancy/childhood 20–21, 21 heterogeneity 19 late-phase response see late asthmatic response (LAR) onset 4 outcome in adult life 22–23 pathology see airway pathology as progressive disease 25 relapse in adulthood 23 types 355 Asthma Collaboration Study 14 asthma diaries, childhood asthma 704
Asthma Management Plan 675, 676, 676, 682 Asthma Quality of Life Questionnaire (AQLQ) 483 asthma severity airway inflammation relationship 344 allergen exposure and 493–494 assessment 676–677 children 700 determination, transcription factors role 317–318 exercise-induced 423 genetic factors 354 increased by allergen exposure 494 mild/moderate, definition 700 severe, definition 700 atelectasis 704 atenolol 440 atmospheric pollutants see air pollution atopy 384 airway hyperresponsiveness prevalence 387, 388 anti-allergic drugs for 651, 651–652 assessment/investigation 450 asthma relationship 5, 13, 126, 355 in children 21 occupational asthma 398 as risk factor 354 definition 384 genetics 32, 354 linkage studies 32 nonatopic vs atopic asthma (children) 21 origin of term 383 pet ownership and allergen sensitization 496–497 prevalence and increase in 384 preventive strategies 652 allergen avoidance 496 Th2 phenotype 346 atrial natriuretic peptide (ANP; ANF) 188, 335 clearance by lung 188 clearance receptors, inhibition in pulmonary hypertension treatment 188 inactivation mechanisms 335 infusion, effects 335 as new bronchodilators 643 plasma levels during exercise 335, 335, 337 urodilatin 643 atropine 327 bronchodilator action 527 effect on thromboxane A2 mimetic action 223 pharmacology 527, 528 side-effects 532 structure 529 ‘attenuated fibroblast sheath’ 70 autoantigen, cytotoxic T cell recognition 127 autonomic control airway caliber, anticholinergic bronchodilator 527, 527–528
749
airway smooth muscle 323, 323 autoreceptors, muscarinic 327 axoneme 150 axon reflex mechanism 331, 332, 333 azithromycin, COPD exacerbation treatment 580 B b2-agonists see beta (b2)-agonists B7.1 (CD80) 103, 172 B7.2 (CD86) 103, 172 bacteria lipopolysaccharide 100, 246 normal flora, respiratory tract 574 bacterial colonization chronic bronchitis 574 COPD exacerbation 730 stable COPD 415 bacterial infections antibiotic use in asthma/COPD 573–585 see also antibiotics childhood asthma trigger 701 COPD exacerbations 63, 414, 577–578 COPD pathogenesis/progression 414–415 important bacterial pathogens in COPD 578 Mycoplasma pneumoniae infections 187, 573 serological studies, chronic bronchitis 575 ventilator support, complications 614 vicious circle hypothesis 578, 578 barotrauma, ventilator support 614 Baseline Dyspnea Index (BDI) 483 basement membrane collagen type IV in 212 subepithelial, deposition 71–72 thickened in asthma 350 basophils 91–97 activation 92–93 IgE-dependent 92 FceRI expression 92 homeostasis 94 origin and fate 91 priming and inhibition 93 recruitment 92 role in asthma 94–95, 346 animal models 94 humans 94–95 viral infections 412 role in COPD 95 B cells activation, adhesion molecules role 206 atopic asthma 126 COPD 127 pulmonary 123 viral infections 413 virus-induced asthma 413 beclomethasone airway blood flow changes 180, 181 comparative studies, COPD 665
750
Index
behavioral interventions, smoking cessation 715–716 Berodual® 532 beta (b)-adrenoceptors 329 function in asthma 329, 350 genetically dysfunctional 691 uncoupled in severe asthma 350 beta (b2)-adrenoceptors agonist structure/function relationship 522, 522–523 amino acid sequence 35 corticosteroid mechanism of action 549 function adrenaline effect 334 cytokines effect 329 gene, as candidate gene for asthma 33–34 gene polymorphisms 33–34, 524–525 Arg16 33–34, 524 Glu27 37, 524 Gly16 34, 524 single-nucleotide (SNPs) 354, 524–525, 691 treatment response prediction 525 beta (b2)-agonists 521–526 acute asthma management 694 adverse effects and mortality 690 airway smooth muscle relaxation mechanisms 521, 521 albuterol see albuterol childhood asthma 700, 705 clinical pharmacology 523, 523 commonly used agents 522 COPD exacerbation treatment 731 exercise-induced asthma management 425 for exercise limitation in COPD 426 factors affecting response to b2-adrenoceptor polymorphism 33–34 downregulation by IL-1b 350 G-protein regulatory cycle 521, 522 inhibition of early asthmatic response 385 long-acting 385 chronic asthma 679 comparative studies 663–664 with inhaled corticosteroids in asthma 679 salmeterol/fluticasone 664 see also formoterol; salmeterol long-term effects 523–524 mechanism of action 172, 521–522 need for new treatments 641 oral, cost-benefit analysis 664 receptor structure/function relationship 522, 522–523 short-acting (SABA) asthma exacerbation treatment 680 dose and administration 680 indications 680 side-effects 680 see also salbutamol; terbutaline
short-term effects 523 side-effects 641, 690 smooth muscle remodeling reduced 74 theophylline interaction 541 beta (b-)blockers 329 asthma exacerbation 439, 440, 690 mechanism 329, 329, 440 prevention 328 bronchoconstriction due to 328, 334 contraindicated in airway obstruction 439 nonselective, severe asthma due to 440 selectivity 440 betaxolol 440 biochemical markers need for additional markers 457 sputum, asthma vs COPD 451, 452 biological response modifiers, cytokines as 120 biopsy see bronchial biopsy birthweight, COPD association 362 bleomycin injury, growth factors involved in fibrosis 285, 286 blood flow, tracheobronchial corticosteroid-induced changes 180, 180, 181 decrease by albuterol 180, 180 increased by endothelin-1 178, 299 regulation 178 subepithelial (mucosal) 177 see also tracheobronchial circulation blood gases see arterial blood gases blood supply, bronchial tree 58 blue bloaters 372, 448 B lymphocytes see B cells bone metabolism, corticosteroid sideeffects 557–558 bradykinin 170, 237 antagonists 240, 568 bronchoconstriction 239 inhibition by nitric oxide 240 mechanisms 240 cough 240 effect on airway smooth muscle 239 increased by allergen provocation 240 inflammatory response in viral infections 410 inhaled clinical effects 239 cough due to 326 intranasal administration 410 receptor 238 ligand 238 structure 238 synthesis, asthma 239 brain natriuretic peptide (BNP) 335 breastfeeding, protection against asthma 15 breathing exercises, childhood asthma 708 breathing techniques Buteyko breathing technique 637–638 yoga (pranayama), asthma 638
breathlessness see dyspnea British Thoracic Society childhood asthma management 705, 705 childhood asthma severity 699–700 treatment of asthma exacerbations 682 bromhexine 721 3–bromotyrosine 247, 249 bronchi arterial supply 58 constriction see bronchoconstriction dilatation, asthma, CT 467–468 normal anatomy 57 venous flow 58 bronchial arteries 177 anatomy 177 constriction by endothelin-1 299 bronchial biopsy airway eosinophils in asthma 116–117 asthma 343 COPD 364 ‘gold standard’ in asthma 457 bronchial capillaries 177 permeability and dilatation in asthma 187 bronchial circulation 58, 58 neutrophil sequestration 134 see also tracheobronchial circulation bronchial glands, normal 61 bronchial hyperresponsiveness airway remodeling association 67 childhood asthma 700 COPD 26 early life risk factor for respiratory illness 26 role in persistent asthma 23 exercise effect in COPD 424–425 ‘intrinsic’ 26 by platelet activating factor 297 reactive oxygen species associated 246–247 see also airway hyperresponsiveness (AHR) bronchial neutrophilia 451 bronchial provocation tests, childhood asthma 704 bronchial reactivity tests, childhood asthma 704 bronchial wall thickening radiographical/morphological abnormalities (asthma) 467, 468, 468–469 reported prevalence 467 bronchiectasis 58 allergic bronchopulmonary aspergillosis 389 high resolution CT 476 morphological abnormalities, asthma 467–468 bronchioles, normal anatomy 57 bronchiolitis acute viral 702, 703 management 706
Index
constrictive see constrictive obliterative bronchiolitis bronchiolitis obliterans, childhood asthma vs 702 bronchiolitis obliterans with organizing pneumonitis (BOOP) 284 bronchitis acute, COPD exacerbation 728 children 699 chronic see chronic bronchitis in infancy, increased risk of wheezing in adults 25 ‘spastic’ 699 bronchoalveolar lavage (BAL) asthma 343 COPD 364 eosinophils role in asthma 116 histamine levels 291, 293 leukotriene recovery 229 bronchoconstriction adenosine causing (animals) 295 allergen-induced, reduction by prostaglandin E2 224, 225 angiotensin II action 335 antibiotics causing 440 beta-blockers causing 328, 334, 440 bradykinin-induced see bradykinin by cholinergic agents 439 cholinergic nerve action 326, 328 cycloxygenase metabolites causing 222 cysteinyl leukotrienes mediating 228–229, 441 see also cysteinyl leukotrienes endothelins causing 298, 300 ET-1 298, 299 exercise-induced see exercise-induced bronchoconstriction exercise-induced asthma 422, 423 inhibitory muscarinic receptor action 327 life-threatening, aspirin-intolerant asthma 441 matrix degrading proteinases involved 279, 279–280 platelet activating factor inducing 297 prostaglandin D2 (PGD2) causing 222 prostaglandin F2a (PDF2a) causing 222, 439 thromboxane A2 causing 223 bronchoconstrictors airway response to 45–46 calcium response in airway smooth muscle 165 site of response 46 bronchodilatation i-NANC nerves mediating 330 slowly adapting receptors role 324–325 bronchodilator nerves, asthma 351 bronchodilators b2-adrenoceptor agonists 521–526 see also beta (b2)-agonists airway response to 44–45
assessment 44–45 variability 44 anticholinergic see anticholinergic bronchodilators Berodual® 532 Combivent® 532 COPD exacerbations prevention 722, 734 treatment 731 COPD treatment 44, 718–720 choice of drug/formulation 718–719, 719 combination therapy 719 frequency of use 719 long-acting 720 magnitude of response 718 quality of life improvements 722 response variations 718 short-acting vs long-acting 719, 719 DuoVent® 532 new drugs 642–643, 643 atrial natriuretic peptides 643 large conductance calcium-activated channels (maxi-K) 643 new anticholinergics 642–643 potassium channel openers 643 reduced efficacy after antagonist treatment 439 reversibility to, testing 449 theophylline 535–545 see also theophylline V/Q mismatch deterioration 184 see also individual bronchodilators bronchogram emphysema 62, 62–63 normal 57, 57, 62 bronchoscopy asthma 59, 343 childhood asthma 704 bronchospasm adenosine-induced 295 exercise-induced asthma 423 Broncho-Vaxom (OM-85 BV ) 635 bronchus-associated lymphoid tissue (BALT) 119 budesonide clinical efficacy, asthma 552, 553 comparative studies, health economics 663 exercise-induced asthma 425–426 improvement rate in chronic asthma 677 metabolism 555 bullectomy, surgery 627 bupropion, smoking cessation 514, 515, 516, 716 clinical trials 514, 516 Buteyko breathing technique 637–638 BW755C (lipoxygenase inhibitor), airway hyperresponsiveness prevention 222 C C5a see under complement C57BL/6 mice
751
allergen-induced airway hyperresponsiveness eosinophil role in 81 IgE and mast cells role 80–81 effect of sulfur dioxide exposure 84–85 cachexia, TNF-a role 373 cadherins 204, 205 function 205 cadmium 361 COPD etiology 361, 362 emphysema association 371 calcitonin gene-related peptide (CGRP) 324, 333 calcium homeostasis in airway smooth muscle 166–168 phospholipase C activation 169, 170 sensitivity of myofilaments 167–168 signaling see calcium signaling calcium-ATPases, sarco-endoplasmic reticulum (SER)-associated 165 calcium channel(s) large conductance calcium-activated channels (maxi-K) 643 receptor-operated (ROCC) 166 store-operated (SOCC) 165, 166 theophylline mechanism of action 537 calcium channel blockers, pulmonary hypertension 606–607 calcium-sensitive protein kinases 308 calcium signaling, in airway smooth muscle 165–168 agonist-induced contraction 165, 166 bronchoconstrictor-induced response 165 calcium homeostasis 166–168 calcium sources 166 pathways regulating calcium influx 165–166, 166 receptor-coupled 166 amplification 166–167 modulators 167, 168 stimuli in asthma influencing 168, 169 calmodulin, requirement by nitric oxide synthase 308 CAM families see cell adhesion molecules Canadian Thoracic Society, alpha-1 protease inhibitor replacement 717 capacitative model 165 capsaicin 333 carbachol, airway responsiveness, genetics 31–32 carbocysteine 636 carbon dioxide exercise-induced changes in COPD 424 partial pressure (PCO2 ), asthma vs COPD 49 retention, acute asthma 692 carbon monoxide 461–462 exhaled factors affecting measurement 462
752
Index
carbon monoxide—cont levels in asthma/COPD 462 measurement 462 oxidative stress link 462 sources 461 formation 461–462 carbon monoxide diffusing capacity (DLCO) 49, 450 carbon monoxide transfer 49, 51 single-breath CO transfer test 49 carbon monoxide transfer coefficient (KCO) 48, 49, 51 asthma vs COPD 51, 52 carboxypeptidase N (kininase 1) 238 cardiac output, ventilator support effects 614 cartilage, collagens 212 caspase inhibitors 186, 371 catecholamines adrenaline see adrenaline circulating 334–335 inactivation by sulfation 145 inhaled, metabolism by epithelial cells 145 see also noradrenaline cathepsin(s) 647 secretion by macrophage 105 cathepsin B 275 cathepsin C 275 cathepsin G (CG) 274, 370 inhibition by SLPI 275 cathepsin H 275 cathepsin K 275 cathepsin L 275 cathepsin S 275 CC chemokines 100, 101, 102, 255 eosinophil chemoattraction 257 receptors 255, 256 regulation of lymphocyte homing 124, 125 released from epithelial cells 146 CCR2 expression, by macrophage 268 CCR2 inhibitors 646 CCR3 antagonists 646 development 258 on eosinophils, chemokines binding to 112, 257, 258, 646 eotaxin receptor 112, 257, 258 CCR4 antagonists 646 CD4, anti-CD4 antibody, asthma 601 CD4 T cells see T cells CD8 T-cells COPD 4, 61, 127–128, 366–367 granzymes and perforin secretion 268 inflammatory process 127 role in viral infections 127, 411 see also cytotoxic T lymphocytes (CTL) CD14, lipopolysaccharide interaction 100 CD28 265 ligands 265 CD40 265 CD44 172, 204
function 205 CD80 (B7.1) 103, 172 CD86 (B7.2) 103, 172 celecoxib 441 cell adhesion, blockers 651 cell adhesion molecules 203–209 airway inflammation 205–207, 206, 550 antibodies effect 205–206, 651 functions 206–207 ICAM-1 and VCAM-1 205 leucocyte homing 205–206, 550 in airway remodeling process 69, 73 antibodies to 205–206, 651 eosinophil–epithelial cell interactions 147, 345 eosinophil migration 112 see also cell migration on eosinophils 345 expression by airway smooth muscle cells 172 blockade 205–206, 207, 651 cytokines influencing 267 by epithelial cells 147 inhibition by corticosteroids 550 families 203–205 functions 172 epithelial repair 207 leucocyte activation 206–207 smooth muscle cell activation 207 leucocyte–airway smooth muscle interaction 172 neutrophil–endothelial 133–134, 134 see also integrins; specific cell adhesion molecules cell–cell adhesion cadherins role 205 eosinophil–epithelial cell interactions 147, 345 immunoglobulin supergene family members 204 integrins role 203 neutrophil–endothelial 133–134, 134 cell–matrix adhesion integrins role 203 proteoglycans 205 see also extracellular matrix cell migration eosinophils 112, 113, 205, 267, 345–346 epithelial cells during repair 149 fibroblasts 139–140 see also fibroblast(s) inflammatory cells, importance of MMPs 280 leucocyte homing 205–206, 255 lymphocytes 119, 124–125, 125 neutrophils 133, 133–134 cellular immune response viral infections 411 see also T cells cephalosporins, treatment of COPD exacerbation 580 C-fibers see C nerve fibers
c-fos 291 Charcot Leyden Crystal (CLC) protein 115 chemiluminescence, nitric oxide measurement 309 chemokines 255–260 asthma 256–258 CC family 100, 101, 102, 255 see also CC chemokines COPD pathogenesis 256, 369 CXC family 101, 255 see also CXC chemokines eosinophil chemoattraction 112, 112, 257–258 functions 101, 255 mediated by G proteins 102, 255 regulation of lymphocyte homing 124–125 inhibitors 646 list of chemokines/names 256 receptors 255, 256 on eosinophils 257, 258 eotaxins 257, 258 on Th2 cells 258 as therapeutic targets 258 released by airway smooth muscle 171–172 epithelial cells 146 macrophage 100 mast cells 94 secretion, inhibition by dexamethasone 172 structure 255, 257 chemotaxins 101 chemotaxis eosinophils 112–113, 345 fibroblasts 332 monocytes 278 T cells 124, 125 chest radiography 450, 465 acute exacerbation of chronic bronchitis 574–575 see also radiography childhood asthma 699–711 age at diagnosis 20, 20 age of onset of symptoms 699, 701, 701–702 ambulatory follow-up 704 chronic persistent 22–23 age of onset 20–21 atopy relationship 21, 22 outcome 22–23 contributing/triggering factors 700–701 costs 699 differential diagnosis 702 forms 20–21, 21 history taking 703 incidence 699 investigations 703–704 special 704 mortality 699 natural history 701–702 nonpharmacological management 707–708
Index
outcome 22–23, 702 physical examination 703 prognosis 702, 702 remission 15, 22–23 relapse in adulthood 23 schooling and 708–709 severity classification 699–700 treatment 705–707 acute severe asthma 707 corticosteroids 706, 707, 707, 708 drug delivery routes 705–706 guidelines 705, 705 principles 705, 708 successful 708 Childhood Asthma Management Program (CAMP) 25 children asthma-like symptoms due to infections 20, 24 persistence 25 bronchial responsiveness, implications 26 impaired lung function 21 infections lacking, asthma association 346, 354, 384 lung function development 23, 23–24, 24–25 see also lung function wheezing, different phenotypes 20–21, 21 chiropractic spinal manipulation, asthma 638 Chlamydia pneumoniae in asthma 573 COPD exacerbation 730 chlorofluorocarbons (CFCs), asthma induced by 439 ‘choke-points’ 48 choline acetyltransferase 326 cholinergic agents, bronchoconstriction 439 cholinergic nerves 326–329 airway control 326, 327 COPD 328, 328 bradykinin-induced bronchoconstriction 240 endothelins effect 300 modulation 328 muscarinic receptors 326–328 nitric oxide as braking mechanism 328, 330, 331 role in asthma 328–329, 351 role in COPD 329 tracheobronchial blood flow regulation 178 cholinergic reflexes 328 cholinergic tone, increased in asthma 328 mechanisms 328–329 chondrodysplasias 215 chondroitin sulfate 213 chromatin structure, corticosteroid effects 548, 549 chromosomal associations, asthma 32–33
chromosome 5q 32 chromosome 11q 32 chromosome 2p 33 chromosome 4 32 chromosome 5q 32 chromosome 6 32 chromosome 11q 32 b-chain of high-affinity IgE receptor 34 microsatellite marker D11S97 32 chromosome 12q, asthma association 32 chronic asthma management see management of chronic asthma (adult) persistent see chronic persistent asthma chronic bronchitis 7, 371–372 acute episodes 728, 730 see also acute exacerbations of chronic bronchitis animal models 82–86 airway inflammation due to SO2 83 airway obstruction and hyperresponsiveness 83–84 comparisons and characteristic traits 85 role of C-fibers 84 sulfur dioxide effect in mice 84–85, 85 sulfur dioxide effect on epithelial cells 82 sulfur dioxide effect on mucus secretion 82–83 bacterial colonization of airway 574 blood eosinophilia as risk factor of airway obstruction 248 defining features 361 expiratory pressure–volume curves 52 increased expression of TGFb and EGF 269 leukotrienes produced 231 pathogenesis 371–372 pathology 61, 64 prevalence 10 rhinovirus-induced exacerbations 730 submucosal glands and mucus secretion 158 see also chronic obstructive pulmonary disease (COPD) chronic disease, asthma as 3–4, 7, 344 chronic eosinophilic bronchitis 345 see also asthma chronic obstructive pulmonary disease (COPD) asthma differentiation/overlap see asthma asthma similarities/differences 3, 3–4, 4 characteristics 4, 4 comorbid conditions 361 definitions 3, 7, 361, 447 limitations 6 early-onset see early-onset COPD extrapulmonary manifestations 53, 54 heterogeneity 19
753
inflammation characteristics 4 intermediate phenotype with asthma 13–15 occupational see occupational COPD onset 4 pathology see airway pathology smoking relationship see smoking systemic effects 372–374 underdiagnosis 10 see also chronic bronchitis; emphysema chronic persistent asthma 22–23 allergens associated 23 atopy relationship 21–22 causes 354–355 definition 675 early onset 20–21 factors influencing 21, 23 severe 684–685 Chronic Respiratory Questionnaire (CRQ) 482, 483, 484 Churg–Strauss syndrome 677, 680 zafirlukast/montelukast 567 chymase, released by mast cells and basophils 94 a-chymotrypsin 330 ciclesonide (new corticosteroid) 561 ciclosporin see cyclosporin A cilia beating 157 kinin-induced increase 239 structure and function 150 ciliary dyskinesia, primary 700, 702 ciliary neurotrophic factor 326 ciliated epithelial cells effect of sulfur dioxide 82 structure and function 150 cimetidine 567 histamine tachyphylaxis inhibited 224 ciprofloxacin, treatment of COPD exacerbation 583 cost-effectiveness 665–666 circadian variations adrenaline (epinephrine) 334 airway hyperresponsiveness (AHR) 385 peak expiratory flow rates 449 circulation see bronchial circulation; pulmonary blood vessels; tracheobronchial circulation citric acid, cough stimulation 326 c-kit 91, 92 clarithromycin, treatment of COPD exacerbation 580 classification of asthma childhood 699–700 for management purposes 675 classification of COPD, acute exacerbations 581–582, 582 climate allergen control 490–491, 494 chronic asthma management and 683 effect on exercise-induced asthma 422, 423 clinical course asthma 354–355, 691
754
Index
clinical course—cont see also natural history clinical features asthma 4, 5, 355, 447–448 acute exacerbations 692 allergen-induced 387–388 COPD comparison 452 COPD 4, 5, 361 systemic 372–374 Clinical Practice Guidelines 657–658 clinical trials, leukotriene modifiers 231 clonidine 516 C nerve fibers 325 activation by cigarette smoke 334 adenosine effect on 295 in airway disease 333 functions 325 response to inflammatory mediators 325 sensitivity to hypo/hypertonic saline 325 sulfur dioxide-induced bronchitis (animals) 84 coal miners, COPD 400 cocaine, crack 441 cold air, effect on exercise-induced asthma 422 colds see common colds collagen(s) 211–212 cartilage 212 a-chain synthesis 212 lung extracellular matrix 211, 211–212 ‘overmodified’ 212 receptors, integrin distribution in lung tissue 203 secretion stimulated by endothelin-1 300 structure 211–212 turnover in emphysema 278 collagenases 276 collagen type I, mutations in osteogenesis imperfecta 214 collagen type III 212 collagen type IV 212 deposition in asthma 350 collagen type V 212 deposition in asthma 350 mutations in Ehlers–Danlos syndrome 214 collagen type XVIII 212 collectins 36 columnar epithelium 57 damage/detachment 68–69 Combivent®, bronchodilator 532 combustion products, COPD due to 401 common colds COPD exacerbation 730 IL-6 levels 729 treatment 416 see also rhinovirus infections communication, patient/health care professional 738–739, 740 guidelines 739
comparative studies see health economics complement 300–301 in asthma 348–349 C3a, level in asthma 301 C5a COPD 367 IL-8 synthesis and 256 level in asthma 301 C5a receptor 348 deletion in mice 301 effect on airway function 301 receptors 301 sCR1 301 role in airway disease 301 synthesis 300 in virus infections 410 complementary/alternative medicine, asthma 637–638 acupuncture 638 breathing techniques 637–638 chiropractic spinal manipulation 638 efficacy 637 herbal medicines 638 homeopathy 638 management of chronic asthma 682 safety 638 yoga 638 compliance with treatment 738–739, 739 bronchodilators in COPD 718 children 705–706 depression affecting 721 need for new treatments 641 see also noncompliance compressed gas oxygen 592, 592 computed tomography (CT) asthma vs COPD diagnosis 451 CT abnormalities/lung function test relationships 474 dynamic studies 469 emphysema 472–474 diagnosis 473 indications 471 morphological abnormalities 469–470, 472, 472–474, 473 quantifying extent 473–474 high resolution see high-resolution computed tomography (HRCT) imaging techniques 465–466 morphological abnormalities, asthma 467–470 bronchial dilatation/bronchiectasis 467–468 bronchial wall thickening 468, 468–469 patient selection, lung volume reduction surgery 628–629 radiation considerations 466 small airways disease 470, 470, 475 spiral CT/multidetector CT 465–466 congenital anomalies, childhood asthma vs 702 connective tissue, lung asthma 216
COPD 215 corticosteroid side-effects (inhaled) 558 see also extracellular matrix connective tissue disorders 214–215 connective tissue growth factor (CTGF) 287 constrictive obliterative bronchiolitis chest radiography 475 high resolution CT 475, 475 ‘context-dependency’ of phenotype markers 20 controlled ventilation, ventilator support 611 control of asthma 675–676 concept 675 see also management of chronic asthma COPD see chronic obstructive pulmonary disease (COPD) coronavirus infections 730 cor pulmonale 187 decreased expired nitric oxide 183 pulmonary hypertension in COPD 606 corticosteroids 547–564 add-on therapy 554 airway hyperresponsiveness reduced 552 airway remodeling reduced 74 cell function, effects 550–551, 551 childhood asthma 706, 707, 708 ciclesonide 561 clinical efficacy in asthma (inhaled) 552–554 comparisons 553–554, 633 dose–response studies 553 irreversible airway changes prevention 553 mortality reduction 553 studies in adults 552–553 studies in children 553 comparative studies asthma 553–554, 633 COPD 665 health economics 663 corticosteroid-resistant asthma 559–560 mechanisms 560 corticosteroid-sparing therapy 555, 599, 600 cost-effectiveness 663 dissociated 561, 648 effect on allergen-induced airway response 386 effect on asthmatic inflammation 551–552 exercise-induced asthma 425–426 exhaled nitric oxide reduced 310 future directions 560–561, 648 growth retardation 706, 707, 707 infective exacerbation treatment 415 inflammatory genes targeted 548–550, 549, 552 adhesion molecules 550
Index
anti-inflammatory proteins 549 b2-adrenoreceptors 549 in COPD 560 cytokines 549–550 inflammatory enzymes 550 inflammatory receptors 550 lipocortin-1 synthesis 549 nitric oxide synthase 308, 550 inhaled, in chronic asthma 554–555, 677–679 add-on therapy 554 anti-leukotrienes with 554 clinical effects 554, 678, 678 cost-effectiveness 554 dose and administration 554, 679 dose titration 677 down titration 678–679 intermittent use 679 long-acting b-agonists with 554, 679 theophylline with 554 inhaled, in COPD 560 clinical studies 560 exacerbation treatment 731–732 long-term, exacerbation prevention 734 long-term studies in COPD 450 reduced decline of lung function in COPD 26 metabolism 555 molecular mechanisms 547–551 classical model 548 effect on cell function 550–551 effect on chromatin structure 548, 549 gene transcription 547, 549 glucocorticoid receptors 547 mucus secretion inhibition 551 NF-jB inhibition 410, 548 target genes in inflammation control 548–550 transcription factor interaction 548 monitoring of effects in asthma, by exhaled nitric oxide 310, 310–311 mucus hypersecretion therapy 160 need for new treatments 641 neutrophil survival 135, 551 new drugs 560–561, 648 nitric oxide synthase regulation 308, 650 pharmacokinetics 555, 555–556 reversibility of COPD 450 side-effects 556, 556–559, 641, 679 bone metabolism 557–558 CNS effects 558 connective tissue 558 in COPD exacerbations 732 delivery system effect 556–557 dysphonia 556 growth 558 hematological effects 558 hypothalamic–pituitary–adrenal (HPA) axis 557 inhaled steroids 556, 556–559
metabolic effects 558 ocular effects 558 oropharyngeal candidiasis 556 pharyngeal 679 safety in pregnancy 558–559 systemic 556–559, 679 systemic 559 acute severe asthma 559 asthma exacerbation treatment 681 clinical effects 681 dose and administration 681 drugs for dose reduction 681 mechanism of action 681 side-effects 681 theophylline with 554 synergy prediction 537 see also glucocorticoid(s); steroids corticosteroid-sparing therapy 555, 599, 600 cortisol 336 in asthma 352 effect on airway caliber 336, 352 cost(s), asthma/COPD 11–12, 689 childhood asthma 699 UK asthma 659–661, 660 COPD 661, 661–662, 662 US asthma 659 COPD 661, 661 see also health economics cost–benefit analysis 658 comparative studies, asthma care in emergency rooms/hospitals 664–665 nebulizers vs. MDI 664 oral b-agonists 664 see also health economics cost–effectiveness analysis 658–659 corticosteroids 663 patient education/self-management 664 smoking cessation 666 costimulation inhibitors 651, 651 cough 325–326 ACE inhibitors 439 bradykinin-induced 240, 326 chronic, in children 699 COPD 61 exacerbations 728 increased sensitization 326, 326 management in COPD 721 mucus clearance 157 nocturnal, in children 699 persistent, GOLD staging system for COPD 714 stimulation by citric acid 326 unproductive 447 cough receptors 157, 325 cough reflex 325–326 afferent nerves 325–326 slowly adapting receptors involved 324–325 CREB-binding protein (CBP) 246, 316, 547
755
corticosteroid mechanism of action 547 Creola bodies 350 cromolyn sodium, comparative studies 664 cromones 633–634 add-on therapy 633–634 adverse effects 634 allergen-induced asthma 633 anti-inflammatory effects in asthma 633 bronchial challenge 633 comparison with inhaled steroids 633 COPD treatment 634 exercise-induced asthma 633 first-line prophylactic therapy, asthma 634 mechanism of action 633 place in asthma management 634 see also nedocromil sodium; sodium cromoglycate c-Src-Ras-MEK signaling pathway 155 C-type natriuretic peptide (CNP) 335 CXC chemokines 101, 125, 255 IL-8 see interleukin-8 (IL-8) receptors 255, 256 antagonists 258, 646 CXCR1 and CXCR2 256 regulation of lymphocyte homing 125, 125 released from airway smooth muscle 171–172 epithelial cells 146 CXCR antagonists 258, 646 cyanosis 692 cyclic AMP (camp) pathway, b-agonist mechanism of action 172 cyclic AMP response element binding proteins (CREB) 246 see also CREB-binding protein (CBP) cyclopentyl-adenosine (CPA) 295 cyclosporin A chronic asthma 600, 681 immunosuppressant action 600, 651 T cell inhibition, NF-AT blocking 650 transcription factor inhibitors 650 cycloxygenase 221, 440 COX-1 221, 440, 441 COX-2 221, 440 inhibitors 222, 441 see also indomethacin metabolites see arachidonic acid products cystatin C 275–276 cystatins 275–276 cysteine (thiol) proteinases 275–276 functions 275 inhibitors 275–276 cysteine residues, in oxidant/redox signaling 246 cysteinyl leukotrienes airway narrowing 228 antagonists 566, 643–644
756
Index
cysteinyl leukotrienes—cont see also montelukast; pranlukast; zafirlukast aspirin-intolerant asthma 224 asthma pathogenesis 347, 459 biological effects in asthmatic response 228–229 bronchoconstrictor effects 228–229, 441, 459 duration 228–229 sensitivity to 229 definition 227 in exercise refractoriness 224, 224 in exhaled breath 459 mucus hypersecretion 160, 231 pathology of chronic asthma 228 receptors 230 blockade 230–231, 231 recovery/measurement in asthma 229–230 see also leukotriene C4 (LTC4); leukotriene D4 (LTD4); leukotriene E4 (LTE4) cystic fibrosis 150–151, 700 childhood asthma vs 702 infections inducing mucus hypersecretion 160 investigations 704 cytokeratin 14, expression after airway injury 147 cytokine(s) 261–271 in airway lumen after allergens 198 antigen presentation role 262, 265 anti-inflammatory 262, 265, 353, 353 asthma 261–268, 348, 348 airway remodeling 267–268 antigen presentation and cytokine release 262, 265 cell and cytokine interactions 266 eosinophil-associated cytokines 266–267 mast cell maturation 266 role in IgE response 265–266 types expressed 261–262, 269 b2-receptor function affected 329 classification 261, 262 COPD 268–269 cell and cytokine interactions 267 exacerbation 373, 728 pathogenesis 369 profile and types produced 268 properties 268–269 smoking influence 268 types expressed 269 definition 261 drug targets 549–550 effect on adhesion molecule expression 267 epithelial cell repair 150 exhaled breath 460 expression in asthma 261–262 virus infections 410 IL-1 receptor agonists 646
inhibitors 644–647 chemokine inhibitors 646 interleukin-4 644–645 interleukin-5 644 interleukin-9 645 interleukin-13 645 STAT-6 inhibitors 645 Th2 cytokine inhibition 644–645 TNF-a inhibitors 645 see also tumor necrosis factor-a (TNF-a) inhibitory 265, 646–647 interferon-c see interferon-c profibrotic, in asthma 350 pro-inflammatory 261, 262 kinin-induced release 239–240 sources and effects 264 receptors and receptor superfamilies 262 released by airway smooth muscle 171–172 eosinophils 111, 262, 266–267 lymphocytes 120–123, 261, 262 macrophage 262 mast cells 92, 94, 262, 266, 344 release increased by rhinoviruses 728 sources and effects 263–265 T cell activation regulation 124 T cell expression see T cells in viral infections, roles and upregulation 410 see also individual cytokines cytokine gene cluster 35 cytokine suppressant anti-inflammatory drugs (CSAIDs) 650, 650 cytotoxic T lymphocytes (CTL) 120 autoantigen in COPD 127 see also CD8 T-cells D death see mortality definitions 3–6, 7 activity limitations 481 airway remodeling 67 asthma 3, 7, 447 chronic persistent 675 mild/moderate 700 occupational 395 severe 700 COPD 3, 7, 361, 447 cysteinyl leukotrienes 227 cytokines 261 disability/impairment 481–482 emphysema 62 limitations 6 patient education 737 plasma exudation 195 status asthmaticus 689 demand devices, oxygen therapy 593 demographics 15 dendritic cells 103 antigen-presentation 345 in asthma 345 viral infections 411
corticosteroid effects on 550, 551 T cell activation 103, 123, 345 depression, COPD 373, 721 management 721 dermatan sulfate 213 Dermatophagoides 384–385 desensitization see allergen(s), desensitization desloratadine 567 desmopressin, uptake, altered tracheobronchial circulation 179 desmosine, urinary excretion 215 development of asthma, prediction from airway responsiveness 14 development of new therapies 642 dexamethasone, chemokine secretion inhibition 172 diagnosis, of asthma/COPD 447–455 additional tests 449–450, 452 airway inflammation assessment see airway inflammation allergen-induced asthma 388 asthma criteria 448, 448 COPD exacerbations 727, 727 failure/undiagnosed patients 10, 448 minimum requirements 447–449 sexual bias 4 stable COPD 713–715 diet childhood asthma management 708 management of chronic asthma 682 differential diagnosis 448, 448 asthma vs COPD 447, 452, 452–453, 713 ancillary tests 452 imaging 450–451 childhood asthma 702 diffusing capacity for carbon monoxide (DLCO) see carbon monoxide diffusing capacity (DLCO) dipyridamole 295 disability assessment 481–486 as component of health status questionnaires 483 concept/definition 481–482 long-term progression 484 measurement 482–483 reasons for 484 in routine practice 484–485 mechanisms 482, 482 disease management programs, health economics 665 diurnal rhythm see circadian variations doxapram, COPD exacerbation management 732 drug abuse, intravenous 441 COPD etiology 362 emphysema induction 361, 439 drug-induced asthma 439–442 aspirin see aspirin-induced asthma beta-blocker action 439, 440 illicit drugs see drug abuse NSAIDs 440–442
Index
drugs for acute exacerbations of COPD see acute exacerbations of COPD for chronic asthma see management of chronic asthma eosinophilic inflammation control 117 idiosyncratic effects 440 plasma exudation inhibition 198 transport, altered tracheobronchial circulation 179 see also individual drugs/drug groups dry powder inhalers bronchodilators in COPD 718 children 706 DuoVent®, bronchodilator 532 dusts cigarette smoke interaction 402 COPD due to 400, 401 Dutch hypothesis 14, 46, 362–363 dyspnea acute asthma 692 COPD 448, 717–718 mechanism 482 reduction in COPD treatment 717–718, 720, 731 scales 482–483 E early asthmatic response (EAR) 385, 385 drugs inhibiting 385, 386 pathogenic mechanisms 386 early-onset COPD 14 susceptibility factors 15 East London COPD Study 727, 728 ebastadine 567 economic aspects see health economics ecstasy (MDMA) 441 eczema 5 edema effect on airway caliber 179 pathogenesis in asthma 178 pulmonary, acute, nitrogen dioxide causing 435 education 737–742 asthma/COPD association 15 chronic asthma management 683–684 patient views/experiences asthma 738 COPD 737–738 see also patient education; selfmanagement Ehlers–Danlos syndrome 214–215 collagen mutations 214 eicosanoids in exhaled breath 458–459 functions 458 released by basophils/mast cells 93–94 spectrum of mediators 221 synthetic pathways 221 see also prostaglandin(s); thromboxane (Tx) elafin 275, 648
elastase:antielastase hypothesis, emphysema pathogenesis 277 elastases emphysema pathogenesis 277, 370 inhibitors (elafin) 275, 648 neutrophil see neutrophil elastase elastic fibers 212 distribution/properties and stability 212 elastic recoil 213 see also lung elastic recoil pressure elastin 212 destruction in emphysema 215, 370 markers for 215 microfibrils 213 solubilization by elastase 274 Elk-1 246 emotional factors, childhood asthma triggered 701 emphysema 7, 185–186, 268 a1–antitrypsin deficiency see alpha-1 protease inhibitor cadmium association 371 carbon monoxide transfer coefficient (KCO) 52 centrilobular (centriacinar) 62, 470, 472 pathology 62, 62–63, 63 characteristics 4 collateral ventilation 46 CT abnormalities 469–470, 473 definition 62 diagnosis, computed tomography 470, 473 distal acinar 63 drug abuse inducing 361, 439 elastin destruction 215, 277, 370 expiratory pressure–volume curves 52 histopathological types 470 HIV infection 362, 371 increased lung cell death 186 lung cell maintenance failure 185–186 lung destruction 370 mast cell role 95 lung transplantation survival 629–630 macrophage proteinases role 105 mantle 63 morphological abnormalities (CT) 472, 472–474, 473 nutritional factors associated 362 panacinar (panlobular) 62–63, 470, 473 pathogenesis 370 animal models 278–279 elastase:antielastase hypothesis 277 neutrophil and macrophage proteinase interactions 279, 279 proteinases involved see matrix degrading proteinases pathology 62–63, 64, 277, 361 periseptal/paraseptal 63, 470, 473 prevalence 10 protease/antiprotease theory 132, 135, 185, 370
757
quantification of extent by CT 473–474 radiographic abnormalities 470–471, 471, 472 rare causes 371 repair processes 371 smoking relationship 48 see also smoking susceptibility, MMP expression 278 see also chronic obstructive pulmonary disease (COPD) end-of-life issues, COPD 723 endopeptidases 273 characteristics 273 see also matrix degrading proteinases endoperoxides 222 endothelial cell(s) adhesion molecules expressed 204, 345 apoptosis 186, 371 emphysema 185 changes induced by oxidative stress 183 corticosteroids effects 551, 551 gaps, plasma leak via 196 growth inhibition by TGFb 186 lung structure maintenance 371 VEGF dependence 371 endothelial cell adhesion molecules 204, 345 leucocyte homing 205–206 see also intercellular adhesion molecule-1 (ICAM-1); vascular cell adhesion molecule 1 (VCAM-1) endothelin(s) 297–300 alveolar macrophage as source 297 antagonists 298–299, 644 pulmonary hypertension 189, 606 selective 298–299 therapeutic development 300 asthma 300, 349 bronchoconstriction 298, 300 COPD 300 pathogenesis 369 effect on airways 298–300, 299 effect on cholinergic transmission 300 genes 297 inflammatory cells/mediator changes 300 inhibition of inducible nitric oxide synthase 349 receptors 298 role in airway disease 300 role in airway remodeling 71 synthesis and metabolism 297–298, 298 endothelin-1 (ET-1) 141 airway smooth muscle proliferation 299 asthma 300, 349 increased blood flow 178, 299 increased expression 141 bronchial artery constriction 299 bronchoconstriction 298, 299, 300
758
Index
endothelin-1 (ET-1)—cont collagen secretion 300 COPD pathogenesis 300, 369 effect on airways 298–300, 299 fibroblast migration stimulation 141 inhibitors, potential role 141 mucus glycoprotein secretion stimulated 300 smooth muscle mitogen 73 synthesis and metabolism 297 endothelin-2 (ET-2), effect on airways 298 endothelin-3 (ET-3) 297 effect on airways 298 effect on cholinergic neurotransmission 300 endothelin-converting enzyme (ECE) 297, 298 endothelium, neutrophil interaction 133–134, 134 endothelium-dependent vascular relaxation, impairment in COPD 183 endothelium-derived relaxing factor see nitric oxide endotoxin, goblet cell metaplasia 155 endurance training, COPD 622 enprofylline 535 adenosine role in allergy and 296 environmental factors asthma association 354 atopy and asthma prevalence 384 childhood asthma management 708 enzyme inhibitors 647, 647–648 a1-antitrypsin (a1-AT) see alpha-1 protease inhibitor (a1-antitrypsin) cathepsins 647 matrix metalloproteinases 647–648 neutrophil elastase inhibitors 647 proteinase-3 647 secretory leukoprotease inhibitor (SLPI) 275, 368–369, 648 serpins (serum protease) 36, 275, 648 tryptase inhibitors 647 eosinophil(s) 111–118 activation 114 epithelial cell injury by 145 by platelet activating factor 297 substances associated 114 adhesion 345 airway luminal entry vs apoptosis 199, 201 allergen-induced airway hyperresponsiveness 81–82 apoptosis 135, 195, 199 asthma 280 steroid action 199 in asthma 115–117, 345–346 bronchial biopsy studies 116–117 bronchoalveolar lavage studies 116 granule proteins in pathogenesis 115 late-phase response 113, 113–114 mediators involved 116, 346
peripheral blood eosinophils 116 reactive oxygen species production 247, 345 therapy 117 viral infections 412–413 chemoattractants 112, 112–113 chemokines 112, 257–258 chemokine receptors 257, 258 chemotaxis 112–113, 345 clearance 199, 201, 201 COPD pathogenesis 117, 367 corticosteroid effects on 550, 551 cytokines secreted 262, 266–267 degranulation 114 complement stimulating 301 distribution 112 effector functions 114, 114–115 elevated count allergy 13 COPD 364, 367 epithelial cell interactions 147, 345 exudation 195 functions 257 granules and contents of 114 major basic protein see major basic protein (MBP) plasma exudation 201 proteins 114–115, 115 homing, selectins and adhesion molecule role 205, 345–346 hypodense 114, 116 inflammation inhibition strategies 648, 649 interleukin-5 inhibitor action 644 life cycle 111–112 maturation/proliferation 266–267 mediators produced 111, 115, 116 migration 112, 205, 267, 345–346 morphology 111, 111 number in sputum, exhaled nitric oxide correlation 310, 310 peripheral blood 116 production 111–112 reactive oxygen species produced 244, 247, 345 pathway 245 receptors 112 recruitment 345 survival in airways 346 TGFb expression 268 eosinophil cationic protein (ECP) 115 eosinophil-derived neurotoxin (EDN) 115 eosinophil differentiation factor see interleukin-5 (IL-5) eosinophil granule proteins (EPO) 247 eosinophilia airway luminal 199 allergic bronchopulmonary aspergillosis 389 in COPD 127 GM-CSF effect 285 IL-5 elevation 111 in late-phase asthma response 113, 113–114
peripheral blood, airway obstruction risk factor 248 sputum 451 eosinophil peroxidase (EPO) 115, 244 eotaxin-1 112, 140 eotaxin-2 112, 257 eotaxin-3 257 eotaxins 257 eosinophil chemoattraction 112, 257, 267 mechanism of action 112, 257–258 functions 267 production, Th2 cytokines role 258 epidemiology, asthma/COPD 7–18 asthma 7–18 acute 689 gender differences 14 incidence 7–8 increasing incidence 8 COPD 7–18 exacerbations 727–728 gender differences 14 demographics 15 difficulties of international comparisons 7 incidence 7–8 determining ‘true’ time of 20 morbidity and mortality 12 see also mortality prevalence see prevalence utilization and hospitalization trends 11–12 see also hospitalization epidermal growth factor (EGF) 283, 286 COPD pathogenesis 369 epithelial cell repair 149, 286 expression increased in chronic bronchitis 269 fibroblast migration/proliferation stimulation 141 goblet cell metaplasia 371 mucin production and 155–156, 156 epidermal growth factor-like (EGF) motifs, fibrillin-1 213 epidermal growth factor receptor (EGFR) 155–156 activation and consequences of 69 COPD 69 goblet cell numbers 155 increased expression in asthma 69, 71 inhibitors, goblet cell differentiation prevention 160 ligands 69 mucin production 72–73, 155–156, 156 mechanism 158 role in airway remodeling 69, 71 smooth muscle mitogen 73 tyrosine kinase inhibitors 160 epinephrine see adrenaline (epinephrine) episodic asthma 675 epithelial cells, airway 57, 145–154 acetylcholine release 326
Index
activation by smoke 367 adhesion molecule expression 147 airway remodeling 150 asthma 347, 347 catecholamine metabolism 145 cilia, structure and function 150 COPD 367, 370 neutrophil and macrophage interactions 367 corticosteroid effects 551, 551 damage 67–70, 145–146, 350 causes 68, 145, 350, 370 COPD pathogenesis 370 effect on airway smooth muscle 146 fibrosis relationship 69–70 by major basic protein 115 mechanisms 145–146 reactive oxygen species inducing 247 repair see below viral-induced 409 differentiation 150–151 goblet cells 151, 160 enzymes 145–146 eosinophil interactions 147, 345 in exudate 195 histamine effect 292 immune response role 409, 409 inflammation 146–147 as initiators 146 inflammatory mediator release 146–147 anti-inflammatory mediators 146–147 asthma 347 IL-8 146 proinflammatory mediators 146 matrix metalloproteinase expression 150 reactive oxygen/nitrogen species formation 246 repair 67–70, 147–150, 148, 283, 372 adhesion molecules role 207 COPD pathogenesis 371 cytokines role 150 epidermal growth factor 149, 286 histology 201 impairment by smoke 371 in vivo 198–199 matrix proteins 147, 148, 149 migration of cells 149 process 148 TGF-b role 149 response in viral infections 409, 410 rhinovirus 409, 410 shedding-like denudation 198, 199, 343, 350 asthma pathogenesis 199, 343, 350 COPD exacerbations 199 events after 199 transport of plasma across 196 virus entry 409 viruses effect 409, 409–410 see also goblet cells
epithelial lining fluid (ELF) reactive oxygen species production 248 smoke redox reactions 244 epithelial–mesenchymal interaction 67, 185 epithelial mucous metaplasia see mucous metaplasia epithelium-derived inhibitory factor 146 E-selectin eosinophil homing 205 inhibition, effects on neutrophils 206 inhibitors 601 esophageal reflux 328 see also gastro-esophageal reflux estrogen, effect on airways 337 ET-1 see endothelin-1 (ET-1) etanercept 645 ethane 349, 460 exhaled 460, 461, 461 etiology, of asthma allergens see allergen-induced asthma chronic persistent asthma 354–355 drugs see drug-induced asthma exercise see exercise-induced asthma irritants 395, 396, 397 etiology, of COPD 362, 362–364, 370, 434, 717 drug abuse 362 nutritional factors 362 see also alpha-1 protease inhibitor; infections; smoking European air pollution study (PEACE) 701 European Community Respiratory Health Survey 31 European Respiratory Health Survey 14 European Respiratory Society (ERS) criteria 7 COPD staging 714, 715 evidence-based medicine 657 exacerbations, asthma/COPD 5–6 asthma see acute exacerbations of asthma COPD see acute exacerbations of COPD inflammatory response 132 exercise 421–429 adrenaline concentrations 334, 335, 337 anabolic threshold in COPD 424, 425 in asthma, management of limitation 425–427 asthma induced by see exerciseinduced asthma atrial natriuretic peptide concentrations 188, 335, 335, 337 capacity, lung transplantation 630 childhood asthma investigation 704 trigger 700, 701, 708 in COPD 423–425 bronchial hyperreactivity 424–425
759
decreasing capacity cycle 424 limitations 423, 482 management of limitation 425–427 physiological abnormalities 423–424 endurance, chronic oxygen therapy effects 590 running vs swimming 421–422, 701 training see exercise training as trigger 421–429, 700, 701, 708 exercise-induced asthma 421–423 allergenic environment and pollution 422–423 children 700, 701, 708 climatic conditions affecting 422, 423 clinical severity 423 lung function changes 421, 422 management 425–427, 680 cromones 633 pathogenesis 350 pathophysiology 423 pattern of exercise 422 refractoriness see exercise refractoriness rehabilitation 426–427 severity/duration 422 types of exercise 421–422 exercise-induced bronchoconstriction 179 arachidonic acid metabolite role (hypothesis) 224, 224 leukotriene D4-receptor antagonist action 224 reduced by indomethacin 223, 223 reduced by prostaglandin E2 223, 224 exercise refractoriness 223, 422 histamine-stimulated inhibitory prostaglandin release 224 mechanism 224, 224 prostaglandin release 422, 423 exercise training, asthma 426 exercise training, COPD 426–427, 622, 720 aerobic 622 endurance 622 chronic oxygen therapy effects 590 exercise prescription 622 leg fatigue 620 lower extremity 622–623 physiological outcome 621, 621 pulmonary rehabilitation 620–625, 720 strength training, 622 upper extremity 622–623 ventilatory muscle 623–624 exhaled breath condensate 457–460 contamination 458 factors affecting measurements 458 hydrogen peroxide 458 method 457, 458, 458 origin of markers 457 exhaled markers 365, 457 see also nitric oxide expiratory flow limitation during forced expiration 47–48
760
Index
expiratory flow limitation—cont testing method 48 during tidal breathing 48 see also peak expiratory flow rates expiratory pressure–volume curves 51–53, 52 asthma 52, 52–53 COPD 51–52, 52 impact on airway function 53 extracellular matrix 211–218 cell adhesion see cell–matrix adhesion changes in asthma 139, 215–216 changes in COPD 139, 215–216 composition 70, 71, 139, 211–214 collagens 211–212 elastin 212 fibronectin 214 integrins 214 laminin 214 microfibrils 213 proteoglycans 213–214 degradation by neutrophil elastase 277, 278 diffuse deposition 72 effect on airway remodeling 71 excess deposition, COPD 215 expression, growth factors inducing 284 fibroblasts 139 functions 211 lung function and 214 proteinases degrading see matrix degrading proteinases protein synthesis 139–140 remodeling 70 consequences 71–72 extracellular regulated kinase (ERK) MAP kinase pathway 299 exudation, of plasma see plasma exudation F F2-isoprostane 248 15–F2t-isoProstane 248 factor XII, kallikrein generation 237 familial aggregation, asthma 29, 31 familial risk, asthma 30 farm workers, COPD 401 fatigue 482 fenoterol, controversy over adverse effects 680 Fenton reaction 244, 245 fexafenadine 567 fibrillin-1 213 domains 213 mutation in Marfan syndrome 215 fibrillin-2 213 fibrin–fibronectin gel 198–199, 200 fibroblast(s) 139–144 accumulation, growth factors inducing 284 asthma 139 chemotaxis, tachykinins stimulating 332 COPD 139
distribution 139 extracellular matrix and 139 function 139 regulation 140, 140 mediators released 140 proliferation, TGF-b effect 286–287 prostaglandins effect 104 regulation of migration/proliferation 139–140 mediators inhibiting 142 mediators stimulating 140–142 a-smooth muscle actin expression 70 fibroblast growth factor (FGF) 268, 286 angiogenesis in asthma 268 types (FGF-1/FGF-2) 286 fibronectin 147, 214 epithelial cell migration and repair 149, 372 gene organization/splicing 147, 149 receptors, integrin distribution in lung tissue 203 role in airway remodeling 71, 372 fibrosis, lung see pulmonary fibrosis Finland, asthma incidence 8 fire fighters, COPD 401, 402 FLAP (5–lipoxygenase activating protein) 189, 227 inhibitors 644 flunisolide 555 fluoroquinolones, COPD exacerbation 580 fluticasone airway blood flow changes 180, 180, 181 comparative studies 664 efficacy 552, 554 food allergens, childhood asthma management 708 forced expiratory volume in 1 s (FEV1) acute asthma 692, 694 asthma, plateau effect of bronchoconstrictors 59 childhood asthma 704 COPD staging 714 diagnostic test 449 disability measurement 484, 485 early-life determinants of 25 exercise-induced changes in asthma 422 in COPD 424, 424 FVC ratio (Tiffeneau index) 8, 714, 715 heritability 30 improvement on bronchodilator use 449 negative correlation with nitrotyrosine 460 smoking history relationship 13, 25–26 effect of smoking at different life stages 14 forced vital capacity (FVC) exercise-induced changes in asthma 422 in COPD 424, 424
FEV1 ratio (Tiffeneau index) 8, 714, 715 foreign body aspiration 704 childhood asthma vs 702 formoterol 522, 522, 524 comparative studies 663, 664 effect on allergen-induced airway response 385 fossil fuel, burning 431 fractional inspired oxygen concentration (FIO2) 612 free radicals see reactive oxygen species (ROS) functional limitation questionnaires 483 functional residual capacity (FRC) asthma 53 bronchodilator action 45 response to methacholine test and 44 fungal spores, allergens 384 fungi, allergic bronchopulmonary mycoses 388 future therapies 641–656 G gas(es) blood see arterial blood gases irritant, COPD due to 401 pollutants see air pollutants gas chromatography 460 gastro-esophageal reflux 328 childhood asthma vs 702 management 708 GATA-3 315, 317 GCP-2 (CXCL6) 256 gelatinase A 276 gelatinase B 276 gender influence 14–15 airway function 24 childhood asthma 701, 701–702 diagnosis of asthma/COPD 4 smoking 24 gene–environment interactions 3–4, 19, 29 asthma 354, 354 effect on lung function 26 genes, susceptibility 33–36 asthma 33–36, 690–691 COPD 36, 319, 364 identification approach 29 gene targeting, COPD pathogenesis 278–279 gene therapy 652–653 a1-antitrypsin (a1-AT) 648 genetic heterogeneity 29 genetics/genetic factors 29–40 analytical approaches 30–32, 31 asthma 37, 354, 355, 448, 690–691 candidate genes 33–36, 690–691 childhood asthma 700 genome screen 33, 34 linkage studies 32 twin studies 30–31 atopy 354 COPD 29–30, 37, 363–364
Index
candidate genes 36, 319, 364 experimental allergen-induced airway hyperresponsiveness 81 ‘intrinsic’ bronchial hyperresponsiveness 26 linkage studies 32–33 terms (glossary) 29, 30 genome screen, asthma 33, 34 Germany, asthma associated with air pollution 434 glaucoma 440 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 3, 11, 361, 713 COPD staging system 714, 714–715 COPD treatment guidelines 714, 715 bronchodilators 718 mucolytics 721 narcotics contraindication 720 glucagon 337 glucocorticoid(s) 318–319 asthma treatment 315 acute asthma 694–695 COPD treatment 602, 720 influence on health status 722 smokers 717 effect on tracheobronchial circulation 180 eosinophil reduction in airway 117 functions/actions 318–319 histone acetylation inhibition 319, 319 mechanisms of action 315, 319 nuclear translocation 319 receptor-binding affinity, allergen exposure 495 receptors 319 corticosteroids mechanism 547, 548, 548 side-effects 319 transcription factor action 318–319 see also corticosteroids glucocorticoid response elements (GREs) 319, 547 corticosteroid molecular mechanisms 547 glutamate 323 c-glutamylcysteine synthetase (c-GCS), upregulated by oxidative stress 250 glutathione as antioxidant 635, 636 gene expression induction 250 regulation of redox signaling pathway 246 upregulated synthesis in smokers 250–251 glycerol, iodinated 721 glycosaminoglycans, role in airway remodeling 71 GM-CSF see granulocyte-macrophage colony-stimulating factor (GM-CSF) goblet cells hyperplasia 157 hypersecretion, fatal asthma 157, 157
metaplasia 157, 367 allergen-induced 158 chronic bronchitis 371 IL-4 and IL-13 role 158 inhibition 160 stimuli inducing 156, 371 mucin production 155, 159 mucus secretion see mucus neutrophil-dependent degranulation 157 prevention 160 production, EGFR role 155–156 GOLD guidelines see Global Initiative for Chronic Obstructive Lung Disease (GOLD) gold miners, COPD 400–401 gold salts chronic asthma 681 glucocorticoid-sparing effect 599, 600 immunomodulatory therapy in asthma 599–600 G protein(s) b2-adrenoceptor agonists mechanism 521, 522 chemokine functions mediated by 102, 255 phospholipase C isoform regulation 170 smooth muscle cell proliferation 170 subunits 170 G-protein coupled receptor (GPCR), activation airway smooth muscle cell growth 171 calcium homeostasis in airway smooth muscle 167 grain dust 370, 401, 402 Gram staining 574, 575 granulocyte-macrophage colonystimulating factor (GM-CSF) 104, 283, 285 airway remodeling 283 in asthma 285, 346 COPD pathogenesis 369 eosinophilia 285, 346 eosinophil requirement 346 fibrosis 285 neutrophil survival 369 release by, epithelial cells 146 sources and effects 264, 285 granulomatosis, bronchocentric 704 granzymes, CD8 T cells producing 268 growth childhood asthma and 703 corticosteroid effect on children 558, 706, 707, 707 growth factors 283–289 airway disease 283–284 airway smooth muscle proliferation 267–268 animal models 287–288 characteristics of specific factors 284–287 COPD pathogenesis 369 epithelial cell repair 149–150 fibroblasts/myofibroblast
761
accumulation 284 fibrosis after epithelial damage 70 in lung 283–284 lung development (normal) 185 lung maintenance program 186 macrophage-derived 103–104 matrix expression induction 284 release by basophils and mast cells 94 proteolytic enzymes during remodeling 71 role in airway remodeling 70–71 sources and effects 265 see also specific growth factors H H1 receptors 291, 292 antagonists 386 H2 receptors 291, 292 antagonists 224, 291, 567 H3 receptors 291, 292 antagonists 567 Haber–Weiss reaction 244, 245 Haemophilus influenzae COPD exacerbation 730 vaccines 635 handicap, terminology 481 health economics 657–671 Clinical Practice Guidelines 657–658 comparative studies, asthma 662–665 anti-leukotriene antagonists 664 care in emergency rooms/hospitals 664–665 disease management programs 665 inhaled corticosteroids 663 inhaled cromolyn sodium 664 long-acting b2-agonists 663–664 patient education 664 pharmacotherapy 660, 663 self-management programs 664 specialty consultation 664 comparative studies, COPD 665–666 corticosteroids, cost-effectiveness 665 home-based care 666 home oxygen 666 lung transplantation 666 lung volume reduction 666 patient education 666 pharmacologic interventions 665–666 smoking cessation 666 cost–benefit analysis 658 cost–effectiveness analysis 658–659 economic burden of asthma/COPD 659, 659–662 economic value of family-provided care 662 Medicare costs, COPD 662 special characteristics of asthma costs 659, 661 see also cost(s) evidence-based medicine 657 maximizing value 662
762
Index
health economics—cont pharmaco-economics, COPD exacerbation 582–583 treatment guidelines 657–658 health service utilization 11–12 health status, in COPD 722 heat exchange, altered tracheobronchial circulation and 179 heat shock proteins, hsp90 547, 548 heme oxygenase 461–462 heme oxygenase-1 (HO-1) 251 heme peroxidases 244 heparan sulfate 213 herbal medicines, asthma 638 heritability asthma 29 COPD 29–30 see also genetics/genetic factors heritable disorders of connective tissue (HDCT) 214–215 15–HETE 353 high affinity IgE receptor (FceRI) see immunoglobulin E (IgE) high-molecular-weight (HMW) kininogen 237 high-resolution computed tomography (HRCT) 466 airway function assessment 44 alveolar function assessment 48–49 asthma vs COPD 450–451, 451 bronchial wall thickening 468 bronchiectasis 476 constrictive obliterative bronchiolitis 475 histamine 291–293 airway contraction 224, 291 cysteinyl leukotriene action comparison 228–229 airway disease 291, 293 antihistamine action 567 effects on airways 291, 292, 567 exudative response induction 197 inhibitory prostaglandin release, exercise refractoriness 224 levels, COPD 95 plasma exudation and 197, 198, 291 rapidly adapting receptors response 325 receptors 291 released by basophils 93–94 released by mast cells 93–94 asthma exacerbation 293 synthesis and release 291 tachyphylaxis 224 histamine N-methyltransferase (HMT) 291 histamine test 14 bronchial response, in infants/children 26 histone acetylases (HAT) 316 histone acetylation 316, 318 inhibition by glucocorticoids 319, 319, 548, 549 histone deacetylases (HDACs) 316, 548
history-taking, asthma/COPD 447–448 childhood asthma 703 HIV infection, emphysema 362, 371 HLA class I 36 HLA class II 123 gene polymorphisms 36 occupational asthma and 398 Hoe 140 (icatibant) 240 home-based care 666 home cooking pollutants, COPD etiology and 362, 370 homeopathy, allergen-induced asthma 638 hormones, airway caliber control 336–337 see also humoral control mechanisms hospitalization 11–12 asthma 12, 15 acute 689, 690 air pollution effect 434 COPD, air pollution effect 434–435 COPD exacerbation 727 supported discharge 733 treatment 731–732 trends 11–12, 15 house dust mites/allergens 22, 384–385, 683 avoidance 495–496, 501–507 childhood asthma management 708 bed and bedding 490, 496 carpets and upholstered furniture 490–491 chronic asthma exacerbation 683 control 490–491, 491 Der p 2 490 distribution/aerodynamic properties 489 effect exacerbated by nitrogen dioxide 436 exposure in early infancy 497 humidity requirement 490–491 HOX genes, upregulated by retinoic acid 186 humidity, effect on exercise-induced asthma 422 humoral control mechanisms 334–337 asthma and COPD 337 hormones 336–337 vasoactive peptides 334–336 see also vasoactive peptides humoral immune response 123 Hunter syndrome 215 Hurler syndrome 215 Hutteries group, asthma 32 hyaluronic acid, role in airway remodeling 71 hydraulic hypothesis, luminal entry of plasma 196 hydrocarbons, exhaled 460–461 factors affecting levels 460 source and measurement 460 hydrocortisone, intravenous, acute severe asthma 559 hydrocortisone sodium succinate 441
hydrogen ions, exhaled breath 460 hydrogen peroxide airway smooth muscle contraction 369 in exhaled breath 458 formation 244, 458 xanthine/xanthine oxidase reaction 249 marker of oxidative stress 247, 458 measurement as marker of oxidant burden 248 smokers vs nonsmokers 458 hydroquinone, in tar phase of smoke 244 hydroxyl radical 243 formation 244 iron involvement 244, 245 4–hydroxy-2–nonenal (4–HNE) 245–246, 248 biological actions 250 lipid peroxidation product 245–246, 250 11b-hydroxysteroid dehydrogenase 352 5–hydroxytryptamine see serotonin ‘hygiene’ hypothesis (childhood infections reduced) 346, 354, 384, 701 hyperalgesia 351 hypercapnia chronic, in COPD 49 COPD exacerbation 730 management 732 permissive 613, 695 in severe asthma 49 hyperemia, reactive 179 exercise-induced asthma 423 hyperesthesia, airway, afferent nerve sensitivity increased 326 hyperglycemia 732 hyperinflation of lungs 58 acute asthma 692, 694, 695 radiographic abnormalities, asthma 466–467 reduction in COPD by bronchodilators 718, 731 hypersensitivity, type I 13 allergic bronchopulmonary mycoses 389 see also allergy hypertension, pulmonary see pulmonary hypertension hyperthyroidism 337 hyperventilation cold air, in COPD 424–425 exercise-induced asthma 422, 423 hypokalaemia, b2-adrenoceptor agonists 524 hyposensitization, allergy 707–708 hypothalamic–pituitary–adrenal (HPA) axis, corticosteroid side-effect 557 hypoventilation, controlled 613, 695 hypoxemia acute asthma 693 air travel 593–594 COPD exacerbation causes 730–731
Index
management 732 indications for ventilator support 611 mechanisms during sleep 591 pathophysiology of oxygenation 587, 588 hypoxia, survival in COPD and 722 I IBERPOC Project 10–11 ICAM-1 see intercellular adhesion molecule-1 (ICAM-1) icatibant (Hoe 140) 240, 568 iduronate 2 sulfatase 215 IjB inhibitor, NF-jB inhibition 649 imaging 450–451, 465–480 future prospects 475–476 techniques 465–466 chest radiography see chest radiography CT see computed tomography (CT) digital radiography 465 magnetic resonance imaging (MRI) 466, 474 see also radiography immediate hypersensitivity see hypersensitivity, type I immotile cilia syndrome (ciliary dyskinesia) 700, 702 immune response adaptive, innate immune control 103, 104 cell-mediated see cellular immune response; T cells epithelial cells role 409, 409 humoral 123 innate see innate immune system immunoglobulin(s) 123 intravenous (IVIG), in asthma 600 immunoglobulin A (IgA) 123 immunoglobulin E (IgE) allergen-induced airway hyperresponsiveness 80–81 anti-IgE antibody see anti-IgE antibodies/therapy asthma pathophysiology 344–345 basophil activation 92 binding of allergens 34 class switching 265 elevated in virus infections 413 genetics of allergy and 31 high-affinity receptor (FceRI) 266 anti-IgE humanized MAb 652 b-chain polymorphisms 34–35 expression by basophils 92 expression by mast cells 80, 92 gene polymorphism 354 mast cell priming 93 Syk kinase inhibitors 650 IL-4 inhibitor action 644 low-affinity receptors (FceRII) 345 mast cell activation 92 occupational asthma pathophysiology 395 recombinant humanized monoclonal
antibody 117, 652 synthesis 34, 266 IL-4 role 265–266, 644 interleukins regulating 36 total serum levels chromosomal associations 32, 33 HLA class II polymorphisms and 36 segregation analysis 32 virus-induced asthma 413 immunoglobulin G (IgG) FccRII 92 opsoninization 123 immunoglobulin supergene family 204, 204 immunohistology, asthma 126 immunomodulators 599–603, 651 immunomodulatory therapy in asthma 599, 599–601 anti-CD4 antibody 601 anti-IgE antibody 601, 652 anti-IL-5 humanized MAbs 644 cyclosporin A 600 gold salts 599–600 humanized monoclonal antibodies 601 immunosuppressants 651 intravenous immunoglobulins (IVIG) 600 methotrexate 600 newer immunomodulators 601 sirolimus (rapamycin) 601 soluble IL-4 receptors (altrakincept) 644 tacrolimus see tacrolimus see also individual agents immunomodulatory therapy in COPD 601, 601–602, 651 glucocorticoids 602 immunoreceptor tyrosine-based activation motif (ITAM) 92 immunoreceptor tyrosine-based inhibition motif (ITIM) 92 immunostimulatory DNA sequences 652 immunosuppressants 651 immunotherapy, preventative strategies 652 impairment, definition 481 incidence, asthma/COPD 7–8, 20 incomplete penetrance, definition 29 indomethacin airway hyperresponsiveness prevention 222, 223, 223 effect on allergen-induced airway response 386 infants asthma forms 20–21, 21 bronchial responsiveness, implications 26 lung function age-related changes 23, 23, 24 levels 23, 24, 25 premature 15 wheezy see wheezy infants infections, respiratory tract 407–420
763
as asthma trigger 407–413 epidemiology 407 viruses see viral infections bacterial, COPD exacerbations 414 childhood, lack and asthma link 346, 354, 384, 701 childhood asthma trigger 701 COPD etiology 362, 413–415, 717 bacteria/viruses 414 epidemiology 414 COPD exacerbation 6, 414, 729–730 bacterial infections 414 viral infections 415 COPD progression, bacterial infections role 414–415 lung function growth affected by 24–25 mucus hypersecretion 160 therapy 415–416, 717 see also antibiotics inflammation 315 acute asthma 344, 351 epithelial cell injury by 145 acute-on-chronic 262, 316, 344 airway see airway inflammation airway epithelial cells role 146–147 see also epithelial cells, airway characteristics in asthma 4, 13 chronic, in asthma 344, 351–352 COPD 268, 277–278 cytokines involved 268–269 macrophages role 100–102 neurogenic 333–334, 351 plasma exudation 195, 197–198 process 131–132 resolution 135 signs 351 viral infections 409–410 inflammatory cells 243, 244, 345 activation, by platelet activating factor 297 airway nerve interactions 323, 324 asthma 344–347 acute exacerbations 691–692 COPD 365–367 endothelins effect 300 histamine effects 291 interactions in COPD 367 lung damage mediated by smoke and 370 migration, importance of MMPs 280 see also individual cell types inflammatory disease asthma as 3, 7, 343–344 chronic 3–4, 7 nasal 196 inflammatory mediators 68, 221–340, 345 asthma 347–349 acute exacerbations 691–692 chemokines 255–260 cilia function 150 C nerve fiber response 325 COPD exacerbation 728–729, 729
764
Index
inflammatory mediators—cont COPD pathogenesis 367–374 cytokines role 261–269 growth factors 283–289 ion channel changes due to 350 kinins 237–242 leukotrienes 227–235 matrix degrading proteinases 273–282 proinflammatory gene expression 250 prostanoids 221–226 reactive oxygen species 250 released by airway epithelial cells 146–147 eosinophils 115, 116 lymphocytes 121–122, 125 macrophages 100–101, 105, 106 mast cells 93, 93–94 neutrophils 132, 134 see also cytokine(s) role in airway remodeling 70–71 smooth muscle remodeling 73 see also individual groups of mediators (as listed above) infliximab 645 influenza acute exacerbations of COPD 577, 577 antiviral drug treatment 416, 635 epithelial cell destruction 409 vaccination 415–416, 634 COPD exacerbation prevention 579 efficacy/adverse effects 634 recommendations 634 influenza A, treatment 416 influenza virus, entry/receptor 409 inhalational exposures COPD etiology 362 see also air pollution; smoke/smoking inhalers bronchodilators in COPD 718 devices, childhood asthma 705 see also metered-dose inhaler (MDI) inheritance, asthma/COPD 29–30 genetic models 31–32 see also genetics/genetic factors innate immune system control of adaptive immune response 103, 104 macrophage recognition of organisms 99–100 activation 102–103 innervation see airway nerves inositol trisphosphate, smooth muscle proliferation 170 insulin-like growth factor (IGF-I) 285–286 epithelial cell repair 149 in fibroproliferative disease 286 receptor 285–286 insulin-like growth factor (IGF-II) 285–286 overexpression in animals 286 integrins 203, 214 a5b1 149 avb6 149
counter receptors 203, 204 distribution 203, 204 eosinophil expression 112, 345 epithelial cell migration 149 expression/function 203 regulation 149 inhibitors 651 leucocyte activation 206 structure 203 subunits, distribution in lung tissue 203, 203 intercellular adhesion molecule-1 (ICAM-1) 204 antibodies to 345 eosinophil–epithelial cell interaction 147 expression by airway smooth muscle cells 172 endothelial cells 345 epithelial cells 147 expression increased by TNFa 268 expression regulation by NF-jB 317–318 importance in asthma 147 leucocyte homing 205–206 monoclonal antibodies to 205, 651 rhinovirus entry via 409, 416 upregulation, viral infections 410 intercellular adhesion molecule-2 (ICAM-2), knockout mice 206 interferon-a, nasal 416 interferon-c 646 allergen-induced asthma 646 fibroblast proliferation inhibition 142 functions 122 source and effects 263 Th1 cells releasing 121–122, 263 interleukin-1 (IL-1) airway remodeling and fibrosis 285 functions 124 IL-1b 285 in COPD 269 downregulation of response to b2-agonists 350 leucocytosis induction 269 sources and effects 285 IL-1ra 124, 285 sources and effects 265 receptor agonists 646 sources and effects 264 T cell stimulation 124 in viral infections 410 interleukin-2 (IL-2) 120–121 functions 121 IL-2R 128 release by Th1 cells 120–121, 263 sources and effects 263 interleukin-3 (IL-3), sources and effects 263, 348 interleukin-4 (IL-4) 35, 121 asthma 126, 348 cells synthesizing/releasing 141, 262 basophils 94 Th2 cells 121, 141, 262, 316 effects on fibroblasts in asthma 141
eotaxin production stimulation 258 functions 121, 348 gene polymorphisms 691 single-nucleotide polymorphisms 354 goblet cell metaplasia and mucin gene upregulation 158 IgE synthesis 265–266 IL-4Ra 265 increased expression in asthma 36, 141 inhibitors 644–645 soluble IL-4 receptors (altrakincept) 644 STAT-6 inhibitors 645 receptor polymorphisms 36 sources and effects 263 interleukin-5 (IL-5) in asthma 348 cells synthesizing 262 control, eosinophilic inflammation reduction 117 functions 348 increased expression in asthma 348 inhibitors 644 isocyanate-induced asthma 396 knockout mice 81 monoclonal antibody 346 occupational asthma 396 production, control 111 role in eosinophil chemotaxis/migration 113, 266, 346 role in eosinophil production 111, 266–267 sources and effects 263, 348 transgenic mice, eosinophil role in airway hyperresponsiveness 81 interleukin-6 (IL-6) COPD exacerbation 373 increased in sputum 728, 729 release by epithelial cells 146 smooth muscle cell hyperplasia 172 sources and effects 264 in sputum, experimental rhinovirus infections 728 in viral infections 410 interleukin-8 (IL-8) 146 biological actions 256 cells expressing 269 in COPD 256, 269, 369 functions 269, 369 increased in sputum, COPD exacerbation 728–729, 730 neutrophil chemoattractant 146, 256, 413 release by epithelial cells 146 sources and effects 264, 369 synthesis 256 virus-induced asthma 413 interleukin-9 (IL-9) 121 in asthma 348 functions 121, 348 inhibitors 645 produced by Th2 cells 121
Index
sources and effects 263 interleukin-10 (IL-10) 121 airway responsiveness increased by 25 anti-inflammatory action 353, 353 defective secretion (asthma) 353 functions 121 gene polymorphisms 354 lymphocyte source 121 production in RSV infections 24–25 recombinant 646 sources and effects 265 interleukin-11 (IL-11) sources and effects 264 in viral infections 410 interleukin-12 (IL-12) anti-inflammatory action 353 cells producing 124 recombinant 646–647 release by Th1 cells 263 source and effects 263 Th0–Th1 shift induction 124 Th1 and Th2 balance 346 interleukin-13 (IL-13) 35, 121 in asthma 346, 348 eotaxin production stimulation 258 functions 121, 348 genotype associated with asthma 35 goblet cell metaplasia 158 inhibitors 645 mucin gene expression induction 73 released by basophils 94 sources and effects 263 T cells producing 121 Th1 and Th2 balance 346 Th2 phenotype induction 346 interleukin-15 (IL-15) functions 124 sources and effects 263 T cell chemotaxis 124, 125 interleukin-16 (IL-16) proinflammatory 125 regulation of lymphocyte homing 125 sources and effects 264 interleukin-17 (IL-17) sources and effects 264 T cells producing 121 interleukin-18 (IL-18) functions 124 source and effects 263 sources and effects 265 T cell regulation 124 intermittent mandatory ventilation 611 International Study of Asthma and Allergies in Children (ISAAC) 7, 9 intravascular inflammation, asthma 187 intravenous immunoglobulin (IVIG) therapy 600 intrinsic asthma 355 in-utero events, asthma development 20 importance 12, 14, 16 iodinated glycerol 721 ion channels, inflammatory mediators modulating 350 ipratropium bromide 327, 528, 529 asthma exacerbation treatment 681
combination therapy 532 COPD treatment 719 albuterol vs 718 comparative studies 665 prevention of exacerbations 722 salmeterol vs 719, 719 smokers 717 for exercise limitation in COPD 426 pediatric airways disease 530–531 side-effects 532 sleep quality 532 iron content of alveolar macrophage in smokers 248 hydroxyl radical formation and 244, 245 membrane lipid peroxidation 244, 245 irritant gases, COPD due to 401 irritant-induced asthma 395, 397 agents causing 395, 396 pathology 397 isocyanates 395, 396 ISOLDE Study 722, 734 isoprenaline, failure of airways to relax to 329 isoprene, excretion 461 8-isoprostane 248, 250, 349, 368 in exhaled breath 459 isoprostane(s) 250, 459 isoprostane 8–isoPGF2a 248, 250 itraconazole, allergic bronchopulmonary mycosis 389 J JUN N-terminal kinase (JNK) 319 K kallikrein 237 synthesis 237 keliximab (Th2 cell inhibitors) 651–652 keratinocyte growth factor (KGF) 286 ketanserin 293, 567 killer inhibitory receptors (KIRs) 413 kininase 1 (carboxypeptidase N) 238 kininase 2 see angiotensin-converting enzyme (ACE) kininases 238, 238 kininogenases 237 kininogens 237 kinins 237–242 action in airway 239–240 cilia beat frequency increase 239 formation and metabolism 237–238 in airways 239–240 asthma/COPD 239 degradation 238 sites 237 intervention studies 240 mechanisms of action 240 proinflammatory molecule release 239–240 receptor antagonists (B2) 240 receptors 238–239
765
B1 and B2 238–239, 239 bradykinin-induced bronchoconstriction mechanism 240 genes 238 structure 237, 238 Kit ligand 91, 92 knockout mice ICAM-2 206 interleukin-5 (IL-5) 81 MMP-12 105, 370 platelet-derived growth factor (PDGF) 285 STAT6 318 L lactic acid, exhaled breath 460 lactic acidosis 424, 620 lamina propria incorrect use of term 57 plasma protein delivery 196, 197 lamina reticularis 139 thickening 139, 141, 216 laminin 214 heparan sulfate interaction 213 receptors, integrin distribution in lung tissue 203 late asthmatic response (LAR) 385, 385 b2-agonists effects 385, 386 drugs inhibiting 386 eosinophilia mechanism 113, 113–114 pathogenic mechanisms 386–387 latent transforming growth factor betabinding proteins (LTBP) 213 leucocytes activation, cell adhesion molecule role 206–207 airway smooth muscle cell interaction 172 homing, endothelial cell adhesion molecule role 205–206 migration 205–206, 255 see also individual white cells leucocytosis, IL-1b inducing 269 leukotriene(s) 221, 227–235 anti-leukotrienes 565, 565–567 see also anti-leukotrienes asthma 227–231, 347 COPD 231, 367–368 cysteinyl see cysteinyl leukotrienes in exhaled breath 459, 459 formation and metabolism 101, 227, 228 inhibition 117, 230–231 initiation of synthesis 101 macrophage role 100–101, 106 measurements and recovery 229 inhibitors 160, 230 mucus secretion 160, 231 NSAID-induced asthma mechanism via 440–441 receptor blockade 117, 230–231, 347 chronic asthma management 680 clinical trials 230–231
766
Index
leukotriene(s)—cont inhibition of induced asthma 230 leukotriene B4 (LTB4) COPD 367–368 in exhaled breath 459, 459 5-lipoxygenase (5-LO) inhibitors 566, 643–644 see also zileuton neutrophil influx 231, 367–368, 459 receptor antagonists 566, 644 release by airway epithelial cells 146 synthesis 227 leukotriene C4 (LTC4) bronchoconstrictor effects 228–229, 441, 459 in exhaled breath 459, 459 functions 227 produced, by eosinophils 116 released by mast cells and basophils 93–94 synthesis 227 leukotriene C4 (LTC4) synthase 227 gene polymorphism 441 leukotriene D4 (LTD4) bronchoconstrictor effects 228–229, 459 in exhaled breath 459, 459 receptor antagonist effect on exercise-induced bronchoconstriction 224 inhibition of induced asthma 230 smooth muscle mitogen 73 synthesis and function 227 leukotriene E4 (LTE4) bronchoconstriction 228–229 excretion rates 229, 230, 441 in exhaled breath 459, 459 recovery and measurement in asthma 229 synthesis 227 lifestyle, chronic asthma management 682 linkage studies 32–33 lipid peroxidation catalysed by iron 244, 245 markers 248, 460 by reactive oxygen species 245–246, 246 aldehyde measurement as marker 248 products 248 lipocortin-1 549 lipopolysaccharide (LPS) 100, 246 lipopolysaccharide-binding protein (LBP) 100 lipoxins 227 anti-inflammatory effects 353 5-lipoxygenase DNA sequence variants 37 inhibitors 117, 441, 566, 643–644 5-LO activating protein (FLAP) inhibitors 644 BW755C 222 pulmonary hypertension treatment 189
see also zileuton 5-lipoxygenase activating protein (FLAP) 189, 227 inhibitors 644 liquid oxygen, therapy 592, 592 L-NAME 298, 644 London smog 431, 434 long-term oxygen therapy 587–597 impact on patient’s life 738 loratadine 567 low birthweight, COPD association 362 lower respiratory infections see infections, respiratory tract low-molecular-weight (LMW) kininogen 237 L-selectin, inhibition effects on neutrophils 206 inhibitors 601 LTB4 see leukotriene B4 (LTB4) lung age-related changes 186 apoptosis of cells 186 cell maintenance 185 defective in emphysema 185–186 defense mechanisms, impairment in COPD 370–371 development in utero 24 dynamic compliance 51 extracellular matrix see extracellular matrix formation/development 185 growth, COPD association 362 injury reactive oxygen species causing 245, 246 TGF-b role in remodeling after 287 pathophysiology see pulmonary physiology remodeling TGF-b role 287 see also airway remodeling resistance see peripheral lung resistance; total lung resistance volumes 51–54 lung–airway coupling, reduced, airway hyperresponsiveness 45 lung capillaries in emphysema 185 reduction in COPD 183 lung elasticity 51–54, 53, 213 dynamic compliance 51 expiratory pressure–volume curves 51–53, 52 microfibrils 213 lung elastic recoil pressure (PL) 44, 49 effect on airway smooth muscle function 44 loss in COPD 51, 53, 53, 61 lung function bronchodilator response 44–45 exercise-induced changes asthma 421, 422 COPD 424, 424
extracellular matrix 214 factors determining levels 23, 23–24 early decline (adolescent) 23, 24, 25, 26 low level in infancy 23, 23–24, 24 rapid decline (adults) 23, 24, 25–26 growth during childhood 24–25 determinants 21, 24–25 infections affecting 24–25 in utero growth affecting 24–25 reduced rate 25 impairment/loss airway reactivity relationship 362–363, 363 children 21 hypothetical mechanisms leading to 23, 23–24 slowed in COPD by smoking cessation 716 level at birth 23, 24, 25 persistent asthma 23 rates of decline, inflammatory factors affecting 26 twin studies 30 lung function tests 448–449 asthma 5, 676 asthma vs COPD 452 childhood asthma 704 COPD 5 relationship to CT abnormalities 474 Lung Health Study 13, 45, 716, 717 lung transplantation 627–628 COPD treatment 721 costs 666 exercise capacity 630 quality of life 630 survival, emphysema 629–630 lung volume reduction surgery (LVRS) 627, 720 COPD treatment 720 cost-benefits 666 patient selection 628–629 physiological effects 628 pulmonary hypertension treatment 190 rationale 628 results 629, 629 LY93111 (anti-leukotriene) 644 lymphocytes 119–130 activation, airway smooth muscle cell action 172–173 asthma 126–127 virus-induced 411–412 COPD 127–128 homing/trafficking bronchus-associated lymphoid tissue (BALT) 119 regulation by chemokines 124–125, 125 regulation in lung 123 suppressive effect of alveolar macrophages 345, 353 in virus infections 411 see also B cells; T cells
Index
lymphokines 261, 348 lysine aspirin 441 lysylbradykinin 237 receptor 238 structure 238 synthesis, asthma 239 M a2-macroglobulin functions 275 plasma exudation 197 macrophage(s) 99–109 accumulation in airspace 277–278 activation by smoke 104–105, 277 T-cell-independent 102–103 in airway antigen presentation 265, 345 cytokines released by 265 alveolar 103, 345 activation in smokers 248 cytokines secreted 262 endothelin source 297 IGF-I secretion 286 iron content in smokers 248 macrophage elastase production 268 nitric oxide synthesis 309 suppressive effect on lymphocytes 345, 353 T cell response control 123 in viral infections 411 antigen presentation 265, 345 anti-inflammatory role 345 in asthma 105–106, 345 effector phase of immune response 106 initiation of Th2 response 105–106 cathepsin secretion 105 chemokine release 100 in COPD 104–105, 366 neutrophil/epithelial cell interactions 367 proteinases 105 corticosteroid effects 550, 551 definition 99 immune response initiation 103 inflammatory response 100–102 amplification role 100 in COPD 105, 366 matrix degrading proteinases from 105, 268, 274, 274 mechanism of damage by particulates 435 mediators released 100–101, 105, 106, 277, 345, 366 chemokines 100 cytokines 262 microbes/microbial product recognition 99–100 MMP-12 synthesis 278 origin and distribution 99 pattern-recognition receptors (PRR) 99
polymorphonuclear cell recruitment 100, 104 proteinases 105 pulmonary 103, 105 in smokers 248 T cell activation 103 in viral infections 411 macrophage-derived growth factors, tissue remodeling and repair 103–104 macrophage elastase (MMP-12) 268, 276 a1-antitrypsin inactivation 278 gene targeting in mice 278 neutrophil elastase interactions 279, 279 synthesis by macrophage and monocyte chemotaxis 278 macrophage inflammatory protein (MIP) 127 magnetic resonance imaging (MRI) 466, 474 major basic protein (MBP) 114 airway epithelial damage pathogenesis 115 airway hyperresponsiveness induced by 81 asthma pathogenesis 115 release by eosinophils 114 structure 114–115 major histocompatibility complex (MHC) see HLA class I; HLA class II malnutrition, management in COPD 636–637 management of asthma acute see acute exacerbations of asthma allergen-induced 388 children see childhood asthma management of chronic asthma (adult) 675–687, 682 aims 675–676 assessment see assessment of asthma; diagnosis asthma classification for 675 commitment (education and reviews) 683–684 concept of control 675 drug therapy 677–682 exacerbations 680–681 first-line 677–680 score for severity and dose titration 677 second-line (prevention) 680 stable asthma, anticholinergics 530, 530 theophylline 540–541 see also beta (b2)-agonists; corticosteroids of exacerbations 680–681, 682 see also acute exacerbations of asthma future prospects/changes 685–686 interventions 677–683
767
lifestyle factors 682 long-term 675 optimal control criteria 676 partnership in care 676 plan see Asthma Management Plan reduction of aggravating factors 683 severe persistent asthma 684–685 time to achieve control 676 management of COPD (exacerbations) see acute exacerbations of COPD management of COPD (stable) 713–726 by COPD stage 716 drug therapy anticholinergics 531, 531 antidepressants 721 anti-tussives 721 bronchodilators 718–720, 731 first-line 718 glucocorticoids 720 mucolytics 721 narcotics 720 see also anticholinergic bronchodilators; bronchodilators; corticosteroids end-of-life issues 723 goals 713, 713 exacerbation prevention 722 prevention of disease progression 715–717 symptom relief 717–721 health-related quality of life 722 management issues 722–723 prolongation of life and 722–723 pulmonary rehabilitation 720 surgery 720–721 weakness management 721 manganese superoxide dismutase (MnSOD) 251 MAP kinase inhibitors 650 Marfan syndrome 215 margination eosinophils 112 neutrophils 133 mast cells 91–97 activation 92–93 activators 92 IgE-dependent 92, 344 IgE-independent 92–93 allergen-induced airway hyperresponsiveness 80–81 in asthma 94–95, 126–127, 344–345 animal models 94 early asthmatic response 386 late-phase response 114 role in pathogenesis 94–95 viral infections 412 in COPD 95 corticosteroid effects 550, 551 degranulation adenosine mediating 295 early asthmatic response due to 386 desensitization 95
768
Index
mast cells—cont development and heterogeneity 91–92 FceRI expression 80, 92 granules, constituents 94 homeostasis 94 maturation/proliferation 266 mediators released 92, 93, 93–94 cytokines 92, 94, 266, 344 early asthmatic response due to 386 tryptase 274–275 origin and fate 91 priming and inhibition 93 receptors 91 recruitment 92 structural features 92 Syk kinase inhibitors 650 tryptase 280 virus infections 412 matrilysin 276, 278 matrix degrading proteinases 273–282 asthma 279, 279–280 airway remodeling 280 bronchoconstriction 279–280 cell proliferation and survival 280 inflammatory cell migration 280 status asthmaticus 280 COPD 277–279, 369–370 a1-antitrypsin deficiency and emphysema 279 animal models of pathogenesis 278–279 inflammation and proteinases 277–278 cysteine (thiol) proteinases 275–276 from macrophage 274, 274 MMPs see matrix metalloproteases (MMPs) from neutrophils 274, 274, 370 serine proteinases 273–275 sources, and characteristics 274 types 273, 274 matrix metalloproteases (MMPs) 276–277, 647–648 abnormal expression 276 airway remodeling in asthma 71, 280 COPD pathogenesis 273, 370 expression by epithelial cells 150 expression in smokers 278 functions 273 individual MMPs 276 induction, cell adhesion molecules role 207 inhibitors 647–648 lung cell maintenance and 186 MMP-1 overexpression in transgenic mice 278 MMP-3 71 MMP-9 71, 280, 370 MMP-12 see macrophage elastase MMP-12 knockout mice 105, 370 pulmonary macrophage releasing 105, 268 secretion and activation 276 serine proteinase interactions 279, 279
structural domains 276 synthesis by fibroblasts 140 tissue inhibitors see tissue inhibitors of metalloproteinase (TIMP) maximum mid-expiratory flow, exerciseinduced changes 422 maximum voluntary ventilation (MVV), exercise-induced changes in COPD 424, 424 MDMA (ecstasy) 441 mechanical ventilation see ventilator support mediator antagonists 565–571 antihistamines 567 anti-leukotrienes 565–567 bradykinin antagonists 568 cysteinyl-leukotriene antagonists 566 endothelin antagonists 644 5-lipoxygenase inhibitors 566 new agents 643, 643–644 PAF antagonists 568 serotonin antagonists 567–568 thromboxane inhibitors 568 see also individual groups of antagonists (as above) medical history, asthma/COPD 447–448, 452 membrane lipid peroxidation see lipid peroxidation membrane-type metalloproteinases (MT-MMPs) 276 menstrual asthma 337 mesenchymal–epithelial interaction 67, 185 metabolon 100–101 leukotriene synthesis 100, 101 metal fumes, COPD due to 401 metered-dose inhaler (MDI) 555, 706 asthma exacerbation by CFCs in 439 bronchodilators in COPD 718 childhood asthma 705, 706 in mechanically ventilated COPD patients 613, 613 nebulizers vs., cost-benefit analysis 664 pressure-activated (pMDI) 706 spacers 555, 705, 706 methacholine response/challenge 14, 197 airway hyperresponsiveness in COPD 45 in animals 83–84, 85 asthma vs COPD 425 bronchoconstriction, lung volume effect 44 childhood asthma 700 COPD 424–425 methotrexate, chronic asthma 600, 681 methoxamine, airway blood flow decrease 180, 180 methylcysteine 636 methylphenidate 439 methylprednisolone, COPD exacerbation treatment 731 methylxanthines 535, 535–545
COPD exacerbation treatment 731 see also theophylline metoprolol 440 microbial flora, respiratory tract, normal 574 microfibril-associated glycoprotein (MAGP) 213 microfibril-associated proteins (MFAP) 213 microfibrils 213 microorganisms lipopolysaccharide recognition by macrophage 100 recognition by macrophages 99–100 microvascular leakage asthma 178, 196, 350–351 see also vascular permeability ‘middle lobe syndrome’ 704 millers, COPD 401 mineral particulates, COPD due to 400–401 miners, COPD 400–401 mitogen(s), airway smooth muscle 1 69, 73, 280 mitogen-activated protein kinase (MAPK) activation, by reactive oxygen species 246 AP-1 activation 318 modipafant (PAF antagonist) 568 monitoring of asthma chronic asthma management 684 exhaled nitric oxide as measure 310, 310–311 monoclonal antibodies, humanized anti-IgE humanized MAb 117, 652 cell adhesion blockers 651 immunomodulatory therapy in asthma 601, 644, 652 keliximab, Th2 cell inhibitors 651–652 monocyte(s) chemokines synthesized 101–102 chemotaxis, MMP-12 role 278 response to chemotaxins 101 serine proteinases in 278 in viral infections 411 monocyte chemotactic protein 1 (MCP-1) 124, 268, 366, 369 monocyte chemotactic protein 3 (MCP-3) 112 monocyte inflammatory protein-1a (MIP-1a) 124 monocyte inflammatory protein-1b (MIP-1b) 369 monocyte/neutrophil elastase inhibitor 275 montelukast 230, 566, 643 chronic asthma management 680 chronic persistent asthma, clinical trials 231 Churg–Strauss syndrome 567 mechanism of action 566, 643 morbidity, asthma/COPD 12 mortality 12
Index
asthma 12, 12, 157 acute 689, 690 air pollution effect 434 childhood 699 common causes 10 COPD 11, 12, 12 acute exacerbations 733 air pollution effect 435 prediction from airway responsiveness 14 MRC Dyspnea Scale 482, 483 MUC2 gene 155 MUC5AC gene 155, 156, 158 mucin 155 asthma 158 gene expression 72, 73 induced by neutrophil elastase 278 upregulation by IL-4 and IL-13 158 genes 155 production 155–156 cell multiplication vs differentiation 155 EGFR activation 155–156, 156, 158, 159 increased 72, 158 neutrophils effect 159, 159 overview 159 stimuli and mechanisms 155, 158 stimuli in asthma 158 stimuli in COPD 159–160 secretion 156–157, 159, 159 stimuli 156 transcription 155 see also mucus mucin-secreting cells 155–163 mucociliary clearance 157 airway blood flow effect 179 COPD 151 eosinophil clearance 199, 201, 201 impairment in smokers 151 mucoid impaction syndrome 704 mucolytic drugs 636, 721 mucopolysaccharidoses (MPS) 215 mucosa, airway extravasated protein as bioactive protein source 197 thickness increase 179 mucous balls, oxygen therapy complication 593 mucous glands 72 mucous metaplasia 69, 72–73 sites 72 mucous plugs asthma 60, 63, 63, 72, 343, 351 COPD 72, 159 mucus 155–163 cells secreting increase in number/size 72 see also goblet cells; submucosal glands clearance 157 composition and changes in 72 hypersecretion see mucus hypersecretion
properties 155 asthma 158 thixotropic characteristic 157 regulation in asthma 157–158, 351 in COPD 158–159 secretion 150–151 allergen-induced 156 conducting/peripheral airways 157 corticosteroid effect 551, 551 effect of chronic SO2 82–83 endothelin-1 stimulating 300 epithelial cells role 150–151 induced by platelet activating factor 297 leukotrienes role 231 mechanism 150–151 neutrophils role 157 overview 159 substance P stimulating 331 see also mucin mucus glands, chronic bronchitis 61, 158 mucus hypersecretion 82–83, 157 airway infections causing 160 airway wounding causing 156 animal models 82–83, 83, 84 cholinergic mechanisms 329 chronic asthma 157, 351 chronic bronchitis 371 clinical relevance in asthma 157–158 clinical relevance in COPD 158 COPD 158, 329 fatal asthma 157, 157 future therapies 160 mechanisms leading to 83, 158 treatment 160 see also mucus, secretion multiple inert gas elimination technique (MIGET) 49, 184 multiplexins 212 muscarinic blockers allergen-induced airway response 386 see also anticholinergic bronchodilators muscarinic receptors 326–328 abnormal expression in asthma 328 distribution/localization 328 inhibitory (autoreceptors) 327 defective in asthma 327 M1 receptors 326–327 M2 receptors 326, 327, 328 M3 receptors 326, 327 selective antagonists 642–643 subtypes 326–327, 327, 527, 528 muscle decreased mass in COPD 424 skeletal, apoptosis 373 smooth, in airways see airway smooth muscle (ASM) weakness in COPD 373, 620, 721 mycoplasma infections 187 Mycoplasma pneumoniae infection 573 myeloblastin (proteinase 3) 274 myeloperoxidase (MPO) 135
769
increase in neutrophils in smokers 248 reactive oxygen species produced 244 myofibroblasts 139 characteristics 70 differentiation, interferon-c role 142 distribution 139 growth factors inducing 284 hyperplasia 70 matrix deposition in asthma 70 proliferation, cytokines influencing 267 structure 139 N NADPH oxidase 244 narcotics, COPD treatment 720 nasal cannulae, oxygen therapy 593 nasal inflammatory disease 196 nasal test methodologies 195–196 National Ambulatory Medical Care Survey 12 National Health and Nutrition Examination Survey (NHANES III) 8, 9 National Health Interview Survey 9 National Institute of Heart, Lung and Blood Diseases 11 National Institutes of Health Global Initiative for Asthma (GINA) guidelines 699 natriuretic peptides 335 natural history, asthma/COPD 19, 19–28 asthma 4, 19, 19–28, 20–23 age effect 15 COPD 4, 19, 19–28, 23–26 initial phase 20 methodological approach 19–20 pre-illness period 19 see also lung function natural killer (NK) cells 119–120 cell killing by 413 in COPD 127, 367 functions 413 virus-induced asthma 413 nebulized bronchodilators, bronchoconstriction induced by 439 nebulizers cost-benefit analysis, vs. MDI 664 wet bronchodilators in COPD 719 for children (asthma) 706 nedocromil sodium 633, 634, 664 chronic asthma management 680 effect on allergen-induced airway response 386 exercise-induced asthma 425 nerve growth factor 326 nerves, airway see airway nerves neural control 323–334 asthma 351 interactions between pathways 323 neuropeptide release 324
770
Index
neuraminidase inhibitors 416, 635 neurogenic inflammation airway disease 333–334 asthma 351 neurokinin A (NKA) 74, 324, 331 in bronchoalveolar lavage fluid 333 fibroblast migration/proliferation stimulation 142 neurokinin receptors 332, 333 NK1 and NK2 331 neuromuscular blocking agents 614 neuropeptides 323–324 airway 330–331 airway inflammation 331 COPD pathogenesis 369 as cotransmitters in airway nerves 324, 324 fibroblast migration/proliferation stimulation 142 synthesis and release 331 tracheobronchial blood flow regulation 178 types and localization 334 neuropeptide Y (NPY) 324, 369 neuropsychological effects, chronic oxygen therapy 590–591 neurotransmitters airway nerves 323, 324, 324 asthma pathogenesis 351 see also acetylcholine (ACh); noradrenaline neurotrophins 326 neutral endopeptidase (NEP) 145 endothelin metabolism 298 inhibitors 298, 332–333, 334 kinin inactivation 238 tachykinin degradation 332 neutrophil(s) 131–137, 346, 365–366 abnormal function 134–135 consequences 135 accumulation, E-/L-selectin inhibition effect 206 activation by platelet activating factor 297 activation by smoke epithelial cell injury by 145 site 133, 366 airway disease, pathogenic role 134–135 airway obstruction in COPD 131 asthma 346, 413 animal models 132 exacerbation 132, 346, 366 blood count, airflow limitation relationship 249 chemotactic factors 131, 131, 132 IL-8 released from epithelial cells 146, 256, 413 in COPD 268, 365–366 airway obstruction 131 animal models 132 elastase role 132 exacerbation 132, 249, 346, 366, 728 IL-8 level correlation 256, 728
macrophage/epithelial cell interactions 367 pathogenic mechanisms 134–135, 256,365–366, 366 superoxide anion production 249 corticosteroids effect on 135, 551 effect of chronic SO2 exposure (animals) 83, 84, 85 elastase see neutrophil elastase endothelium interaction 133–134, 134 granules, elastase 274, 277 influx in asthma 132 influx in COPD 365 LTB4 involvement 231, 367–368, 459 in smokers 365, 458 interleukin-8 actions/synthesis 256 leukotriene B4 synthesis 227 lung inflammation 131–132, 134–135, 365–366, 366 matrix degrading proteinases from 274, 274 mucin production and secretion 72, 158, 159, 159 mucus secretion in asthma 157 myeloperoxidase increase in smokers 248 proteases 134 increase release in COPD 135, 365 reactive oxygen species production 134–135, 247, 249 smoking and 134–135 recruitment 100, 159, 346, 365, 413 IL-8 levels linked in COPD exacerbation 728 macrophage role 100, 104 by smoke 105, 133 release, IL-1b inducing 269 sequestration 249 in bronchial circulation 134 in smokers 365, 458 superoxide anion production 248, 249 survival, COPD 365, 369 toxic mechanisms 134, 135 trafficking (lung) 132–134, 365 circulating and marginating pools 133, 365 emigration 133, 133–134 margination and sequestration 133 viral infections 413 neutrophil elastase 105, 159, 274, 370, 647 chronic bronchitis 371 COPD 132, 277–278, 365 deficiency in mice 278–279 extracellular matrix degradation 277, 278 increased release and damage 135, 277, 278 inhibitors 160 a1-antitrypsin (a1-AT) 647, 648 SLPI 275 MMP-12 interactions 279, 279
mucin gene expression induced 278 sources 274, 277 neutrophilia bronchial/sputum 451 chronic airway 366 NF-jB 36, 317–318 activation genes expressed after 317 oxidants 369 by reactive oxygen species 246, 250 by stimuli exacerbating asthma 318 by TNFa 268 in asthma 352 corticosteroids action 548, 549 functions 317–318 IjB inhibitor 649 inhibition by glucocorticoids 319, 410 mucin transcription 155 theophylline, nuclear translocation 537 transcription factor inhibitor action 649 nicotine addiction 715 neurophysiological/clinical evidence 510 withdrawal syndrome 510, 511 nicotine replacement therapy 513–514, 514, 515, 716 blood nicotine levels 514 contraindications 513–514, 515 product types 513, 514, 515 therapy combinations 513 nifedipine, pulmonary hypertension 606–607 nimesulide 441 nitration, smoking -induced increase 250 nitrergic mechanisms, tracheobronchial blood flow regulation 178 nitric oxide (NO) 307–314 airway response to viral infections 410 asthma 135, 309–311, 349, 350 alternative sources 311 monitoring 310, 310–311 as braking mechanism for cholinergic system 328, 330, 331 COPD 311, 311 epithelium-derived inhibition of contractions 146 exhaled 309, 451, 459–460 asthma vs COPD diagnosis 451, 452 asthma vs sleep apnea 460–461 eosinophil level correlation 310, 310 increased in asthma 309–310, 460 increased in COPD 249, 311, 311, 365 measurement 309 normal in stable COPD 311, 365 role in asthma monitoring 310, 310–311
Index
smoking cessation association 365 formation 307, 307–309 enzymatic 307, 307 nonenzymatic 308–309 functions 307, 410 inhibition of bradykinin-induced bronchoconstriction 240 lower airway, decreased, in COPD 183 measurement in expirate 309 oxidation to peroxynitrite 309 proinflammatory properties 309, 309 pulmonary hypertension treatment 189, 189, 606 role in allergic disorders 309 Th1 cell suppression 172 as vasodilator 309, 606 nitric oxide synthase (NOS) 307 in airway smooth muscle cells 172–173 cellular distribution 308, 308 constitutive (cNOS) 308, 308 downregulation by smoke 311 inducible (iNOS) 308, 308 increased in COPD 250 inhibition by endothelin 349 isoforms and nomenclature 307–308, 308 regulation 308 transcription 308 types I-III 307–308, 308 nitric oxide synthase inhibitors 330, 644 aminoguanidine 644 corticosteroids 550 L-NAME 298, 644 nitrite, exhaled breath 459 nitrogen dioxide air pollution 431 air quality standards 432 mechanisms of damage by 435–436 nitroglycerin, pulmonary hypertension treatment 189 nitroprusside, pulmonary hypertension treatment 189 S-nitrosothiols deficiency 459 nitric oxide release 308, 459 nitrotyrosine 250, 459 negative correlation with FEV1 460 nocturnal asthma clinical efficacy of inhaled corticosteroids 552 cortisol effect on airways 336 theophylline 541 Nocturnal Oxygen Therapy Trial (NOTT) 588–589, 591 nonadrenergic, noncholinergic (NANC) mechanisms inhibition by serotonin 293 tracheobronchial blood flow regulation 178 nonadrenergic, noncholinergic (NANC) nerves 330–334 in asthma 351 inhibitory (i-NANC) 330
noncompliance 738–739, 739 need for new treatments 641 see also compliance with treatment noninvasive positive pressure ventilation (NIPPV) 732–733 COPD exacerbation management 732, 732–733 indications 733 late treatment failure in COPD 733 non-smokers COPD 13 smokers vs, hydrogen peroxide 458 non-steroidal anti-inflammatory drugs (NSAIDs) see NSAID-induced asthma noradrenaline (norepinephrine) 323, 329, 335 actions/functions 335 normal microbial flora, respiratory tract 574 nortriptyline, smoking cessation 516 Nottingham Extended Activity of Daily Living Scale 483 Nottingham Health Profile 630 NPC 567 (B2 kinin receptor antagonist) 240 NSAID-induced asthma 439, 440–442 possible mechanisms/hypothesis 440–441 see also aspirin-induced asthma nuclear factor jB (NF-jB) see NF-jB nutritional factors, COPD etiology 362 O obesity 682 management in asthma/COPD 637, 637 occupational agents 395–406 asthma due to 395–397, 396 controlled exposure 399 COPD 400–401, 400–403 dose–response 398 exposure assessment in COPD 402 exposure avoidance 400 permissible exposure limits 398 smoking relationship 401–402 types 396 occupational allergens 385 occupational asthma 126, 354–355, 395–400 agents causing 395–397, 396 IgE-dependent 395 IgE-independent 395–396 immunological mechanisms 395–396 atopy and 398 compensation (industrial) 400 costs 400 definition 395 diagnosis 398–399 epidemiology 397, 397–398 exposure factors influencing 398 host determinants influencing 398 impairment/disability assessment 400
771
investigations 399, 399 management 399–400 pathology 397 pre-employment testing 399–400 prevention 400 smoking effect 398 occupational COPD 400–403, 401 compensation (industrial) 402–403 epidemiology 400–401 exposure assessment 402 management 402–403 natural history 402 prevalence rates 401 prevention 403 smoking relationship 401–402 Olympic athletes, asthmatic 425 OM-85 BV (Broncho-Vaxom) 635 Omp proteins 279 opiates, COPD treatment 720 organic dusts, COPD due to 401 oseltamivir 416, 635 osteogenesis imperfecta 214 osteoporosis, corticosteroid side-effect 557–558 outcome, asthma in adult life 22–23 children 22–23, 702 ovalbumin goblet cell metaplasia 156 mouse sensitization and challenge 79–80 oxidants, inhaled burden, measurement 248 proinflammatory gene expression 250 reactive oxygen species formation 244–245 from smoking 248 oxidative stress adverse effects 368–369 antioxidant gene expression induced 250–251 asthma 246, 349 COPD 248–250, 368 exhaled carbon monoxide linked 462 markers/measures of 248, 249, 250 hydrogen peroxide 247, 458 surrogate markers 247 mucin production and secretion 159, 159 proinflammatory gene expression increased 250 in smokers 248–250, 460 vascular endothelial cell changes 183 oxitropium, asthma exacerbation treatment 681 oxygen fractional inspired oxygen concentration (FIO2) 612 free radicals see reactive oxygen species (ROS) partial pressure, acute asthma 692 transport, inefficient in COPD and exercise effect 424 oxygen concentrators 592, 592, 666
772
Index
oxygen therapy acute asthma management 695 administration devices 593 air travel 593–594 chronic, effects 587–591, 589 exercise 590 neuropsychologic 590–591 oxygen cost of ventilation 590 pulmonary hemodynamics 588–590 sleep 591 survival 587–588 complications 593 compressed gas oxygen 592, 592 COPD 722 demand devices, electronic 593 for exercise limitation in COPD 426 home oxygen, cost effectiveness 666 indications 592 liquid oxygen 592, 592 long-term 587–597 COPD 183 impact on patient’s life 738 modes of delivery 592, 592 mucous balls 593 nasal cannulae 593 nocturnal, COPD 722 Nocturnal Oxygen Therapy Trial (NOTT) 588–589, 591 oxygen concentrators 566, 592, 592 pathophysiology of oxygenation 587, 588 prescription guidelines 592–593 pulmonary hypertension, clinical studies 606 reservoir cannulae 593 transtracheal catheters 593 ozagrel 568 ozone 436 air pollution 431 air quality standards 432 mechanisms of damage by 436 physiological effects 436 P PAF-acetylhydrolase 296, 347 deficiency 296–297 paradoxical pulse 692 parasympathetic nerves 323, 326 beta blocker interaction 440 see also cholinergic nerves participation restrictions, definition 481 particulates, exposure 4, 431 air quality standards 432 challenge studies 435 COPD 401 deposition in respiratory tract 431–432, 433 mechanisms of damage by 435 sources and types 431 partnership in care 676 passive smoking asthma relationship 12 childhood asthma 701 COPD etiology 362
pathogen-associated molecular patterns (PAMP) 99–100 pathogenesis of asthma see pathophysiology of asthma pathogenesis of COPD 361–379, 365 bacterial infection role 414–415 chronic bronchitis 371–372 emphysema 370 hypothetical mechanisms leading to 23, 23 inflammatory cells 365–367 inflammatory mediators 367–374 integration of concepts 364 lung damage 370 lung defense 370–371 repair mechanisms 371 summary 372 tissue remodeling 372 see also airway inflammation pathology see airway pathology pathophysiology of asthma 343–359 acute exacerbations 691–692 airway hyperresponsiveness 344 anti-inflammatory mechanisms 352–353 arachidonic acid metabolites 221 exercise-induced 423 genetic influences 354 inflammation effect on airways 349–352 see also airway inflammation inflammatory cells 344–347 see also individual cell types inflammatory mediators 347–349 occupational asthma 395–397 overview 349 severe persistent asthma 685 transcription factors 352, 352 unanswered questions 354–355 patient compliance see compliance patient education 737 asthma self management 739–741, 741 comparative studies, asthma 664 COPD exacerbation 734 health economics, COPD 666 pulmonary rehabilitation 619–620 cost-benefits 666 pattern-recognition receptors (PRR) 99 PDE inhibitors see phosphodiesterase (PDE) inhibitors PEACE study 434 peak expiratory flow rates (PEFR) acute asthma 694 asthma assessment 676 childhood asthma 704–705 diagnosis of asthma/COPD 449 diurnal variability 449 GOLD staging system for COPD 714 measurements/monitoring 449 monitoring, value and problems 705 serial measurement, occupational asthma diagnosis 398–399
waking (amPEF), asthma severity assessment 676–677, 677 pediatric chronic obstructive lung diseases (PCOPD) 700 Penh, sulfur dioxide effects in mice 84–85, 85 penicillins, COPD exacerbation treatment 580 pentane excretion 460–461 peptidases, kinin degradation 238 peptide immunotherapy 652 perforin, CD8 T cells producing 268 peribronchial fibrosis, COPD 361, 372 peribronchial plexus 177 peripheral lung resistance, increased asthma 47 COPD 46, 47, 372 sites 46–47 peroxynitrite anions 247, 250, 368, 459 nitric oxide oxidation to 309 phagocytes reactive oxygen species production 243, 244, 244 see also macrophage(s); neutrophil(s) phagocytosis, frustrated, neutrophil elastase release 277 pharmaco-economics, acute exacerbations of COPD 582–583 see also health economics pharmacogenetics 37 future therapies 652 phenol sulfotransferases 145 phosphatidylinositol 3–kinase (PI3K) signaling pathway airway smooth muscle proliferation 170–171 vascular smooth muscle proliferation 171 phosphodiesterase (PDE) inhibitors new anti-inflammatory agents 648–649 PDE-4 inhibitors 648–649, 650 goblet cell metaplasia inhibition 160 PDE-7 inhibitors 649 PDE isoenzymes 536 pulmonary hypertension treatment 190 side-effects 649 theophylline 535–536, 536 phospholipase A2 (PLA2) 227, 296 cytosolic (cPLA2) 227 secretory (sPLA2) 227 phospholipase C (PLC) 169 activation 170 isoenzymes 169 control by G proteins 170 smooth muscle proliferation 170 phospholipids, peroxidation by reactive oxygen species 245–246, 246 phosphoramidon 298 physical examination 448 acute exacerbation of asthma 693 childhood asthma 703 physical training see exercise training
Index
pilocarpine 439 pink puffers 372, 448 pituitary adenylate cyclase activating peptides 331 PK test 383 plasma exudation 195–202, 196, 196 acute asthma 691 bioactive protein source in airway 197 definition 195 epithelial repair in vivo 198–199 function 195, 196 histamine causing 291 inhibition 197 drugs 198 luminal eosinophil delivery relationship 199 a2–macroglobulin 197 neurogenic 197–198 plasma release and luminal entry 196–197 sequential induction 198 plasma leak, formation 196 plasma proteins oxidation, smoking -induced increase 250 source in diseased airway mucosa 197, 197 platelet activating factor (PAF) 221, 296–297 antagonists 297, 347, 568 in asthma pathogenesis 347 bronchoconstriction induced by 297 inhibition 297 catabolism 296 COPD pathogenesis 368 effect on airways 296, 297 inhibitors 160 mucus secretion 160 receptors 297 role in airway disease 297, 368 structure 296 synthesis and metabolism 296, 296–297 platelet activating factor (PAF) acetylhydrolase 296, 347 deficiency 296–297 platelet-derived growth factor (PDGF) airway remodeling and fibrosis 285 fibroblast migration/proliferation stimulation 141 functions 104, 265 idiopathic pulmonary fibrosis 284 PDGF-A knockout mice 285 production 70 receptors 285 role in airway remodeling 70–71 smooth muscle mitogen 73 sources and effects 265, 285 structure 285 platelet endothelial cell adhesion molecule (PECAM-1) 204 platinum 395 pleiotropy 29 plethysmography 51, 84–85 plicatic acid 395
pneumococcal vaccines 635 COPD, prevention of acute exacerbations 579 efficacy/adverse effects 635 pneumonia, in infancy, increased risk of wheezing in adults 25 pneumothorax, spontaneous, Marfan syndrome 215 pollutants, airborne see air pollution polygenic inheritance 29 polymorphonuclear cells (PMNs) see neutrophil(s) polyunsaturated fatty acids, peroxidation 245 positive end-expiratory pressure (PEEP) 613 acute asthma 695 intrinsic (PEEPi) 52 positive pressure ventilation invasive 611–612 noninvasive 615, 695 post-capillary venules 58, 58 potassium channel openers, bronchodilators 643 potassium iodide 721 poverty, asthma association 15 pranlukast 230, 566, 643 chronic asthma management 680 chronic persistent asthma, clinical trials 231 mechanism of action 566, 643 precapillary arteries, in COPD 185 prednisolone 559 COPD exacerbation treatment 731–732 pre-employment testing 399–400 pregnancy, smoking during 12, 20, 24 pre-kallikrein 237 preproendothelin-1 297 pressure support ventilation 612 pressure–volume curves see expiratory pressure–volume curves prevalence, asthma/COPD 8–11 age-related 8, 8, 15 asthma 8–9, 9, 354 children 9 demographic factors 15 COPD 7, 8–9, 9–11, 10 preventative strategies 652 prevention of asthma 20, 676, 680 see also specific drugs and conditions proendothelins 297 progesterone, effect on airways 337 prognosis, childhood asthma 702, 702 prognostic factors, COPD pH 733 weight loss 372–373, 373 pro-inflammatory agents calcium sensitivity impairment 168 target for calcium homeostasis in smooth muscle 166–168 propranolol 440 prostaglandin(s) 221 asthma pathogenesis 221–222 classes 222
773
COPD pathogenesis 368 exercise refractoriness and 422, 423 inhibitory 222, 223–224 exercise refractoriness mechanisms and 224, 224 histamine-stimulated release 224 leukotriene-stimulated release 224 reduction of airway response to agonists 223 see also prostaglandin E2 (PGE2) receptors, terminology 221 stimulatory 222, 222–223 see also prostaglandin D2 (PGD2) see also eicosanoids prostaglandin D2 (PGD2) 222 in asthma 351 bronchoconstriction due to 222 released by mast cells and basophils 93–94 sources and release 222 prostaglandin E2 (PGE2) anti-inflammatory actions 458 in asthma 353 as ‘brake’ on bronchoconstriction 441 cells producing 142, 368 airway smooth muscle cells 173 epithelial cells 146 fibroblast proliferation inhibition 104, 142 reduction in allergen-induced bronchoconstriction 224, 225 relaxation of airway smooth muscle 223 prostaglandin F2a (PDF2a) 222 bronchoconstriction due to 222, 439 sources and release 222 prostanoids 221–226 in exhaled breath 458–459 terminology 221 see also prostaglandin(s) protease/antiprotease imbalance 132, 135, 185, 370 a1-protease inhibitor see alpha-1 protease inhibitor proteases released by basophils 93–94 released by mast cells 93–94 proteinase 3 (PR3) 274, 370 inhibitors 647 proteinases 273–282 COPD 277–278, 369–370 definition and actions 273 macrophage, in COPD 105 see also matrix degrading proteinases proteins, exhaled breath 460 protein tyrosine kinase (PTK), AP-1 activation 318 proteoglycans 213–214 cell–matrix adhesion 205 structure 213 proteolytic enzymes role in airway remodeling 71 see also proteases; proteinases provocation concentration for wheezing (PCW) 704
774
Index
P-selectin, eosinophil homing 205 P-selectin glycoprotein ligand-1 (PSGL-1) 204 Pseudomonas aeruginosa COPD exacerbation 730 c-Src-Ras-MEK signaling pathway 155 mucus hypersecretion induction 160 pseudoxanthoma elasticum 215 psychiatric disorders, prevalence, COPD 737–738 psychological management, childhood asthma 708 PTEN (tumor suppressor) 170 pulmonary angiography, COPD 183, 184 pulmonary arteries, thickening in COPD 183, 184, 185 pulmonary arteriole, in COPD 185 pulmonary artery pressure decrease by atrial natriuretic peptide 188 factors influencing 184 increased in COPD exacerbation 731 pulmonary blood flow 49 in COPD during exercise 423 pulmonary blood vessels 183–193 changes in asthma and status asthmaticus 187 evidence for involvement in COPD 183–184 hypoxic vs nonhypoxic vasoconstriction 184 V/Q mismatch in COPD 184 pulmonary capillaries, in COPD during exercise 423 pulmonary edema, acute, nitrogen dioxide causing 435 pulmonary fibrosis 214 asthma 350 COPD 215, 372 etiology and pathogenesis 214, 372 growth factors involved 283–284 idiopathic 283 growth factors involved 284 interleukin-1 role 285 macrophage-derived growth factors role 103–104 platelet-derived growth factor role 285 TGF-b effect 69, 70, 287 TNF-a actions 284 Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ-M) 483 pulmonary function tests see lung function tests pulmonary gas exchange 49, 49 assessment 49, 50, 51 pulmonary hemodynamics, oxygen therapy effects 588–590 pulmonary hypertension clinical studies 606–608
oral vasodilators 606–607 oxygen 606 pathogenesis in COPD 184, 605 pathophysiology in COPD 605–606 pulmonary vasodilators 605–609, 606 rationale 606 usage guidelines 607–608 treatment in COPD 183, 187–190 ACE inhibitors 606 almitrine 188–189 angiotensin synthesis inhibitors 606 atrial natriuretic factor 188 clinical drug trials 188 drugs 187–190 endothelin antagonists 189, 606, 644 future strategies 190 5-lipoxygenase inhibitors 189 lung volume reduction surgery 190 nifedipine 606–607 nitric oxide 189, 189, 606 phosphodiesterase inhibitors 190 pulmonary perfusion, gas exchange assessment 49 pulmonary physiology 43–56 airway function 43–48 alveolar function 48–51 lung elasticity and volumes 51–54 see also expiratory pressure–volume curves see also airflow limitation; airway function pulmonary rehabilitation 617–626 American Thoracic Society (ATS) 427 concept 617 COPD 720 dimensions 619 eligibility criteria 618, 618 exercise-induced asthma 426–427 exercise limitation in COPD 426–427 goals 617–618 long-term outcome 624–625 lower/upper extremity training 622–623 nonpharmacological treatment 618–625 education 619–620 exercise training 620–625 see also exercise training patient education, cost-benefits 666 quality of life 624–625 ventilatory muscle training 623–624 pulmonary surfactant 36 gene polymorphisms 36 pulmonary vascular remodeling, hypoxia-induced 606 pulmonary vasoconstriction, hypoxic vs nonhypoxic 184 pulmonary vasodilatation, atrial natriuretic factor causing 188 pulmonary vasodilators see under pulmonary hypertension; vasodilators pulsus paradoxus 692 pyridostigmine 439
Q quality of life acupuncture, asthma 638 assessment in COPD 722 chiropractic spinal manipulation, asthma 638 COPD exacerbations 728 Nottingham Health Profile, lung transplants 630 pulmonary rehabilitation 624–625 quinone, in tar phase of smoke 244 quinone radical 244 R radiography acute exacerbation of chronic bronchitis 574–575 constrictive obliterative bronchiolitis 475 digital 465 emphysema 470–471, 471, 472 plain chest see chest radiography radiographic abnormalities, asthma 466–467, 467 bronchial wall thickening 467 hyperinflation 466–467 ranitidine 567 RANTES 106, 112, 171–172, 265, 412 rapamycin (sirolimus) 601, 651 rapidly adapting receptors (RARs) 325, 435 reactive nitrogen species (RNS) 244, 245, 246 biological actions 250 mechanisms of effects on airways 245–246, 246 production LPS-stimulated airway epithelial cells 246 smoking-induced increase 250 reactive oxygen species interaction 247, 249–250 reactive oxygen species (ROS) 243–254 in alveolar space 248–249 asthma 246–248 airway epithelial injury 247 bronchial hyperresponsiveness 246–247 biochemical markers of 248, 249, 249, 250 biological effects 247, 368–369 in blood 249 cell-derived 244 sources 244 COPD pathogenesis 368–369 lipid peroxidation by 245–246, 246 product formation 248, 250 lung inflammation pathogenesis 243, 243 molecules included 243, 369 mucin synthesis and 1560 production 244, 244, 368–369 eosinophil granule proteins role 247 by eosinophils 244, 245, 247, 345
Index
in epithelial lining fluid 248 by inflammatory mediators 247 inhaled oxidants and smoke causing 244–245 lipopolysaccharide-stimulated airway epithelial cells 246 by neutrophils 134–135, 243, 247 by phagocytes 243 xanthine/xanthine oxidase reaction 249 proinflammatory gene expression 250 reactive nitrogen species interaction 247, 249–250 signal transduction role 246 reaginic antibody 383 receptor tyrosine kinase (RTK) activity, smooth muscle proliferation 169, 170 reflux reflex 328 rehabilitation, pulmonary see pulmonary rehabilitation relapse, asthma, in adulthood 23 Relenza (zanamivir) 416, 635 remodeling of airways see airway remodeling renin–angiotensin system 335–336 reservoir cannulae, oxygen therapy 593 residual volume, acute asthma 692 respiratory acidosis, indications for ventilator support 611 respiratory alkalosis 692 respiratory burst, eosinophils 115 respiratory failure acute, ventilator support 611–616 COPD 723 management, COPD exacerbation 732 respiratory muscles, accessory, acute asthma 692 respiratory rates, acute asthma 692 respiratory stimulants, COPD exacerbation management 732 respiratory syncytial virus (RSV) 20, 21 acute viral bronchiolitis 702, 703 childhood asthma trigger 701 COPD exacerbation 415 effect on lung function in children 24–25 enriched immunoglobulin 416 lung function deficit due to 26 treatment of infection 416 wheezy infants 702–703 respiratory tract deposition of particles 431–432, 433 infections see infections normal microbial flora 574 restriction enzymes, RsaI 34–35 retinoic acid lung maintenance 186 retinoid receptor activation 320 RGD motifs, fibrillin-1 213 rhinitis, allergic see allergic rhinitis rhinovirus infections 407 airway epithelial cell response 409, 410
cellular responses 412, 413 childhood asthma trigger 701 COPD exacerbation 415, 730 cytokine production increased by 728 experimental 408 IL-6 levels in sputum 728 physiological effects 409 lower airway 408–409 macrophage response 411 receptor 409, 416 inhibitors 416 Th1 and Th2 cytokines 411 treatment 416 ribavirin 416 right ventricular performance, factors influencing 184 rimantadine 635 rimantidine 416 risk factors asthma 15, 354 COPD 13, 15, 36 Ritalin 439 rofecoxib 441 running, exercise-induced asthma and 421–422, 701 S Safety data sheets (SDS) 398 salbutamol asthma exacerbation treatment 680 Combivent® 532 early asthmatic response inhibition 385 for exercise limitation in COPD 426 pediatric airways disease 530–531 saline inhalations, sputum-producing 198 salmeterol comparative studies 664 effect on allergen-induced airway response 385 ipratropium vs in COPD 719, 719 see also beta (b2)-agonists sarafotoxin 300 sarco-endoplasmic reticulum (SER) 165 calcium-ATPases associated (SERCA) 165 sarcoidosis 371 SB225002 (CXCR2 antagonist) 258 scopolamine 528, 529 seasonal asthma 675 seasonal factors airway hyperresponsiveness (AHR) 385 COPD exacerbation 729 see also climate secretagogue 197 secretions, mucus see mucus secretory leukoprotease inhibitor (SLPI) 275, 368–369, 648 segregation analysis 31–32 selectins 204, 204 inhibitors 651 role in leucocyte homing 205–206 self-management 737–742
775
advice in asthma 741 advice in COPD 740 comparative studies, asthma 664 guidelines 739, 740 patient education, asthma 739–741, 741 semiquinone radicals 244, 248 Sendai virus infection 155 sensory nerves see afferent nerves seratrodast (thromboxane inhibitor) 568 serine metalloproteases, role in airway remodeling 71 serine proteinases 273–275 inhibitors serpins 36, 275 see also alpha-1 protease inhibitor matrix metalloproteinase interactions 279, 279 in monocytes 278 S1 family 273 secreted by neutrophils 370 structural characteristics 273 see also neutrophil elastase serotonin (5-HT) 293 effect on airways 293, 293 plasma levels in asthma 293 receptors 293 role in airway disease 293 synthesis and metabolism 293 serotonin antagonists 567–568 of 5-HT2 receptors 293, 567 ketanserin 293, 567 tianeptine 293, 568 serous cells 155 enlargement in COPD 159 serpins (serum protease inhibitors) 36, 275, 648 elafin 275, 648 mechanism of action 648 Seventh Day Adventists, asthma associated with air pollution 434 severe persistent asthma 684–685 see also chronic persistent asthma severity of asthma see asthma severity sex differences see gender influence sex hormones 337 Sickness Impact Profile (SIP) 483 signaling system calcium, in smooth muscle see calcium signaling, in airway smooth muscle cilia 150 c-Src-Ras-MEK pathway 155 phosphatidylinositol 3–kinase (PI3K) pathway 170–171 signal transduction reactive oxygen species role 246 redox pathways 246 silo filler’s disease 435 single nucleotide polymorphisms (SNPs) 37, 354 b2-adrenoceptors 354, 524–525, 691 asthma 354 sirolimus (rapamycin) 601, 651 Six Cities Study (US) 433
776
Index
skeletal muscle see muscle skin-prick tests 450 allergy 13 childhood asthma 700–701 occupational asthma 398 sleep apnea 461 hypoxemia, chronic oxygen therapy 591 quality anticholinergic bronchodilators 591 ipratropium 591 slowly adapting receptors (SARs) 324–325 slow-reacting substance of anaphylaxis (SRS-A) 227 small airways disease ancillary CT abnormalities, asthma 470, 470 high resolution CT in constrictive bronchiolitis 475, 475 imaging 474–475, 475 smoke/smoking 12–13 adolescents 12, 14, 25 airway hyperresponsiveness 45 airway repair mechanisms impaired by 371 alveolar septal cell apoptosis 186 antioxidant gene expression upregulation 250–251 asthma relationship 5, 12–13 effect on asthma 509 exposure and childhood asthma 701 in-utero events 12, 14, 16, 20 passive smoking 12 avoidance, childhood asthma 708 blood nicotine levels 514 carbon monoxide transfer reduction 51 chronic bronchitis/emphysema, natural history 510 as a chronic disease 510–511, 715 C nerve fibers activation 334 composition of smoke 244, 248, 368 COPD relationship 5, 9, 13, 19, 29, 61 effect on COPD 509 emphysema pathogenesis 48, 277, 370 etiological 67, 277, 319, 362 lung function development 24 cytokine release in COPD 268 dose and timing effect 12, 14 drug interventions in COPD 717 effects at different life stages 14 EGFR expression enhancement 69 emphysema pathogenesis 48, 277, 370 endothelial cell apoptosis 186 FEV1 decline 25–26, 510 FEV1 prediction 13 fibroblast inhibition 140 gas and tar phases of smoke 244
iron content of alveolar macrophages 248 lung damage mediated by 370 lung defense impairment by 370–371 lung inflammatory changes 62, 131 macrophage activation 104–105, 277, 370 macrophage changes 248 maternal 12–13, 20, 24 matrix metalloproteinase expression 278 mucin production 156, 159 mucociliary clearance impairment 151 neutrophil changes 248 neutrophil elastase link in emphysema 132 neutrophil recruitment 105, 133 nicotine addiction/withdrawal 510, 511 nitric oxide synthase downregulation 311 occupational asthma and 398 occupational COPD relationship 401–402 oxidant burden on lung 248 oxidative stress 248–250 passive see passive smoking prevalence 9 reactive nitrogen species formation 250 reactive oxygen species formation 244–245 by neutrophils 134–135 smoking cessation 509–520, 516 alternative therapies 516 assessment of reversibility of airway changes 364 benefits 510, 716–717, 717 COPD 364, 373–374 cost–effectiveness analysis 666 counseling/behavioral therapies 511–513, 512 brief interventions 512 intensive interventions 512–513 defeatist attitudes 716 depression associated 373–374, 721 effectiveness 511–516 increased exhaled nitric oxide 365 intervention delivery/setting 516–517 pharmacological treatment 716 pharmacotherapy 513–516 bupropion 514, 515, 516, 716 clonidine 516 nicotine replacement therapy 513–514, 514, 515 nortriptyline 516 see also nicotine replacement therapy practical steps (five A’s) 517, 517–518 prevention of COPD progression 715–717 quit plan 518 relapse after 716
respiratory disease patients 517 self-help 513 strategies for 715–717 T cell infiltration in COPD reversible 127–128 transtheoretical model of change 517–518, 518 US Lung Health Study 500, 510 smooth muscle airways see airway smooth muscle vascular see vascular smooth muscle socioeconomic factors asthma hospitalization 15 asthma mortality 12 sodium cromoglycate 633, 634, 634 adenosine-induced bronchospasm inhibited 295 chronic asthma management 680 effect on allergen-induced airway response 386 exercise-induced asthma management 425 Sp1 transcription factor 318 spacers, for metered-dose inhalers 555, 705, 706 spinal manipulation, asthma 638 spirometry 448–449 sputum analysis in asthma vs COPD 451 biochemical markers in asthma vs COPD 451, 452 culture 574–575, 577–578 diagnosis of acute exacerbation of chronic bronchitis 574–575, 577–578 eosinophilia 451 Gram stain 574–575 increased interleukins, COPD exacerbation 728 induced/induction 451, 457 airway inflammation in COPD 365 COPD exacerbation 728 neutrophilia 451 persistent, GOLD staging system for COPD 714 production in COPD 61, 448 chronic bronchitis 61 COPD exacerbations 728 management 721 sequential induction 198 squamous metaplasia, COPD 69 stable asthma/COPD, management see entries beginning management staging, stable COPD 713–715 comparisons between systems 714, 714–715 limitations 715, 715 starvation 371 STAT6 317, 318 inhibitors 645 knockout mice 318 STATs 318 status asthmaticus definition 689
Index
ingested/injected allergens causing 387 lung morphology 187, 187 matrix degrading proteinase role 280 vascular alterations 187 see also acute exacerbations of asthma stem cell factor, sources and effects 264 steroid-resistant asthma 319 steroids cell adhesion molecule expression inhibition 172 eosinophil apoptosis 199 inhaled, occupational asthma 400 plasma exudation inhibition 198 reversibility of asthma, testing 449–450 see also corticosteroids; glucocorticoid(s) St George’s Respiratory Questionnaire (SGRQ) 482, 483, 484, 722 COPD exacerbations 728 strength training, COPD 622 Streptococcus pneumoniae COPD exacerbation 730 vaccines see pneumococcal vaccines stromelysins 276 SU5416 (VEGF receptor blocker) 186 subepithelial (mucosal) blood flow 177 subepithelial fibrosis, asthma 350 subepithelial plexus 177 submucosal capillaries 58, 58 submucosal glands 155 mucin expression 158 substance P 74, 324, 331 actions 331–332 asthma 351 in bronchoalveolar lavage fluid 333 chronic bronchitis 369 fibroblast migration/proliferation stimulation 142 mucus secretion stimulation 331 sulfur dioxide air pollution 431 air quality standards 432 mechanisms of damage by 435 sulfur dioxide, chronic exposure airway inflammation (experimental) 83 animal model of chronic bronchitis 82–85 effect on ciliated epithelial cells 82 effect on mucus secretion 82–83 effects in animals mice 84–85 rats and dogs 82–84 role of C-fibers in bronchitis due to 84 superoxide anion 243, 369 production acute COPD exacerbation 249 by neutrophils 134–135 in smokers 248 xanthine/xanthine oxidase reaction 249
superoxide dismutase (SOD) 244 suplatast tosilte 160 suramin (cathepsin inhibitor) 647 surgery 627–632 bullectomy 627 COPD treatment 720–721 lung transplantation 627–628 see also lung transplantation lung volume reduction 627 see also lung volume reduction surgery (LVRS) susceptibility genes see genes susceptibility markers 19–20 determinants influencing 20 sweat tests 704 Sweden, asthma incidence 8 swimming, exercise-induced asthma and 421–422, 701 Syk kinase inhibitors, mast cells 650 sympathetic nervous system 323, 329 tracheobronchial blood flow regulation 178 sympathomimetics, effect on airway blood flow 180, 180 T tachykinins 74, 331–333 actions 331–332, 332, 332 antagonist 333, 334 degradation 332–333 distribution/synthesis 331 effect on airways 331–332, 332 evidence against role in asthma 333–334 evidence supporting role in asthma 333 receptors 331 see also neurokinin A (NKA); substance P tachyphylaxis b2-adrenoceptor agonists 524 histamine 224 tacrolimus immunomodulatory therapy in asthma 601 as immunosuppressant 651 T-lymphocyte inhibition 650 transcription factor inhibitors 650 talcosis 439 Tamiflu (oseltamivir) 416, 635 T cell receptor (TCR), activation, macrophages in asthma 106 T cells 119–120 activation 120 adhesion molecules role 206 cytokines regulating 124 dendritic cells 103, 123, 345 macrophage role 103 in asthma 126–127, 346 CD4 helper cells 120 asthma 4, 59, 126–127, 346 stimulation by IL-1 124 Th1 and Th2 subtypes see below virus infections 411 CD45RO 120
777
chemotaxis, IL-15 role 124, 125 in COPD 127–128, 366–367 reversibility with smoking cessation 127–128 corticosteroids effects 550, 551 costimulation inhibitors 651, 651 cytokines 261 clinical outcome dependent on 123 interferon-c 121–122 interleukins 120–121 Th1 and Th2 (summary) 122, 122–123 see also Th1 cytokines,Th2 cytokines (below) cytotoxic see cytotoxic T lymphocytes (CTL) differentiation 317, 318 transcription factors involved 317, 318 functions, interleukins regulating 124 immunosuppressant action 651 naive 317 NF-AT blocking by cyclosporin A / tacrolimus 650 recruitment, virus infections 411–412 regulation in lung 123 suppressive effects of alveolar macrophages 345, 353 Th0 cells 261, 316 interleukins expressed 121 Th0–Th1 shift induction, by IL-12 124 Th1 cells 59, 261, 316 IL-2 release 120–121 immune response regulation 122, 122 interferon-c release 121–122 suppression by nitric oxide 172 virus infections 411 Th1 cytokines 59, 70, 120, 120–123 sources and effects 263 summary 122, 122–123 virus infections 411 Th1/Th2 balance 346 asthma 346, 346 virus infections in asthma 411–412, 412 Th1/Th2 model 122, 122–123 Th1 vs Th2 differentiation 346 transcription factors role 316–317, 318 Th2 cells 59, 261, 316 activation 262 activation by dendritic cells 103 activation in allergen-induced asthma 257 antigen presentation 262 asthma 68, 126, 346, 411–412, 412 chemokine receptors 258 costimulation inhibitors 651, 651 cytokine inhibition 644–645 eotaxin production 258 immune response regulation 122, 122 immunosuppressants 651
778
Index
T cells—cont inhibitors 651, 651–652 mucin gene expression increased 72 nitric oxide stimulating 309 preventative strategies, asthma 652 response initiation by macrophage in asthma 105–106 Th2 cytokines 59, 70, 120, 120–123, 262 in asthma 126, 346 chronic airway inflammation 262 goblet cell metaplasia 156, 158 IL-4 production 121 IL-9 production 121 interferon-c 646 interleukins produced 120, 121 sources and effects 263 summary 122, 122–123 virus infections 411 ‘Th2 response’ 59 theophylline, immunomodulatory effects 538–539 tenascin 269 receptors, distribution in lung tissue 203 terbutaline asthma exacerbation treatment 680 comparative studies, COPD 665 early asthmatic response inhibition 385 terfenadine 567 adenosine-induced bronchospasm inhibited 295 exercise-induced asthma 425 terminal bronchioles, normal 62 terminal transferase alpha UTP nick end labeling (TUNEL) 186 tetracyclines, treatment of COPD exacerbation 580 thapsigargin 165–166 theophylline 535–545, 538 actions 295–296 acute asthma management 540, 681, 694 adenosine inhibition 295 adenosine receptor antagonism 536 airway smooth muscle effects 537–538 anti-inflammatory effects 538 apoptosis inhibition 537 asthma exacerbation treatment 681 calcium ion flux interference 537 cellular effects 537, 537–539 chemistry 535 chronic asthma management 540–541, 680 clearance 539, 539 clinical use 540–541 comparative studies, COPD 665 COPD exacerbation treatment 731 COPD treatment 541, 719 corticosteroids with, add-on therapy 554 corticosteroid synergy prediction 537
dose and administration 540, 681 effect on allergen-induced airway response 386, 538 effect on transcription 537 endogenous catecholamine release 536 for exercise limitation in COPD 426 extrapulmonary effects 539 future uses 542 immunomodulatory effects 538–539 interaction with b-agonists 541 intravenous administration 540 mechanism of action 731 mediator inhibition 536–537 molecular mechanisms of action 535, 535–537 nocturnal asthma 541 oral administration 540 pharmacokinetics 539–540 phosphodiesterase inhibition 535–536, 536, 648–649 pulmonary hypertension treatment 190 routes of administration 540 side-effects 541–542, 681 smooth muscle remodeling reduced 74 thiobarbituric acid reactive substances (TBARS) 248, 250 elevation in COPD 250 thiol proteinases see cysteine (thiol) proteinases thioredoxin, regulation of redox signaling pathway 246 thrombin 141, 170 fibroblast migration/proliferation stimulation 141 thromboxane (Tx) 221 in asthma 351 half-life 222 inhibitors 568 receptor, terminology 221 thromboxane A2 223 acetylcholine release 223 bronchoconstriction mechanisms 223 functions/actions 223 mimetic (U46619) 223 smooth muscle constriction 223 thromboxane B2 223 thyroid hormones 337 effect on airway function 337 tianeptine 293, 568 tidal breathing method 704 Tiffeneau index (FEV1:FVC ratio) 8, 714, 715 timolol 440 tiotropium 528, 529, 643 tissue inhibitors of metalloproteinase (TIMP) 268, 276–277 synthesis by fibroblasts 140 TIMP-1 276, 277 elevated in status asthmaticus 280 elevation in asthma 280 TIMP-2 276, 277, 280 TIMP-3 276
TIMP-4 276 tissue kallikreins 237 inhibitors 240 synthesis, asthma 239 T lymphocytes see T cells Toll-like receptors (TLR) 100 functions 100 TLR2 100 TLR6 100 total lung capacity (TLC), asthma 52 total lung resistance 46 asthma 47 bronchodilator response in COPD 44 COPD 47 increase, causes 46 toxic particles/gases see air pollution; particulates, exposure toxins, inhaled, COPD pathogenesis 370 trachea, cartilage rings 44 tracheobronchial circulation 177–182 airway mucosal blood flow in asthma 178, 180 drugs influencing 180, 180 asthma 350–351 acute vascular responses 178 blood flow increase, effect on drug/mediator uptake 179 blood flow regulation 178 drugs affecting 180, 180–181 increase in asthma 178, 350 vasoconstrictors and vasodilators affecting 178 chronic responses 178–179 chronic bronchitis and emphysema 179 vessel formation in asthma 179 functional consequences of changes 179 microvascular hyperpermeability (asthma) 178, 196, 350–351 mucosal thickness 179 subepithelial (mucosal) blood flow 177 therapeutic approaches 179–181 vasculature 177, 177–178 see also bronchial circulation transcription factors 315–321 activation 316 by reactive oxygen species 246, 250 asthma 316, 316–319, 348, 352, 352 common to various cell types 316 COPD 319–320 clinical manifestations 320 disease susceptibility 319–320 cross-talk 316, 317 functions 315 glucocorticoid action 318–319 inhibitors anti-inflammatory agents 649–650 cyclosporin A and tacrolimus 650 modulation of inflammatory genes 316, 317 as nuclear messengers 316 selective actions 315
Index
structural characteristics 315–316 Th1/Th2 cell differentiation 316–317 see also AP-1 transcription factor; NF-jB transforming growth factor alpha (TGF-a) expression by lung epithelium 71 function 104, 286 overexpression in animals 286 transforming growth factor beta (TGFb) 69, 286–287 airway remodeling 287, 372 COPD pathogenesis 369, 372 distribution 140–141 expression/release in airways 283 by eosinophils 268 by epithelial cells 147 by macrophage 186 fibroblast migration stimulation 140–141 fibrosis association 69, 70, 287, 372 idiopathic pulmonary 284 functions 70, 104, 286 increased expression 70 asthma and COPD 141, 283 chronic bronchitis 269 isoforms 286 lung maintenance role 185 profibrotic effects 69, 70, 286, 372 receptors 286 sources and effects 265 as tumor suppressor 186 wound repair mediated 149 transgenic animals growth factor action 287–288 inflammatory mediator role in remodeling 70 transgenic mice IL-5 expression, eosinophil role 81 matrix degrading proteinases in emphysema 278 MMP-1 overexpression 278 overexpression of IL-13 and IFN-c 278 transient wheezing of infancy 20, 21 Transition Dyspnea Index (TDI) 483 transmission disequilibrium testing 32, 33 transplantation see lung transplantation transtracheal catheters, oxygen therapy 593 treatment guidelines 657–658 treatment of asthma see management of asthma treatment of COPD see management of COPD triamcinolone acetonide 559 triggers, of asthma/COPD 383–444 acute exacerbations of asthma 691 aggravating factors in chronic asthma 683 allergens 383–393 atmospheric pollutants 431–437
COPD exacerbation triggers 728, 729–730 drugs 439–443 exercise 421–429 infections see infections occupational agents 395–406 see also individual conditions/triggers trimellitic anhydride 395 trimethoprim–sulfamethoxazole, COPD exacerbation 580 tropoelastin 212 tryptase 274–275 bronchoconstriction association 279, 279–280 inhibitors 160, 280, 647 levels, COPD 95 mast cells 94, 280 released by mast cells and basophils 94 smooth muscle proliferation 280 tumor necrosis factor-a (TNF-a) 124 a*1/2 alleles 36 airway epithelial cells stimulation 246 airway remodeling and fibrosis 284 angiogenesis in asthma 268 cachexia association 373 cells producing 264, 268 in COPD 268–269, 369 exhaled breath 460 functions 264, 268, 284 in viral infections 410 increased in asthma 283, 348 inflammation increased in asthma 284 inhibitors infliximab 645 soluble TNF-receptors (etanercept) 645 theophylline 536–537 intraperitoneal injections (animal) 369 polymorphism 36, 268 COPD 320 reactive oxygen/nitrogen species formation 246 receptors (TNF-R) 124 regulation of lymphocyte activation in lung 124 structure 284 synthesis 284 TNF-308 polymorphism 36, 268 tunnel workers 401, 402 Turbuhaler DPI device 706 twin studies childhood asthma 700 dizygotic/monozygotic 30–31 lung function 30 tyrosine kinase inhibitors 650 tyrosine residues, eosinophil-induced damage by 247 U U46619 (thromboxane A2 mimetic) 223 UCSD Shortness of Breath Questionnaire 483
779
underdiagnosis, COPD 10 underweight, COPD 424 United States, asthma/COPD incidence 8, 15 urodilatin 335, 643 urotensin II 336 V vaccines/vaccination COPD exacerbation prevention 733 COPD management 717 Haemophilus influenzae vaccines 635 immunostimulatory DNA sequences 652 influenza vaccines see influenza, vaccination OM-85 BV (Broncho-Vaxom) 635 pneumococcal vaccines see pneumococcal vaccines specific allergens (desensitization) 652 virus infection prevention 415–416 vagal reflex, bradykinin-induced bronchoconstriction 240 vagal tone asthma 329 COPD 44, 46 vagus nerve 324 vascular cell adhesion molecule 1 (VCAM-1) 204 expression by airway smooth muscle cells 172 by endothelial cells 345 regulation by NF-jB 317–318 virus-induced 410 leucocyte homing 205–206 vascular changes, airway remodeling 73–74 vascular endothelial growth factor (VEGF) absence, endothelial cell apoptosis 371 airway remodeling 74 decreased levels in emphysema 185 endothelial cell apoptosis and 186 receptor II (KDR), inhibition 186 vascular permeability increased in asthma 178, 350–351 kinin generation and 237 mediators, drugs inhibiting release 198 vascular responses see pulmonary blood vessels; tracheobronchial circulation vascular smooth muscle platelet activating factor effect 297 proliferation, PI3K pathway 171 vasoactive intestinal polypeptide (VIP) 323–324, 331 asthma 351 COPD 369 functions/actions 331, 351 neurotransmitter for i-NANC nerves 330, 331 vasoactive peptides 334–336
780
Index
vasoactive peptides—cont catecholamines (circulating) 334–335 vasoconstriction, hypoxic vs nonhypoxic 184 vasoconstrictors, tracheobronchial blood flow regulation 178 vasodilatation albuterol action 180, 180 asthma 178 histamine causing 291 vasodilators, pulmonary 605–609 tracheobronchial blood flow regulation 178 usage guidelines 607–608 VCAM-1 see vascular cell adhesion molecule 1 (VCAM-1) venous blood flow, bronchial tree 58 ventilation–blood flow imbalance 49, 50, 51 ventilation/perfusion inequality see V/Q mismatch ventilator support 611–616 acute asthma management 695 ancillary therapy 613–614 metered-dose inhaler 613, 613 neuromuscular blocking agents 614 assist-control ventilation 611 barotrauma 614 cardiac output effects 614 complications 614 controlled ventilation 611 COPD exacerbation management 732, 732 –733 indications 611 infection 614 intermittent mandatory ventilation 611 invasive positive pressure ventilation 611–612 modes of mechanical ventilation 611–612 comparison 612, 612 non-invasive positive pressure ventilation 615, 695 pathophysiology of weaning failure 614 positive end-expiratory pressure see positive end-expiratory pressure (PEEP) pressure support ventilation 612 timing of weaning process 614 ventilator settings 612–613 fractional inspired oxygen concentration (FIO2) 612 inspiratory flow rate 613 permissive hypercapnia (controlled hypoventilation) 613 respiratory rate 613 tidal volume 613
trigger sensitivity 612–613 weaning 614 very late activation (VLA) antigens see VLA antigens vicious circle hypothesis, bacterial infections 578, 578 video questionnaire, asthma 7 viral infections 407 asthma trigger cellular response 411–413 effect on airway epithelial cells 409, 409–410 effect on airway smooth muscle 410–411 epidemiology 407 experimental infections 407–408 mechanisms 408, 408 CD8 T-cells role 127, 411 childhood asthma trigger 701 COPD etiology 362 COPD exacerbation 63, 414, 728, 729–730 evidence 415 inflammation 409–410 leukotriene B4 (LTB4) release 146 rhinoviruses see rhinovirus infections types 407 wheezing due to 20, 21, 407 see also individual virus infections vitamin C 416 vitronectin, receptors, integrin distribution in lung tissue 203 VLA antigens 120, 128 VLA-4 345 antibodies 205–206 humanized monoclonal antibodies 651 V/Q mismatch 49 acute asthma 693 bronchodilator effect 184, 188 COPD 184 exacerbation 730–731 pulmonary hypertension treatment in COPD 188 V/Q ratios 49 W water exchange, altered tracheobronchial circulation and 179 weakness, COPD 373, 620 management 721 weight loss, COPD 372–373, 373 western red cedar asthma 395, 396 wheezing acute asthma 692 adults, risk increased by bronchitis/pneumonia in children 25
asthma 23, 447 factors influencing, bronchial responsiveness in infants/children 26 history, asthma relapse in adulthood 23 IL-10 response to RSV infections and 24–25 impaired lung function in children 21 in infants see wheezy infants nonatopic 21, 21 patterns in infants/children, factors affecting 703, 703 prevalence 10 child phenotypes 20–21, 21 provocation concentration for (PCW) 704 remission in early life 20 RSV infection 20, 21, 24–25 transient, of infancy 20, 21 viral infections 20, 21, 407 wheezy infants 702–703 management 705, 706 transient 20, 21 Winnipeg Criteria 574 wood workers, COPD 401 World Health Organization (WHO) COPD prevalence prediction 10 disability definition 481 wound repair, epithelial 147–150, 148 X xanthine/xanthine oxidase reaction, reactive oxygen species formation 249 xenobiotics, metabolism, airway epithelial cell role 145 Y yoga, asthma 638 Z zafirlukast 230, 566, 643 chronic asthma management 680 chronic persistent asthma, clinical trials 231 Churg–Strauss syndrome 567 mechanism of action 297, 566, 643 zanamivir 416, 635 zileuton 230, 441 chronic persistent asthma, clinical trials 231, as 5-lipoxygenase inhibitor 566, 643–644 serum alanine-aminotransferase increases 566 zinc gluconate 416 zyleutin, chronic asthma management 680