Advances in Combination Therapy for Asthma and COPD E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 750

Veröffentlichungsjahr: 2011

Beschreibung

Aimed at specialists in respiratory medicine, this new book comprehensively reviews the variety of agents currently available for treatment of asthma, COPD, and other airway diseases and covers practical guidelines as well as challenges and complications in their use. Advances in Combination Therapy for Asthma and COPD is the first book to address the complexity of multi-agent therapy and deal with management issues in an integrated fashion.  A review of currently available agents and their applications, as well as new therapies soon to become available are outlined. Advantages of combined therapies and additional considerations that arise from multi-agent programs are highlighted.

Leseprobe

Contents

Cover

Title Page

Copyright

Contributors

Preface

Chapter 1: Similarities and differences in the pathophysiology of asthma and COPD

1.1 Introduction

1.2 Pulmonary function abnormalities in asthma and COPD

1.3 Risk factors for asthma and COPD

1.4 Cellular inflammation in asthma and COPD

1.5 Distribution and consequences of inflammation in asthma and COPD

1.6 Patterns of epithelial injury in asthma and COPD

1.7 Airway hyperresponsiveness

1.8 Beta-receptor blockers

1.9 Differential diagnosis of asthma and COPD

1.10 Overlap syndrome

1.11 Conclusion

Chapter 2: Glucocorticoids: pharmacology and mechanisms

2.1 Introduction

2.2 Chemical structures

2.3 The molecular basis of inflammation

2.4 Cellular effects of glucocorticoids

2.5 Glucocorticoid receptors

2.6 Glucocorticoid activation of gene transcription

2.7 Suppression of inflammatory genes

2.8 Steroid resistance

2.9 Interaction with β2-adrenergic receptors

2.10 Conclusions

Chapter 3: Inhaled corticosteroids: clinical effects in asthma and COPD

3.1 Introduction

3.2 Anti-inflammatory activity of corticosteroids

3.3 Routes of administration

3.4 Absorption and fate of corticosteroids

3.5 Currently available inhaled corticosteroids

3.6 Efficacy in asthma

3.7 Efficacy in COPD

3.8 Side effects of ICS

3.9 Conclusions

Chapter 4: LABAs: pharmacology, mechanisms and interaction with anti-inflammatory treatments

4.1 Galenical forms of LABAs: formulations, isomers, enantiomers, diasteriomers and salts

4.2 Absolute and functional β2-adrenoceptor selectivity

4.3 Cellular organization of receptor clusters: functional structure of the β2-adrenoceptor and mode of signalling

4.4 Dimers and oligomers: homo- and heterodimerism/oligomerism

4.5 Pharmacogenomics of the β2-adrenoceptor and adenylate cyclase polymorphism in relation to LABAs

4.6 Understanding the ‘reassertion’ paradox, ‘exosites’ and relative speed of onset: the membrane diffusion microkinetic model of LABA action

4.7 Regulation and desensitization

4.8 Full versus partial agonism (pharmacological efficacy)

4.9 Beta-blockers not LABAs?

4.10 Non-receptor-mediated effects?

4.11 Biochemical basis of functional antagonism and its critical role in LABA action in disease and exacerbations

4.12 Molecular cooperativity between LABAs and steroids

4.13 Perspective

Chapter 5: Long- and ultra-long-acting β2-agonists

5.1 Introduction

5.2 Long-acting β2-agonists

5.3 Novel ultra-long-acting β2-agonists

5.4 Conclusion

Chapter 6: The safety of long-acting beta-agonists and the development of combination therapies for asthma and COPD

6.1 Introduction

6.2 Asthma-related mortality and beta-agonist exposure

6.3 Long-acting beta-agonists and increased asthma-related mortality

6.4 Safety and efficacy of LABA therapy in asthma: retrospective analyses

6.5 Efficacy of LABA therapy as a component of combination therapy with ICS for the management of asthma

6.6 Scientific basis of the beneficial and adverse effects of beta-agonist therapy: in vitro data and the beta-agonist paradox

6.7 Conclusions regarding the safety of LABA therapy as a component of combination therapy with ICS for the management of asthma

6.8 Beta-agonist therapy and adverse events in COPD

6.9 Safety and efficacy of LABA therapy in the management of COPD: the clinical evidence

6.10 Role of LABA therapy as a component of combination therapy with ICS for the management of COPD

6.11 Conclusions regarding the safety of LABA therapy as a component of combination therapy for the management of COPD

6.12 Pharmacogenetics of LABAs and combination therapy

6.13 Safety and efficacy of LABA therapy and the development of combination therapies for the management of asthma and COPD

6.14 Summary and future directions

Acknowledgement

Chapter 7: Inhaled combination therapy with glucocorticoids and long-acting β2-agonists in asthma and COPD, current and future perspectives

7.1 Pharmacological management guidelines of asthma and COPD

7.2 Steroid treatment in asthma

7.3 Effects of adding LABA to inhaled glucocorticoids in asthma

7.4 Steroid treatment in COPD

7.5 Effects of LABAs in COPD

7.6 Combination inhalers versus two separate inhalers for inhaled GCS and LABAs

7.7 Regular treatment alone versus additional formoterol-containing combinations as reliever therapy

7.8 Currently available combination inhalers

7.9 Upcoming and alternative combinations of inhaled GCS and LABAs

7.10 Future of combined inhalation therapy in respiratory disease

Chapter 8: Novel anti-inflammatory treatments for asthma and COPD

8.1 Introduction

8.2 Current asthma and COPD therapies

8.3 The need for new therapies

8.4 Improving current therapies

8.5 Targeting chemokines and their receptors in asthma and COPD

8.6 Targeting T-cell-derived and proinflammatory cytokines in asthma and COPD

8.7 Targeting adhesion molecules in asthma and COPD

8.8 Growth factor blockers in asthma and COPD

8.9 Mucous cells, submucosal glands and mucus production in asthma and COPD

8.10 Infections in asthma and COPD

8.11 Intracellular signalling pathways

8.12 Inhibition of transcription factors in asthma and COPD

8.13 Antioxidants in asthma and COPD

8.14 Immunomodulation and anti-allergy treatments in asthma and COPD

8.15 Conclusions

Acknowledgements

Chapter 9: Novel biologicals alone and in combination in asthma and allergy

9.1 Introduction

9.2 Targets of therapy

9.3 Interleukin-4

9.4 Interleukin-5

9.5 Interleukin-13

9.6 Tumor necrosis factor-α

9.7 Immunoglobulin E

9.8 DNA vaccines

9.9 Future directions

9.10 Conclusion

Chapter 10: Anti-infective treatments in asthma and COPD

10.1 Introduction

10.2 Current guidelines

10.3 Acute exacerbations of asthma

10.4 Increased susceptibility to infection in asthmatics

10.5 Role of atypical bacteria in asthma

10.6 Role of viruses in asthma exacerbations

10.7 Anti-infectives in COPD exacerbations

10.8 Use of antibiotics in stable COPD

10.9 Role of vaccination

10.10 Conclusion

Chapter 11: Long-acting muscarinic antagonists in asthma and COPD

11.1 Introduction

11.2 Innervation of the airways

11.3 Cholinergic mechanisms in asthma and COPD

11.4 Role of long-acting anticholinergic bronchodilators in obstructive lung disease

11.5 Summary

Chapter 12: Phosphodiesterase inhibitors in obstructive lung disease

12.1 Introduction

12.2 Phosphodiesterase enzymes

12.3 Different pharmacological agents blocking PDE4

12.4 Biological effects of PDE4 inhibition, preclinical information

12.5 Clinical effects of PDE4 inhibition in COPD

12.6 Effects of PDE4 inhibitors on systemic processes in COPD

12.7 Side effects of PDE4 inhibitors

12.8 PDE4 inhibitors in COPD management plans

12.9 Future prospects with PDE4 inhibitors in obstructive airways disease

12.10 Summary

Chapter 13: Biological therapies in development for COPD

13.1 Introduction

13.2 Inflammatory cells involved in the pathogenesis of COPD

13.3 Cytokines and chemokines in COPD

13.4 Development of biological agents in COPD

13.5 Conclusions

Chapter 14: ‘Triple therapy’ in the management of COPD: inhaled steroid, long-acting anticholinergic and long-acting β2-agonist

14.1 Introduction

14.2 Long-acting inhaled anticholinergic (LAMA) and β2-agonist (LABA) bronchodilators

14.3 Treatment strategies for COPD

14.4 Inhaled corticosteroids and COPD

14.5 Combination treatment with ICS, LAMA and LABA: ‘triple therapy’

14.6 Extracted data from TORCH and UPLIFT studies

14.7 Conclusions

Index

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Library of Congress Cataloguing-in-Publication Data

Advances in combination therapy for asthma and COPD / [edited by] Jan Lötvall, William Busse. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-72702-7 (cloth) 1. Lungs–Diseases, Obstructive–Chemotherapy. 2. Asthma–Chemotherapy. 3. Polypharmacy. 4. Chemotherapy, Combination. I. Lötvall, Jan. II. Busse, W. W. (William W.) [DNLM: 1. Asthma–drug therapy. 2. Drug Therapy, Combination. 3. Pulmonary Disease, Chronic Obstructive–drug therapy. WF 553] RC776.O3A33 2011 616.2′3061–dc23 2011023057

A catalogue record for this book is available from the British Library.

This book is published in the following electronic format: ePDF: 9781119998631; WileyOnline Library: 9781119998624; epub: 9781119978466; Mobi: 9781119978473

Contributors

Ian M. Adcock Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK Gary P. Anderson Lung Disease Research Group, Departments of Pharmacology and Medicine, University of Melbourne, Parkville, Australia Peter J Barnes Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK Eugene R. Bleecker Wake Forest University Health Sciences, Center for Human Genomics and Personalized Medicine, Medical Center Boulevard, USA William W. Busse Division of Allergy and Immunology, Department of Medicine, University of Wisconsin, Madison, USA Gaetano Caramori Centre of Research on Asthma and COPD, University of Ferrara, Ferrara, Italy Mario Cazzola Unit of Respiratory Diseases, Department of Internal Medicine, University of Rome ‘Tor Vergata’, Rome, Italy K. Fan Chung Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK Ronald Dahl Department of Respiratory Diseases, Aarhus University Hospital, Denmark Sebastian L. Johnston Department of Respiratory Medicine, National Heart and Lung Institute, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK Paul A. Kirkham Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK Jan Lötvall Krefting Research Centre, University of Gothenburg, Göteborg, Sweden M. Diane Lougheed Department of Medicine, Division of Respirology, Queen's University, Ontario, Canada Bo Lundbäck Krefting Research Centre, University of Gothenburg, Sweden Jonathan D.R. Macintyre Department of Respiratory Medicine, National Heart and Lung Institute, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK Maria Gabriella Matera Unit of Pharmacology, Department of Experimental Medicine, Second University of Naples, Naples, Italy J. Morjaria Department of Infection, Inflammation and Repair, University of Southampton, Southampton, UK Desmond M. Murphy McMaster University Medical Center, Ontario, Canada Sharmilee M. Nyenhuis Division of Allergy and Immunology, Department of Medicine, University of Wisconsin, Madison, USA Paul M. O’Byrne McMaster University Medical Center, Ontario, Canada Denis E. O’Donnell Department of Medicine, Division of Respirology, Queen's University, Ontario, Canada Josuel Ora Clinical Research Fellow, Respiratory Investigation Unit, Kingston General Hospital and Queen's University, Ontario, Canada Victor E. Ortega Wake Forest University Health Sciences, Center for Human Genomics and Personalized Medicine, Medical Center Boulevard, USA Riccardo Polosa Ospedale Santa Marta, U.O.C di Medicina Interna e Medicina d’Urgenza, Catania, Italy J. Christian Virchow Department of Pneumology / Intensive Care Medicine Klinik I / Zentrum für Innere Medizin Universitätsklinikum, Rostok, Germany

Preface

The management of both asthma and COPD has improved substantially over the last 25 years, with the introduction of new inhaled therapies, primarily through local treatment with inhaled glucocorticoids and long-acting beta-2-agonists as well as long-acting anti-cholinergic drugs. Despite this improvement, evidence argues that there are extensive unmet needs in both disease groups, and further development of management is needed. In recent years, a substantial number of new medicines are being developed, and many of those are due to become clinically available shortly. For example, new once daily long-acting beta-2-agonists have become available for the treatment of obstructive lung disease. Furthermore, a series of combination products that have the potential to have advantages to current therapies are in different stages of development. The specific mechanisms by which these therapies function, how the components affect disease processes, and how these drugs can interact, are discussed in detail in the different chapters of this book.

In parallel with progress being made in older classes of drugs for asthma and COPD, totally new drugs are being developed as we are learning more and more about mechanisms of these diseases. Thus, a vast number of biological compounds, targeting specific processes within the immune system, are currently being developed for both diseases. These are especially exciting, as they may have the capacity to fundamentally stop specific disease processes.

This book is suitable for any clinician or scientist interested in mechanisms of COPD and/or asthma, and principles by which these diseases can be managed in both the short- and long-term future. It is suitable both as a reference, and as an inspiration for future research and management.

Finally, I wish to thank all the authors of the chapters in the book for having believed in the project, and for having authored their respective sections very professionally. Every author is an undisputed leader in his respective field, and this work would not have been possible without their strong commitment. I also wish to thank the project manager of the book, Mr Jonathan Gregory, who has been very supportive during its development.

Jan Lötvall Editor

1

Similarities and differences in the pathophysiology of asthma and COPD

J. Christian Virchow

Department of Pneumology, University Medical Clinic, Rostock, Germany

1.1 Introduction

In the early 1960s, when pulmonary function testing was limited to spirometry, a hypothesis was put forward that pulmonary diseases with similar clinical symptoms and spirometry findings such as asthma, chronic bronchitis and emphysema might be different expressions of one disease entity, in which both endogenous (host) and exogenous (environmental) factors would play a role in the pathogenesis.1 More refined diagnostic tools such as bodyplethysmography or helium-based pulmonary function analysis, which can measure pulmonary hyperinflation, were not available at that time. Pathophysiological as well as immunological characteristics of asthma such as IgE, mast cells and their mediators, leukotrienes, T-cell subsets, cytokines and chemokines had not been discovered. Still, the proposal that asthma, chronic obstructive pulmonary disease (COPD) and chronic bronchitis or emphysema might have a common pathogenic background has been repeated,2 and even now there is some debate about whether asthma and COPD should be regarded as:

two different diseases in one lung;two diseases with one common pathogenesis; orone disease with different clinical phenotypes.

These hypotheses reflect some of the clinical uncertainties that can arise when end-stage COPD and bronchial asthma have to be distinguished based on spirometry and clinical findings alone. This can be especially challenging in patients who smoke on top of an atopic background.

Epidemiological, genetic and pathophysiological data collected in the past 50 years, however, allow a relatively clear separation of COPD and asthma into rather distinct entities. These findings, which will be summarized below, make a common pathogenic origin for bronchial asthma and COPD most unlikely.

Among the epidemiological features that can separate asthma from COPD are differences in the age of onset,3,4 different risk factors5–10 and comorbidities,11–16 differences in the genetic background17–20 and differences in prognosis. While asthma is generally associated with a normal life expectancy, this is significantly reduced in COPD. Furthermore, marked differences in inflammatory cells and mediators21,22 present in the airways and lungs result in different patterns of inflammation and their intrabronchial and intrapulmonary distribution. As a consequence of these there are distinctly different features in the respective impairment of pulmonary function, different responses to airway irritants in bronchoprovocation tests,23,24 as well as marked differences in response to treatment and a different prognosis. These will be discussed in more detail below:

The clinical hallmark of asthma is episodic symptoms related to airflow limitation, often in response to external specific (allergen) or non-specific (airway irritants) factors. The characteristic feature of COPD in industrialized countries (which is also its main risk factor) is the long-term exposure to inhaled tobacco smoke or biomass combustion (the latter being more relevant to developing countries).

Asthma and COPD can sometimes be difficult to separate due to similarities in reported symptoms, airflow limitation and response to treatment. While individual patients may occasionally evade a clear separation into either asthma or COPD these patients are more likely an exception than the rule. These are often patients with asthma who have a longstanding smoking history or patients with a smoking history who develop intrinsic asthma. However, they do not support the hypothesis of a common pathogenetic origin or common pathogenetic pathways. The fact that end-stage asthma and COPD can display a number of pathophysiological similarities rather reflects the fact that the lung and its airways have a limited spectrum of responses to endogenous or exogenously induced inflammation irrespective of the origin of the insult. It would be unscientific to understand this limited spectrum of reactions, however, as evidence for a common pathogenesis. In an analogy, while end-stage fibrosing lung disease can appear with similar symptoms and even histopathology, irrespective of the underlying interstitial lung disease and the causative agents, a common pathogenesis is not suspected.

Accordingly, the so-called Dutch hypothesis from 1961 has been refuted in the past decades due to increasing knowledge about the underlying inflammatory processes in asthma and more recently in COPD.

From a clinical perspective, early stages of asthma as well as COPD can be differentiated based on patients’ history and clinical, laboratory and pulmonary function findings (Table 1.1).

Table 1.1 Typical clinical features of COPD.

FeatureAsthmaCOPDAge of onsetChildhood/adolescence>40 yearsSmoking history prior to onsetRareCommonNocturnal symptomsCommonRareDyspnoeaVariableOn exertionAllergyCommonRareCourseVariableProgressiveAirflow obstructionVariableFixedFEV1 reversibilityGood, >20%Limited, <20%Airway hyperresponsivenessCharacteristic featureOccasionallyResponse to corticosteroids+++(+)Sputum production++ to +++ FEV1, forced expiratory volume in 1 second.

It should be noted that none of the clinical features on its own clearly distinguishes asthma from COPD. Recent studies indicate that the forced expiratory volume in 1 second (FEV1)-reversibility to large doses of brochodilators in COPD can change over time,25 possibly to a degree indistinguishable from bronchial asthma. Nevertheless, in severe COPD pulmonary function abnormalities are usually not responsive to β2-agonists and/or corticosteroids and the absolute magnitude of response still differs.

Therefore, with increasing

smoking historyirreversibility of the airflow obstructionagedyspnoea on exertionPaco2comorbidities such as coronary heart disease, arteriosclerosis, depression, osteoporosis, etc.

there is a rise in the likelihood that the patient has COPD.

1.2 Pulmonary function abnormalities in asthma and COPD

Pulmonary function abnormalities in asthma and COPD can be very similar. Both are characterized by airflow obstruction but careful analysis can reveal noticeable differences in pulmonary function testing that help to differentiate asthma from COPD (Table 1.2).

Table 1.2 Pulmonary function abnormalities in asthma and COPD.

AbnormalityAsthmaCOPDSite of airflow obstructionCentral airwaysPeripheral airwaysReversibilityFrom +++ to +From + to ++HyperinflationFrom + to ++ (dynamic)From +++ to ++ (largely fixed)Airflow obstruction increases in response to hyperinflation++++Airway resistanceInspiratory and expiratory ++Expiratory ≫ than inspiratory (expiratory airway collapse)Hypercapnic respiratory failureOnly in severe, acute asthma attacksChronic hypercapnic failure possibleAirway hyperresponsivenessCharacteristic – direct and indirect stimuliNot uniformly present – only direct stimuliDiffusion capacityNot impairedReduced

Site of airflow obstruction

In asthma the site of the predominant airflow obstruction is usually located in the central airways. During severe attacks or in severe cases peripheral airways are also affected. In asthma, airway wall thickening due to airway remodelling increases with asthma severity and contributes to fixed airflow obstruction.26

Airflow obstruction in COPD, however, especially when associated with emphysema, is usually located in the peripheral airways. One of the mechanisms responsible for airflow obstruction in COPD is a dynamic collapse of the small airways during expiration due to an increase in intrathoracic pressure.27 Central airway obstruction in COPD is also caused by airway collapse due to tracheobronchial instability.

Bronchodilator response

In addition, the responses to bronchodilators in COPD and asthma differ, although this has been partially challenged by recent data.25 Asthma is usually associated with a good response to bronchodilators, which can cause a complete reversibility to normal values of airflow obstruction. This is limited, however, in severe and/or longstanding cases. In COPD the administration of high doses of bronchodilators has been associated with an unpredictable variability in airflow obstruction.25 However, this variability less pronounced than in asthma and more closely related to pulmonary hyperinflation. Airway resistance, as measured by bodyplethysmography, is usually evenly distributed between inspiration and expiration in asthma while in COPD airflow resistance is usually more pronounced during expiration, due to hyperinflation and expiratory airway collapse.

Arterial CO2 tension (PaCO2)

Patients with asthma, even during episodes of symptomatic airway obstruction, rarely display hypercapnic respiratory failure. Instead, low to hypocapnic PaCO2 values are characteristic for asthma. Elevated PaCO2 levels during symptomatic asthma attacks are indicators of impending respiratory arrest. In contrast, in COPD elevated PaCO2 levels and chronic hypercapnic respiratory failure are common in more severe cases due to chronic fatigue of the respiratory pump.

Diffusion capacity

Diffusion capacity for carbon monoxide (DLCO) is rarely if ever impaired in asthma. In COPD, however, a reduction in the diffusion capacity is a typical finding and useful to separate COPD from asthma.

Overlap between asthma and COPD

There is little doubt that asthma can present with features of COPD such as poorly reversible airflow obstruction, and COPD can display a marked reversibility in airflow obstruction. Yet, asthma and COPD are unlikely to represent different ends of a spectrum of similar diseases just because of similar pulmonary function abnormalities that are shared with other acute or chronic lung diseases such as cystic fibrosis, post-tuberculosis-syndromes, end-stage sarcoidosis or bronchiolitis. Neither the fact that some patients with asthma can have a progressive course nor the observation that some patients with COPD can have a marked reversibility of their airflow obstruction are suggestive of pathogenic similarities. It appears likely, however, that patients with asthma who smoke can develop features of COPD in addition to their asthma. Their asthma is usually more severe and responds less well to corticosteroids.28 These patients have not been studied in detail, and a clinical separation into asthmatic and COPD-related contributions to individual cases’ symptoms is difficult.

Table 1.3 Asthma or COPD?

AsthmaCOPDSymptomsEpisodicLittle variability in symptomsAge of onsetChildhood/adolescence>40 years of ageFirst episodeUsually dramaticSlowly progressive/unnoticedPrognosisGood; usually little or no progressLimited – chronic progressiveTreatmentGood response to glucocorticosteroidsLittle response

1.3 Risk factors for asthma and COPD

Genetic

A large number of loci and genes with polymorphisms have been identified as possible susceptibility genes for asthma or special features of asthma such as bronchial hyperresponsiveness.29 Many of these include genes for mediators and/or receptors associated with atopy such as interleukin-4 (IL-4), IL-13 and others.

In contrast, one of the models for COPD that is associated with a single-gene background is the hereditary alpha-1-antiproteinase deficiency. Whether genetic polymorphisms in other genes encoding for antiproteases or proteases are also linked to COPD pathogenesis is currently under investigation.30

However, there is little concordance between genetic risk factors for asthma and COPD, again suggesting that a common underlying pathogenesis is unlikely.

Environmental

Atopy has been identified as a major risk factor for asthma,31,32 and a large proportion of patients with asthma experience asthmatic symptoms after inhalation and/or ingestion of allergens. The direct effects of allergens on pulmonary function and symptoms can be demonstrated in challenge models such as inhaled or segmental allergen challenge33 (Figure 1.1). Accordingly, the prevalence for atopy is significantly increased in asthma (with the exception of intrinsic asthma) while there is no evidence for such an association in patients with COPD.22 Yet, the precise role of IgE-mediated allergic reactions in the pathogenesis of chronic asthma remains unclear. In contrast, there is no challenge model for COPD. The identified risk factor in the vast majority of cases in the Western world is the chronic inhalation of cigarette smoke.34

Figure 1.1 Endobronchial changes following segmental allergen challenge. Anterobasal segment of the right lower lobe. Left: Before allergen deposition; right: 5 minutes following allergen challenge. Mucosal oedema, bronchoconstriction and airway secretions can be seen within minutes following endobronchial allergen deposition. This is a feature specific for allergic asthma. Reproduced with permission from Virchow JC Jr, Walker C, Hafner D, Kortsik C, Werner P, Matthys H, and Kroegel C. T cells and cytokines in bronchoalveolar lavage fluid after segmental allergen provocation in atopic asthma, Am. J. Respir. Crit. Care Med. 1995;151:960–968, © American Thoracic Society.

Comorbidities for asthma and COPD

A positive family history for atopy or allergic diseases is a strong risk factor for asthma. Children with a positive family history for asthma who have atopic dermatitis have a high risk of developing asthma themselves. Typically, comorbidities in asthma are also risk factors and they often precede the onset of asthma in individual cases. Allergic rhinitis, atopic dermatitis and sinus disease frequently develop prior to the onset on asthma. A specific subset of patients with asthma, of which about two-thirds are of the intrinsic phenotype, also have an acquired sensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indometacin and others.35 The common mode of action of these drugs is the inhibition of cyclooxygenase I. In these patients ingestion, local application or inhalation of these drugs will result in severe asthma attacks. This acquired syndrome of intolerance against NSAIDs occurs on top of a persistent and progressive asthma. This syndrome, formerly termed aspirin-sensitive-asthma, or AIA, has therefore been labelled as aspirin-exacerbated respiratory disease (EARD).35 Intolerance to NSAIDs is not associated with COPD.

In contrast, in COPD comorbidities such as coronary heart disease, arteriosclerosis, depression and osteoporosis36,37 are also consequences of the main risk factor for COPD, namely smoking. There is still debate about whether or not they represent true comorbidities or rather concomitant diseases caused by the same risk factor. True comorbidities of COPD might be differences in risk-taking behaviour and factors associated with social status, both of which have been associated with smoking prevalence. In contrast to asthma there is no association with family history for COPD; the noteworthy exception is that the likelihood for smoking is increased in the offspring of parents who smoke. Whether this is merely a behavioural trait or evidence for a genetic transmission is still debated. Small birthweight (and possibly other susceptibility parameters) have also been associated with COPD.38 Involvement of the upper airways in COPD has not been studied in detail but appears to be substantially less compared to asthma. The reasons why only a proportion of smoking individuals will eventually develop COPD is still unclear.39,40 However, the proportion appears to be substantially higher than previously expected. The prevalence of atopy in patients with COPD is not increased.

Atopy as a risk factor for asthma: intrinsic asthma

Allergic asthma has been associated with the atopic phenotype. It is now clear that not all asthma is allergic,41,42 but many patients, especially of early onset, have elevated IgE concentrations and increased levels of specific IgE. While allergic mechanisms play an important role in acute asthma exacerbations following allergen exposure their role in the pathogenesis of chronic asthma is still unclear. In particular, in intrinsic asthma elevated IgE concentrations cannot be documented, and atopic mechanisms are not involved in the clinical picture of intrinsic asthma, which usually starts in adulthood and includes chronic nasal and sinus polyposis.

1.4 Cellular inflammation in asthma and COPD

Asthma

The pathogenesis of asthma has been associated with a number of inflammatory cells and mediators. The cells that are usually increased in peripheral blood, in sputum and in airway biopsies and that have been associated with asthma severity as well as response to corticosteroid treatment are eosinophils. These cells appear to be causally related to asthmatic inflammation and subsequent symptoms. Therapeutic approaches to reduce eosinophil numbers and/or function have been associated with improvements in asthma of different severity.43–45

Other cells present in increased numbers and increased activation status are cells associated with the atopic-allergic phenotype such as mast cells and basophils. Upon interaction of cell-bound allergen-specific IgE and allergen, mast cells and basophils release histamine and other bronchoactive mediators such as leukotrienes. Dendritic cells of the myeloid as well as the plasmacytoid phenotype46 infiltrate the airways following allergen challenge to orchestrate an immune response. Allergic as well as intrinsic asthma has been associated with an accumulation of activated T-cells of the T-helper cell phenotype, which can release a number of cytokines involved in asthmatic inflammation.33 In atopic patients there are increased concentrations of cytokines such as IL-4, IL-13 and IL-5. All have been shown to increase eosinophil survival but IL-5 appears to be the most potent cytokine to attract and activate eosinophils. IL-4 and IL-13 are released in response to allergen exposure and are involved in initiating and maintaining an IgE response. Interleukin-5 is crucial for eosinophil activation and survival and can be found in elevated concentrations in allergic as well as in intrinsic asthma.41 Recent studies suggest that effective blockade of IL-5 in asthma can result in improvement of clinically relevant outcomes such as a reduction in asthma exacerbations.44,45 Other mediators of relevance to the eosinophilia in asthma are CCL5 and eotaxin, and the leukotrienes C4, D4 and E4, which are released by a number of cells including mast cells and eosinophils. They are chemotactic for eosinophils and induce a long-lasting contraction of airway smooth muscle. Their pathogenetic role in asthma has been demonstrated by specific leukotriene receptor antagonists that block the CysLT1 receptor and reduce asthma-related symptoms such as airflow obstruction and asthma exacerbations.47,48

COPD

The cellular inflammation in COPD in contrast, is characterized by an increase in macrophages, neutrophils and dendritic cells, especially of the myeloid DC phenotype, which have a reduced expression of chemokine receptors required for the migration to regional lymph nodes.49

In addition, there appear to be increased numbers or percentages of CD8+ T-lymphocytes, termed Tc1-type cells. Their precise role has not been established and an exact phenotypic characterization of these cells and their precise function is still lacking. The increase in endobronchial neutrophils seen in a majority of patients with COPD has also been associated with COPD pathogenesis. Neutrophils can release elastase and other proteases that can irreversibly damage pulmonary structures leading to tissue degradation and pulmonary emphysema.

Mediators relatively uniquely expressed in COPD are leukotriene B4 (LTB4) and the chemokine CXCL-8 (interleukin-8) while bronchoconstrictory mediators such as histamine or cysteinyl-leukotrienes, which play a role in asthma pathophysiology, are not elevated in COPD.22 Eosinophils have been recovered mainly during COPD exacerbations but their responsiveness to corticosteroids differs. In stable COPD eosinophil numbers are usually not elevated.

1.5 Distribution and consequences of inflammation in asthma and COPD

Despite some crude similarities between asthma and COPD, the distribution of inflammation and its consequences are markedly different (Table 1.4).50 In asthma, histopathological examination of endobronchial biopsies reveals epithelial shedding, to which a number of mechanisms contribute. Collagen and myofibroblast deposition below the epithelium, which results in basement membrane thickening, has been described as a feature specific to asthmatic airways.51 In addition a marked hypertrophy of the smooth muscle layer of the airways can be observed in asthma, which has been related to the degree of airflow obstruction in asthma.52 Recently, neoangiogenesis in asthmatic airways has been described.53 Destruction of lung parenchyma and the development of emphysema is not a typical feature of asthma. In contrast to COPD, where mortality has been associated with COPD exacerbations,54 mortality in asthma has not been linked to the number of exacerbations but rather to the severity of asthma attacks.

Table 1.4 Epithelial injury in asthma and COPD.

AsthmaCOPDEpithelial fragility/sheddingSquamous cell metaplasiaCollagen deposition/basement membrane thickeningBronchiolar fibrosisHypertrophy/hyperplasia of the airway smooth muscle layerGlandular hypertrophyAngiogenesis

The airway epithelium in COPD is characterized by squamous cell metaplasia of the bronchial epithelium and a bronchiolar fibrosis,55 and the development of emphysema. Smooth muscle constriction or hypertrophy is not a feature of COPD. The inflammation in COPD is arranged in lymphocyte-containing follicles suggesting an adaptive immune response in the airways.56,57

Both asthma and COPD are characterized by submucosal gland hypertrophy, which can contribute to mucus production and airflow obstruction. The precise contribution of submucosal glands to the pathophysiology of asthma and COPD might be considerable but has been insufficiently studied.

1.6 Patterns of epithelial injury in asthma and COPD

Most of the changes described above in asthma can be observed predominantly in the more central airways, from where they can spread to more peripheral airways as observed in more severe asthma. However, COPD is located predominantly in the small airways, where destruction of lung parenchyma leading to pulmonary emphysema occurs (Table 1.5).55

Table 1.5 Distribution of airway inflammation in asthma and COPD.

AsthmaCOPDCentral airwaysSmall airwaysInvolvement of peripheral airways in severe asthmaDestruction of lung parenchyma, emphysema

1.7 Airway hyperresponsiveness

Airway hyperresponsiveness (AHR) to direct (e.g. histamine, methacholine) as well as indirect (adenosine, cold air, exercise) stimuli is a characteristic pathophysiological feature of asthma. Its pathogenesis in asthma is most likely multifactorial. Several features of asthma pathophysiology contribute to this hyperresponsiveness. These include structural changes to the airways, such as airway remodelling, which result in fixed airflow obstruction, but also inflammatory changes. Recently, the role of neurotrophins and their effects on neurogenic remodelling of the airways has been added to the mechanisms contributing to AHR.58 While inflammatory contributions to AHR can be reversible following treatment a complete loss of airway hyperresponsiveness in asthma is an uncommon event suggesting that the pathogenesis of AHR cannot be explained by inflammation alone. Airway hyperresponsiveness in asthma does not show a plateau effect to increasing doses of the respective stimulus. Thus, with increasing dose of stimulus the asthmatic airway will constrict further, which is characteristic neither for normal airways nor for airways in COPD.

In contrast to asthma, airway hyperresponsiveness in COPD is typically limited to direct stimuli such as histamine suggesting that the airway response in COPD is largely determined by airway calibre rather than an inflammatory bronchoconstriction.

1.8 Beta-receptor blockers

Asthmatic airways have a peculiar sensitivity to beta-receptor blockers. Exposure of patients with asthma even to low doses or even topical application can result in deterioration of asthma control and severe and long-lasting bronchospasm. The precise mechanisms responsible for this unique pathophysiological feature of asthma are incompletely understood but may be associated with postsynaptic regulation of neurotransmitter release in the airways. While bronchial asthma is a contraindication for beta-blockers their use in COPD is not associated with any deterioration of pulmonary function, again suggesting fundamental differences in asthma and COPD.

Furthermore, the chronic, unbalanced use of β2-agonists in asthma has been associated with a tachyphylaxis to the bronchoprotective effects of β2-agonists and possibly a loss in asthma control and an increase in asthma deaths.59 This has not been observed for COPD, where the bronchodilator response to β2-agonists is in general lower than in asthma but where chronic use of β2-agonists has not been associated with a loss of effect or a loss of control of COPD.

1.9 Differential diagnosis of asthma and COPD

The differential diagnosis of asthma and COPD include a large number of diseases such as:

gastro-oesophageal reflux disease;vocal-cord dysfunction syndrome;hyperventilation syndrome;pulmonary oedema;congestive heart failure;carcinoid syndrome;tumours that obstruct central airways;pneumothorax;tracheomalacia;bronchiolitis obliterans;recurrent pulmonary emboli;pulmonary vasculitis;collagen vascular diseases;Swyer-James syndrome, etc.

All of these can, however, also occur together with asthma or COPD, which can further complicate diagnostic accuracy.

However, the fact that end-stage lung disease in severe asthma or COPD can at times be clinically indistinguishable is determined by the possible pattern of response of the affected organ. Whether so-called neutrophilic asthma (in which neutrophils are the predominant inflammatory cell in the airways) represents a ‘burned out’ variant of chronic (severe) asthma where the asthma-specific cellular inflammation is replaced by a non-specific, neutrophil-dominated pathology is unclear and requires further studies. Similarly, the precise role of neutrophils in the ‘neutrophil-dominated’ pathology of COPD is uncertain. While neutrophils can contribute to parenchymal destruction with elastin-degrading enzymes their contribution to a COPD-specific inflammation is still unclear.

1.10 Overlap syndrome

It has been emphasized for a long time that there are a number of patients who are not reflected in clinical studies and who present with features of both COPD and asthma. This condition has been referred to as ‘overlap syndrome’, and it has been proposed that it can be recognized by the coexistence of increased variability of airflow in a patient with incompletely reversible airway obstruction.60 These patients may have either mild allergic asthma with a smoking history, or a longstanding asthma with progressive decline in pulmonary function, or have developed adult-onset, intrinsic asthma coexistent with a prior smoking history. Although inflammatory (neutrophils) and physiological features (smoking history, decline in pulmonary function, increasing age, recurrent exacerbations) in these patients can resemble classical COPD a prior history of asthma clearly contributes to their pathogenesis. Due to the fact that these patients are generally excluded from clinical trials, mainly based on their incomplete response to bronchodilators, the generalisibility from such trials to the general asthma (and COPD) population is limited.60 Whether the pathogenetic features of asthma and COPD actually converge60 in this population or whether different pathologies result in similar outcomes remains a controversial issue and will require future research. Increased attention to the course of bronchial asthma in relation to other chronic obstructive airway disease, especially in older people, is needed to improve care and subsequently prognosis with improved health outcomes.61

1.11 Conclusion

Despite the fact that asthma and COPD can at times present with similar symptoms and similar changes in pulmonary function there is little evidence suggesting a common pathogenesis. In some, usually those asthma patients who smoke or who have been smoking, the individual contribution of asthma and smoking to the signs and symptoms of the disease can be difficult to separate. Especially in older patients with longstanding asthma and loss of reversibility, separation from COPD can be difficult. This patient group has usually been omitted from clinical studies. Despite the fact that a considerable number of patients are affected by this condition it is not well represented in guidelines and the general physician's perception. One of the main differences between asthma and COPD today remains that asthma can be treated while COPD can be prevented. However, at present there is little evidence that asthma can be prevented, while the response of COPD to currently available therapy is limited. This calls for future research to address the long-term consequences of either disease in order to develop specific therapies with improved health outcomes for asthma as well as COPD.

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2

Glucocorticoids: pharmacology and mechanisms

Peter J. Barnes

National Heart and Lung Institute, Imperial College, London, UK

2.1 Introduction

Glucocorticoids (glucocorticosteroids or corticosteroids) are widely used to treat a variety of inflammatory and immune diseases. The most common use of glucocorticoids today is in the treatment of asthma and other allergic diseases, and inhaled glucocorticoids are now established as first-line treatment in adults and children with persistent asthma. Despite intense efforts by the pharmaceutical industry it has proved extraordinarily difficult to find any new treatment that comes close to the therapeutic benefit of glucocorticoids in asthma.1 This chapter focuses on the cellular and molecular mechanisms of glucocorticoids that are relevant to asthma and also discusses why they do not appear to work in some patients with asthma or in patients with chronic obstructive pulmonary disease (COPD). There have been major advances in understanding the molecular mechanisms whereby glucocorticoids suppress inflammation, based on recent developments in understanding the fundamental mechanisms of gene transcription.2,3 These advances have important clinical implications, as they will lead to a better understanding of the inflammatory mechanisms of many diseases and may lead to the development of new anti-inflammatory treatments in the future. The new understanding of these molecular mechanisms also helps to explain how glucocorticoids are able to switch off multiple inflammatory pathways, and it also provides insights into why glucocorticoids apparently fail to work in patients with steroid-resistant asthma and in patients with COPD.

2.2 Chemical structures

The adrenal cortex secretes cortisol (hydrocortisone) and, by modification of its structure, it was possible to develop derivatives, such as prednisolone and dexamethasone, with enhanced glucocorticoid effects but with reduced mineralocorticoid activity. These derivatives with potent glucocorticoid actions were effective in asthma when given systemically but had no anti-asthmatic activity when given by inhalation. Further substitution in the 17α ester position resulted in steroids with high topical activity, such as beclometasone dipropionate (BDP), triamcinolone, flunisolide, budesonide and fluticasone propionate, which are potent in the skin (dermal blanching test) and were later found to have significant anti-asthma effects when given by inhalation (Figure 2.1).

Figure 2.1 Chemical structures of inhaled corticosteroids.

2.3 The molecular basis of inflammation

Understanding the molecular mechanisms involved in asthmatic inflammation is necessary in order to understand how glucocorticoids so efficiently suppress airways inflammation in asthma. Patients with asthma and allergic rhinitis have a specific pattern of inflammation in the airways that is characterized by degranulated mast cells, infiltration of eosinophils and increased number of activated T-helper 2 (Th2 cells).4 Suppression of this inflammation by glucocorticoids controls and prevents these symptoms in the vast majority of patients. Multiple mediators are produced in allergic diseases, and the approximately 100 known inflammatory mediators that are increased include lipid mediators, inflammatory peptides, chemokines, cytokines and growth factors.5 There is increasing evidence that structural cells of the airways, such as epithelial cells, airway smooth muscle cells, endothelial cells and fibroblasts, are a major source of inflammatory mediators in asthma. Epithelial cells may play a particularly important role, as they may be activated by environmental signals and they may release multiple inflammatory proteins, including cytokines, chemokines, lipid mediators and growth factors.

Inflammation is mediated by the increased expression of multiple inflammatory proteins, including cytokines, chemokines, adhesion molecules, and inflammatory enzymes and receptors. Most of these inflammatory proteins are regulated by increased gene transcription, which is controlled by proinflammatory transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), that are activated in asthmatic cells.6 For example, NF-κB is markedly activated in epithelial cells of asthmatic patients, and this transcription factor regulates many of the inflammatory genes that are abnormally expressed in asthma. NF-κB may be activated by rhinovirus infection and allergen exposure, both of which exacerbate asthmatic inflammation.

Chromatin remodelling

Chromatin consists of DNA and basic proteins called histones, which provide the structural backbone of the chromosome. It has long been recognized that histones play a critical role in regulating the expression of genes and determine which genes are transcriptionally active and which ones are suppressed (silenced). The chromatin structure is highly organized as almost two metres of DNA have to be packed into each cell nucleus. Chromatin is made up of nucleosomes, which are particles consisting of 146 base pairs of DNA wound almost twice around an octamer of two molecules each of the core histone proteins H2A, H2B, H3 and H4.7 Expression and repression of genes is associated with remodelling of this chromatin structure by enzymatic modification of the core histone proteins, particularly by acetylation. Each core histone has a long N-terminal tail that is rich in lysine residues, which may become acetylated, thus changing the electrical charge of the core histone. In the resting cell DNA is wound tightly around core histones, excluding the binding of the enzyme RNA polymerase II, which activates gene transcription and the formation of messenger RNA. This conformation of the chromatin structure is described as closed and is associated with suppression of gene expression. Gene transcription only occurs when the chromatin structure is opened up, with unwinding of DNA so that RNA polymerase II and basal transcription complexes can now bind to DNA to initiate transcription.

Histone acetyltransferases and coactivators

When proinflammatory transcription factors, such as NF-κB and AP-1, are activated they bind to specific recognition sequences in DNA and subsequently interact with large coactivator molecules, such as cyclic adenosine monophosphate response element binding protein (CREB)-binding protein (CBP). These coactivator molecules act as the molecular switches that control gene transcription and all have intrinsic histone acetyltransferase (HAT) activity.7 This results in acetylation of core histones, thereby reducing their charge, which allows the chromatin structure to transform from the resting closed conformation to an activated open form. This results in unwinding of DNA, binding of TATA box binding protein (TBP), TBP-associated factors and RNA polymerase II, which then initiates gene transcription. This molecular mechanism is common to all genes, including those involved in differentiation, proliferation and activation of cells. Of course this process is reversible and deacetylation of acetylated histones is associated with gene silencing. This is mediated by histone deacetylases (HDACs), which act as corepressors, together with other corepressor proteins that are subsequently recruited.

These fundamental mechanisms have now been applied to understanding the regulation of inflammatory genes in diseases such as asthma and COPD.8,9 In a human epithelial cell line activation of NF-κB, by exposing the cell to inflammatory signals such as interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) or endotoxin, results in acetylation of specific lysine residues on histone H4 (the other histones do not appear to be so markedly or rapidly acetylated), and this is correlated with increased expression of genes encoding inflammatory proteins, such as granulocyte-macrophage colony stimulating factor (GM-CSF).10

Histone deacetylases and corepressors

The acetylation of histone that is associated with increased expression of inflammatory genes is counteracted by the activity of HDACs, of which 11 that deacetylate histones are now characterized.11,12 There is now evidence that the different HDACs target different patterns of acetylation.13 In biopsies from patients with asthma there is an increase in HAT and a reduction in HDAC activity, thereby favouring increased inflammatory gene expression.14 With this background it is now possible to understand better why glucocorticoids are so effective in suppressing this complex inflammatory process that involves the increased expression of multiple inflammatory proteins. HDACs act as corepressors in consort with other corepressor proteins, such as nuclear receptor corepressor (NCoR) and silencing mediator of the retinoid and thyroid hormone receptor (SMRT), forming a corepressor complex that silences gene expression.15

2.4 Cellular effects of glucocorticoids

Glucocorticoids are the only therapy that effectively suppresses the inflammation in asthmatic airways, and this underlies the clinical improvement in asthma symptoms and prevention of exacerbations. At a cellular level glucocorticoids reduce the numbers of inflammatory cells in the airways, including eosinophils, T-lymphocytes, mast cells and dendritic cells (Figure 2.2). These remarkable effects of glucocorticoids are produced through inhibiting the recruitment of inflammatory cells into the airway by suppressing the production of chemotactic mediators and adhesion molecules and by inhibiting the survival in the airways of inflammatory cells, such as eosinophils, T-lymphocytes and mast cells. Epithelial cells may be a major cellular target for inhaled glucocorticoids. Thus glucocorticoids have a broad spectrum of anti-inflammatory effects in asthma, with inhibition of multiple inflammatory mediators and inflammatory and structural cells. It is probably the broad anti-inflammatory profile of glucocorticoids that accounts for their marked clinical effectiveness in asthma. Attempts to find alternative treatments that are more specific, such as inhibitors of single mediators, have usually been unsuccessful, emphasizing the importance of simultaneously inhibiting many inflammatory targets. Any explanation of the anti-inflammatory effects of glucocorticoids needs to account for this broad spectrum of anti-inflammatory effects.

Figure 2.2 Cellular effects of glucocorticoids.

2.5 Glucocorticoid receptors

Glucocorticoids diffuse readily across cell membranes and bind to glucocorticoid receptors (GR) in the cytoplasm. Cytoplasmic GR are normally bound to proteins, known as molecular chaperones, such as heat shock protein-90 (HSP90) and FK-binding protein, that protect the receptor and prevent its nuclear localization by covering the sites on the receptor that are needed for transport across the nuclear membrane into the nucleus.16 There is a single gene encoding human GR but several variants are now recognized, as a result of transcript alternative splicing, and alternative translation initiation.17 The receptor GRα binds glucocorticoids whereas GRβ is an alternatively spliced form that binds to DNA but cannot be activated by glucocorticoids. GRβ has a very low level of expression compared to GRα. The GRβ isoform has been implicated in steroid-resistance in asthma, although whether GRβ can have any functional significance has been questioned in view of the very low levels of expression compared to GRα.18

Glucocorticoid receptors may also be modified by phosphorylation and other modifications, which may alter the response to glucocorticoids by affecting ligand binding, translocation to the nucleus, trans-activating efficacy, protein–protein interactions or recruitment of cofactors.19 For example, there are a number of serine/threonines in the N-terminal domain where glucocorticoid receptors may be phosphorylated by various kinases.

Once glucocorticoids have bound to GR, changes in the receptor structure result in dissociation of molecular chaperone proteins, thereby exposing nuclear localization signals. This results in rapid transport of the activated glucocorticoid receptor-glucocorticoid complex into the nucleus, where it binds to DNA at specific sequences in the promoter region of glucocorticoid-responsive genes known as glucocorticoid response elements (GRE). Two glucocorticoid receptor molecules bind together as a homodimer and bind to GRE, leading to changes in gene transcription. Interaction of GR with GRE classically leads to an increase in gene transcription (trans-activation), but negative GRE sites have also been described where binding of GR leads to gene suppression (cis-repression)20 (Figure 2.3). There are few well-documented examples of negative GREs, but some are relevant to glucocorticoid side effects, including genes that regulate the hypothalamic-pituitary axis (proopiomelanocortin and corticotrophin-releasing factor), bone metabolism (osteocalcin) and skin structure (keratins).

Figure 2.3