Asthma - Basic Mechanisms and Clinical Management

Cover

Contents

Preface

Foreword to the second edition

Contributors

Chapter 1. Epidemiology

Introduction

Diagnosis of asthma

Asthma in children

Factors influencing development of childhood asthma

Childhood asthma and AHR

Prognosis of childhood asthma

Asthma in adults

AHR in adults

Risk factors for adult asthma

Evidence for increasing severity of asthma

Mortality from asthma

Risk factors for asthma mortality

References

Chapter 2. Genetics

Introduction

Methods of finding disease genes in asthma

Problems in genetic studies of asthma

Modes of inheritance of atopy, BHR and asthma

Genetic studies of atopy and asthma

Genetic studies of BHR and asthma

Conclusion

References

Chapter 3. Airway Pathology in Asthma

Introduction

Sputum and bronchoalveolar lavage

Appearances at post-mortem

Loss of surface epithelium

Thickening of the epithelial 'basement membrane'

Increased numbers of mucus-secreting cells

Enlargement of bronchial smooth muscle mass

Bronchial vasculature, congestion and oedema

Recruitment of inflammatory cells

Airway wall nerves

Conclusions

Acknowledgements

References

Chapter 4. Physiology

Introduction

Factors restricting and amplifying induced airway narrowing in vivo

Sites of airway narrowing in asthma

Effects of posture and sleep on airway function

Response to increasing severity of airway narrowing

Conclusions

References

Chapter 5. Airway Smooth Muscle Cells: Structure and Function

Introduction

Morphology

Ion channels

Phosphatidylinositides and calcium

Physiological mechanisms

Conclusion

References

Chapter 6. Mast Cells and Basophils

Introduction

Mast cell heterogeneity

Mast cells. basophils and adhesion molecules

Distribution and morphology of human lung mast cells

BAL in extrinsic asthma

Immunologically induced mediator release

BAL mast cells steroid therapy in asthma

Antiasthmatic drugs and the inhibition of histamine release from pulmonary mast cells

Role of basophils in allergy and asthma

Role of mast cells in early asthmatic reactions

Role of mast cells in late asthmatic reactions and cytokine production

Acknowledgements

References

Chapter 7. Monocytes, Macrophages and Dendritic Cells

Introduction

Role of mononuclear phagocytes in inflammatory mechanisms of asthmatic disease

Changes in phenotype and function of monocytes and macrophages in asthma

Effects of glucocorticoids on monocyte/macrophage function

Conclusion

References

Chapter 8. Eosinophils

Introduction

Biochemistry and function

Receptors and degranulation

Mechanisms of eosinophil accumulation

The eosinophil in asthma

Monitoring of asthma by eosinophil markers

Pharmacological control of the eosinophil

Conclusions

References

Chapter 9. Lymphocytes

Introduction

Lymphocytes are strongly implicated in the pathogenesis of asthma

Overview of lymphocyte responses to inhaled foreign antigens

Perspective: defects in termination of immune responses may cause chronic disease

Acknowledgement

References

Chapter 10. Epithelial Cells

Introduction

Morphology of the airway epithelium

Airway epithelium and hyperresponsiveness

Epithelial cell-derived mediators

Adhesion molecules and the airway epithelium

Immunoregulation

Culture of human airway epithelial cells in vitro

Summary

References

Chapter 11. Pathophysiology of Airway Mucus Secretion in Asthma

Introduction

Airway mucus

Airway mucus-secreting cells

Mucus abnormalities in asthma

Consequences of airway mucus hypersecretion and hyperviscosity

Inducers of airway mucus secretion

Pharmacological treatment of mucus hypersecretion in asthma

Conclusions

Acknowledgements

References

Chapter 12. Tracheobronchial Circulation

Introduction

Organization and control of the tracheobronchial circulation

Role of the tracheobronchial circulation in asthma

Conclusion

References

Chapter 13. Adhesion Molecules

Introduction

Leucocyte adhesion receptors

Expression of adhesion receptors in allergic disease

Role of adhesion receptors in leucocyte migration in allergic disease

In vivo studies of adhesion receptor antagonists in models of allergic inflammation

Summary

References

Chapter 14. Microvascular-Epithelial Exudation of Plasma

Introduction

Exudation pathways

Acute challenge-induced microvascular-epithelial exudation

Mucosal exudation of plasma in disease

Roles of exuded plasma

On the inward perviousness in asthma

Airway epithelial restitution in a plasma-derived gel

References

Chapter 15. Prostaglandins and Thromboxane

Introduction

Arachidonic acid metabolism

Cyclooxygenase products

Prostaglandin and thromboxane receptors

Role of COX products in asthma

Stimulatory prostaglandins and thromboxane

Inhibitory prostaglandins

Conclusions

References

Chapter 16. Cysteinyl Leukotrienes

Introduction

Formation and metabilism of the leukotrienes

Leukotrienes in asthma

Conclusions

References

Chapter 17. Kinins

Introduction

Structure, formation and metabolism

Receptors and general pharmacological properties

Kinin formation in airway inflammation

Effects of kinins on airways

Mechanisms of action

Summary

Acknowledgements

References

Chapter 18. Chemokines

Introduction

Discovery and structure

Cell sources

Regulation

Chemokines as chemoattractants and cell activators

Chemokine receptors

Expression and release of chemokines in asthma

Conclusion

References

Chapter 19. Lymphokines

Introduction

Type 1 and type 2 T-cells

Actions of type 2 cytokines relevant to asthma

Evidence of T-cell cytokine production in asthma

T-cell cytokines in non-atopic asthma

Factors determining type 1 or type 2 T-cell development

Alteration of established type 1 or type 2 cytokine profile

Potential for intervention

Conclusion

References

Chapter 20. Other Mediators of Asthma

Introduction

Histamine

Platelet-activating factor

Oxygen radicals

Complement

Serotonin

Eosinophil proteins

Endothelin

References

Chapter 21. Nitric Oxide

Introduction

Generation of NO

Effects of NO on airway function

Exhaled NO

Therapeutic implications

References

Chapter 22. Neural Control of Airway Function in Asthma

Introduction

Afferent nerves

Parasympathetic nerves

Adrenergic control

References

Chapter 23. Humoral Control of Airway Tone

Introduction

Vasoactive peptides

Hormones

Circulating inflammatory mediators

Oxygen and carbon dioxide

Conclusions

References

Chapter 24. NANC Nerves and Neuropeptides

Introduction

Non-adrenergic non-cholinergic (NANC) nerves

VIP and related peptides

Tachykinins

CGRP

Neurogenic inflammation

Other neuropeptides

Role of neuropeptides in asthma

References

Chapter 25. Transcription Factors

Basal and regulated transcription

NF-kB, the Rel family of proteins and lkB proteins

AP-1 and related transcription factors

CCAAT/enhancer-binding proteins and NF-IL-6

JAK-STAT pathway

Glucocorticoid receptors

Cross-talk between transcription factors and their transduction pathways

Transcription factors in asthma

References

Chapter 26. Airway Remodelling

Introduction

Structural changes in the airway walls in asthma

Extracellular matrix

Smooth muscle

Summary

Acknowledgements

References

Chapter 27. Pathophysiology of Asthma

Introduction

Asthma as an inflammatory disease

Inflammatory cells

Structural cells

Inflammatory mediators

Effects of inflammation

Transcription factors

Anti-inflammatory mechanisms in asthma

Genetic influences

Unanswered questions

References

Chapter 28. Allergens

Introduction

Atopy

Inhaled allergens

Allergic bronchopulmonary aspergillosis

Ingested/injected allergens

Acknowledgements

References

Chapter 29. Occupational Asthma

Introduction: initiators and provokers of asthma

Irritant-induced asthma

Causes of hypersensitivity-induced occupational asthma

Importance of hypersensitivity-induced occupational asthma

Occupational asthma and hypersensitivity

Determinants of hypersensitivity-induced occupational asthma

Diagnosis of hypersensitivity-induced occupational asthma

Investigation of hypersensitivity-induced occupational asthma

Outcome of hypersensitivity-induced occupational asthma

Management of occupational asthma

References

Chapter 30. Infections

Introduction

Epidemiology of respiratory infections and wheezing

Mechanisms of virus-induced airway hyperresponsiveness

Summary

Acknowledgements

References

Chapter 31. Asthma Provoked by Exercise, Hyperventilation and the Inhalation of Non-isotonic Aerosols

Introduction

Respiratory water loss and conditioning of inspired air

Role of the bronchial circulation

Generation and deposition of non-isotonic aerosols in the respiratory tract

Comparison between challenge with exercise and hyperventilation and challenge with non-isotonic aerosols

Mechanisms by which a change in osmolarity and airway drying induce airway narrowing

Effect of pharmacological agents

References

Chapter 32. Atmospheric Pollutants

Ozone

Nitrogen dioxide

Sulphur dioxide

Summary

References

Chapter 33. Drug-induced Asthma

B-Blockers

Additives

ACE inhibitors

Local anaesthetics

Other drugs

References

Chapter 34. Aspirin-induced Asthma

History and definition

Pathogenesis

Clinical presentation

Diagnosis

Differential diagnosis

Prevention and treatment

References

Chapter 35. Allergen Avoidance

Introduction

Indoor allergens as a cause of asthma

Primary sensitization

Allergen exposure and asthma severity

Are threshold values useful?

Allergen avoidance

Allergen Avoidance: Practical Measures

Allergen avoidance in asthma prevention

Conclusions

References

Chapter 36. B-Adrenoceptor Agonists

Introduction

Molecular pharmacology

Clinical pharmacology

Differences between B-agonists

Efficacy and safety of inhaled B-agonists

Oral B-agonists

References

Chapter 37. Anticholinergic Bronchodilators

Introduction

Rationale for use of anticholinergic bronchodilators

Pharmacology

Clinical efficacy

Side-effects

Clinical recommendations

References

Chapter 38. Theophylline

Introduction

Historical background

Chemistry

Molecular mechanisms of action

Effects

Pharmacokinetics

Routes of administration

Clinical use

Side-effects

Future of theophylline

References

Chapter 39. Cromones

Introduction

Pharmacokinetics

Effects on inflammatory cells and nerves

Evidence for anti-inflammatory actions

Mechanisms of action

Clinical studies in asthma

References

Chapter 40. Glucocorticosteroids

Introduction

Molecular mechanisms

Effects on cell function

Effects on asthmatic inflammation

Clinical efficacy of inhaled steroids

Pharmacokinetics

Side-effects of inhaled steroids

Clinical use of inhaled steroids

Systemic steroids

Glucocorticoid resistance in asthma

References

Chapter 41. Mediator Antagonists

Introduction

Antihistamines

Leukotriene antagonists

Prostaglandin inhibitors

Platelet-activating factor (PAF) antagonists

Phospholipase inhibitors

Bradykinin antagonists

Antioxidants

Adenosine antagonists

NO synthase inhibitors

Endothelin antagonists

Basic protein inhibitors and heparin

Inflammatory enzyme inhibitors

Combined inhibitors

References

Chapter 42. Immunomodulators

Clinical need

Immunosuppressive therapy in asthma

Newer immunosuppressive agents

Conclusions

References

Chapter 43. Future Therapies for Asthma

Introduction

New bronchodilators

Mediator antagonists

Cytokines and cytokine inhibitors

Anti-inflammatory drugs

Gene therapy

Conclusions

References

Chapter 44. Management of Severe Asthma

Introduction

General assessment and management

Specific treatment for severe acute asthma

Assisted ventilation

Management of catastrophic asthma

Other measures

Summary

References

Chapter 45. Management of Asthma in Adults

Introduction

Classificationofasthma for purposes ofmanagement

Aims of management

Asthma management plan

Treatment of the patient with severe persistent asthma

Likely future changes to management

References

Chapter 46. Asthma in Children

Introduction

Anatomical and physiological factors

Wheezing illness

Natural history

Risk factors and prevention

Growth

Pharmacokinetics and pharmacodynamics

Assessment of the clinical condition

Irreversible airway obstruction

Treatment

Special age groups

Severe acute asthma/status asthmaticus

Immunotherapy

General measures

References

Chapter 47. Pharmacoeconomics of Asthma Treatments

Introduction

Principles and applications of pharmaco economics

Cost-benefit analysis

Cost-effectiveness analysis

Asthma outcomes for pharmacoeconomic evaluation

Pharmacoeconomics of asthma pharmacotherapy

Conclusions

References

Chapter 48. Education and Self-management

Introduction

Health professional education and guidelines

Compliance

How do we improve communication?

Self-management

Conclusion

References

Index

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