Asthma: Basic Mechanisms and Clinical Management
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Table of contents
- Contentsxiii
- Prefacev
- Foreword to the second editionvii
- Contributorsix
- Chapter 1. Epidemiology1
- Introduction1
- Diagnosis of asthma1
- Asthma in children2
- Factors influencing development of childhood asthma5
- Childhood asthma and AHR11
- Prognosis of childhood asthma11
- Asthma in adults12
- AHR in adults14
- Risk factors for adult asthma15
- Evidence for increasing severity of asthma16
- Mortality from asthma17
- Risk factors for asthma mortality19
- References21
- Chapter 2. Genetics35
- Introduction35
- Methods of finding disease genes in asthma35
- Problems in genetic studies of asthma37
- Modes of inheritance of atopy, BHR and asthma37
- Genetic studies of atopy and asthma38
- Genetic studies of BHR and asthma41
- Conclusion43
- References44
- Chapter 3. Airway Pathology in Asthma47
- Introduction47
- Sputum and bronchoalveolar lavage48
- Appearances at post-mortem48
- Loss of surface epithelium49
- Thickening of the epithelial 'basement membrane'51
- Increased numbers of mucus-secreting cells51
- Enlargement of bronchial smooth muscle mass53
- Bronchial vasculature, congestion and oedema56
- Recruitment of inflammatory cells57
- Airway wall nerves58
- Conclusions59
- Acknowledgements60
- References60
- Chapter 4. Physiology65
- Introduction65
- Factors restricting and amplifying induced airway narrowing in vivo65
- Sites of airway narrowing in asthma69
- Effects of posture and sleep on airway function76
- Response to increasing severity of airway narrowing77
- Conclusions83
- References83
- Chapter 5. Airway Smooth Muscle Cells: Structure and Function89
- Introduction89
- Morphology89
- Ion channels96
- Phosphatidylinositides and calcium100
- Physiological mechanisms101
- Conclusion105
- References106
- Chapter 6. Mast Cells and Basophils113
- Introduction113
- Mast cell heterogeneity114
- Mast cells. basophils and adhesion molecules115
- Distribution and morphology of human lung mast cells116
- BAL in extrinsic asthma117
- Immunologically induced mediator release118
- BAL mast cells steroid therapy in asthma120
- Antiasthmatic drugs and the inhibition of histamine release from pulmonary mast cells120
- Role of basophils in allergy and asthma121
- Role of mast cells in early asthmatic reactions122
- Role of mast cells in late asthmatic reactions and cytokine production122
- Acknowledgements123
- References123
- Chapter 7. Monocytes, Macrophages and Dendritic Cells127
- Introduction127
- Role of mononuclear phagocytes in inflammatory mechanisms of asthmatic disease128
- Changes in phenotype and function of monocytes and macrophages in asthma128
- Effects of glucocorticoids on monocyte/macrophage function134
- Conclusion136
- References137
- Chapter 8. Eosinophils141
- Introduction141
- Biochemistry and function142
- Receptors and degranulation147
- Mechanisms of eosinophil accumulation148
- The eosinophil in asthma149
- Monitoring of asthma by eosinophil markers150
- Pharmacological control of the eosinophil150
- Conclusions151
- References151
- Chapter 9. Lymphocytes159
- Introduction159
- Lymphocytes are strongly implicated in the pathogenesis of asthma161
- Overview of lymphocyte responses to inhaled foreign antigens163
- Perspective: defects in termination of immune responses may cause chronic disease176
- Acknowledgement177
- References177
- Chapter 10. Epithelial Cells187
- Introduction187
- Morphology of the airway epithelium187
- Airway epithelium and hyperresponsiveness190
- Epithelial cell-derived mediators190
- Adhesion molecules and the airway epithelium194
- Immunoregulation195
- Culture of human airway epithelial cells in vitro196
- Summary197
- References199
- Chapter 11. Pathophysiology of Airway Mucus Secretion in Asthma205
- Introduction205
- Airway mucus205
- Airway mucus-secreting cells207
- Mucus abnormalities in asthma208
- Consequences of airway mucus hypersecretion and hyperviscosity213
- Inducers of airway mucus secretion216
- Pharmacological treatment of mucus hypersecretion in asthma218
- Conclusions221
- Acknowledgements222
- References222
- Chapter 12. Tracheobronchial Circulation229
- Introduction229
- Organization and control of the tracheobronchial circulation229
- Role of the tracheobronchial circulation in asthma231
- Conclusion234
- References234
- Chapter 13. Adhesion Molecules239
- Introduction239
- Leucocyte adhesion receptors240
- Expression of adhesion receptors in allergic disease242
- Role of adhesion receptors in leucocyte migration in allergic disease244
- In vivo studies of adhesion receptor antagonists in models of allergic inflammation246
- Summary246
- References248
- Chapter 14. Microvascular-Epithelial Exudation of Plasma253
- Introduction253
- Exudation pathways254
- Acute challenge-induced microvascular-epithelial exudation257
- Mucosal exudation of plasma in disease259
- Roles of exuded plasma261
- On the inward perviousness in asthma262
- Airway epithelial restitution in a plasma-derived gel263
- References265
- Chapter 15. Prostaglandins and Thromboxane269
- Introduction269
- Arachidonic acid metabolism270
- Cyclooxygenase products271
- Prostaglandin and thromboxane receptors271
- Role of COX products in asthma272
- Stimulatory prostaglandins and thromboxane273
- Inhibitory prostaglandins275
- Conclusions277
- References278
- Chapter 16. Cysteinyl Leukotrienes281
- Introduction281
- Formation and metabilism of the leukotrienes281
- Leukotrienes in asthma283
- Conclusions289
- References290
- Chapter 17. Kinins297
- Introduction297
- Structure, formation and metabolism298
- Receptors and general pharmacological properties300
- Kinin formation in airway inflammation301
- Effects of kinins on airways301
- Mechanisms of action302
- Summary303
- Acknowledgements304
- References304
- Chapter 18. Chemokines309
- Introduction309
- Discovery and structure310
- Cell sources312
- Regulation312
- Chemokines as chemoattractants and cell activators313
- Chemokine receptors316
- Expression and release of chemokines in asthma317
- Conclusion318
- References319
- Chapter 19. Lymphokines329
- Introduction329
- Type 1 and type 2 T-cells329
- Actions of type 2 cytokines relevant to asthma331
- Evidence of T-cell cytokine production in asthma333
- T-cell cytokines in non-atopic asthma335
- Factors determining type 1 or type 2 T-cell development336
- Alteration of established type 1 or type 2 cytokine profile336
- Potential for intervention337
- Conclusion337
- References337
- Chapter 20. Other Mediators of Asthma343
- Introduction343
- Histamine343
- Platelet-activating factor346
- Oxygen radicals349
- Complement351
- Serotonin353
- Eosinophil proteins354
- Endothelin354
- References357
- Chapter 21. Nitric Oxide369
- Introduction369
- Generation of NO369
- Effects of NO on airway function371
- Exhaled NO375
- Therapeutic implications382
- References383
- Chapter 22. Neural Control of Airway Function in Asthma389
- Introduction389
- Afferent nerves392
- Parasympathetic nerves393
- Adrenergic control399
- References403
- Chapter 23. Humoral Control of Airway Tone409
- Introduction409
- Vasoactive peptides409
- Hormones413
- Circulating inflammatory mediators415
- Oxygen and carbon dioxide415
- Conclusions417
- References417
- Chapter 24. NANC Nerves and Neuropeptides423
- Introduction423
- Non-adrenergic non-cholinergic (NANC) nerves425
- VIP and related peptides428
- Tachykinins434
- CGRP436
- Neurogenic inflammation438
- Other neuropeptides444
- Role of neuropeptides in asthma446
- References447
- Chapter 25. Transcription Factors459
- Basal and regulated transcription459
- NF-kB, the Rel family of proteins and lkB proteins460
- AP-1 and related transcription factors464
- CCAAT/enhancer-binding proteins and NF-IL-6464
- JAK-STAT pathway465
- Glucocorticoid receptors466
- Cross-talk between transcription factors and their transduction pathways466
- Transcription factors in asthma469
- References471
- Chapter 26. Airway Remodelling475
- Introduction475
- Structural changes in the airway walls in asthma475
- Extracellular matrix478
- Smooth muscle481
- Summary483
- Acknowledgements483
- References484
- Chapter 27. Pathophysiology of Asthma487
- Introduction487
- Asthma as an inflammatory disease488
- Inflammatory cells489
- Structural cells491
- Inflammatory mediators493
- Effects of inflammation495
- Transcription factors499
- Anti-inflammatory mechanisms in asthma499
- Genetic influences500
- Unanswered questions501
- References503
- Chapter 28. Allergens507
- Introduction507
- Atopy508
- Inhaled allergens508
- Allergic bronchopulmonary aspergillosis518
- Ingested/injected allergens520
- Acknowledgements520
- References520
- Chapter 29. Occupational Asthma529
- Introduction: initiators and provokers of asthma529
- Irritant-induced asthma530
- Causes of hypersensitivity-induced occupational asthma531
- Importance of hypersensitivity-induced occupational asthma532
- Occupational asthma and hypersensitivity532
- Determinants of hypersensitivity-induced occupational asthma534
- Diagnosis of hypersensitivity-induced occupational asthma536
- Investigation of hypersensitivity-induced occupational asthma537
- Outcome of hypersensitivity-induced occupational asthma541
- Management of occupational asthma542
- References543
- Chapter 30. Infections547
- Introduction547
- Epidemiology of respiratory infections and wheezing547
- Mechanisms of virus-induced airway hyperresponsiveness556
- Summary564
- Acknowledgements564
- References564
- Chapter 31. Asthma Provoked by Exercise, Hyperventilation and the Inhalation of Non-isotonic Aerosol569
- Introduction569
- Respiratory water loss and conditioning of inspired air570
- Role of the bronchial circulation572
- Generation and deposition of non-isotonic aerosols in the respiratory tract574
- Comparison between challenge with exercise and hyperventilation and challenge with non-isotonic aero574
- Mechanisms by which a change in osmolarity and airway drying induce airway narrowing576
- Effect of pharmacological agents578
- References581
- Chapter 32. Atmospheric Pollutants589
- Ozone589
- Nitrogen dioxide591
- Sulphur dioxide592
- Summary593
- References593
- Chapter 33. Drug-induced Asthma597
- B-Blockers597
- Additives600
- ACE inhibitors601
- Local anaesthetics602
- Other drugs602
- References603
- Chapter 34. Aspirin-induced Asthma607
- History and definition607
- Pathogenesis608
- Clinical presentation611
- Diagnosis612
- Differential diagnosis613
- Prevention and treatment613
- References614
- Chapter 35. Allergen Avoidance617
- Introduction617
- Indoor allergens as a cause of asthma618
- Primary sensitization621
- Allergen exposure and asthma severity622
- Are threshold values useful?623
- Allergen avoidance625
- Allergen Avoidance: Practical Measures633
- Allergen avoidance in asthma prevention640
- Conclusions640
- References641
- Chapter 36. B-Adrenoceptor Agonists651
- Introduction651
- Molecular pharmacology651
- Clinical pharmacology658
- Differences between B-agonists661
- Efficacy and safety of inhaled B-agonists662
- Oral B-agonists669
- References670
- Chapter 37. Anticholinergic Bronchodilators677
- Introduction677
- Rationale for use of anticholinergic bronchodilators677
- Pharmacology679
- Clinical efficacy681
- Side-effects685
- Clinical recommendations686
- References686
- Chapter 38. Theophylline689
- Introduction689
- Historical background689
- Chemistry690
- Molecular mechanisms of action690
- Effects693
- Pharmacokinetics696
- Routes of administration697
- Clinical use698
- Side-effects701
- Future of theophylline701
- References702
- Chapter 39. Cromones707
- Introduction707
- Pharmacokinetics708
- Effects on inflammatory cells and nerves708
- Evidence for anti-inflammatory actions711
- Mechanisms of action711
- Clinical studies in asthma712
- References718
- Chapter 40. Glucocorticosteroids725
- Introduction725
- Molecular mechanisms725
- Effects on cell function732
- Effects on asthmatic inflammation735
- Clinical efficacy of inhaled steroids736
- Pharmacokinetics738
- Side-effects of inhaled steroids739
- Clinical use of inhaled steroids745
- Systemic steroids746
- Glucocorticoid resistance in asthma748
- References755
- Chapter 41. Mediator Antagonists767
- Introduction767
- Antihistamines767
- Leukotriene antagonists768
- Prostaglandin inhibitors772
- Platelet-activating factor (PAF) antagonists773
- Phospholipase inhibitors774
- Bradykinin antagonists775
- Antioxidants775
- Adenosine antagonists776
- NO synthase inhibitors776
- Endothelin antagonists777
- Basic protein inhibitors and heparin777
- Inflammatory enzyme inhibitors777
- Combined inhibitors778
- References778
- Chapter 42. Immunomodulators783
- Clinical need783
- Immunosuppressive therapy in asthma784
- Newer immunosuppressive agents790
- Conclusions791
- References791
- Chapter 43. Future Therapies for Asthma795
- Introduction795
- New bronchodilators796
- Mediator antagonists801
- Cytokines and cytokine inhibitors805
- Anti-inflammatory drugs807
- Gene therapy813
- Conclusions814
- References814
- Chapter 44. Management of Severe Asthma821
- Introduction821
- General assessment and management821
- Specific treatment for severe acute asthma823
- Assisted ventilation827
- Management of catastrophic asthma828
- Other measures830
- Summary831
- References831
- Chapter 45. Management of Asthma in Adults835
- Introduction835
- Classificationofasthma for purposes ofmanagement836
- Aims of management837
- Asthma management plan837
- Treatment of the patient with severe persistent asthma852
- Likely future changes to management853
- References854
- Chapter 46. Asthma in Children859
- Introduction859
- Anatomical and physiological factors860
- Wheezing illness860
- Natural history861
- Risk factors and prevention863
- Growth864
- Pharmacokinetics and pharmacodynamics864
- Assessment of the clinical condition865
- Irreversible airway obstruction868
- Treatment869
- Special age groups883
- Severe acute asthma/status asthmaticus884
- Immunotherapy888
- General measures889
- References890
- Chapter 47. Pharmacoeconomics of Asthma Treatments903
- Introduction903
- Principles and applications of pharmaco economics904
- Cost-benefit analysis905
- Cost-effectiveness analysis906
- Asthma outcomes for pharmacoeconomic evaluation907
- Pharmacoeconomics of asthma pharmacotherapy907
- Conclusions924
- References914
- Chapter 48. Education and Self-management917
- Introduction917
- Health professional education and guidelines917
- Compliance918
- How do we improve communication?919
- Self-management922
- Conclusion924
- References924
- Index927
- Color Plate SectionPlate1
Now available in its Third Edition, Asthma: Basic Mechanisms and Clinical Management has become the reference text in asthma. This highly successful text sheds new light on the basic physiological and molecular mechanisms of asthma, how current treatments work, and how best to apply the latest knowledge to control this important disease. The Third Edition has undergone radical revision and includes several new chapters. It retains the virtues of the previous volumes by bringing together all of the recent research findings by internationally recognized experts on the causative mechanisms of asthma, including in-depth clinical aspects and therapy. The book presents an integrated approach toward the treatment of this disease with new concepts, changes in asthma management, and the development of new therapeutic agents. Asthma provides extensive references for researchers and clinicians who need to keep abreast of recent developments in this rapidly expanding field.
Key Features
* Comprehensive coverage of both basic science and clinical aspects of asthma
* Extensively referenced throughout
Key Features
* Comprehensive coverage of both basic science and clinical aspects of asthma
* Extensively referenced throughout