Asthma (eBook)

Cover 1
Contents 14
Preface 6
Foreword to the second edition 8
Contributors 10
Chapter 1. Epidemiology 28
Introduction 28
Diagnosis of asthma 28
Asthma in children 29
Factors influencing development of childhood asthma 32
Childhood asthma and AHR 38
Prognosis of childhood asthma 38
Asthma in adults 39
AHR in adults 41
Risk factors for adult asthma 42
Evidence for increasing severity of asthma 43
Mortality from asthma 44
Risk factors for asthma mortality 46
References 48
Chapter 2. Genetics 62
Introduction 62
Methods of finding disease genes in asthma 62
Problems in genetic studies of asthma 64
Modes of inheritance of atopy, BHR and asthma 64
Genetic studies of atopy and asthma 65
Genetic studies of BHR and asthma 68
Conclusion 70
References 71
Chapter 3. Airway Pathology in Asthma 74
Introduction 74
Sputum and bronchoalveolar lavage 75
Appearances at post-mortem 75
Loss of surface epithelium 76
Thickening of the epithelial 'basement membrane' 78
Increased numbers of mucus-secreting cells 78
Enlargement of bronchial smooth muscle mass 80
Bronchial vasculature, congestion and oedema 83
Recruitment of inflammatory cells 84
Airway wall nerves 85
Conclusions 86
Acknowledgements 87
References 87
Chapter 4. Physiology 92
Introduction 92
Factors restricting and amplifying induced airway narrowing in vivo 92
Sites of airway narrowing in asthma 96
Effects of posture and sleep on airway function 103
Response to increasing severity of airway narrowing 104
Conclusions 110
References 110
Chapter 5. Airway Smooth Muscle Cells: Structure and Function 116
Introduction 116
Morphology 116
Ion channels 123
Phosphatidylinositides and calcium 127
Physiological mechanisms 128
Conclusion 132
References 133
Chapter 6. Mast Cells and Basophils 140
Introduction 140
Mast cell heterogeneity 141
Mast cells. basophils and adhesion molecules 142
Distribution and morphology of human lung mast cells 143
BAL in extrinsic asthma 144
Immunologically induced mediator release 145
BAL mast cells steroid therapy in asthma 147
Antiasthmatic drugs and the inhibition of histamine release from pulmonary mast cells 147
Role of basophils in allergy and asthma 148
Role of mast cells in early asthmatic reactions 149
Role of mast cells in late asthmatic reactions and cytokine production 149
Acknowledgements 150
References 150
Chapter 7. Monocytes, Macrophages and Dendritic Cells 154
Introduction 154
Role of mononuclear phagocytes in inflammatory mechanisms of asthmatic disease 155
Changes in phenotype and function of monocytes and macrophages in asthma 155
Effects of glucocorticoids on monocyte/macrophage function 161
Conclusion 163
References 164
Chapter 8. Eosinophils 168
Introduction 168
Biochemistry and function 169
Receptors and degranulation 174
Mechanisms of eosinophil accumulation 175
The eosinophil in asthma 176
Monitoring of asthma by eosinophil markers 177
Pharmacological control of the eosinophil 177
Conclusions 178
References 178
Chapter 9. Lymphocytes 186
Introduction 186
Lymphocytes are strongly implicated in the pathogenesis of asthma 188
Overview of lymphocyte responses to inhaled foreign antigens 190
Perspective: defects in termination of immune responses may cause chronic disease 203
Acknowledgement 204
References 204
Chapter 10. Epithelial Cells 214
Introduction 214
Morphology of the airway epithelium 214
Airway epithelium and hyperresponsiveness 217
Epithelial cell-derived mediators 217
Adhesion molecules and the airway epithelium 221
Immunoregulation 222
Culture of human airway epithelial cells in vitro 223
Summary 224
References 226
Chapter 11. Pathophysiology of Airway Mucus Secretion in Asthma 232
Introduction 232
Airway mucus 232
Airway mucus-secreting cells 234
Mucus abnormalities in asthma 235
Consequences of airway mucus hypersecretion and hyperviscosity 240
Inducers of airway mucus secretion 243
Pharmacological treatment of mucus hypersecretion in asthma 245
Conclusions 248
Acknowledgements 249
References 249
Chapter 12. Tracheobronchial Circulation 256
Introduction 256
Organization and control of the tracheobronchial circulation 256
Role of the tracheobronchial circulation in asthma 258
Conclusion 261
References 261
Chapter 13. Adhesion Molecules 266
Introduction 266
Leucocyte adhesion receptors 267
Expression of adhesion receptors in allergic disease 269
Role of adhesion receptors in leucocyte migration in allergic disease 271
In vivo studies of adhesion receptor antagonists in models of allergic inflammation 273
Summary 273
References 275
Chapter 14. Microvascular-Epithelial Exudation of Plasma 280
Introduction 280
Exudation pathways 281
Acute challenge-induced microvascular-epithelial exudation 284
Mucosal exudation of plasma in disease 286
Roles of exuded plasma 288
On the inward perviousness in asthma 289
Airway epithelial restitution in a plasma-derived gel 290
References 292
Chapter 15. Prostaglandins and Thromboxane 296
Introduction 296
Arachidonic acid metabolism 297
Cyclooxygenase products 298
Prostaglandin and thromboxane receptors 298
Role of COX products in asthma 299
Stimulatory prostaglandins and thromboxane 300
Inhibitory prostaglandins 302
Conclusions 304
References 305
Chapter 16. Cysteinyl Leukotrienes 308
Introduction 308
Formation and metabilism of the leukotrienes 308
Leukotrienes in asthma 310
Conclusions 316
References 317
Chapter 17. Kinins 324
Introduction 324
Structure, formation and metabolism 325
Receptors and general pharmacological properties 327
Kinin formation in airway inflammation 328
Effects of kinins on airways 328
Mechanisms of action 329
Summary 330
Acknowledgements 331
References 331
Chapter 18. Chemokines 336
Introduction 336
Discovery and structure 337
Cell sources 339
Regulation 339
Chemokines as chemoattractants and cell activators 340
Chemokine receptors 343
Expression and release of chemokines in asthma 344
Conclusion 345
References 346
Chapter 19. Lymphokines 360
Introduction 360
Type 1 and type 2 T-cells 360
Actions of type 2 cytokines relevant to asthma 362
Evidence of T-cell cytokine production in asthma 364
T-cell cytokines in non-atopic asthma 366
Factors determining type 1 or type 2 T-cell development 367
Alteration of established type 1 or type 2 cytokine profile 367
Potential for intervention 368
Conclusion 368
References 368
Chapter 20. Other Mediators of Asthma 374
Introduction 374
Histamine 374
Platelet-activating factor 377
Oxygen radicals 380
Complement 382
Serotonin 384
Eosinophil proteins 385
Endothelin 385
References 388
Chapter 21. Nitric Oxide 400
Introduction 400
Generation of NO 400
Effects of NO on airway function 402
Exhaled NO 406
Therapeutic implications 413
References 414
Chapter 22. Neural Control of Airway Function in Asthma 420
Introduction 420
Afferent nerves 423
Parasympathetic nerves 424
Adrenergic control 430
References 434
Chapter 23. Humoral Control of Airway Tone 440
Introduction 440
Vasoactive peptides 440
Hormones 444
Circulating inflammatory mediators 446
Oxygen and carbon dioxide 446
Conclusions 448
References 448
Chapter 24. NANC Nerves and Neuropeptides 454
Introduction 454
Non-adrenergic non-cholinergic (NANC) nerves 456
VIP and related peptides 459
Tachykinins 465
CGRP 467
Neurogenic inflammation 469
Other neuropeptides 475
Role of neuropeptides in asthma 477
References 478
Chapter 25. Transcription Factors 490
Basal and regulated transcription 490
NF-kB, the Rel family of proteins and lkB proteins 491
AP-1 and related transcription factors 495
CCAAT/enhancer-binding proteins and NF-IL-6 495
JAK-STAT pathway 496
Glucocorticoid receptors 497
Cross-talk between transcription factors and their transduction pathways 497
Transcription factors in asthma 500
References 502
Chapter 26. Airway Remodelling 506
Introduction 506
Structural changes in the airway walls in asthma 506
Extracellular matrix 509
Smooth muscle 512
Summary 514
Acknowledgements 514
References 515
Chapter 27. Pathophysiology of Asthma 518
Introduction 518
Asthma as an inflammatory disease 519
Inflammatory cells 520
Structural cells 522
Inflammatory mediators 524
Effects of inflammation 526
Transcription factors 530
Anti-inflammatory mechanisms in asthma 530
Genetic influences 531
Unanswered questions 532
References 534
Chapter 28. Allergens 538
Introduction 538
Atopy 539
Inhaled allergens 539
Allergic bronchopulmonary aspergillosis 549
Ingested/injected allergens 551
Acknowledgements 551
References 551
Chapter 29. Occupational Asthma 560
Introduction: initiators and provokers of asthma 560
Irritant-induced asthma 561
Causes of hypersensitivity-induced occupational asthma 562
Importance of hypersensitivity-induced occupational asthma 563
Occupational asthma and hypersensitivity 563
Determinants of hypersensitivity-induced occupational asthma 565
Diagnosis of hypersensitivity-induced occupational asthma 567
Investigation of hypersensitivity-induced occupational asthma 568
Outcome of hypersensitivity-induced occupational asthma 572
Management of occupational asthma 573
References 574
Chapter 30. Infections 578
Introduction 578
Epidemiology of respiratory infections and wheezing 578
Mechanisms of virus-induced airway hyperresponsiveness 587
Summary 595
Acknowledgements 595
References 595
Chapter 31. Asthma Provoked by Exercise, Hyperventilation and the Inhalation of Non-isotonic Aerosols 600
Introduction 600
Respiratory water loss and conditioning of inspired air 601
Role of the bronchial circulation 603
Generation and deposition of non-isotonic aerosols in the respiratory tract 605
Comparison between challenge with exercise and hyperventilation and challenge with non-isotonic aerosols 605
Mechanisms by which a change in osmolarity and airway drying induce airway narrowing 607
Effect of pharmacological agents 609
References 612
Chapter 32. Atmospheric Pollutants 620
Ozone 620
Nitrogen dioxide 622
Sulphur dioxide 623
Summary 624
References 624
Chapter 33. Drug-induced Asthma 628
B-Blockers 628
Additives 631
ACE inhibitors 632
Local anaesthetics 633
Other drugs 633
References 634
Chapter 34. Aspirin-induced Asthma 638
History and definition 638
Pathogenesis 639
Clinical presentation 642
Diagnosis 643
Differential diagnosis 644
Prevention and treatment 644
References 645
Chapter 35. Allergen Avoidance 648
Introduction 648
Indoor allergens as a cause of asthma 649
Primary sensitization 652
Allergen exposure and asthma severity 653
Are threshold values useful? 654
Allergen avoidance 656
Allergen Avoidance: Practical Measures 664
Allergen avoidance in asthma prevention 671
Conclusions 671
References 672
Chapter 36. B-Adrenoceptor Agonists 682
Introduction 682
Molecular pharmacology 682
Clinical pharmacology 689
Differences between B-agonists 692
Efficacy and safety of inhaled B-agonists 693
Oral B-agonists 700
References 701
Chapter 37. Anticholinergic Bronchodilators 708
Introduction 708
Rationale for use of anticholinergic bronchodilators 708
Pharmacology 710
Clinical efficacy 712
Side-effects 716
Clinical recommendations 717
References 717
Chapter 38. Theophylline 720
Introduction 720
Historical background 720
Chemistry 721
Molecular mechanisms of action 721
Effects 724
Pharmacokinetics 727
Routes of administration 728
Clinical use 729
Side-effects 732
Future of theophylline 732
References 733
Chapter 39. Cromones 738
Introduction 738
Pharmacokinetics 739
Effects on inflammatory cells and nerves 739
Evidence for anti-inflammatory actions 742
Mechanisms of action 742
Clinical studies in asthma 743
References 749
Chapter 40. Glucocorticosteroids 756
Introduction 756
Molecular mechanisms 756
Effects on cell function 763
Effects on asthmatic inflammation 766
Clinical efficacy of inhaled steroids 767
Pharmacokinetics 769
Side-effects of inhaled steroids 770
Clinical use of inhaled steroids 776
Systemic steroids 777
Glucocorticoid resistance in asthma 779
References 786
Chapter 41. Mediator Antagonists 798
Introduction 798
Antihistamines 798
Leukotriene antagonists 799
Prostaglandin inhibitors 803
Platelet-activating factor (PAF) antagonists 804
Phospholipase inhibitors 805
Bradykinin antagonists 806
Antioxidants 806
Adenosine antagonists 807
NO synthase inhibitors 807
Endothelin antagonists 808
Basic protein inhibitors and heparin 808
Inflammatory enzyme inhibitors 808
Combined inhibitors 809
References 809
Chapter 42. Immunomodulators 814
Clinical need 814
Immunosuppressive therapy in asthma 815
Newer immunosuppressive agents 821
Conclusions 822
References 822
Chapter 43. Future Therapies for Asthma 826
Introduction 826
New bronchodilators 827
Mediator antagonists 832
Cytokines and cytokine inhibitors 836
Anti-inflammatory drugs 838
Gene therapy 844
Conclusions 845
References 845
Chapter 44. Management of Severe Asthma 852
Introduction 852
General assessment and management 852
Specific treatment for severe acute asthma 854
Assisted ventilation 858
Management of catastrophic asthma 859
Other measures 861
Summary 862
References 862
Chapter 45. Management of Asthma in Adults 866
Introduction 866
Classificationofasthma for purposes ofmanagement 867
Aims of management 868
Asthma management plan 868
Treatment of the patient with severe persistent asthma 883
Likely future changes to management 884
References 885
Chapter 46. Asthma in Children 890
Introduction 890
Anatomical and physiological factors 891
Wheezing illness 891
Natural history 892
Risk factors and prevention 894
Growth 895
Pharmacokinetics and pharmacodynamics 895
Assessment of the clinical condition 896
Irreversible airway obstruction 899
Treatment 900
Special age groups 914
Severe acute asthma/status asthmaticus 915
Immunotherapy 919
General measures 920
References 921
Chapter 47. Pharmacoeconomics of Asthma Treatments 934
Introduction 934
Principles and applications of pharmaco economics 935
Cost-benefit analysis 936
Cost-effectiveness analysis 937
Asthma outcomes for pharmacoeconomic evaluation 938
Pharmacoeconomics of asthma pharmacotherapy 938
Conclusions 955
References 945
Chapter 48. Education and Self-management 948
Introduction 948
Health professional education and guidelines 948
Compliance 949
How do we improve communication? 950
Self-management 953
Conclusion 955
References 955
Index 958
Color Plate Section 354