Asthma: Basic Mechanisms and Clinical Management

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