Pharmacology of Asthma

ISBN-13: 9783642758577 / Angielski / Miękka / 2012 / 320 str.

Clive P. Page; Peter J. Barnes; A. G. Alexander

Opis

This volume forms part of a prestigious series and covers the latest advances in our understanding of the pathophysiology and treatment of asthma. Our understanding of asthma has changed dramatically in recent years, and much of this new information is brought together in this volume written by inter- nationally recognised authorities. The aim of the book is to review in depth the changing concepts of inflammatory processes in asthma and to discuss the implications for research of this common chronic disease. Many of the advances in and future therapy our understanding of asthma have originated from a pharmacological approach, and this volume highlights the promising new options for pharma- cological intervention. It is hoped this book will be invaluable for research scientists and clinic- ians involved in asthma research and will be a major reference resource for chest physicians and those involved in the development of novel pharmaceu- tical entities. Each chapter is extensively referenced, generously illustrated with clear diagrams and photographs, and represents a state-of-the-art review of this growing area. c.P. PAGE P.l. BARNES Contents CHAPTER 1 The Pathology of Asthma: An Overview L.A. LAmNEN and A. LAmNEN. With 10 Figures ...................... 1 A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 1 . . . . . . . . . . . . . . . B. Methods to Investigate the Pathology of Human Asthma ............ 1 C. Bronchial Epithelium and Inflammatory Cells in Asthmatic Patients Between Attacks ........................... 2 I. Mast Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 4 . . . . . . . . . . . . . . II. Eosinophils ............................................... 7 III. Neutrophils.............................................. 10 D. Bronchial Epithelial Inflammation During an Asthma Attack. . . . . .. . 10 E. Epithelial Regeneration .... . . . . . . . . . . . . . . . . . . . . . . .. . . 12 . . . . . . . . .

Spis treści

1 The Pathology of Asthma: An Overview.- A. Introduction.- B. Methods to Investigate the Pathology of Human Asthma.- C. Bronchial Epithelium and Inflammatory Cells in Asthmatic Patients Between Attacks.- I. Mast Cells.- II. Eosinophils.- III. Neutrophils.- D. Bronchial Epithelial Inflammation During an Asthma Attack.- E. Epithelial Regeneration.- F. Airway Smooth Muscle.- G. Bronchial Glands.- H. Neural Pathways.- I. Epithelium.- II. Neuroepithelial Bodies and Neuroendocrine-Like (Granule-Containing) Cells.- I. Nerves and Other Airway Structures.- J. Bronchial Circulation.- K. Leakage of the Bronchial Vascular Bed in Patients with Asthma.- L. Conclusion.- References.- 2 The Contribution of Inflammatory Cells to the Pathogenesis of Asthma.- A. Inflammation and Inflammatory Cells.- B. Pathological Evidence for Inflammation in Asthma.- C. Microvascular Leakage.- D. Neutrophils.- E. Eosinophils.- F. Mast Cells and Basophils.- G. Monocytes and Macrophages (Mononuclear Phagocytes).- H. Platelets.- I. Lymphocytes.- J. Concluding Comments.- References.- 3 Inflammatory Mediators.- A. Introduction.- I. Cellular Origin of Mediators.- II. Mediator Effects.- III. Mediator Receptors.- IV. Mediator Interactions.- V. Mediator Antagonists.- B. Histamine.- I. Synthesis and Metabolism.- II. Histamine Receptors.- III. Airway Effects.- IV. Role in Asthma.- C. Cyclooxygenase Products.- I. Synthesis and Metabolism.- II. Receptors.- III. Airway Effects.- 1. Airway Smooth Muscle.- 2. Secretion.- 3. Inflammatory Effects.- IV. Role in Asthma.- D. Lipoxygenase Products.- I. Synthesis and Metabolism.- II. Receptors.- III. Airway Effects.- 1. Airway Smooth Muscle.- 2. Secretion.- 3. Vascular Effects.- 4. Cellular Activation.- 5. Effects on Bronchial Responsiveness.- IV. Role in Asthma.- E. PAF.- I. Origin.- 1. Synthesis.- 2. Cellular Origin.- 3. Metabolism.- II. Receptors.- III. Airway Effects.- 1. Airway Smooth Muscle.- 2. Airway Secretions.- 3. Vascular Effects.- 4. Inflammatory Cell Activation.- 5. Bronchial Hyperresponsiveness.- IV. Role in Asthma.- 1. Release of PAF in Asthma.- 2. PAF Antagonists.- F. Kinins.- I. Formation and Metabolism.- II. Receptors.- III. Airway Effects.- IV. Role in Asthma.- G. Adenosine.- I. Origin.- II. Receptors.- III. Actions.- IV. Role in Asthma.- H. Complement.- I. Origin and Metabolism.- II. Receptors.- III. Airway Effects.- 1. Smooth Muscle Contraction.- 2. Vascular Effects.- 3. Mucus Secretion.- 4. Chemotaxis and Cell Activation.- 5. Bronchial Hyperresponsiveness:.- IV. Role in Asthma.- I. Serotonin.- I. Origin.- II. Receptors.- III. Airway Effects.- J. Chemotactic Factors.- K. Oxygen Radicals.- L. Conclusions.- References.- 4 Pharmacology of Airway Smooth Muscle.- A. Introduction.- B. E/C Coupling Mechanisms.- I. The Airway Smooth Muscle Cell.- II. Activator Calcium Ions and E/C Coupling.- 1. Coupling Mechanisms.- 2. Extracellular Activator Ca2+.- 3. Intracellular Activator Ca2+.- III. Biochemical Basis of Airway Smooth Muscle Contraction.- C. E/C Uncoupling Mechamisms.- I. ?-Adrenoceptor Agonists.- 1. ?-Agonist-Induced Relaxation In Vitro: General Properties.- 2. Role of Cyclic Adenosine Monophosphate (cAMP) Accumulation in the Relaxant Actions of ?-Adrenoceptor Agonists.- 3. ?-Agonists and the Ca2+ Sensitivity (or Responsiveness) of the Contractile Machinery.- 4. ?-Agonists and Inhibition of Ca2+ Influx.- 5. ?-Agonists and Inhibition of Ca2+ Release from Intracellular Stores.- 6. ?-Agonists and Promotion of Ca2+ Sequestration by Intracellular Stores.- 7. ?-Agonists and Ca2+ Extrusion.- II. Alkylxanthines.- 1. Alkylxanthine-Induced Relaxation In Vitro: General Properties.- 2. Role of cAMP Accumulation in the Relaxant Actions of Alkylxanthines..- 3. Alkyxanthines and Reduction in the Ca2+ Sensitivity (or Responsiveness) of the Contractile Machinery.- 4. Alkylxanthines and Inhibition of Ca2+ Influx.- 5. Alkylxanthines and Inhibition of Ca2+ Release from Intracellular Stores.- 6. Alkylxanthines and Promotion of Ca2+ Sequestration by Intracellular Stores.- 7. Alkylxanthines and Ca2+ Extrusion.- D. Future Trends in the Development of Bronchodilator Drugs.- References.- 5 Neural Mechanisms in Asthma.- A. Introduction.- B. Cholinergic Mechanisms.- I. Increased Vagal Tone.- II. Reflex Bronchoconstriction.- III. Increased Acetylcholine Release.- IV. Muscarinic Receptors.- V. Cholinergic Mechanisms in Asthma.- VI. Cholinergic Mechanisms in COAD.- VII. Muscarinic Receptor Subtypes.- C. Adrenergic Mechanisms.- I. Adrenergic Innervation.- II. Circulating Catecholamines.- III. ?-Adrenoceptors.- IV. ?-Adrenoceptors.- D. NANC Nerves and Neuropeptides.- I. NANC Inhibitory Nerves.- II. Increased NANC Excitatory Nerves.- III. Tachykinins.- IV. Calcitonin Gene-Related Peptide.- V. Axon Reflex Mechanisms.- VI. Modulation of NANC Bronchoconstriction.- E. Conclusions.- References.- 6 Pharmacology and Therapeutics of ?-Adrenoceptor Agonists.- A. Introduction.- B. The Molecular Nature of the ?-Adrenoceptor and Its Relationship to Adenylate Cyclase.- I. The ?-Adrenoceptor.- II. Regulatory Proteins.- III. Adenylate Cyclase.- IV. ?-Adrenoceptor Desensitization.- C. Density and Distribution of ?-Adrenoceptors in the Lung.- I. Radioligand Binding Studies.- II. Autoradiography.- 1. Trachea.- 2. Parenchyma.- D. Therapeutic Sites of Action.- I. Airway Smooth Muscle.- II. Secretory Cells and Cilia.- III. Tracheobronchial Microvessels.- IV. Cholinergic Nerves.- V. Mast Cells.- VI. Inflammatory Cells.- 1. Eosinophils.- 2. Lymphocytes.- 3. Polymorphonuclear Leukocytes.- 4. Macrophages.- 5. Platelets.- 6. Anti-Inflammatory Action in Asthmatic Airways.- E. The Status of ?-Adrenoceptor Function in Asthma.- I. In Vivo Studies.- II. In Vitro Studies.- 1. Isolated Human Leukocytes.- 2. Isolated Human Bronchi.- 3. Radioligand Binding Studies and Autoradiography in Lung.- F. The Importance of ?2-Adrenoceptor Selectivity and Efficacy.- I. ?2 Selectivity.- II. Efficacy.- G. Adverse Reactions to ?-Adrenoceptor Agonists.- I. Skeletal Muscle Tremor.- II. Cardiac Effects.- III. Changes in Plasma Constituents.- 1. Potassium.- 2. Glucose.- 3. Lipids.- IV. PaO2.- V. Neuropharmacological Effects.- VI. Hypersensitivity.- H. Therapeutic Actions of ?-Agonists.- I. Adrenaline.- II. Ephedrine.- III. Isoprenaline.- IV. Selective ?2-Agonists.- V. Prodrugs.- VI. Clinical Application.- I. Concluding Remarks.- References.- 7 Pharmacology of Anti-Asthma Xanthines.- A. Introduction.- I. Developmental Aspects.- II. Chemistry and Subdivision of Xanthines.- B. Clinical Use.- I. Acute Severe Asthma.- II. Chronic Asthma.- III. Chronic Obstructive Pulmonary Disorders.- C. Mode of Action of Xanthines.- I. Smooth Muscle Relaxation or Inhibition?.- II. Airway Anti-Inflammatory Actions.- III. Anti-Asthma Actions Outside the Airways?.- IV. Subcellular Mechanisms of Action.- V. Role of Endogenous Adenosine.- D. Conclusion.- References.- 8 Glucocotricosteroids in Asthma.- A. Mechanism of Action of Glucocorticosteroids.- I. Induction of Protein Synthesis.- 1. Lipocortins.- 2. Other Proteins Modulated by Glucocorticosteroids.- II. Effects on Cell Activation and Recruitment.- III. Other Effects.- 1. Vascular Permeability and Effects on Vascular Endothelium.- 2. Effects on ?-Adrenoceptors.- 3. Effects on Airway Function.- B. Clinical Use.- I. Pharmacokinetics of Steroids.- II. Routes of Administration.- 1. Oral.- 2. Intravenous.- 3. Inhaled.- III. Side Effects.- 1. Adrenal Suppression.- 2. Systemic Side Effects.- 3. Local Side Effects.- IV. Use in Clinical Practice.- 1. Acute Asthma.- 2. Chronic Asthma.- C. Future Developments.- References.- 9 Pharmacology of Prophylactic Anti-Asthma Drugs.- A. Cromoglycate and Nedocromil.- I. Cellular Pharmacology.- 1. Mast Cells and Basophils.- 2. Neutrophils, Eosinophils, Monocytes, and Platelets.- II. Biochemical Pharmacology.- III. Animal Pharmacology.- 1. Anaphylactic Bronchospasm.- 2. Sensory Reflexes.- IV. Human Pharmacology.- B. Ketotifen.- I. Pharmacology In Vitro.- II. Animal Pharmacology.- 1. Antihistamine, Antiallergic Properties.- 2. Inhibition of PAF-Induced Airway Hyperreactivity.- III. Human Pharmacology.- 1. Blockade of Responses to Spasmogens and Allergens.- 2. Reversal of ?-Adrenergic Receptor Tachyphylaxis.- 3. Double-Blind Placebo-Controlled Clinical Trials.- C. Pharmacological Analysis.- I. Cromoglycate and Nedocromil.- II. Ketotifen.- References.- 10 Pathophysiology and Pharmacology of Aspirin-Induced Asthma.- A. Introduction.- B. Definition and Main Clinical Features.- I. Major Offenders and Safe Alternatives.- II. Salicylates.- III. Paracetamol.- IV. Pyrazolones.- V. Tartrazine.- VI. Glucocorticosteroids.- C. Pathogenesis.- I. Allergic Mechanisms.- II. Abnormal Reactivity of Bradykinin Receptors.- III. Acetylation of Proteins.- IV. Complement Involvement.- V. The Cyclooxygenase Theory.- 1. Formulation of the Theory.- 2. Early Explanations.- 3. Participation of LTs.- 4. Platelet Involvement.- 5. Compartmentalization of Eicosanoids in the Lungs.- 6. Viral Infection.- D. Diagnosis.- E. Prevention and Therapy.- References.