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Handbook of Experimental Pharmacology Volume 98 Editorial Board G.V.R. Born, London P. Cuatrecasas, Ann Arbor, MI H. Herken, Berlin Pharmacology of Asthma Contributors A.G.Alexander, P.J.Barnes, K.F. Chung, R.J.Flower, L.G.Garland R.G.Goldie, S.T.Holgate, A.B. Kay, A. Laitinen, L.A.Laitinen K.M.Lulich, C.P.Page, J.W.Paterson, R.Pauwels, e.G.A.Persson I.W.Rodger, M.Schmitz-Schumann, R.C.Small, S.F.Smith A. Szczeklik, e. Virchow, J.W. Wilson Editors Clive P. Page and Peter 1. Barnes Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona CLIVE P. PAGE, B.Sc.,Ph.D. Reader in Pharmacology Department of Pharmacology King's College University of London Manresa Road London SW3 6LX, Great Britain PETER J. BARNES, M.A.,D.M.,D.Sc.,FRCP Professor of Thoracic Medicine Department of Thoracic Medicine National Heart and Lung Institute Dovehouse Street London SW3 6L Y, Great Britain With 45 Figures ISBN-13:978-3-642-75857-7 e-ISBN-13 :978-3-642-75855-3 DOL: 10.1007/978-3-642-75855-3 Library of Congress Cataloging-in-Publication Data. Pharmacology of asthma 1 contributors, A.G. Alexander ... let al.]; editors, Clive P. Page and Peter J. Barnes. p. cm. -(Handbook of experimental pharmacology; v. 98) Includes bibliographical references. Includes index. ISBN-13:978-3-642-75- 857-7 1. Asthma-Pathophysiology. 2. Antiasthmatic agents-Testing. 3. Bronchodi- lator agents-Testing. 4. Asthma-Chemotherapy. I. Alexander; A.G. II. Page, c.P. III. Barnes, Peter J., IV. Series. [DNLM: 1. Asthma-drug therapy. 2. Asthma-pathology. 3. Inllammation- physiopathology. WI HA51L v. 98 / WF 553 P5359] QP905.H3 vol. 98 [RC591] 615'.1 s-dc20 [616.2'38] DNLM/DLC for Library of Congress. This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broad- casting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under provisions of the German Copyright Law of September 9, 1965, in its version of June 24, 1985, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1991 Softcover reprint the hardcover 1s t edition 1991 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Typesetting: Best-set Typesetter Ltd., Hong Kong 27/3130-543210 - Printed on acid-free paper List of Contributors A.G. ALEXANDER, Department of Allergy and Clinical Immunology, National Heart & Lung Institute, Dovehouse Street, London SW3 6LY, Great Britain P.J. BARNES, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, Great Britain K. F. CHUNG, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6L Y, Great Britain R.J. FLOWER, Department of Biochemical Pharmacology, St. Bartholomew's Hospital Medical College, Charterhouse Square, London EC1M 6BQ, Great Britain L.G. GARLAND, Anti-Inflammatory Research: Research Division, The Well- come Research Laboratories, Langley Court, South Eden Park Road, Beckenham, Kent BR3 3BS, Great Britain R. G. GOLDIE, Department of Pharmacology, University of Western Australia, Perth, Nedlands, 6009, Western Au.stralia S.T. HOLGATE, Immunopharmacology Group, Medicine 1 and Clinical Phar- macology, Level D, Centre Block, Southampton General Hospital, Tremona Road, Southampton S09 4XY, Great Britain A.B. KAY, Department of Allergy and Clinical Immunology, National Heart & Lung Institute, Dovehouse Street, London SW3 6LY, Great Britain A. LAITINEN, Department of Electron-Microscopy, University of Helsinki, Mannerheimintie 172, SF-00280 Helsinki, Finland, and Department of Medical and Physiological Chemistry, University of Lund, Box 94, S-22100 Lund, Sweden L.A. LAITINEN, Department of Lung Medicine, University of Lund, Univer- sity Hospital of Lund, S-22185 Lund, and Explorative Clinical Research, AB Draco, Box 34, S-22100 Lund, Sweden K.M. LULlCH, Department of Pharmacology, University of Western Australia, Perth, Nedlands, 6009, Western Australia VI List of Contributors e.P. PAGE, Department of Pharmacology, King's College, University of London, Manresa Road, London SW3 6LX, Great Britain J.W.PATERSON, Department of Pharmacology, University of Western Aus- tralia, Perth, Nedlands, 6009, Western Australia R. PAUWELS, Department of Respiratory Diseases, State University, Aca- demic Hospital, De Pintelaan 185, B-9000 Gent, Belgium e.G.A.PERSSON, AB Draco, Box 34, S-22IDO Lund, Sweden I.W. RODGER, Department of Physiology and Pharmacology, Royal College, University of StrathcIyde, 204 George Street, Glasgow G1 1XW, Great Britain M. SCHMITZ-SCHUMANN, Hochgebirgsklinik Davos-Wolfgang, Asthma- und Allergieklinik, CH- 7265 Davos-Wolfgang, Switzerland R.e. SMALL, Department of Physiological Sciences, Medical School, Univer- sity of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, Great Britain S.F. SMITH, Department of Medicine, Charing Cross and Westminster Medical Schoor, Fulham Palace Road, London W6 8RF, Great Britain A. SZCZEKLlK, Copernicus Academy of Medicine, Department of Medicine, ul. Skawinska 8, 31-066 Krakow, Poland e. VIRCHOW, Hochgebirgsklinik Davos-Wolfgang, Asthma- und Allergie- klinik, CH-7265 Davos-Wolfgang, Switzerland J.W. WILSON, Immunopharmacology Group, Medicine 1 and Clinical Phar- macology, Southampton General Hospital, Tremona Road, Southampton S09 4XY, Great Britain Preface 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 and future therapy of this common chronic disease. Many of the advances in 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 F. Airway Smooth Muscle ........................................ 13 G. Bronchial Glands. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 13 H. Neural Pathways ............................................. 14 I. Epithelium ............................................... 14 II. Neuroepithelial Bodies and Neuroendocrine-Like (Granule-Containing) Cells . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . .. 15 I. Nerves and Other Airway Structures ............................ 16 J. Bronchial Circulation ......................................... 16 K. Leakage of the Bronchial Vascular Bed in Patients with Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 17 L. Conclusion .................................................. 19 References .................................................... " 20 CHAPTER 2 The Contribution of Inflammatory Cells to the Pathogenesis of Asthma A.G. ALEXANDER, J.W. WILSON, S.T. HOLGATE, and A.B. KAY. With 5 Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 27 A. Inflammation and Inflammatory Cells. . . . . . . . . . . . . . . . . . . . . . . . . . .. 27 B. Pathological Evidence for Inflammation in Asthma ................ 28 C. Microvascular Leakage ...................................... " 29 D. Neutrophils.................................................. 30 x Contents E. Eosinophils.................................................. 32 F. Mast Cells and Basophils ...................................... 35 G. Monocytes and Macrophages (Mononuclear Phagocytes) ........... 37 H. Platelets..................................................... 38 I. Lymphocytes................................................ 39 J. Concluding Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 42 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 44 CHAPTER 3 Inflammatory Mediators P.J. BARNES, K.F. CHUNG, and C.P. PAGE. With 5 Figures... .... . ... .. 53 A. Introduction................................................ 53 I. Cellular Origin of Mediators .............................. 53 II. Mediator Effects ........................................ 54 III. Mediator Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 55 IV. Mediator Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 57 V. Mediator Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 57 B. Histamine.................................................. 57 I. Synthesis and Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 58 II. Histamine Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 58 III. Airway Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 59 IV. Role in Asthma ......................................... 60 C. Cyclooxygenase Products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 61 I. Synthesis and Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 61 II. Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 63 III. Airway Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 63 1. Airway Smooth Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 63 2. Secretion ......................... '. . . . . . . . . . . . . . . . . .. 64 3. Inflammatory Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 64 IV. Role in Asthma ......................................... 64 D. Lipoxygenase Products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 65 I. Synthesis and Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 65 II. Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 66 III. Airway Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 67 1. Airway Smooth Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 67 2. Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 67 3. Vascular Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 67 4. Cellular Activation. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. 68 5. Effects on Bronchial Responsiveness. . . . . . . . . . . . . . . . . . . .. 68 IV. Role in Asthma ......................................... 68 E. PAF ....................................................... 69 I. Origin ................................................. 69 1. Synthesis ............................................ 69 2. Cellular Origin ....................................... 70 3. Metabolism.......................................... 70 Contents XI II. Receptors.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 71 III. Airway Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 71 1. Airway Smooth Muscle .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 71 2. Airway Secretions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 72 3. Vascular Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 72 4. Inflammatory Cell Activation. . . . . . . . . . . . . . . . . . . . . . . . . .. 73 5. Bronchial Hyperresponsiveness . . . . . . . . . . . . . . . . . . . . . . . .. 74 IV. Role in Asthma ......................................... 75 1. Release of P AF in Asthma ............................. 75 2. P AF Antagonists ..................................... 77 F. Kinins ..................................................... 78 I. Formation and Metabolism ............................... 78 II. Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 79 III. Airway Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 79 IV. Role in Asthma ......................................... 80 G. Adenosine.................................................. 81 I. Origin ................................................. 81 II. Re<;:eptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 81 III. Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 81 IV. Role in Asthma ......................................... 82 H. Complement............. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 82 I. Origin and Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 82 II. Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 83 III. Airway Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 83 1. Smooth Muscle Contraction ....... . . . . . . . . . . . . . . . . . . . .. 83 2. Vascular Effects " . . . . . . . . . . . . . . . . . . . . . . • . . . . . . . . . . . .. 84 3. Mucus Secretion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 84 4. Chemotaxis and Cell Activation. . . . . . . . . . . . . . . . . . . . . . . .. 84 5. Bronchial Hyperresponsiveness ........ ; . . . . . . . . . . . . . . .. 84 IV. Role in Asthma ......................................... 85 I. Serotonin.................................................. 85 I. Origin ................................................. 85 II. Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 86 III. Airway Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 86 J. Chemotactic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 86 K. Oxygen Radicals ............................................ 87 L. Conclusions ................................................ 88 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 89 CHAPTER 4 Pharmacology of Airway Smooth Muscle I. W. RODGER and R. C. SMALL. With 6 Figures. . . . . . . . . . . . . . . . . . . . . .. 107 A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 107 B. E/C Coupling Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 107 XII Contents I. The Airway Smooth Muscle Cell ......................... " 107 II. Activator Calcium Ions and E/C Coupling . . . . . . . . . . . . . . . . . .. 108 1. Coupling Mechanisms ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 108 2. Extracellular Activator Ca2+ . . . . . . . . . . . . . . . . . . . . . . . . . . .. 109 3. Intracellular Activator Ca2+. ............................ 111 III. Biochemical Basis of Airway Smooth Muscle Contraction ...... 114 C. E/C Uncoupling Mechamisms ............ '" .................. 119 I. I3-Adrenoceptor Agonists ................................. 120 1. I3-Agonist-Induced Relaxation In Vitro: General Properties.. 120 2. Role of Cyclic Adenosine Monophosphate (cAMP) Accumulation in the Relaxant Actions of p-Adrenoceptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . .. 120 3. p-Agonists and the Ca2+ Sensitivity (or Responsiveness) ofthe Contractile Machinery ........................... 121 4. p-Agonists and Inhibition of Ca2+ Influx ................ " 122 5. p-Agonists and Inhibition of Ca2+ Release from Intracellular Stores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 125 6. p-Agonists and Promotion of Ca2+ Sequestration by Intracellular Stores ................................. 126 7. p-Agonists and Ca2+ Extrusion ......................... 127 II. Alkylxanthines.......................................... 127 1. Alkylxanthine-Induced Relaxation In Vitro: General Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 127 2. Role of cAMP Accumulation in the Relaxant Actions of Alkylxanthines ........ ; . . . . . . . . . . . . . . . . . . . . . . . . . . .. 127 3. Alkyxanthines and Reduction in the Ca2+ Sensitivity (or Responsiveness) of the Contractile Machinery. . . . . . . . .. 129 4. Alkylxanthines and Inhibition of Ca2+ Influx. . . . . . . . . . . . .. 129 5. Alkylxanthines and Inhibition of Ca2+ Release . from Intracellular Stores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 130 6. Alkylxanthines and Promotion of Ca2+ Sequestration by Intracellular Stores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 132 7. Alkylxanthines and Ca2 + Extrusion ...................... 133 D. Future Trends in the Development of Bronchodilator Drugs ....... 133 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 134 CHAPTER 5 Neural Mechanisms in Asthma P.l. BARNES. With 9 Figures ...................................... 143 A. Introduction................................................ 143 B. Cholinergic Mechanisms ...................................... 145 I. Increased Vagal Tone ................................... 145 II. Reflex Bronchoconstriction .............................. 145

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