Pharmacology of Asthma

332 Pages·1991·17.03 MB·English

by  D.Sc., Peter J. Barnes M.A., D.M.

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.
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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