Table Of ContentProgress in Inflammation Research
Series Editor
Prof. Dr. Michael J. Parnham
PLiVA
Research Institute
Prilaz baruna Filipovica 25
10000 Zagreb
Croatia
T Cells in Arthritis, P. Miossec, W. van den Berg, G. Firestein (Editors), 1998
Chemokines and Skin, E. Kownatzki, J. Norgauer (Editors), 1998
Medicinal Fatty Acids, J. Kremer (Editor), 1998
Inducible Enzymes in the Inflammatory Response, D. A. Willoughby, A. Tomlinson (Editors),
1999
Cytokines in Severe Sepsis and Septic Shock, H. Redl, G. Schlag (Editors), 1999
Fatty Acids and Inflammatory Skin Diseases, J.-M. Schroder (Editor), 1999
Immunomodulatory Agents from Plants, H. Wagner (Editor), 1999
Cytokines and Pain, L. Watkins, S. Maier, (Editors), 1999
In vivo Models of Inflammation, D. Morgan, L. Marshall, (Editors), 1999
Pain and Neurogenic Inflammation, S. D. Brain, P: Moore (Editors), 1999
Forthcoming titles:
Apoptosis and Inflammation, James D. Winkler (Editor), 1999
Novel Inhibitors of Leukotrienes, G. Folco, B. Samuelsson, R.c. Murphy (Editors), 1999
Vascular Adhesion Molecules and Inflammation, J. D. Pearson (Editor), 1999
Metalloproteinases as Targets for Anti-Inflammatory Drugs, K.M.K. Bottomley, D. Bradshaw,
J.S. Nixon (Editors), 1999
Free Radicals and Inflammation, P. Winyard, D. Blake, Ch. Evans, (Editors), 1999
Gene therapy in Inflammatory Diseases, Ch. Evans, P. Robbins (Editors), 1999
Anti-Inflammatory Drugs in Asthma
Anthony P. Sampson
Martin K. Church
Editors
Springer Basel AG
Editors
Dr. Anthony P. Sampson
Prof. Martin K. Church
Immunopharmacology Group
Southampton General Hospital
Tremona Road
Southampton, S016 6YD
UK
A CIP catalogue record for this book is available from the Library of Congress, Washington D.C., USA
Deutsche Bibliothek Cataloging-in-Publication Data
Anti-inflammatory drugs in asthma I Anthony B. Sampson ;
Martin K. Church (ed.). - Springer Basel AG, 1999
(progress in inflammation research)
ISBN 978-3-0348-9757-0 ISBN 978-3-0348-8751-9-(eBook)
DOI 10.1007/978-3-0348-8751-9
The publisher and editor can give no guarantee for the information on drug dosage and administration contained in
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This work is subject to copyright. AII rights are reserved, whether the whole or part of the material is concerned,
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be obtained.
© 1999 Springer Basel AG
Originally published by Birkhăuser Verlag in 1999
Softcover reprint of the hardcover 1s t edition 1999
Printed on acid-free paper produced from chlorine-free pulp. TCF =
Cover design: Markus Etterich, Basel
ISBN 978-3-0348-9757-0
987654321
Contents
List of contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
James L. Lordan and Ratko D;ukanovic
Anti-inflammatory drugs in asthma: the pathophysiology of asthma. . . . . . . . . . . . 1
Peter J. Barnes
Corticosteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 35
Hermann Tenor and Christian Schudt
Phosphodiesterases in asthma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 87
Joanna S. Thompson Coon and Anne E. Tattersfield
~2-Agonists ....................................................................... 137
Guy F. Joos, Renaat A. Peleman and Romain A. Pauwels
Mast cell stabilizing drugs ........................................................ 153
Zuzana Diamant and Anthony P. Sampson
Anti-Ieukotriene therapy for asthma .............................................. 169
U Cher Loh and Neil C. Barnes
Immunomodulators ............................................................... 199
Francesco Patalano
Anti-lgE agents ................................................................... 215
Steven 1. Compton and Andrew F. Walls
Mast cell proteases as new targets for therapeutic intervention in asthma ....... 229
Paul S. Foster and Simon P. Hogan
Cytokine and adhesion molecule antagonists .................................... 251
Index .............................................................................. 273
List of contributors
Neil C. Barnes, Department of Respiratory Medicine, The London Chest Hospital,
Bonner Road, London E2 9X, UK
Peter J. Barnes, Department of Thoracic Medicine, National Heart and Lung Insti
tute, Dovehause St., London SW3 6 LY, UK; e-mail: [email protected]
Li Cher Loh, Department of Respiratory Medicine, The London Chest Hospital,
Bonner Road, London E2 9JX, UK
Steven J. Compton, Immunopharmacology Group, University of Southampton,
Southampton General Hospital, Southampton, S016 6YD, UK;
e-mail: [email protected]. uk
Zuzana Diamant, Erasmus University Medical Centre Rotterdam, Department of
Respiratory Diseases, Dr Molewaterplein 40, NL-3015 GD Rotterdam, The Nether
lands; e-mail: [email protected]
Ratko Djukanovic, University Medicine (810), Level D, Centre Block, Southampton
General Hospital, Tremona Road, Southampton, S016 6YD, UK
Paul S. Foster, Division of Biochemistry and Molecular Biology, John Curtin School
of Medical Research, Australian National University, Acton ACT 0200;
e-mail: [email protected]
Simon P. Hogan, Division of Biochemistry and Molecular Biology, John Curtin
School of ~dical Research, Australian National University, Acton ACT 0200;
e-mail: [email protected]
Guy F. Joos, Department of Respiratory Diseases, University Hospital Ghent, De
Pintelaan 185, B-9000 Ghent, Belgium; e-mail: [email protected]
List of contributors
James L. Lordan, University Medicine (810), Level D, Centre Block, Southampton
General Hospital, Tremona Road, Southampton, S016 6YD, UK;
e-mail: [email protected]
Francesco Patalano, SkyePharma AG, Eptingerstr. 51, CH-4132 Muttenz, Switzer
land; e-mail: [email protected]
Romaine A. Pauwels, Department of Respiratory Diseases, University Hospital
Ghent, De Pintelaan 185, B-9000 Ghent, Belgium
Renaat A. Peleman, Department of Respiratory Diseases, University Hospital
Ghent, De Pintelaan 185, B-9000 Ghent, Belgium
Anthony P. Sampson, Immunopharmacology Group, Level F, Centre Block (825),
Southampton General Hospital, Tremona Road, Southampton, S016 6YD, UK;
e-mail: [email protected]
Christian Schudt, Byk Gulden Lomberg, Chemische Fabrik GmbH. Byk Gulden
Strasse 2, D-78467 Konstanz, Germany; e-mail: [email protected]
Anne E. Tattersfield, Division of Respiratory Medicine, ity Hospital, Mucknall
Road, Nottingham, NG IPB, UK
Hermann Tenor, Byk Gulden Lomberg, Chemische Fabrik GmbH, Byk Gulden
Strasse 2, D-78467 Konstanz, Germany; e-mail: [email protected]
Joanna S. Thompson Coon, Division of Respiratory Medicine, City Hospital, Huck
naIl Road Nottingham, NG5 IPB, UK; e-mail: [email protected]
Andrew F. Walls, Immunopharmacology Group, University of Southampton, Mail
point 837, Southampton General Hospital, Southampton, S016 6YD, UK;
e-mail: [email protected]
viii
Anti-inflammatory drugs in asthma: The pathophysiology of
asthma
James L. Lordan and Ratko Djukanovic
University Medicine (810), Level D, Centre Block, Southampton General Hospital, Tremona
Road, Southhampton, 5016 6YD, UK
Introduction
Asthma is a chronic condition characterised by widespread, variable and reversible
airflow obstruction which is either spontaneous or pharmacologically induced. The
underlying pathophysiological feature of asthma is increased airway responsiveness
which develops on a basis of diffuse bronchial inflammation. The prevalence of
asthma is increasing worldwide despite improved treatment which has resulted from
a more comprehensive understanding of its pathogenesis [1].. In most countries asth
ma affects between 4 and 8 % of the popu lation, with a trend towards an increase
in morbidity as judged by increased hospital admissions [2]. The reasons for this are
unclear, but environmental factors SUcD. as indoor and outdoor air pollution and
changes in lifestyle are considered to be amongst the contributing factors.
Asthma is clearly a complex process mediated by inflammatory cells and the
formed and structural elements of the airway, involving numerous cytokines,
chemokines, and costimulatory and adhesion molecules that interact in a complex
network (Fig. 1). There is accumulating evidence establishing a link between chron
ic inflammation and remodelling of the airways in asthma. The present evidence of
relatively permanent, irreversible structural changes found at an early stage in asth
ma supports the recommendations of current asthma management guidelines that
effective anti-inflammatory treatment be introduced at an early stage in the man
agement of asthma.
Asthma has been closely associated with atopy, the ability to generate an IgE
response to environmental allergens which is detected by positive skin tests to one
or more allergens, although it is interesting to note that only one-fifth of atopic indi
viduals actually develop asthma. Whilst the presence of allergen specific IgE has
been considered to be central to allergic responses in human allergic disease, studies
using IgE-deficient mice have demonstrated that bronchial eosinophilic inflamma
tion and airway hyperresponsiveness (AHR) can occur in the absence of IgE [3]. To
what extent these observations are relevant to human disease remains to be eluci
dated. Clinical studies using a humanised monoclonal antibody to IgE show that
Anti·lnflammatory Drugs in Asthma, edited by A.P. Sampson and M.K. Church
© 1999 Birkhauser Verlag Basel/Switzerland 1
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Anti-inflammatory drugs in asthma: The pathophysiology of asthma
despite a dramatic depletion of IgE from the circulation with the prevention of the
early and late phase response to allergen challenge, the clinical response in allergic
asthmatics is quite poor [4, 5]. These studies suggest that while IgE is likely to be
contributing to the inflammatory process in asthma, other immune mechanisms
must be operating in parallel [6].
The genetiC basis of asthma
There is evidence from family aggregation studies to support an important role for
genetic contributionfactors into the development of atopy and asthma. The preva
lence of asthma in first-order relatives of asthmatics is 20-25% compared with
4-5% in the general population [1]. The relative contribution of genetic factors to
the onset of allergy and asthma is estimated at 40-60% [7]. Twin studies, including
a large study of 7000 same-sex twins by Edfors-Lubs, provide evidence for the
genetic contribution to the. onset of asthma, with concordance for asthma in
monozygotic twins being 19%, and only 4.8% for dizygotic twins, who share less
common genetic material [8]. Asthma is a complex genetic disorder, with studies
suggesting a polygenic inheritance pattern which interacts with environmental fac
tors to express the full clinical and pathophysiological phenotype [1].
Genetic studies are being used to characterise and map the genes responsible for
the asthmatic phenotype. Studies in British families by Cookson and colleagues were
the first to provide evidence of linkage of atopy to a marker (DIIS97) on chromo
some llq13 in the vicinity of genes for CD20 (a B cell marker) and FceRI-/3, the /3
component of the high affinity IgE receptor [9-12]. An iso-leucine to leucine poly
morphism at position 181 was identified in the FceRI-/3 gene and was found in 15%
of individuals, being associated with the phenotype of high total serum IgE [13]. A
polymorphism (Glu 237-Gly) was found in 5.3% of the population in a study by
Hill and colleagues and this was associated with AHR and atopy [5014]. There is
Figure 1
The inflammatory process in asthma involves the activation of Th2 type T cells by antigen
presenting cells (APCs) resident in the airway wall (i.e. dendritic cells). T cell derived
cytokines, including Interleukin-4 and IL-13 promote the switching of B cells to the synthe
sis of IgE. Cytokines are involved in the activation and differentiation of eosinophils and
mast cells with release of pro-inflammatory mediators, leading to epithelial damage, bron
choconstriction and symptoms of asthma. The bronchial epithelium plays an active role by
the release of mediators and cytokines. MHC, major histocompatibility complex class II;
TCR, T cell receptor; Fc£RI, high affinity IgE receptor; MBP, major basic protein; ECp,
eosinophil cationic protein; LT, leukotrienes; PGD2, Prostaglandin D2.
3
