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Inducible Enzymes in the Inflammatory Response
Derek A. Willoughby
Annetle Tomlinson
Editors
Springer Basel AG
Editors
Prof. Derek A. Willoughby
Dr. Annetle Tomlinson
Department of Experimental Pathology
St. Bartholomew's and
The Royal London School of Medicine and Dentistry
Charterhouse Square
London, EC1 M 6BQ
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
Induclble enzymes In the Inflammatory response / ed. by DA Willoughby, A. Tomlinson -Basel ; Boston;
Berlin : Birkhăuser, 1999
(progress in inflammation research)
ISBN 978-3-0348-9755-6 ISBN 978-3-0348-8747-2 (eBook)
DOI 10.1007/978-3-0348-8747-2
The publisher and editor can give no guarantee for the information on drug dosage and administration contained in
this publication. The respective user must check its accuracy by consulting other sources of reference in each individual
case.
The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that
they are exempt from the relevant protective laws and regulations or free for general use.
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 lSt edition 1999
Printed on acid-free paper produced from chlorine-free pulp. TCF =
Cover design: Markus Etlerich, Basel
ISBN 978-3-0348-9755-6
987654321
Contents
List of contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. vii
Preface............................................................................ ix
Michel Pairet, Joanne van Rhyn and Manuel Distel
Overview of COX-2 in inflammation: from the biology to the clinic............. 1
Adrian J. Hobbs and Salvador Moncada
Inducible nitric oxide synthase and inflammation................................ 31
Dean Willis
Overview of HO-1 in inflammatory pathologies ................................. 55
Vivienne R. Winrow and David R. Blake
Inducible enzymes in the pathogenesis of rheumatoid arthritis. . . . . . . . . . . . . . . . .. 93
Lee D.K. Buttery and Julia M. Polak
iNOS and COX-2 in atherosclerosis .............................................. 109
Michael P. Seed, Derek Gilroy, Mark Paul-Clark, Paul R. Colville-Nash,
Dean Willis, Annette Tomlinson and Derek A. Willoughby
The role of the inducible enzymes cyclooxygenase-2, nitric oxide synthase
and heme oxygenase in angiogenesis of inflammation ........................... 125
Sergio H. Ferreira, Fernando Q. Cunha and Stephen Hyslop
Role of the inducible forms of cyclooxygenase and nitric oxide
synthase in inflammatory pain .................................................... 149
Bernd C. Kieseier and Hans-Peter Hartung
Neuroinflammation ............................................................... 169
Contents
Annette Tomlinson and Derek A. Willoughby
Inducible enzymes in inflammation: advances, interactions and conflicts .. ..187
Index .............................................................................. 207
vi
List of contributors
David R. Blake, The Royal National Hospital for Rheumatic Diseases, Upper
Borough Walls, Bath BA1 1RL; e-mail: [email protected]
Lee D.K. Buttery, Department of Histochemistry, Imperial College School of Medi
cine, Hammersmith Campus, Du Cane Road, London W12 ONN, UK;
e-mail: [email protected]. uk
Paul R. Colville-Nash, Experimental Pathology, William Harvey Research Institute,
St. Bartholomew's and The Royal London School of Medicine and Dentistry, Char
terhouse Square, London EC1M 6BQ, UK;
e-mail: [email protected]
Fernando Q. Cunha, Department of Pharmacology, Faculty of Medicine Ribeirao
Preto, University of Sao Paulo, Avenida Bandeirantes, 3900, Ribeirao Preto, Sao
Paulo 14051-900 Brazil; e-mail: [email protected]
Manuel Distel, Department of Medicine, Boehringer Ingelheim International, 300
Beach Road, #14-02/04 The Concourse, Singapore, 199555
Sergio H. Ferreira, Department of Pharmacology, Faculty of Medicine Ribeirao
Preto, University of Sao Paulo, Avenida Bandeirantes, 3900, Ribeirao Preto, Sao
Paulo 14051-900 Brazil; e-mail: [email protected]
Derek Gilroy, Experimental Pathology, William Harvey Research Institute, St.
Bartholomew's and The Royal London School of Medicine and Dentistry, Charter
house Square, London EC1M 6BQ, UK; e-mail: [email protected]
Hans-Peter Hartung, Department of Neurology, Karl-Franzens-Universitiit, Auen
bruggerplatz 22, A-8036 Graz, Austria; e-mail: [email protected]
Adrian J. Hobbs, Wolfson Institute for Biomedical Research, University College
London, Rayne Institute, 5 University Street, London WC1E 6JJ, UK
List of contributors
Stephen Hyslop, Department of Pharmacology, Faculty of Medical Science, Univer
sity of Camp in as, Campinas, Sao Paulo, Brazil
Bernd Kieseier, Department of Neurology, Karl-Franzens-Universitat, Auenbrugger
platz 22, A-8036 Graz, Austria; e-mail: [email protected]
Salvador Moncada, Wolfson Institute for Biomedical Research, University College
London, Rayne Institute, 5 University Street, London WCIE 6J], UK
Michel Pairet, Department of Pulmonary Research, Boehringer Ingelheim, Birk
endorfer Str. 65, D-88397 Biberach, Germany; e-mail: [email protected]
heim.com
Mark Paul-Clark, Experimental Pathology, William Harvey Research Institute, St.
Bartholomew's and The Royal London School of Medicine and Dentistry, Charter
house Square, London ECIM 6BQ, UK; e-mail: [email protected]
Julia M. Polak, Department of Histochemistry, Imperial College School of Medi
cine, Hammersmith Campus, Du Cane Road, London W12 ONN, UK;
e-mail: [email protected]. uk
Michael P. Seed, Paneutics, P.O.Box 1358, Swindon SN3 4GP, UK;
e-mail: [email protected]
Annette Tomlinson, Experimental Pathology, William Harvey Research Institute, St.
Bartholomew's and The Royal London School of Medicine and Dentistry, Charter
house Square, London ECIM 6BQ, UK; e-mail: [email protected]
Joanne van Ryn, Department of Pulmonary Research, Boehringer Ingelheim, Birk
endorfer Str. 65, D-88397 Biberach, Germany;
e-mail: [email protected]
Dean Willis, Experimental Pathology, William Harvey Research Institute, St.
Bartholomew's and The Royal London School of Medicine and Dentistry, Charter
house Square, London ECIM 6BQ, UK; e-mail: [email protected]
Derek A. Willoughby, Experimental Pathology, William Harvey Research Institute,
St. Bartholomew's and The Royal London School of Medicine and Dentistry, Char
terhouse Square, London ECIM 6BQ, UK; e-mail: [email protected]
Vivienne R. Winrow, Department of Postgraduate Medicine, University of Bath,
Claverton Down, Bath BA2 7 AY, UK; e-mail: [email protected]
viii
Preface
This volume will be of great value to all those researchers in the area of the inflam
matory response, notably academics, clinicians and members of the pharmaceutical
industry.
The book has in the main been restricted to three inducible enzymes, namely
nitric oxide synthase (iNOS), cyclooxygenase (COX-2) and hemeoxygenase (HO-l),
although matrix metalloproteinases, xanthine oxidoreductase and tissue transgluta
minases are reviewed. The modulation of these enzymes is viewed as possible novel
therapeutic advances in the area of inflammation and also cancer. The latter topic
may well be the subject of a further book.
It will be interesting to observe the progress of such new therapies in the next
decade. Already some of these enzyme modulators have been approved for the treat
ment of inflammatory disease, as evidenced by the new families of COX-2
inhibitors. We believe such advances will herald a series of new and exciting agents
to be included in the clinician's armamentarium in the constant struggle against
inflammatory disease.
The editors wish to thank all contributors to this volume on inducible enzymes.
It should however be stressed that the views expressed by the authors are personal
and do not necessarily reflect those of the editors. Indeed, the reader may find con
flicting statements in a number of the chapters. We believe that this is entirely appro
priate as this volume reflects the latest work in a rapidly developing area.
Finally, the editors would like to express their thanks to Birkhiiuser and their
helpful staff, in particular Janine Kern. We hope the reader enjoys the book and
finds some thought-provoking issues in this wide spectrum of recent advances in a
new and exciting field.
Derek Willoughby
Annette Tomlinson
Overview of COX-2 in inflammation: from the biology to the
clinic
Michel Pairet, Joanne van Ryn and Manuel Distel*
Department of Biological Research and Department of Medicine*, Boehringer Ingelheim,
Birkendorfer Str. 65, 0-88397 Biberach/Riss, Germany
Discovery of COX-2: Key findings
Cyclooxygenase (COX) is part of a bifunctional enzyme, prostaglandin H synthase
(PGHS), which catalyzes the first step in the conversion of membrane phospholipids
(principally, arachidonic acid) into prostanoids (prostaglandins and thromboxanes).
Prostanoids contribute to diverse physiological and pathological processes including
inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs), the prototype of
which is aspirin, owe their therapeutic effects to blockade of prostaglandin synthe
sis through COX blockade [1]. NSAIDs are a heterogenous group of compounds,
often chemically unrelated, which nevertheless share therapeutic effects (i.e. anti
inflammatory, analgesic and antipyretic) and side effects (i.e. gastrointestinal ero
sions, decreased renal function, inhibition of platelet aggregation). Until recently, it
had been widely accepted that a common mechanism (COX inhibition) is responsi
ble for both the therapeutic and the side-effects of NSAIDs. However, this theory
has been refined since the discovery of a second, inducible COX isozyme, COX-2
[2, 3]. It has been proposed that COX-2 inhibition is relevant for the anti-inflam
matory effects of NSAIDs, whereas inhibition of constitutive COX-l is responsible
for the gastric and renal side effects, as well as for the antithrombotic activity of
these agents [4].
The suggestion that an inducible PGHS (for clarity, referred to as COX) existed,
arose from studies in the field of inflammation and reproductive biology. As early
as 1988, it was noticed that in spite of treatment with antibodies raised against
COX purified from ram seminal vesicle (now known to be COX-I), fibroblasts were
still able to increase their prostaglandin biosynthetic activity in response to inter
leukin-l (IL-l) [5, 6]. Prostaglandin synthase activity was also shown to be strong
ly stimulated by bacterial endotoxin in human monocytes in vitro [2] as well as
mouse macro phages in vivo [7]. Importantly, this increase was associated with the
de novo, glucocorticoid-sensitive synthesis of new COX protein [8]. Studies in the
rat ovary also provided evidence that two immunologically distinct forms of COX
exist and that one of these two forms can be selectively regulated by hormones
Inducible Enzymes in the Inflammatory Response, edited by D.A. Willoughby and A. Tomlinson
© 1999 Birkhauser Verlag Basel/Switzerland
