Gastric Cytoprotection: A Clinician’s Guide

227 Pages·1989·6.41 MB·English

by  André Robert (auth.)

Gastric Cytoprotection
A Clinician's Guide
Gastric Cytoprotection
A Clinician's Guide
Edited by
DANIEL HOLLANDER, M.D.
Division 0/ GtlstroenteroloD
Department 0/ Medicine
Univenity 0/ CIl/ifomill-lrvine
Irvine. CIllifomill
and
ANDRZEJ S. TARNAWSKI, M.D., D.Sc.
Vetertlns Adminislnltion Medal emter
Long /JeQch. CIllifomill
and Division 0/ Gastroenterology
Department 0/ Medicine
University 0/ Califomill-Irvine
Irvine. CIllifomill
PLENUM MEDICAL BOOK COMPANY •
NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
Gastric cytoprotection I edited by Daniel Hollander and Andrzej S. Tarnawski.
p. cm.
Includes bibliographies and index.
ISBN 978-1-4684-5699-8
1. Peptic ulcer-Etiology.2. Gastric mucosa. I. Hollander, Daniel. II. Tarnawski, Andrzej.
[DNLM: 1. Gastric Mucosa-cytology. 2. Gastric Mucosa-physiology. 3. Intestinal Mu-
cosa-cytology.4. Intestinal Mucosa-physiology. WI 302 G2545]
RC821.G37 1989
616.3'43071-dc20
DNLM/DLC 89-16101
for Library of Congress CIP
ISBN-13: 978-1-4684-5699-8 e-ISBN-13: 978-1-4684-5697-4
001: 10.1007/978-1-4684-5697-4
© 1989 Plenum Publishing Corporation
Softcover reprint of the hardcover 1s t edition 1989
233 Spring Street, New York, N.Y. 10013
Plenum Medical Book Company is an imprint of Plenum Publishing Corporation
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
Contributors
Adrian Allen • Department of Physiological Sciences, Medical School, Uni
versity of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, England
Gregory L. Eastwood • Gastroenterology Division, University of Mas
sachusetts Medical School, Worcester, Massachusetts 01605
Daniel Hollander • Division of Gastroenterology, Department of Medicine,
University of California-Irvine, Irvine, California 92717
Andrew C. Hunter • Department of Physiological Sciences, Medical
School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2
4HH, England
Jan W. Konturek • Institute of Physiology, Academy of Medicine, 31-531
Krakow, Poland
Stanislaw J. Konturek • Institute of Physiology, Academy of Medicine,
31-531 Krakow, Poland
Anwar H. Mall • Department of Physiological Sciences, Medical School,
University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH,
England
Peter J. Oates • Central Research Division, Pfizer Inc., Department of Met
abolic Diseases, Groton, Connecticut 06340
James Penston • Ninewells Hospital, Dundee DDI 9SY, Scotland
Wynne D. W. Rees • Department of Gastroenterology, Hope Hospital, Uni
versity of Manchester School of Medicine, Salford M6 8HD, England
Andre Robert • Drug Metabolism Research, The Upjohn Company, Kala
mazoo, Michigan 49001
Christopher J. Shorrock • Department of Gastroenterology, Hope Hospi
tal, University of Manchester School of Medicine, Salford M6 8HD,
England
v
Contributors
vi
Jerzy Stachura • Department of Cell Pathology, University Medical School,
31-531 Krakow, Poland; and Division of Gastroenterology, University of
California-Irvine, Irvine, California 92717
Sandor Szabo • Department of Pathology, Brigham & Women's Hospital,
and Department of Pathology, Harvard Medical School, Boston, Mas
sachusetts 02115
Andrzej Tarnawski • Veterans Administration Medical Center, Long
Beach, California 90822; and Division of Gastroenterology, Department of
Medicine, University of California-Irvine, Irvine, California 92717
Donald E. Wilson • Department of Medicine, State University of New
York, Health Science Center at Brooklyn, Brooklyn, New York 11203
Kenneth G. Wormsley • Ninewells Hospital, Dundee 001 9SY, Scotland
Preface
Gastric secretions contain hydrogen ions at a concentration that is more than one
million times higher than their intracellular concentration. This phenomenal
gradient as well as the demonstrated ability of gastric juice to digest tissues has
motivated clinicians and investigators alike to emphasize acid secretion and acid
ablation in studying the pathogenesis and therapy of peptic ulcer disease. Conse
quently, over the past 150 years, we have made considerable progress in under
standing the mechanisms and regulation of acid secretion by the stomach. Not
surprisingly, therapy for both peptic disease and mucosal injury has also been
predominantly directed at either neutralizing acid or suppressing its production.
During the past 10 years, attention has been focused on factors other than
acid in the genesis and therapy of ulcer disease. Work done worldwide demon
strated that acid hypersecretion is not a common event in peptic ulcer disease.
Therefore, we began realizing that factors other than acid secretion may be
important in the genesis of ulcer disease or in gastroduodenal mucosal damage.
In addition, new physiological information has established that the gas
troduodenal mucosa is normally protected by a complex series of events includ
ing mucus and bicarbonate secretion, cell renewal, surface mucosal restitution,
and preservation of the microvasculature and mucosal proliferative zone.
Our increased understanding of how the gastroduodenal mucosa protects
itself has given rise to a general concept referred to as cytoprotection or mucosal
protection. Concepts of cytoprotection have greatly enlarged our overall perspec
tive of peptic ulcer disease and mucosal injury and have also resulted in the
development of new therapeutic approaches to these problems. The cytoprotec
tive approach uses drugs, such as prostaglandins, sucralfate, bismuth com
pounds, antacids, and dietary essential fatty acids, which are precursors of pros
taglandin synthesis.
The concepts of cytoprotection and its specific mechanisms have been pub
lished primarily in journals or books oriented toward the investigator . Yet this
vii
viii Preface
new infonnation needs to be transmitted from the research literature to the
clinical arena. Clinicians must begin to understand these new and exciting con
cepts in order to be able to offer their patients newer therapies in addition to acid
inhibition.
This book attempts to bridge this gap. The authors summarize the present
state of our knowledge, simplify its presentation, and point out the therapeutic
implications of this evolving field. The volume should help elucidate these
concepts for general internists and gastroenterologists alike and, it is hoped,
begin to bridge the gap between the research laboratory and medical practice.
Many of the concepts presented here are still in an evolutionary state. The
precise mechanisms of how the gastroduodenal mucosa protects itself are not
known. Therefore, the reader will have to be tolerant of some lack of clear-cut
explanations for many of the observations. In addition, it should be borne in
mind that we are presenting still-evolving infonnation-infonnation that is still
fresh off the laboratory bench, and about which consensus has yet to be reached
in the medical community. Therefore, the authors presenting the work may not
necessarily agree with each other on every deLail or every explanation.
The authors of these chapters are some of the leading experts in cytoprotec
tion research. They present their personal views of the latest developments in
their areas of expertise. We thank them for their enthusiastic support and willing
ness to contribute to this clinician-oriented book.
We want to thank our administrative assistant, Ms. Nancy Pharo, for her
continuous help, and also to thank the many individuals at Plenum Publishing
Corporation for their help and encouragement.
Daniel Hollander
Andrzej Tamawski
Irvine, California
Contents
Part I. Cytoprotection for the Clinician
Chapter 1
Cytoprotection: Historical Perspective 3
Andre Robert
1. Introduction ............................................. 3
2. Antiulcer Effect without Acid Inhibition ...................... 4
3. Direct Cytoprotection ..................................... 6
4. Differences among Prostaglandins ........................... 7
5. Clinical Studies on Cytoprotection ........................... 7
6. Adaptive Cytoprotection ................................... 7
7. Functional Cytoprotection .................................. 8
8. Intestinal Cytoprotection ................................... 9
9. Conclusions ............................................. 10
Annotated Bibliography ................................... 11
Chapter 2
Acid Hypersecretion: Important Factor
or Innocent Bystander? ..... ...... ........... ................ 13
James Penston and Kenneth G. Worms ley
1. Introduction ............................................. 13
2. Information Interpreted as Indicating a Connection
between Gastric Juice and Duodenal Ulceration ................ 14
2.1. Animal Studies ...................................... 14
2.2. Human Studies ...................................... 15
ix
x Contents
2.3. Response to Treatment ................................ 17
2.4. Relationship between Acid and Pepsin in Gastric Juice ...... 19
3. Analysis of the Evidence for the Role of Gastric Secretion
in Ulcerogenesis ......................................... 19
3.1. Animal Studies ...................................... 19
3.2. Human Studies ...................................... 20
3.3. Response to Treatment ................................ 23
3.4. Relationship between Acid and Pepsin ................... 24
3.5. Heterogeneity ....................................... 25
3.6. MucosalInjury ...................................... 25
4. Association and Causation ................................. 26
4.1. Strength of Association ............................... 26
4.2. Consistency of Observed Association .................... 27
4.3. Specificity of Association ............................. 28
4.4. Temporality ......................................... 28
4.5. Plausibility and Coherence ............................. 28
4.6. Bias ............................................... 29
4.7. Summary: Relationship between Putative Cause
and Disease ......................................... 29
5. Alternative Etiologic Bases for Duodenal Ulceration ............ 30
Annotated Bibliography ................................... 31
Chapter 3
Pathomorphology of Gastric Mucosal Injury 33
Jerzy Stachura
1. Functional Morphology of the Gastric Mucosa ................. 33
2. General Consideration of Cell Injury ......................... 37
3. Pathogenesis of Reversible and Irreversible Cell Injuries ......... 38
3.1. Ischemia ........................................... 38
3.2. Free Radicals ....................................... 38
3.3. Cellular Signaling System ............................. 38
3.4. Cytoskeleton ........................................ 39
3.5. Calcium as Ultimate Cell Killer ........................ 39
4. Gastric Mucosal Injury .................................... 40
4.1. AcuteInjury ........................................ 40
4.2. Chronic Mucosal Injury-Acetic Acid-Induced Ulcers ...... 40
4.3. Stress-Induced Ulcers ................................. 40
Contents xi
4.4. Endogenous Prostaglandins, Thromboxanes, Leukotrienes,
and Platelet Activating Factor .......................... 41
5. Pathogenesis of Gastric Mucosal Injury ....................... 41
6. Relevance to Human Pathology ............................. 43
Annotated Bibliography ................................... 44
Part II. Defensive Mechanisms of the Stomach
Chapter 4
Mechanisms of Mucosal Protection 49
Sandor Szabo
1. Introduction ............................................. 49
2. Anatomical Features of Gastroprotection ...................... 50
2.1. Cell and Organelle Membrane Permeability ............... 50
2.2. Cell Migration (Restitution) and Division (Regeneration) .... 51
2.3. Microcirculation ..................................... 53
2.4. Muscle Tone ........................................ 55
3. Biochemical Processes Relevant to Protection ................. 57
3.1. Mucus and Bicarbonate Secretion ....................... 58
3.2. Hydrophobicity of Phospholipids. . . . . . . . . .. . . . . . . . . . . .. . 60
3.3. Acid Secretion ...................................... 60
3.4. Fluid Flux .......................................... 61
3.5. Free Radical Scavenging .............................. 62
3.6. Release and Action of Enzymes ........................ 62
3.7. Release and Action of Vasoactive Substances ............. 63
4. Mechanisms of Action of Major Groups of Protective Agents .... 63
4.1. Major Chemical Groups ............................... 64
4.2. Individual Drugs ..................................... 68
5. Summary ............................................... 69
Annotated Bibliography ................................... 70
Chapter 5
Mucus Secretion........... ..... ....... ............... .. ..... 75
Adrian Allen, Andrew C. Hunter, and Anwar H. Mall
1. The Nature of the Gastroduodenal Mucus Barrier .............. 75
2. Structure of Mucus and Its Mucin Components ................ 77