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1 Regulatory Gut Peptides in Paediatric Gastroenterology and Nutrition Frontiers of Gastrointestinal Research Vol. 21 Series Editors P. Rozen, Tel Aviv; C. Scarpignato, Parma KARGER Basel Mnchen Paris London New York New Delhi Bangkok SingaporeTokyo Sydney 6th Annual Meeting of the GPGE, Goldegg/Salzburg, May 1-4, 1991 Regulatory Gut Peptides in Paediatric Gastroenterology and Nutrition Volume Editors P. Heinz-Erian, Munich J. Deutsch, Graz G. Granditsch, Vienna 41 figures and 15 tables, 1992 KARGER Basel Mnchen Paris London New York New Delhi Bangkok Singapore Tokyo Sydney Frontiers ofgastrointestinal Research Library of Congress Cataloging-in-Publication Data Gesellschaft fr Pdiatrische Gastroenterologie und Ernhrung. Meeting (6th: 1991: Goldegg im Pongau, Austria) Regulatory gut peptides in paediatric gastroenterology and nutrition: 6th Annual Meeting of the GPGE, Goldegg/Salzburg, May 1-4, 1991 / volume editors, P. Heinz-Erian, J. Deutsch, G. Granditsch. (Frontiers of gastrointestinal research; vol. 21) Includes bibliographical references and index. 1. Gastrointestinal hormones - Congresses. 2. Pediatric gastroenterology - Congresses. 3. Gastrointestinal system - Diseases - Endocrine aspects - Congresses. I. Heinz-Erian, P. (Peter) II. Deutsch, J. (Johann) III. Granditsch, G. (Gerhard)

2 IV. Title. V. Series. [DNLM: 1. Child Nutrition - congresses. 2. Gastrointestinal Diseases - in infancy & childhood - congresses. 3. Gastrointestinal Hormones - physiology - congresses. 4. Infant Nutrition - congresses. 5. Peptides - physiology - congresses. 6. Receptors, Gastrointestinal Hormone - physiology - congresses. W1 FR946E v. 21/ WK 170 G389r 1991] RJ446G '33-dc20 ISBN Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 1992 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Thr AG Offsetdruck, Pratteln ISBN Contents Preface... VII Distribution, Biochemistry and Physiology ofregulatory Gut Peptides in the Gastrointestinal Tract Bishop, A.E.; Polak, J.M. (London): The Neuroendocrine System of the Gut: Visualization...1 Laburthe, M.; Voisin, T.; Couvineau, A.; Darmoul, D.; Blais, A.; Augeron, C.; Laboisse, c.; Salomon, R.; Maoret, J.-J.; Rouyer-Fessard, C. (Paris): Gut Peptide Receptors and Signal Transduction in Intestinal Epithelium: State of the Art Christophe, J.; Waelbroeck, M.; Lambert, M.; Svoboda, M.; Cauvin, A.; Buscail, L.;

3 Winand, J.; Robberecht, P. (Brussels): Gut Peptide Receptors and Signal Transmission in the Exocrine Pancreas and in the Pancreatic Acinar Cell Line AR 4-2J Said, S.I. (Chicago, Ill.): Biological and Physiological Actions of Regulatory Gut Peptides in the Gastrointestinal Tract Brown, J.C. (Vancouver): Metabolic Effects of Regulatory Peptides of the Gastrointestinal Tract Effects of Regulatory Gut Peptides on Basic Functions of the Normal Gastrointestinal Tract Milla, P.J. (London): Regulatory Gut Peptides and Gastrointestinal Transit Flsch, U.R. (Kiel); Schmidt, W.E.; Creutzfeldt, W. (Gttingen); Nitsche, R. (Kiel): Digestive Function and Regulatory Gut Peptides with Special Reference to the Role of Cholecystokinin Krejs, G.J. (Graz): Intestinal Absorption and Secretion: Role of Regulatory Gut Peptides in Man Heinz-Erian, P. (Munich): Gastrointestinal Function in Healthy Children: Significance of Regulatory Gut Peptides Contents VI Regulatory Gut Peptides: Role in Paediatric Growth and Nutrition Lebenthal, E.; Lu, R.B. (Philadelphia, Pa.): Ontogeny of Regulatory Gut Peptides 115 Milner, R.D.G. (Riyadh): Regulatory Gut Peptides and Growth Aynsley-Green, A. (Newcastle upon Tyne); Lucas, A. (Cambridge); Ghatei, M.; Bloom, S.R. (London): Regulatory Gut Peptides in the Perinatal Transition Period Koldovsk, 0.; Philipps, A.; Rao, R.K. (Tuscon, Ariz.); Schaudies, P. (Washington, D.C.): Possible Role of Milk-Borne Peptide Growth Factors for the Breast-Fed Infant Regulatory Gut Peptides in Paediatric Gastrointestinal Disease Nelson-Piercy, C.; Hammond, P.J.; Bloom, S.R. (London): Gastrointestinal Endocrine Tumours during Childhood Milla, P.J. (London): Regulatory Gut Peptides in Hirschsprung's Disease and Other Gut Motility Disorders Hyman, P.E.; Eysselein, V.E. (Torrance, Calif.): Regulatory Peptides in Inflammation, Ulceration, and Tissue Repair: Inflammatory Bowel Disease and Peptic Ulcer Disease... I94 Aynsley-Green, A. (Newcastle upon Tyne); Lucas, A. (Cambridge); Ghatei, M. (London); Lawson, G.R. (Newcastle upon Tyne); Bloom, S.R. (London): Gut Regulatory Peptide Profiles in Acute Gastroenteritis and Necrotising Enterocolitis

4 in Infancy Buchanan, K.D.; Johnston, C.F. (Belfast): Regulatory Peptides in Coeliac Disease and Other Mucosal Intestinal Disorders Teufel, M. (Mannheim); Aynsley-Green, A.; Murphy, M.S. (Newcastle upon Tyne); Heinz-Erian, P. (Munich): Regulatory Gut Peptides and Cystic Fibrosis Hill, I.D.; Lebenthal, E. (Philadelphia, Pa.): Therapeutic Significance of Regulatory Gut Peptides in Childhood Subject Index Preface Growth and function of the gastrointestinal tract are highly dependent on specific interactions of regulatory gut peptides (RGP) with their target tissues. Peptides originating from outside the body, from the circulation or from inter- or intracellular compartments bind to specific receptors and induce - via the activation of cellular signal transduction mechanisms - characteristic biological actions. This occurs by use of a complicated network of interdependent morphological, biological and biochemical pathways, which are themselves subject to genetic regulation. Investigations into these mechanisms have been greatly facilitated since it has been possible to identify RGP - and the molecules interacting with them - by means of specific antibodies and/or radioactive tracers. With their help we can now relatively easily determine the localization as well as the pharmacological and biochemical characteristics of peptidereceptor interactions and subsequent postreceptor events regulating biological functions. The advent of molecular biology makes it now feasible to study the gene expression of RGP and their receptors using hybridization of complementary nucleotide sequences on tissue preparations. Despite great advances in the elucidation of basic biochemical and biological mechanisms involving RGP, comparatively little is known with regard to their physiological and pathophysiological significance. Most of the knowledge available concerns their existence and their pattern of major biological actions in adult animals and much less of this is known in human adults. Similarly, there are some data on RGP in the developing animal, particularly with respect to ontogeny. For healthy children, however, the information on RGP (apart from plasma and tissue concentrations and a few established biological functions) is very limited. Preface VIII It was, therefore, felt timely to compile a series of state-of-the-art

5 reviews on the existence, the cellular mechanisms of action and the biological functions of RGP and their significance in health and disease during the pediatric age period. To this end the present volume consists of 4 sections. In the first section the distribution, biology and physiology of RGP are described in a more general way. The second section relates specific functions of the normal gastrointestinal tract, such as transit, digestion, absorption and secretion, to the action of RGP and finally summarizes what is actually known about these functions in healthy children. The impact of RGP on growth and nutrition in the healthy child as well as the influence of feeding on their release is dealt with in the third section. The fourth section discusses extensively the significance of RGP for pediatric gastrointestinal diseases (including tumors, acute and chronic diarrhea of various etiologies, inflammatory bowel disease and motility disorders) and finally gives an outlook on the now rapidly emerging therapeutic potential of this class of compounds. Most reviews in this volume have been presented at the 6th Annual Meeting of the GPGE ('Gesellschaft fr Pdiatrische Gastroenterologie und Ernhrung') in Goldegg/Austria We thank the members of GPGE who have stimulated us in preparing the meeting and this publication. We would also like to thank S. Karger AG, Medical and Scientific Publishers, Basel, for their efficient preparation of this volume. We are particularly grateful to Milupa AG for their financial backing of publication. Peter Heinz-Erian, Munchen Johann Deutsch, Graz Gerhard Granditsch, Wien