Gastrointestinal Mucosal Protective Mechanisms 160819/ ¢  Gastrointestinal Mucosal Protective

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  • Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Medicine 972

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    Gastrointestinal Mucosal Protective Mechanisms

    Mudolatory Effects of Heliobacter pyroli on the Gastric Mucus Gel Barrier and Mucosal Blood Flow in vivo

    BY

    CHRISTER ATUMA

    ACTA UNIVERSITATIS UPSALIENSISUPPSALA 2000

  • Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine) in Physiologypresented at Uppsala University in 2000

    ABSTRACTAtuma, C. 2000. Gastrointestinal Mucosal Protective Mechanisms. Modulatory Effects ofHelicobacter pylori on the Gastric Mucus Gel Barrier and Mucosal Blood Flow in vivo. ActaUniversitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from theFaculty of Medicine 972. 60 pp. Uppsala. ISBN 91-554-4851-8.

    The gastrointestinal mucus gel layer and blood flow are two important mechanisms forprotection at the preepithelial and subepithelial levels, respectively. Helicobacter pylorimight circumvent these mechanisms and elicit a chronic inflammatory response withconsequent ulcers in the stomach and duodenum. In this thesis, the physical state andproperties of the adherent mucus gel layer was studied from the stomach to colon.Furthermore, the acute and chronic effects of H. pylori on the integrity of the mucus gel layerand mucosal blood flow were studied in the anesthetized rat.

    A translucent mucus gel covers all studied segments of the gastrointestinal tract duringfasting conditions, with the thickest layers in the colon and ileum. Carefully applied suctionrevealed that the mucus gel was a multi-layered structure comprising a firmly adherent layercovering the mucosa, impossible to remove, and a loosely adherent upper layer. The firmlyadherent layer was thick and continuous in the corpus (80m), antrum (154m) and colon(116m), but thin (

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    and quickly desist owing to fatigue and failure of intellectual power,like those who without training accept a race.

    But one who is accustomed to investigation, worming his way and turningin all directions, does not give up the search, I will not say day or night,

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    Erasistratus of Julis (330250 B.C.)

  • CONTENTS

    LIST OF PUBLICATIONS................................................................................................................................... 7

    ABBREVIATIONS ................................................................................................................................................ 8

    INTRODUCTION.................................................................................................................................................. 9

    THE GASTROINTESTINAL TRACT......................................................................................................................... 10Anatomy in brief ........................................................................................................................................... 11

    THE GASTROINTESTINAL MUCUS GEL LAYER ..................................................................................................... 12Mucus glycoproteins..................................................................................................................................... 12Mucus secretion............................................................................................................................................ 13Mucus function ............................................................................................................................................. 14Properties of the mucus layer....................................................................................................................... 14The mucus layer in H. pylori infection ......................................................................................................... 15

    GASTRIC BLOOD FLOW ....................................................................................................................................... 16Blood vessel arrangement ............................................................................................................................ 16Blood flow and mucosal injury..................................................................................................................... 17

    MAST CELLS....................................................................................................................................................... 18Distribution................................................................................................................................................... 18Regulation..................................................................................................................................................... 18Mediators...................................................................................................................................................... 19

    THE PLATELET ACTIVATING FACTOR.................................................................................................................. 19PAF pathophysiology ................................................................................................................................... 19

    NITRIC OXIDE AND MUCOSAL BLOOD FLOW ....................................................................................................... 20NO release .................................................................................................................................................... 20NO pathophysiology ..................................................................................................................................... 21

    HELICOBACTER PYLORI........................................................................................................................................ 22Short history ................................................................................................................................................. 22Epidemiology ................................................................................................................................................ 22H. pylori pathogenicity ................................................................................................................................. 23Animal models of H. pylori infection............................................................................................................ 24

    MATERIALS AND METHODS......................................................................................................................... 25

    ANIMALS AND ANESTHESIA................................................................................................................................ 25SURGICAL PROCEDURE....................................................................................................................................... 25TISSUE PREPARATION......................................................................................................................................... 25

    Corpus .......................................................................................................................................................... 25Antrum .......................................................................................................................................................... 26Intestine ........................................................................................................................................................ 26

    BACTERIAL STRAINS AND GROWTH CONDITIONS ............................................................................................... 27PREPARATION OF THE BACTERIAL WATER EXTRACTS ........................................................................................ 27APPLICATION OF THE BACTERIAL WATER EXTRACTS (PAPERS IIIV)................................................................ 28REMOVAL OF THE GASTROINTESTINAL MUCUS GEL LAYER................................................................................ 28MUCUS GEL THICKNESS MEASUREMENTS (PAPERS I AND II) ............................................................................. 28LASERDOPPLER FLOWMETRY (LDF) MEASUREMENTS (PAPERS III AND IV) ................................................... 29ACID SECRETION (PAPERS IIIV)....................................................................................................................... 31ADMINISTERED DRUGS (PAPER IV).................................................................................................................... 31STATISTICS AND CALCULATIONS........................................................................................................................ 31

    RESULTS AND COMMENTS........................................................................................................................... 33

    PAPER I............................................................................................................................................................... 33PAPER II ............................................................................................................................................................. 34 PAPER III .......................................................................