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Intestinal permeability : a parameter of mucosal dysfunction

Lundin, Pål LU (1997)
Abstract (Swedish)
Popular Abstract in Swedish

I magtarmkanalen upptas ständigt nyttiga näringsämnen, men samtidigt avvisas skadliga bakterier, gifter och allergiframkallande ämnen. I avhandling beskrivs hur tarmens normala barriärfunktion hos råtta och gris kan förändras på konstgjord väg.



I delarbete I har det normala flödet av enzymer från bukspottkörteln till tunntarmen stoppats för att studera dessa enzymers betydelse för tarmens funktion. Upptaget av proteiner från tarmen ökade då bukspottkörtelns saft avleddes. Denna ökning var olika stor för de olika proteinerna, sannolikt beroende på minskad nedbrytning av proteinerna, men även av de stora förändringarna i tarmens miljö såsom pH.



Läkemedel ger... (More)
Popular Abstract in Swedish

I magtarmkanalen upptas ständigt nyttiga näringsämnen, men samtidigt avvisas skadliga bakterier, gifter och allergiframkallande ämnen. I avhandling beskrivs hur tarmens normala barriärfunktion hos råtta och gris kan förändras på konstgjord väg.



I delarbete I har det normala flödet av enzymer från bukspottkörteln till tunntarmen stoppats för att studera dessa enzymers betydelse för tarmens funktion. Upptaget av proteiner från tarmen ökade då bukspottkörtelns saft avleddes. Denna ökning var olika stor för de olika proteinerna, sannolikt beroende på minskad nedbrytning av proteinerna, men även av de stora förändringarna i tarmens miljö såsom pH.



Läkemedel ger ibland en låg biotillgänglighet, d v s det mesta bryts ned i tarmen och en mindre del tas upp till blodet. I arbete II studerades möjligheten att öka det normalt låga upptaget av ett proteinläkemedel genom att ”kapsla in” det i en lipidlösning och på så vis öka dess biotillgänglighet. Upptaget av proteinet ökade avsevärt när det gavs i lipidblandning, utan någon uppenbar skada på tarmen. Lipiderna orsakade detta genom att ge en vidhäftning till tarmens slemhinna och en skyddande effekt mot nedbrytning av proteinet i tarmens relativt aggresiva miljö.



På tarmens insida finns ett slemskikt vars uppgift bl a är att förhindra ett upptag av skadliga ämnen. Slemlagrets barriärfunktion studerades i arbete III, där det tvättades bort, varefter tarmens genomsläpplighet utvärderades med olika markörmolekyler. Avlägsnandet av slemlagret gav ett förhöjt upptag av markör-molekylerna. Upptaget sjönk sedan ned till normal nivå, allt eftersom slemlagret återbildades.



För att kunna studera tarmens genomsläpplighet i en skadad tarm gjordes en akut skada med saltsyra i isolerade tarm slyngor (arbete IV). Här kunde genomsläppligheten för olika markörer, både till och från blodet, mätas. En ökad passage kunde observeras av framför allt de stora proteinmarkörerna.



Orsaken till kroniska tarminflammationer är inte helt kartlagda men både genetiska faktorer och miljöfaktorer är inblandade. För att undersöka sådana inflammationer användes, i arbete V, transgena råttor som spontant utvecklar tarminflammation. Frågan var om en tarminflammation kan uppkomma utan att tarmens barriärfunktion påverkas. Resultat visade att inflammationen utvecklades, trots en intakt barriärfunktion med oförändrad genomsläpplighet. (Less)
Abstract
The gastrointestinal tract has two opposing functions; to absorb nutrients and electrolytes, and to act as a barrier towards hazardous and non-nutritional substances.



In the present thesis the barrier function of the gastrointestinal tract was studied in animal models in vivo, in situ and in vitro. Experimentally induced disorders of the intestinal barriers were evaluated in terms of altered intestinal permeability using different marker molecules, with different permeation patterns and kinetics, depending on size, lipophilicity and stability. The markers used were the proteins bovine serum albumin, ovalbumin and rat serum albumin, oxytocin peptide analogs, and the low molecular weight markers 51Cr-EDTA, 14C-mannitol,... (More)
The gastrointestinal tract has two opposing functions; to absorb nutrients and electrolytes, and to act as a barrier towards hazardous and non-nutritional substances.



In the present thesis the barrier function of the gastrointestinal tract was studied in animal models in vivo, in situ and in vitro. Experimentally induced disorders of the intestinal barriers were evaluated in terms of altered intestinal permeability using different marker molecules, with different permeation patterns and kinetics, depending on size, lipophilicity and stability. The markers used were the proteins bovine serum albumin, ovalbumin and rat serum albumin, oxytocin peptide analogs, and the low molecular weight markers 51Cr-EDTA, 14C-mannitol, and Na-fluorescein.



Diversion of pancreatic juice from the intestine increased peptide absorption. Probably due to the absence of pancreatic enzymes, but also due to an altered luminal milieu such as pH. Peptide formulations with vehicles of medium chain glycerides also enhanced peptide absorption. This was due to different mechanisms, such as a protective effect of the vehicle to luminal degradation and adhesion of the vehicle to mucosa. A reduction of the intestinal mucus layer by a mucolytic agent, increased the passage of markers, which normalized when the mucus was restituted. Acid-induced acute mucosal injury enhanced the bidirectional permeability. In this model, the blood-to-lumen barrier, especially for macromolecules, was suggested to be less restrictive than in the reverse direction. During spontaneous intestinal inflammation, as shown in transgenic rats, no altered intestinal permeability was observed. This suggested that inflammation progressed with intact intestinal integrity.



Intestinal permeability, as a parameter to estimate mucosal integrity, was found to be useful to confirm mucosal dysfunctions. However, evaluation of the abnormal intestinal conditions induced, revealed the importance of chosing relevant models and suitable marker molecules. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Ph.D. Ungell, Anna-Lena, Astra Hässle AB, Mölndal, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Peptide, N-acetylcysteine, Medium-chain glyceride, Mannitol, Macromolecules, Lipid, Kinetics, In vivo, In vitro, In situ, Intestine, Injury, Inflammation, HLA-B27, HCl, Epithelium, Enhancer, dDAVP, 51Cr-EDTA, BSA, Absorption, Albumin, Permeability, Animal physiology, Djurfysiologi
pages
120 pages
defense location
Lecture hall, Dept. of Animal Physiology, Lund University
defense date
1997-06-05 09:00
external identifiers
  • Other:ISRN: LUNBDS/(NBZF/1047)/1-50 (1997)
ISBN
91-628-2445-7
language
English
LU publication?
yes
id
2d312818-1141-4471-8db2-14a7c67f69a0 (old id 29359)
date added to LUP
2007-06-13 11:09:51
date last changed
2016-09-19 08:45:17
@misc{2d312818-1141-4471-8db2-14a7c67f69a0,
  abstract     = {The gastrointestinal tract has two opposing functions; to absorb nutrients and electrolytes, and to act as a barrier towards hazardous and non-nutritional substances.<br/><br>
<br/><br>
In the present thesis the barrier function of the gastrointestinal tract was studied in animal models in vivo, in situ and in vitro. Experimentally induced disorders of the intestinal barriers were evaluated in terms of altered intestinal permeability using different marker molecules, with different permeation patterns and kinetics, depending on size, lipophilicity and stability. The markers used were the proteins bovine serum albumin, ovalbumin and rat serum albumin, oxytocin peptide analogs, and the low molecular weight markers 51Cr-EDTA, 14C-mannitol, and Na-fluorescein.<br/><br>
<br/><br>
Diversion of pancreatic juice from the intestine increased peptide absorption. Probably due to the absence of pancreatic enzymes, but also due to an altered luminal milieu such as pH. Peptide formulations with vehicles of medium chain glycerides also enhanced peptide absorption. This was due to different mechanisms, such as a protective effect of the vehicle to luminal degradation and adhesion of the vehicle to mucosa. A reduction of the intestinal mucus layer by a mucolytic agent, increased the passage of markers, which normalized when the mucus was restituted. Acid-induced acute mucosal injury enhanced the bidirectional permeability. In this model, the blood-to-lumen barrier, especially for macromolecules, was suggested to be less restrictive than in the reverse direction. During spontaneous intestinal inflammation, as shown in transgenic rats, no altered intestinal permeability was observed. This suggested that inflammation progressed with intact intestinal integrity.<br/><br>
<br/><br>
Intestinal permeability, as a parameter to estimate mucosal integrity, was found to be useful to confirm mucosal dysfunctions. However, evaluation of the abnormal intestinal conditions induced, revealed the importance of chosing relevant models and suitable marker molecules.},
  author       = {Lundin, Pål},
  isbn         = {91-628-2445-7},
  keyword      = {Peptide,N-acetylcysteine,Medium-chain glyceride,Mannitol,Macromolecules,Lipid,Kinetics,In vivo,In vitro,In situ,Intestine,Injury,Inflammation,HLA-B27,HCl,Epithelium,Enhancer,dDAVP,51Cr-EDTA,BSA,Absorption,Albumin,Permeability,Animal physiology,Djurfysiologi},
  language     = {eng},
  pages        = {120},
  title        = {Intestinal permeability : a parameter of mucosal dysfunction},
  year         = {1997},
}