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Helicobacter pylori associated effects on inflammatory radical formation and angiotensin II receptors in the stomach

by Elfvin, Anders, PhD

Abstract (Summary)
Helicobacter pylori infection of the stomach always results in mucosal inflammation and a marked systemic immune response. Despite the profound host defence reactions the bacterium avoids elimination and persists in the mucosa. This results in chronic inflammation and an increased risk for peptic ulcers and adenocarcinoma. Still a majority of infected individuals never develop any symptomatic disease. Previous results from our laboratory indicate that H. pylori reduces the power of host defence by restricting gastric NO production by pathogen-derived competitive iNOS inhibitors. It was considered of interest to further investigate not only the H. pylori associated inhibition of nitro-radical formation, but also interactions with the oxy-radical formation in gastric carcinogenesis. Furthermore, because the renin angiotensin system (RAS) recently was ascribed immunomodulatory actions, it was considered of interest to also explore if H. pylori influences the presence and location of this regulatory system in the gastric mucosa. The H. pylori infected Mongolian gerbil was used as the experimental model and was followed up to 18 months after infection. A first aim of this thesis was to by use of histopathology validate the model?s suitability for studies of H. pylori (strains SS1 and TN2GF4) induced gastric mucosal pathology. The results indicate that the H. pylori infected Mongolian gerbil cannot be confirmed as being a cancer model, but it is suitable for studies of acute and chronic mucosal inflammation. The Mongolian gerbil model was then used to elucidate H. pylori strain dependency on the expression of the oxy- and nitro-radical forming enzymes, and to investigate whether H. pylori infection results in inhibition of either or both of the nitro- and oxy-radical formation. Western blotting was used to assess iNOS and MPO expressions as representatives for nitro- and oxy radicalforming pathways, respectively. Radical formation was assessed as presence of nitrotyrosine or by use of NO or H2O2 sensitive microelectrodes. The results confirm that H. pylori infection in Mongolian gerbils despite an up-regulation of nitro- and oxy-radical forming enzymes results in inhibition of radical formation. Response patterns differed over time in relation to the H. pylori strain under study. The results were confirmed in human gastric specimens using similar western blot assessing expression of nitro-and oxy-radical forming enzymes as well as nitrotyrosine. Finally, gene transcripts and immunoreactivity to the angiotensin II receptors AT1R and AT2R were found present in the antral wall of the Mongolian gerbil. The investigation indicated a possible H. pylori strain dependent influence on the AT1R expression. The present studies on experimentally infected Mongolian gerbils and asymptomatic human tissues support strongly that H. pylori avoids to be eliminated from the gastric mucosa by interfering with the nitro- and oxy-radical formation. In addition the investigations also suggest the presence of a H. pylori strain dependent influence on the AT1R expression constituting a novel immunomodulatory principle.
Bibliographical Information:

Advisor:

School:Göteborgs universitet

School Location:Sweden

Source Type:Doctoral Dissertation

Keywords:MEDICINE; Helicobacter pylori; Mongolian gerbil; gastric adenocarcinoma; nitro-radical; iNOS; nitric oxide; nitrotyrosine; oxy-radical; myeloperoxidase; angiotensin II; AT1R; AT2R

ISBN:978-91-628-7326-4

Date of Publication:01/01/2007

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