| Co-Investigator(Kenkyū-buntansha) |
NAGATA Hiroshi Keio University, Internal Medicine, Assistant Professor, 医学部, 専任講師 (00146599)
SUEMATSU Makoto Keio University, Biochemistry, Associate Professor, 医学部, 助教授 (00206385)
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| Research Abstract |
In vitro approach : The genome sequence of bacterial hemeoxygenase was not detected in H.pylori. During the process of NH_2Cl-induced apoptosis, the mitochondrial permeability transition, cytosolic caspase-3 activation and oxidative DNA damage was sequentially occured before the DNA cleavage.
In vivo approach : H.pylori colonization to the stomach of Mongolian gerbils evoked gastric mucosal inflammation and an extensive increase in lipid peroxides and total glutathione. One of the PPIs, rabeprazole, inhibited gastric mucosal H.pylori colonization in gerbils and also attenuated remarkably H.pylori-associated gastric mucosal inflammation including oxygen radical formation in gerbils, possibly by its pharmacological action through the recruitment of reduced glutathione. Gastric mucosal lesion formation in response to H.pylori inoculation was also significantly inhibited by dietary zinc-compound (polaprezinc). Elevated levels of MPO activity, GRO/CINC-1 like protein (CXC chemokine) and TBAR
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S in the gastric muocsa of gerbils 12 weeks after H.pylori inoculation were all attenuated significantly by dietary zinc-compound. Enhanced levels of venular leukocyte activation (decrease in rolling velocity and increase in adhesion number) observed in the gastric muocsa of gerbils after H.pylori inoculation were attenuated significantly by dietary zinc-compound during both early and late phase, suggesting the anti-inflammatory and anti-oxidative actions of zinc-compounds in the develpoment of H.pylori-induced gastric mucosal injury. Separately, mice (C57BL/6) and Mongolian gerbils were orally inoculated with H.pylori (Sydney strain : SS1) and the stomach was examined 9 and 18 months later. Although gastric wall thickening in response to SS1 was more prominent in gerbils, the number of proliferating cell nuclear antigen-positive cells increased to the same extent in both animals. While the levels of DNA fragmentation and caspase-3 activity increased significantly in mice, such parameters were attenuated in gerbils. SS1-induced increase in gastric mucosal caspase-3-dependent apoptosis, which was observed in mice, was attenuated significantly in gerbils, suggesting the causative role of attenuated apoptosis for the higher incidence of gastric carcinogenesis in Mongolian gerbils. In clinicals, H.pylori-positive gastric mucosa showed an increase in HGF level especially in the antral mucosa where CXC-chemokine contents and MPO activity were increased, suggesting the pathogenic role of inflammatory cell infiltration for the production of gastric remodeling and proliferating factors such as HGF. Less
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