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The mechanism of Helicobacter pylori-induced gastric mucosal injury, involvement of heme iron and oxidative stress.

幽门螺杆菌引起胃粘膜损伤的机制、血红素铁和氧化应激的参与。

基本信息

批准号：
11670531
负责人：
SUZUKI Hidekazu
金额：
$ 2.37万
依托单位：
KEIO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

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 … More 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

体外方法：在幽门螺杆菌中未检测到细菌血红素加氧酶的基因组序列。在NH_2Cl诱导的细胞凋亡过程中，线粒体通透性转换、胞浆caspase-3激活和DNA氧化损伤发生在DNA裂解之前。体内实验：H.pylori定植于蒙古沙鼠胃内，引起胃粘膜炎症反应，脂质过氧化物和总谷胱甘肽水平显著升高。PPI之一雷贝拉唑可抑制沙土鼠胃粘膜幽门螺杆菌定植，并显著减弱幽门螺杆菌相关胃粘膜炎症，包括沙土鼠氧自由基形成，可能通过募集还原型谷胱甘肽发挥药理作用。胃粘膜病变的形成，幽门螺杆菌接种也显着抑制饮食锌化合物（polaprezinc）。MPO活性、GRO/CINC-1样蛋白（CXC趋化因子）和TBAR水平升高 ...更多信息饲料中锌化合物对接种H.pylori后12周的沙土鼠胃粘膜中S的含量均有明显的抑制作用。在幽门螺杆菌感染的早期和晚期，饲料锌化合物均能显著减弱沙土鼠胃粘膜微静脉白细胞活化水平的升高（滚动速度降低和粘附数增加），提示锌化合物在幽门螺杆菌引起的胃粘膜损伤的发展过程中具有抗炎和抗氧化作用。另外，小鼠（C57 BL/6）和蒙古沙鼠经口接种幽门螺杆菌（悉尼菌株：SS 1），并在9个月和18个月后检查胃。虽然胃壁增厚响应SS 1沙鼠更为突出，增殖细胞核抗原阳性细胞的数量增加到相同的程度，在这两种动物。虽然DNA片段化和caspase-3活性的水平在小鼠中显著增加，但这些参数在沙鼠中减弱。SS 1诱导的胃粘膜caspase-3依赖性细胞凋亡的增加，这是在小鼠中观察到的，在沙鼠中显着减弱，这表明在蒙古沙鼠胃癌发生率较高的衰减的细胞凋亡的原因作用。在临床上，H. pylori阳性胃粘膜中HGF水平升高，尤其是胃窦粘膜中CXC-趋化因子含量和MPO活性升高，提示炎症细胞浸润在胃重塑和HGF等增殖因子的产生中起致病作用。少