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H.pylori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，在DNA裂解之前依次发生线粒体通透性转变、胞质caspase-3激活和氧化DNA损伤。体内方法：幽门螺杆菌在蒙古沙鼠胃中的定植引起胃粘膜炎症以及脂质过氧化物和总脂质的广泛增加。谷胱甘肽之一，雷贝拉唑，可抑制沙鼠胃粘膜幽门螺杆菌定植，并显着减轻沙鼠胃粘膜幽门螺杆菌相关炎症，包括氧自由基的形成，这可能是通过其通过招募还原型谷胱甘肽的药理作用实现的。饮食中的锌化合物也显着抑制了幽门螺杆菌接种引起的粘膜病变形成接种幽门螺杆菌后 12 周，沙鼠胃粘膜中 MPO 活性、GRO/CINC-1 样蛋白（CXC 趋化因子）和 TBAR S 水平的升高均因膳食锌化合物增强而显着减弱。在胃粘膜中观察到的小静脉白细胞活化水平（滚动速度降低和粘附数量增加）接种幽门螺杆菌后，饮食中的锌化合物在早期和晚期均显着减弱，表明锌化合物在幽门螺杆菌引起的胃粘膜损伤的发展中具有抗炎和抗氧化作用。小鼠（C57BL/6）和蒙古沙鼠口服接种幽门螺杆菌（悉尼株：SS1）和9 个月和 18 个月后检查胃壁，尽管沙鼠中 SS1 引起的胃壁增厚更为明显，但两种动物中增殖细胞核抗原阳性细胞的数量均增加到相同程度。 -3 活性在小鼠中显着增加，这些参数在沙鼠中减弱，在小鼠中观察到 SS1 诱导的胃粘膜 caspase-3 依赖性细胞凋亡增加。 H.pylori 阳性胃粘膜中 HGF 水平升高，尤其是 CXC 趋化因子含量和胃窦粘膜中 HGF 水平升高。 MPO 活性增加，表明炎症细胞浸润对于胃重塑和增殖因子（例如少HGF