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

体外方法：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诱导细胞凋亡的过程中，线粒体通透性转变、胞浆caspase-3激活和DNA氧化损伤在DNA裂解之前依次发生。体内方法：幽门螺杆菌在沙土鼠胃内定植引起胃粘膜炎症，脂质过氧化产物和总谷胱甘肽大量增加。雷贝拉唑可抑制幽门螺杆菌在沙土鼠胃粘膜的定植，并显著减轻幽门螺杆菌引起的胃粘膜炎症，包括沙土鼠体内氧自由基的形成，其药理作用可能是通过募集还原型谷胱甘肽实现的。饲料锌化合物(波拉普锌)也能显著抑制幽门螺杆菌感染后胃粘膜损伤的形成。髓过氧化物酶活性、GRO/CINC样蛋白(CXC趋化因子)和TbAR…水平升高接种幽门螺杆菌12周的沙土鼠胃粘膜中的S含量均显著低于对照组。接种幽门螺杆菌后沙土鼠胃粘膜微静脉白细胞活化水平(滚动速度降低和黏附数增加)在早期和晚期均明显减弱，提示锌化合物在幽门螺杆菌诱导的胃粘膜损伤中具有抗炎和抗氧化作用。将幽门螺杆菌(悉尼株：SS1)分别经口接种小鼠(C57BL/6)和蒙古沙土鼠，9个月和18个月后进行胃部检查。虽然对SS1反应的胃壁增厚在沙土鼠中更为突出，但在两种动物中增殖细胞核抗原阳性细胞的数量都有相同程度的增加。虽然小鼠的DNA片段化水平和caspase-3活性显著增加，但沙土鼠的这些参数有所减弱。在沙土鼠中观察到SS1诱导的胃粘膜caspase-3依赖性细胞凋亡的增加，在沙土鼠中显著减弱，提示细胞凋亡减少是导致沙土鼠胃癌变发生率较高的原因。在临床上，Hp阳性的胃粘膜中HGF水平升高，尤其是在胃窦粘膜中，CXC趋化因子含量和MPO活性增加，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。较少

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