内质网应激在四氯化碳致大鼠急性肝损伤中的作用探讨

目的研究内质网应激在四氯化碳诱导的大鼠急性肝损伤中的变化规律和作用机制。方法采用四氯化碳制备大鼠急性肝损伤模型，动态测定大鼠肝脏GRP78蛋白和caspase 12酶原表达情况，测定大鼠血清ALT、AST水平、肝组织SOD活性、MDA浓度和caspase 3活性变化；采用HE染色和TUNEL法观察肝组织病理形态学和肝细胞凋亡变化。结果四氯化碳染毒后大鼠肝脏GRP78蛋白表达显著增加，caspase 12酶原表达相应减少，呈一定时间依赖方式。大鼠染毒后出现血清ALT、AST水平以及组织MDA含量显著升高，SOD活性明显下降，与对照组有显著性差异（P〈0．01）；染毒后大鼠肝组织caspase 3活性亦显著升高，病理学及TUNEL法检测结果均显示肝脏有严重损伤，大量肝细胞发生凋亡。结论四氯化碳诱导大鼠肝损伤时GRP78和caspase 12的表达变化表明发生了内质网应激反应，其变化趋势和大鼠肝细胞凋亡、病理损伤一致，这一结果提示内质网应激介导的肝细胞凋亡参与了大鼠肝损伤。

Endoplasmic reticulum stress in the development of acute liver injury induced by CCl4 in rats

Objective To investigate endoplasmic reticulum（ER） stress in the development of acute liver injury induced by carbon tetracbloride（CCl4） in rats. Methods Male Sprague-Dawley rats were randomly allocated to establish acute liver injury models by the administration of CCl4 intraperitoneally （i. p）. The expression of GRP78 and caspase-12 in the liver of CCl4-treated rats were determined by Western blot analysis at different time. Serum ALT, AST and liver MDA concentration and SOD activity as well as caspase-3 activity were analyzed following CCl4 injection. Hepatocyte apoptosis was detected by TUNEL method and damage of liver was examined by histopathological means. Results It was shown that administration of CCl4 to rats caused a marked hepatic damage, characterized by significant elevation of serum ALT, AST levels and liver MDA content, caspase-3 activity combined with a remarkable reduction in liver SOD activity when compared with the control group. Histopathologieal observations revealed severe damage such as necrosis, fibrosis, haemorrhage, fatty degeneration. Massive hepatocyte apoptosis took place in the liver of rats following CCl4 treatment. The expression of GRP78 increased significantly from 6 to 36 hours after CCl4 administration while the expression of procaspase-12 decreased markedly at the same time. Conclusion The changes of GRP78 and caspase-12 expression in rats suggested that endoplasmic reticulum stress occurred as a result of CCl4 administration. Hepatocyte apoptosis mediated by endoplasmic retieulum stress might play an important role in the development of acute liver injury caused by CCl4.