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目的:探讨糖调节蛋白78(GRP78)在大鼠肠源性内毒素血症(IETM)促进肝硬化形成过程中的作用。方法:51只雄性Wistar大鼠随机分为肝硬化模型4周组、6周组、8周组及同期正常对照组。采用复合致病因素法诱导大鼠肝硬化,HE染色和VG染色分别观察肝损伤和肝纤维化情况;RT-PCR法和免疫组化法分别检测肝组织GRP78 mRNA及蛋白表达;同时测定血浆中丙氨酸氨基转移酶(ALT)、内毒素、肿瘤坏死因子-α(TNF-α)、同型半胱氨酸(HCY)以及肝组织匀浆中TNF-α、丙二醛(MDA)、Ⅲ型前胶原(PⅢP)水平。结果:(1)随病程进展,各模型组血浆中ALT、内毒素、TNF-α、HCY以及肝组织中GRP78 mRNA、蛋白表达水平、MDA、TNF-α、PⅢP含量和肝组织纤维化指数均逐渐升高并显著高于正常对照组(P<0.05)。(2)血浆中升高的内毒素水平分别与GRP78蛋白、血浆MDA和HCY水平以及肝纤维化指数呈显著正相关(P<0.01);表达增高的GRP78蛋白分别与血浆MDA和HCY水平以及肝纤维化指数呈显著正相关(P<0.01)。结论:GRP78可能在肝硬化形成过程中发挥重要作用;内质网应激很可能是IETM促进肝纤维化乃至肝硬化发生的重要机制。
AIM: To investigate the role of glucose regulatory protein 78 (GRP78) in the promotion of liver cirrhosis by intestinal endotoxemia (IETM) in rats. Methods: Fifty-one male Wistar rats were randomly divided into 4 weeks, 6 weeks, 8 weeks and normal control groups. Liver cirrhosis was induced by compound pathogenic factors, liver injury and hepatic fibrosis were observed by HE staining and VG staining respectively. The expression of GRP78 mRNA and protein in liver tissue were detected by RT-PCR and immunohistochemistry respectively. (ALT), endotoxin, tumor necrosis factor-α (TNF-α), homocysteine (HCY) and liver tissue homogenate, TNF-α, malondialdehyde (MDA) Type procollagen (PⅢP) levels. Results: (1) The levels of ALT, LPS, TNF-α, HCY, GRP78 mRNA and protein, MDA, TNF-α and PⅢP in liver tissue and liver fibrosis index Gradually increased and significantly higher than the normal control group (P <0.05). (2) The elevated endotoxin level in plasma was positively correlated with GRP78 protein, plasma MDA and HCY levels and hepatic fibrosis index (P <0.01), respectively. The increased expression of GRP78 protein correlated with plasma MDA and HCY levels and liver Fibrosis index showed a significant positive correlation (P <0.01). CONCLUSIONS: GRP78 may play an important role in the formation of liver cirrhosis. Endoplasmic reticulum stress is likely to be an important mechanism for IETM to promote hepatic fibrosis and even cirrhosis.