细胞自噬影响实验性大鼠肝纤维化进展的分子机制以及药物抗肝纤维化的作用研究

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目的探讨细胞自噬影响实验性大鼠肝纤维化进展的分子机制以及药物抗肝纤维化的作用。方法将49只SD老鼠随机分成正常对照组、模型对照组、药物治疗组[熊去氧胆酸(UDCA)组、雷帕霉素(RAPA)治疗组、羟氯喹(HCQ)治疗组、羟氯喹和熊去氧胆酸(HCQ+UDCA)治疗组、雷帕霉素和羟氯喹(RAPA+HCQ)治疗组]。造模后分给予媒介、自噬促进剂雷帕霉素(RAPA)、自噬抑制剂羟氯喹(HCQ)、熊去氧胆酸(UDCA)单用或者合用灌胃。治疗4周后,处死所有的老鼠收集肝标本。HE染色检测肝病理变化。Western blot技术检测自噬相关分子ATG-5、Beclin-1以及LC-3Ⅱ。同时,血液标本生物化学方法检测肝功能以及单胺氧化酶(MAO)。结果与模型对照组相比,RAPA治疗组大鼠肝重、肝指数、胶原指数、肝纤维化评分均显著性升高(P<0.05),而其他治疗组大鼠显著降低(P<0.05)。但病理显示HCQ或者与其他药物合用不能改善肝组织细胞坏死和脂肪样变性。Western blot显示与正常对照组肝组织相比,模型对照组肝组织中ATG-5、Beclin-1、LC3-Ⅱ表达量显著增加(P<0.05);与模型对照组鼠肝组织相比,UDCA治疗组和HCQ+UDCA治疗组肝组织自噬相关蛋白表达显著性降低(P<0.05),其他治疗组与模型对照组相比ATG-5、Beclin-1、LC3-Ⅱ表达量明显增强。此外,所有的治疗组大鼠血清TBIL、AST、ALT比模型对照组显著性降低(P<0.05);而与模型对照组相比,RAPA治疗组MAO明显增加(P<0.05),其他治疗组则明显降低(P<0.05)。结论肝纤维化可能涉及到肝脏中细胞自噬水平变化,调节细胞自噬既影响肝脏肝纤维化同时也影响肝脏组织细胞变性以及肝功能。UDCA改善肝脏肝纤维化可能与其调节细胞自噬有关,调节细胞自噬可能为治疗肝纤维化一个新的切入点。 Objective To investigate the molecular mechanism of cell autophagy affecting the progression of hepatic fibrosis in rats and the effect of drugs on hepatic fibrosis. Methods 49 SD rats were randomly divided into normal control group, model control group, drug treatment group (UDCA group, rapamycin (RAPA) group, hydroxychloroquine (HCQ) And ursodeoxycholic acid (HCQ + UDCA) treatment group, rapamycin and hydroxychloroquine (RAPA + HCQ) treatment group]. After the model was given vehicle, autophagy promoter rapamycin (RAPA), autophagy inhibitors hydroxychloroquine (HCQ), ursodeoxycholic acid (UDCA) single or combined gavage. After 4 weeks of treatment, all mice were sacrificed and liver samples collected. HE staining to detect liver pathological changes. Western blot was used to detect autophagy-related molecules ATG-5, Beclin-1 and LC-3II. Meanwhile, blood samples biochemical methods to detect liver function and monoamine oxidase (MAO). Results Compared with the model control group, the liver weight, liver index, collagen index and hepatic fibrosis score of RAPA treatment group were significantly increased (P <0.05), while those of other treatment groups were significantly decreased (P <0.05) . But the pathology shows that HCQ or combined with other drugs can not improve hepatic cell necrosis and steatosis. Western blot showed that the expression of ATG-5, Beclin-1 and LC3-Ⅱ in the model control group was significantly increased compared with that in the normal control group (P <0.05). Compared with the model control group, the expression of UDCA The expressions of ATG-5, Beclin-1 and LC3-Ⅱ in the treatment group and HCQ + UDCA group were significantly lower than those in the model control group (P <0.05). In addition, the serum levels of TBIL, AST and ALT in all the treatment groups were significantly lower than those in the model control group (P <0.05). Compared with the model control group, MAO in the RAPA treatment group was significantly increased (P <0.05) Was significantly lower (P <0.05). Conclusions Hepatic fibrosis may involve changes of autophagy in the liver. Regulating autophagy affects not only hepatic fibrosis but also hepatic cell degeneration and liver function. UDCA to improve liver fibrosis may be related to its regulation of cell autophagy, regulating cell autophagy may be a new entry point for the treatment of liver fibrosis.
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