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目的:观察沙立度胺抗大鼠肝纤维化的疗效和对NF-κB和TNF-α表达的影响。方法:四氯化碳腹腔注射诱导大鼠肝纤维化模型,治疗组于造模同时用沙立度胺10mg.kg-1.d-1和100mg.kg-1.d-1灌胃8周。观察肝组织病理学改变,检测肝功能、血清肝纤维化指标及肝组织羟脯氨酸含量,免疫组化检测NF-κB p65、α-SMA在肝内的表达和分布,Western blotting检测肝组织NF-κB p65、IκBα、TNF-α蛋白的表达,RT-PCR检测肝组织TNF-αmRNA表达。结果:高剂量沙立度胺治疗组肝脏炎症及纤维化程度低于模型组;其ALT、AST水平,HA、LN及羟脯氨酸含量,肝组织细胞核NF-κB p65和肝组织α-SMA蛋白表达,以及肝组织TNF-αmRNA和蛋白表达均低于模型组(P<0.01);而PA水平和细胞质中IκBα蛋白表达高于模型组(P<0.01)。结论:沙立度胺可有效地抑制实验性大鼠肝纤维化的发展,通过抑制IκB解离和降解从而减弱NF-κB通路对TNF-α表达的诱导可能是它发挥疗效的机制之一。
Objective: To observe the effect of thalidomide on liver fibrosis in rats and its effect on the expression of NF-κB and TNF-α. Methods: The model of hepatic fibrosis was induced by intraperitoneal injection of carbon tetrachloride. The rats in the treatment group were treated with thalidomide 10 mg.kg-1.d-1 and 100 mg.kg-1.d-1 for 8 weeks . Liver histopathological changes were observed, liver function, serum levels of hepatic fibrosis and hydroxyproline content were detected. Immunohistochemistry was used to detect the expression and distribution of NF-κB p65 and α-SMA in the liver. Western blotting was used to detect liver tissue The expression of NF-κB p65, IκBα and TNF-α protein were detected by RT-PCR. The expression of TNF-α mRNA in liver tissue was detected by RT-PCR. Results: The levels of ALT and AST, the levels of HA, LN and hydroxyproline, the expressions of NF-κB p65 in liver tissue and α-SMA in liver tissue were significantly higher in high dose thalidomide group than in model group (P <0.01). However, the level of PA and the level of IκBα protein in cytoplasm of model group were higher than that of model group (P <0.01). It is concluded that thalidomide can effectively inhibit the development of hepatic fibrosis in rats. It may be one of the mechanisms by which thalidomide induces TNF-α expression by inhibiting the dissociation and degradation of IκB and thus attenuating NF-κB pathway.