沙立度胺对大鼠肝纤维化核因子-κB和肿瘤坏死因子-α表达的影响

Effects of thalidomide on the expression of NF-κB and TNF-α in experimental hepatic fibrotic rats

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。

AIM ： To study the effects of thalidomide on the expressions of nuclear factor κB （ NF - κB） and tumor necrosis factor - α （ TNF-α） in rat liver fibrosis. METHODS ： The fibrosis of rat liver was induced by intraperitoheal injection of carbon tetrachloride thrice weekly. Meanwhile thalidomide （ 10 mg·kg·^-1·d^-1 or 100 mg·kg^-1·d^-1 ） was given daily by the intragastric route for 8 weeks, Serum alanine aminotransferase （ALT）, aspartate aminotransferase （AST）, prealbumin （PA）, hyaluronic acid （HA） and laminin （LN）, and hydroxyproline （HYP） contents in the liver, NF - κB p65 and α - smooth muscle actin （ α - SMA） protein in the liver, IκBα and TNF-α protein in cytoplasm and NF - κB p65 protein in nucleus and TNF-α mRNA levels in the liver were studied. RESULTS ： Compared with the model group, the Knodell score, serum ALT, AST, HA, LN levels and HYP contents in liver, NF - κB p65 protein in nucleus and α - SMA protein in the liver, and TNF-α mRNA and protein in the liver of rats given high dose of thalidomide were decreased significantly （ P 〈 0. 01 ）. Meanwhile PA level and IκBα protein in cytoplasm were elevated significantly （ P 〈 0. 01 ）. CONCLUSION： Thalidomide exerts its effect on the down - regulation of NF - κB - induced TNF-α via inhibiting dissociation and degradation of IκB and prevents liver fibrosis in rats.