黏附分子在沙利度胺所致大鼠肝纤维化中的作用机制

Effects of thalidomide on adhesion molecules in rat liver fibrosis

目的:观察沙利度胺对大鼠实验性肝纤维化的治疗效果并探讨其作用机制.方法:四氯化碳腹腔注射制备大鼠肝纤维化模型后,应用沙利度胺(100mg/kg)ig分别治疗2、4、6wk作为动态观察时相点.HE染色观察肝组织病理变化,放射免疫法检测血清透明质酸(HA)、层粘连蛋白(LN)、Ⅲ型前胶原(PCⅢ)和Ⅳ型胶原(CⅣ)的表达,免疫组织化学法检测细胞间黏附分子-1(ICAM-1)、血管细胞黏附分子-1(VCAM-1)和E-选择素(E-selectin)蛋白质的表达,逆转录聚合酶链反应法检测ICAM-1、VCAM-1和E-selectin mRNA的表达.结果:与肝纤维化组相比,沙利度胺治疗4 wk、6wk能显著降低大鼠肝组织纤维化积分,显著降低血清HA(176.6±7.5μg/L,173.8±6.7μg/L vs 486.9±12.4μg/L)、LN(38.4±5.8μg/L,34.7±7.3μg/L vs 84.5±5.2μg/L)、PCⅢ(44.3±5.5μg/L,40.2±6.1μg/L vs 65.0±5.6μg/L)、CⅣ(31.8±6.7μg/L,30.4±5.7μg/L vs 55.6±6.5μg/L)的含量(P<0.05),沙利度胺治疗2 wk,4 wk,6 wk组均可显著降低ICAM-1、VCAM-1和E-selectin蛋白和mRNA的表达(P<0.05).结论:沙利度胺可通过下调ICAM-1、VCAM-1和E-selectin表达水平而发挥抗肝纤维化作用.

AIM： To investigate the therapeutic effects and mechanism of thalidomide on hepatic fibrosis in rats. METHODS： Liver fibrosis in rats was induced by intraperitoneal injection of carbon tetrachloride for 4 weeks. The rats were killed at 2, 4 and 6 wk after treatment with 100 mg/kg intragastric thalidomide. Liver fibrosis score was assessed under the light microscope by H＆E staining. Serum hyaluronic acid （HA）, laminin （LN）, procollagen type Ⅲ （PCⅢ） and collagen type Ⅳ were detected by radioimmunoassay. Expression of ICAM-1, VCAM-1 and E selectin were examined by immunohistochemistry, mRNA levels for ICAM-1, VCAM-1, and E selectin was detected by reverse-transcriptase polymerase chain reaction. RESULTS： Compared with the liver fibrosis group, fibrosis score in thalidomide-treated rats （4 or 6 wk） was obviously improved （P 〈 0.05）. Serum HA （176.6 ± 7.5 μg/L, 173.8 ± 6.7 μg/L vs 486.9 ± 12.4 μg/L）, LN （38.4 ± 5.8 μg/L, 34.7 ± 7.3 μg/L vs 84.5 ± 5.2 μg/L）, PCⅢ（44.3±5.5 μg/L, 40.2 ± 6.1 μg/L vs 65.0 ± 5.6 μg/L） and collagenⅣ （31.8 ± 6.7 ,g/L, 30.4 ± 5.7 ,g/L vs 55.6 ± 6.5 μg/L） in rats treated with thalidomide for 4 or 6 wk were significantly lower than those in rats with liver fibrosis （P 〈 0.05）. Expression of ICAM-1, VCAM-1 and E selectin protein and mRNA was significantly reduced in thalido-mide-treated rats, compared with that in rats with liver fibrosis （P 〈 0.05）. CONCLUSION： Thalidomide can reverse liver fibrosis in rats via down-regulation of the expression of ICAM-1, VCAM-1 and E selectin.