雷帕霉素对四氯化碳油致肝纤维化模型大鼠的治疗作用

Therapeutic effect of rapamycin on liver fibrosis model rats induced by carbon tetrachloride oil

目的:探讨雷帕霉素(RAPA)和脾切除对肝纤维化大鼠肝和脾组织中转化生长因子β1(TGF-β1)表达水平及肝和脾组织病理形态学的影响,阐述其治疗肝纤维化的作用。方法:30只大鼠随机分成正常对照组、肝纤维化模型组、RAPA组、脾切除组和联合治疗组,每组6只。以四氯化碳(CCl4)花生油诱导建立大鼠肝纤维化模型。光镜下观察各组大鼠肝和脾组织病理形态学改变;检测TGF-β1在肝和脾组织中的表达水平;动态监测大鼠肝纤维化进程中血清TGF-β1水平的变化。结果:形态学表现为肝纤维化模型组大鼠肝组织呈混合滴性脂肪变,炎症细胞侵润,小胆管增生,纤维间隔增生穿插包绕肝细胞;RAPA组、脾切除组和联合治疗组大鼠肝组织形态呈不同程度的改善,尤以联合治疗组明显。与肝纤维化模型组比较,脾切除组、联合治疗组和RAPA组大鼠肝组织中TGF-β1表达水平降低(P<0.05或P<0.01),与肝纤维化模型组比较,RAPA组大鼠脾组织TGF-β1表达水平降低显著(P<0.01)。与正常对照组比较,肝纤维化模型组和RAPA组大鼠脾组织中TGF-β1表达水平升高(P<0.01);第8周时,与肝纤维化模型组比较,RAPA组、脾切除组和联合治疗组大鼠血清TGF-β1水平降低(P<0.05或P<0.01)。联合治疗组大鼠血清TGF-β1表达水平较脾切除组降低明显(P<0.05),但与RAPA组比较差异无统计学意义(P>0.05)。结论:RAPA和脾切除能显著下调大鼠肝和脾组织中TGF-β1表达水平及血清TGF-β1表达水平,减轻肝组织形态学改变程度,缓解大鼠肝脏纤维变性的进程。

Objective To study the effects of rapamycin （RAPA） and splenectomy on the expression levels of transforming growth factor-β1 （TGF-β1） in liver and spleen tissues of rats with liver fibrosis and the pathological morphology of liver and spleen tissues, and to disscuss its role in the treatment of liver fihrosis. Methods 30 rats were randomly divided into normal control group, RAPA group, liver fibrosis model group, splenectomy group, and combination treatment group; there were 6 rats in each group. Carbon tetrachloride （CC14） peanut oil was used to establish the liver fibrosis rat models. The morphological changes of liver and spleen tissues of the rats in various groups were observed under light microscope; the expression levels of TGF 13l in liver and spleen tissues and the expression level of serm TGF-β1 were detected. Results The morphology results showed that the rats in liver fibrosis model group presented mixing drops of fatty degeneration, and the inflammatory cells invasion, and small bile duct hyperplasia, and there were hyperplasia of fibrous septum wrapping liver cells the pathomorphological changes of the rats in RAPA group, splenectomy group and combination treatment group were improved with different degrees, especially in combination treatment group. Compared with liver fibrosis model group, the expression levels of TGF-β1 of the rats in splenectomy group, combination treeatment group, and RAPA group were decreased （P〈0. 05 or P〈50.01）. Compared with liver fibrosis model group, the expression level of TGF-β1 in spleen tissue of the rats in RAPA group was decreased （P〈0.01）. Compared with normal control group, the expression levels of TGF-β1 in spleen tissue of the rats in liver fibrosis group and RAPA group were increased （P〈0.01）. At the 8th week, compared with liver fibrosis model group, the expression levels of serum TGF-β1 of the rats in RAPA group, splenectomy group, and combination treatment group were decreased （P〈0.05 or P（ 0.01）. Compared with splenectomy group, the expression level of serum TGF-β1 of the rats in combination treatment group was decreased （P〈0.05）, but there was no significant difference of the expression levels of serum TGF-β1 between combination treatment group and RAPA group （P）0.05）. Conclusion RAPA and splenectomy can significantly lower the expression level of serum TGF-13 1 and the expression level of TGF-β1 in liver and spleen tissues of the rats and reduce the morphological changes in the liver tissue and ease the process of liver fibrosis in rats.