基础研究(Basic Research)

紫衫醇对大鼠肝纤维化的抑制作用及机制研究

Published at: 2017年第26卷第9期

叶轲 1 , 白宁 1 , 李劲东 1 , 周乐杜 1 , 王志明 1
1 中南大学湘雅医院 普通外科,湖南 长沙 410008
通讯作者 劲东 李 Email: lijindong302@sina.com
DOI: 10.3978/j.issn.1005-6947.10.3978/j.issn.1005-6947.2017.09.012
基金:
湖南省科技重点研发计划基金资助项目 2015SK20482

摘要

目的:探讨紫衫醇对大鼠肝纤维化的抑制作用及其分子机制。方法:将30只Wistar大鼠随机均分为正常对照组、肝纤维化模型组,肝纤维化模型+紫衫醇组,肝纤维化模型用腹腔注射二甲基亚硝胺每日1次连续7 d诱导,之后,肝纤维化模型+紫衫醇组大鼠给予尾静脉注射紫杉醇液,隔日1次,共3次;实验结束时,处死大鼠观察肝脏病理学和血清学指标变化,及肝组织中肝星状细胞标志物α-SMA的表达。将大鼠肝星状细胞HSC-T6分别用TGF-β1、紫杉醇+TGF-β1处理,以无处理的HSC-T6细胞为对照,分别检测各组细胞纤连蛋白及I、III型胶原mRNA与蛋白的表达。结果:正常对照组肝组织无病理学改变,肝纤维化模型组出现肝纤维化病变,肝纤维化模型+紫杉醇组可见肝组织中度坏死,无明显坏死结节;与正常对照组比较,肝纤维化模型组与肝纤维化模型+紫杉醇组转氨酶、总胆红素(TIBL)、透明质酸(HA)水平均明显升高,白蛋白(ALB)水平明显降低(均P<0.05),后者较前者在TBIL、ALB、HA方面有明显改善(均P<0.05);正常对照组肝组织无明显α-SMA表达,肝纤维化模型组和与肝纤维化模型+紫杉醇组肝组织均有α-SMA表达,后者的α-SMA阳性细胞数明显少于前者(P<0.05);与无处理的HSC-T6细胞比较,TGF-β1与紫杉醇+TGF-β1处理后的HSC-T6细胞纤连蛋白及I、III型胶原mRNA与蛋白均明显上调(均P<0.05),后者的上调程度明显低于前者(均P<0.05)。结论:紫杉醇可抑制大鼠肝纤维化的产生和发展,机制可能与其抑制肝星状细胞中TGF-β信号通路从而减少肝星状细胞活化有关。


Inhibitory effect of paclitaxel on hepatic fibrosis in rats and its mechanism

Abstract

Objective: To investigate the inhibitory effect of paclitaxel on hepatic fibrosis in rats and its mechanism. Methods: Thirty Wistar rats were equally randomized into normal control group, hepatic fibrosis model group and hepatic fibrosis model plus paclitaxel group. Hepatic fibrosis model was induced by intraperitoneal injection of dimethylnitrosamine daily for up to 7 d. After that, the rats in hepatic fibrosis model plus paclitaxel group underwent paclitaxel solution injection via the tail vein once every two days for a total of 3 times. At the end of the experiment, all rats were sacrificed, the pathological changes of liver and some serological variables were observed, and the expressions of the hepatic stellate cell marker α-SMA in the liver tissues were determined. The rat hepatic stellate cell line HSC-T6 was cultured with TGF-β1 or paclitaxel plus TGF-β1, with untreated HSC-T6 cells as control, and then, the expressions of fibronectin and type I and III collagen in each group of cells were determined. Results: No pathological alterations were noted in the liver tissues in normal control group, but histological changes of hepatic fibrosis were developed in hepatic fibrosis group, while only moderate degrees of liver necrosis without evident nodular lesions were observed in hepatic fibrosis model plus paclitaxel group; compared with normal control group, the levels of transaminases, total bilirubin (TBIL) and hyaluronic acid (HA) were increased, while the albumin (ALB) level was decreased significantly in either hepatic fibrosis model group or hepatic fibrosis model plus paclitaxel group (all P<0.05), but the conditions of TBIL, ALB and HA were significantly better in the latter than those in the former (all P<0.05); no obvious α-SMA expression was observed in the liver tissues in normal control group, which was found in the liver tissues in both hepatic fibrosis model group and hepatic fibrosis model plus paclitaxel group, but the number of α-SMA positive cells in the latter was significantly lower than that in the former (P<0.05). Compared with untreated HSC-T6 cells, both mRNA and protein the expressions of fibronectin and type I and III collagen were significantly up-regulated in HSC-T6 cells treated with TGF-β1 alone or treated with paclitaxel plus TGF-β1 (all P<0.05), but their up-regulating degrees was significantly milder in the latter than those in the former (all P<0.05). Conclusion: Paclitaxel can inhibit the occurrence and development of hepatic fibrosis in rats, and the mechanism may be associated with its suppressing TGF-β signaling pathway in hepatic stellate cells and thereby reducing the activation of hepatic stellate cells.


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引用

引用本文: 轲 叶, 宁 白, 劲东 李, 乐杜 周, 志明 王. 紫衫醇对大鼠肝纤维化的抑制作用及机制研究 [J]. 中国普通外科杂志, 2017, 26(9): 1155-1161.
Cite this article as: YE Ke, BAI Ning, LI Jingdong, ZHOU Ledu, WANG Zhiming . Inhibitory effect of paclitaxel on hepatic fibrosis in rats and its mechanism [J]. Chin J Gen Surg, 2017, 26(9): 1155-1161.