Sorafenib and fluvastatin synergistically alleviate hepatic fibrosis via inhibiting the TGFβ1/Smad3 pathway
Sorafenib and fluvastatin synergistically alleviate hepatic fibrosis via inhibiting the TGFβ1/Smad3 pathway
复制标题
索拉非尼和氟伐他汀通过抑制TGFβ1/Smad3通路协同减轻肝纤维化
DOI：
10.1016/j.dld.2017.12.015
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发表时间：
2018-04-01
影响因子：
4.5
通讯作者：
Zhu, Yun
中科院分区：
文献类型：
--
作者：
Cheng, Yang;Zheng, Hang;Zhu, Yun
背景资料：目的：探讨索拉非尼和氟伐他汀联合治疗对肝纤维化的影响及其机制。方法：采用二乙基亚硝胺诱导的大鼠肝纤维化模型，观察索拉非尼和氟伐他汀联合治疗对肝纤维化的影响。探讨了索拉非尼和氟伐他汀对肝细胞和肝星状细胞（HSC）上皮间质转化（EMT）的影响。在大鼠枯否细胞中探索了对TGF β 1表达的共同处理效果。在L02细胞和LX-2细胞中研究了共同治疗对TGF β 1/Smad 3通路调节的影响。结果：索拉非尼和氟伐他汀协同降低大鼠肝脏模型中胶原含量、α-SMA表达、层粘连蛋白水平和透明质酸水平。联合处理显著抑制肝细胞间充质标志物的表达，并促进上皮标志物的表达。联合治疗在统计学上抑制了Kupffer细胞中TGF β 1的产生。在TGF β 1激活的LX-2细胞中观察到EMT的抑制与纤连蛋白和α-SMA表达的上调的减轻平行。从机制上讲，索拉非尼和氟伐他汀通过抑制肝细胞和HSC中T β R II的磷酸化来阻断TGF β 1/Smad 3信号通路。结论：索拉非尼和氟伐他汀协同减轻二乙基亚硝胺诱导的大鼠肝纤维化。索拉非尼联合氟伐他汀治疗肝纤维化可能是一种潜在的联合治疗方法。(C)2017 Editrice Gastroenterologica Italiana S.r.l.由爱思唯尔有限公司出版。保留所有权利。
Background: Effective strategies for the treatment of hepatic fibrosis are urgently in need.Aims: To investigate the effect of the co-treatment of sorafenib and fluvastatin on hepatic fibrosis and the underlying mechanisms.Methods: A diethylnitrosamine-induced hepatic fibrosis rat model was used to evaluate the anti-fibrosis effect. Epithelial mesenchymal transition (EMT) of hepatocytes and hepatic stellate cells (HSCs) in response to sorafenib and fluvastatin was explored. A co-treatment effect on TGF beta 1 expression was explored in the Kupffer cells of rats. The effect of co-treatment on the regulation of the TGF beta 1/Smad3 pathway was investigated in both L02 cells and LX-2 cells.Results: Sorafenib and fluvastatin synergistically reduced collagen content, alpha-SMA expression, lamin level, and hyaluronic acid level in the rat hepatic model. Combination treatment significantly inhibited the expression of mesenchymal markers and promoted the expression of epithelial markers in hepatocytes. Co-treatment statistically suppressed the production of TGF beta 1 in Kupffer cells. Suppression of EMT in parallel with alleviated up-regulation of fibronectin and alpha-SMA expression was observed in TGF beta 1-activated LX-2 cells. Mechanistically, sorafenib plus fluvastatin blocked the TGF beta 1/Smad3 signaling pathway via inhibiting phosphorylation of T beta R II in hepatocytes and HSCs.Conclusions: Sorafenib and fluvastatin synergistically alleviated diethylnitrosamine-induced hepatic fibrosis in rats. Sorafenib plus fluvastatin may be a potential combination treatment for hepatic fibrotic diseases. (C) 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.