The antihepatic fibrotic effects of fluorofenidone via MAPK signalling pathways
The antihepatic fibrotic effects of fluorofenidone via MAPK signalling pathways
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氟非尼酮通过 MAPK 信号通路的抗肝纤维化作用
DOI：
10.1111/eci.12053
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发表时间：
2013-04-01
影响因子：
5.5
通讯作者：
Tao, Lijian
中科院分区：
文献类型：
--
作者：
Peng, Yu;Yang, Huixiang;Tao, Lijian
背景氟非尼酮（AKF-PD）是一种新型吡酮类药物。本研究旨在探讨AKF-PD对二甲基亚硝胺（DMN）诱导大鼠肝纤维化的抑制作用及其与肝星状细胞（hsc）相关的分子机制。材料与方法Wistar大鼠随机分为正常对照组、DMN组、DMN/AKF-PD组和DMN/吡非尼酮（PFD）组。分别对大鼠CFSC-2G和人LX2两种活化的hsc系进行AKF-PD和PFD处理。MTT法分析细胞增殖情况。采用免疫组织化学染色和实时RT-PCR检测I型胶原蛋白的表达。通过实时RT-PCR和/或Western blot检测-平滑肌肌动蛋白（-SMA）、金属蛋白酶组织抑制剂-1 （TIMP-1）、细胞外信号调节激酶（ERK1/2）、p38 MAPK （p38）和c-Jun n末端激酶/应激激活蛋白激酶（JNK）的表达。结果通过降低-SMA和TIMP-1蛋白的表达，AKF-PD显著降低pdgf - bb诱导的hsc的增殖和活化。AKF-PD治疗可减弱pdgf - bb诱导的ERK1/2、p38和JNK磷酸化上调。在纤维化大鼠肝脏中，AKF-PD降低了肝损伤程度和肝纤维化程度，这与在mRNA和蛋白水平上降低I型胶原、-SMA、TIMP-1的表达有关。结论AKF-PD治疗通过抑制hsc增殖和MAPK信号通路激活抑制肝纤维化进展。
Background Fluorofenidone (AKF-PD) is a novel pyridone agent. The purpose of this study is to investigate the inhibitory effects of AKF-PD on dimethylnitrosamine (DMN)-induced liver fibrosis in rats and the involved molecular mechanism related to hepatic stellate cells (HSCs). Materials and methods Wistar rats were randomly divided into normal control, DMN, DMN/AKF-PD treatment and DMN/pirfenidone (PFD) treatment groups. AKF-PD and PFD treatments were, respectively, performed for two activated HSCs lines, rat CFSC-2G and human LX2. The cell proliferation was analysed by MTT. The expression of collagen I was determined by immunohistochemical staining and real-time RT-PCR. The expression of -smooth muscle actin (-SMA), tissue inhibitor of metalloproteinases-1 (TIMP-1), extracellular signal regulated kinase (ERK1/2), p38 MAPK (p38), and c-Jun N-terminal kinase/stress-activated protein kinase (JNK) were also detected by real-time RT-PCR and/or Western blot. Results AKF-PD significantly reduced PDGF-BB-induced proliferation and activation of HSCs, as determined by reducing protein expression of -SMA and TIMP-1. AKF-PD treatment attenuated PDGF-BB-induced upregulation of phosphorylation of ERK1/2, p38 and JNK. In fibrotic rat liver, AKF-PD reduced the degree of liver injury and hepatic fibrosis, which was associated with reduced the expression of collagen I, -SMA, TIMP-1 at both mRNA and protein levels. Conclusion AKF-PD treatment inhibits the progression of hepatic fibrosis by suppressing HSCs proliferation and activation via MAPK signalling pathway.