Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells
Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells
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氟非尼酮通过抑制肝星状细胞的增殖和活化来减轻肝纤维化
DOI：
10.1152/ajpgi.00471.2012
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发表时间：
2014-02-01
影响因子：
4.5
通讯作者：
Tao, Lijian
中科院分区：
文献类型：
--
作者：
Peng, Yu;Yang, Huixiang;Tao, Lijian
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对大鼠肝纤维化的抑制作用及其与肝星状细胞（HSCs）相关的分子机制。二甲基亚硝胺或CCl4治疗大鼠随机分为正常组、模型组、AKF-PD治疗组和吡非尼酮（PFD）治疗组。分别用AKF-PD和PFD处理原代大鼠造血干细胞。分别用溴脱氧尿嘧啶和流式细胞术分析细胞增殖和细胞周期分布。采用Western blot、免疫组化染色和实时RT-PCR检测ⅰ型胶原和α -平滑肌肌动蛋白（α - sma）的表达。Western blot检测细胞周期蛋白D1、cyclin E、p27（kip1）的表达，MEK、ERK、Akt、70-kDa核糖体S6激酶（p70S6K）的磷酸化水平。AKF-PD通过降低I型胶原和α - sma的表达，导致G0/G1期细胞周期阻滞，降低cyclin D-1和cyclin E的表达，促进p27（kip1）的表达，显著抑制pdgf - bb诱导的HSC增殖和活化。AKF-PD还下调pdgf - bb诱导的造血干细胞中MEK、ERK、Akt和p70S6K的磷酸化。在大鼠肝纤维化中，AKF-PD通过降低坏死炎症评分和半定量评分，降低I型胶原和α - sma的表达来减轻肝纤维化。AKF-PD通过ERK/MAPK和PI3K/Akt信号通路抑制hsc的增殖和活化，从而减弱肝纤维化的进展。AKF-PD可能作为一种潜在的新型肝纤维化治疗剂。
Fluorofenidone (AKF-PD) is a novel pyridone agent. The purpose of this study is to investigate the inhibitory effects of AKF-PD on liver fibrosis in rats and the involved molecular mechanism related to hepatic stellate cells (HSCs). Rats treated with dimethylnitrosamine or CCl4 were randomly divided into normal, model, AKF-PD treatment, and pirfenidone (PFD) treatment groups. The isolated primary rat HSCs were treated with AKF-PD and PFD respectively. Cell proliferation and cell cycle distribution were analyzed by bromodeoxyuridine and flow cytometry, respectively. The expression of collagen I and alpha-smooth muscle actin (alpha-SMA) were determined by Western blot, immunohistochemical staining, and real-time RT-PCR. The expression of cyclin D1, cyclin E, and p27(kip1) and phosphorylation of MEK, ERK, Akt, and 70-kDa ribosomal S6 kinase (p70S6K) were detected by Western blot. AKF-PD significantly inhibited PDGF-BB-induced HSC proliferation and activation by attenuating the expression of collagen I and alpha-SMA, causing G0/G1 phase cell cycle arrest, reducing expression of cyclin D-1 and cyclin E, and promoting expression of p27(kip1). AKF-PD also downregulated PDGF-BB-induced MEK, ERK, Akt, and p70S6K phosphorylation in HSCs. In rat liver fibrosis, AKF-PD alleviated hepatic fibrosis by decreasing necroinflammatory score and semiquantitative score, and reducing expression of collagen I and alpha-SMA. AKF-PD attenuated the progression of hepatic fibrosis by suppressing HSCs proliferation and activation via the ERK/MAPK and PI3K/Akt signaling pathways. AKF-PD may be used as a potential novel therapeutic agent against liver fibrosis.