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The antihepatic fibrotic effects of fluorofenidone via MAPK signalling pathways
Author(s) -
Peng Yu,
Yang Huixiang,
Zhu Tingting,
Zhao Menghua,
Deng Yuexia,
Liu Bin,
Shen Hong,
Hu Gaoyun,
Wang Zhaohe,
Tao Lijian
Publication year - 2013
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/eci.12053
Subject(s) - hepatic stellate cell , mapk/erk pathway , western blot , kinase , downregulation and upregulation , p38 mitogen activated protein kinases , signal transduction , protein kinase a , chemistry , hepatic fibrosis , fibrosis , cancer research , microbiology and biotechnology , endocrinology , medicine , biology , biochemistry , gene
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 ( HSC s). 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 HSC s lines, rat CFSC ‐2G and human LX 2. 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 α‐smooth muscle actin (α‐ SMA ), tissue inhibitor of metalloproteinases‐1 ( TIMP ‐1), extracellular signal regulated kinase ( ERK 1/2), 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 α‐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, α‐SMA, TIMP‐1 at both mRNA and protein levels. Conclusion AKF ‐ PD treatment inhibits the progression of hepatic fibrosis by suppressing HSC s proliferation and activation via MAPK signalling pathway.