Journal
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
Volume 43, Issue 4, Pages 358-368Publisher
WILEY
DOI: 10.1111/eci.12053
Keywords
Fluorofenidone; hepatic fibrosis; hepatic stellate cell; MAPK signalling pathway; PDGF-BB
Funding
- National Natural Science Foundation of China [30973579, 30873110, 20972194]
- Hunan province science and technology project [2012FJ4070]
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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.
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