The antihepatic fibrotic effects of fluorofenidone via MAPK signalling pathways
Version of Record online: 26 FEB 2013
© 2013 The Authors. European Journal of Clinical Investigation © 2013 Stichting European Society for Clinical Investigation Journal Foundation
European Journal of Clinical Investigation
Volume 43, Issue 4, pages 358–368, April 2013
How to Cite
Eur J Clin Invest 2013; 43 (4): 358–368
- Issue online: 18 MAR 2013
- Version of Record online: 26 FEB 2013
- Accepted manuscript online: 16 JAN 2013 07:30AM EST
- Manuscript Accepted: 11 JAN 2013
- Manuscript Received: 10 SEP 2012
- National Natural Science Foundation of China. Grant Numbers: 30973579, 30873110, 20972194
- Hunan province science and technology project. Grant Number: 2012FJ4070
- hepatic fibrosis;
- hepatic stellate cell;
- MAPK signalling pathway;
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 α-smooth muscle actin (α-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.
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.
AKF-PD treatment inhibits the progression of hepatic fibrosis by suppressing HSCs proliferation and activation via MAPK signalling pathway.