European journal of clinical investigation · 2013
The antihepatic fibrotic effects of fluorofenidone via MAPK signalling pathways.
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Peng Yu, Yang Huixiang, Zhu Tingting, Zhao Menghua, Deng Yuexia, Liu Bin, Shen Hong, Hu Gaoyun, Wang Zhaohe, Tao Lijian
Аннотация
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 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.
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 HSCs proliferation and activation via MAPK signalling pathway.
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.
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 HSCs proliferation and activation via MAPK signalling pathway.
Предметные рубрики MeSH
AnimalsBlotting, WesternCell ProliferationDimethylnitrosamineHepatic Stellate CellsJNK Mitogen-Activated Protein KinasesLiver CirrhosisMAP Kinase Signaling SystemMaleMitogen-Activated Protein Kinase 8Models, AnimalPyridonesRNA, MessengerRandom AllocationRatsRats, WistarReal-Time Polymerase Chain ReactionTissue Inhibitor of Metalloproteinase-1p38 Mitogen-Activated Protein Kinases