Abstract
Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of α-smooth muscle actin (α-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 μM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg·kg(-1)·day(-1)) administration significantly decreased hepatic collagen deposition and α-SMA expression in CCl(4)-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Animals
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Carbon Tetrachloride
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Cell Proliferation / drug effects*
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Cells, Cultured
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Collagen Type I / metabolism
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Collagen Type I, alpha 1 Chain
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Dose-Response Relationship, Drug
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Enzyme-Linked Immunosorbent Assay
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblast Growth Factor 2 / metabolism
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Hepatic Stellate Cells / drug effects*
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Hepatic Stellate Cells / enzymology
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Hepatic Stellate Cells / pathology
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Indoles / pharmacology*
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Liver / drug effects*
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Liver / enzymology
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Liver / pathology
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Liver Cirrhosis, Experimental / chemically induced
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Liver Cirrhosis, Experimental / enzymology
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Liver Cirrhosis, Experimental / pathology
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Liver Cirrhosis, Experimental / prevention & control*
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MAP Kinase Kinase 1 / genetics
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MAP Kinase Kinase 1 / metabolism
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Male
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Phosphorylation
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Propionates / pharmacology*
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Protein Kinase Inhibitors / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
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Receptor, Fibroblast Growth Factor, Type 1 / metabolism
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Signal Transduction / drug effects
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Time Factors
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Transfection
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Tyrosine
Substances
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Actins
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Ccnd1 protein, rat
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Cdkn1a protein, rat
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Collagen Type I
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Collagen Type I, alpha 1 Chain
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Cyclin-Dependent Kinase Inhibitor p21
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Indoles
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NP 603
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Propionates
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Protein Kinase Inhibitors
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smooth muscle actin, rat
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Fibroblast Growth Factor 2
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Cyclin D1
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Tyrosine
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Carbon Tetrachloride
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Fgfr1 protein, mouse
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Receptor, Fibroblast Growth Factor, Type 1
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 1