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  • Title: All-trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production.
    Author: Hisamori S, Tabata C, Kadokawa Y, Okoshi K, Tabata R, Mori A, Nagayama S, Watanabe G, Kubo H, Sakai Y.
    Journal: Liver Int; 2008 Nov; 28(9):1217-25. PubMed ID: 18397230.
    Abstract:
    BACKGROUND/AIMS: Liver fibrosis with any aetiology, induced by the transdifferentiation and proliferation of hepatic stellate cells (HSCs) to produce collagen, is characterized by progressive worsening in liver function, leading to a high incidence of death. We have recently reported that all-trans-retinoic acid (ATRA) suppresses the transdifferentiation and proliferation of lung fibroblasts and prevents radiation- or bleomycin-induced lung fibrosis. METHODS: We examined the impact of ATRA on carbon tetrachloride (CCl(4))-induced liver fibrosis. We performed histological examinations and quantitative measurements of transforming growth factor (TGF)-beta1 and interleukin (IL)-6 in CCl(4)-treated mouse liver tissues with or without the administration of ATRA, and investigated the effect of ATRA on the production of the cytokines in quiescent and activated HSCs. RESULTS: CCl(4)-induced liver fibrosis was attenuated in histology by intraperitoneal administration of ATRA, and the overall survival rate at 12 weeks was 26.5% without ATRA (n=25), whereas it was 75.0% (n=24) in the treatment group (P=0.0187). In vitro studies disclosed that the administration of ATRA reduced (i) the production of TGF-beta1, IL-6 and collagen from HSCs, (ii) TGF-beta-dependent transdifferentiation of the cells and IL-6-dependent cell proliferation and (iii) the activities of nuclear factor-kappaB p65 and p38mitogen-activated protein kinase, which stimulate the production of TGF-beta1 and IL-6, which could be the mechanism underlying the preventive effect of ATRA on liver fibrosis. CONCLUSIONS: Our findings indicate that ATRA ameliorates liver fibrosis. As the oral administration of the drug results in good compliance, ATRA could be a novel approach in the treatment of liver fibrosis.
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