All-trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production
All-trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production
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DOI：
10.1111/j.1478-3231.2008.01745.x
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发表时间：
2008-10-01
影响因子：
6.7
通讯作者：
Sakai, Yoshiharu
中科院分区：
文献类型：
--
作者：
Hisamori, Shigeo;Tabata, Chiharu;Sakai, Yoshiharu
背景/目的：任何病因的肝纤维化都是由肝星状细胞（HSC）转分化和增殖产生胶原蛋白引起的，其特点是肝功能进行性恶化，导致高死亡率。我们最近报道，全反式视黄酸（ATRA）可抑制肺成纤维细胞的转分化和增殖，并预防放射或博来霉素诱导的肺纤维化。方法：我们检测了 ATRA 对四氯化碳 (CCl(4)) 诱导的肝纤维化的影响。我们对 CCl(4) 处理的小鼠肝组织中给予或不给予 ATRA 的转化生长因子 (TGF)-β 1 和白细胞介素 (IL)-6 进行组织学检查和定量测量，并研究 ATRA 对静止和激活的 HSC 中细胞因子产生的影响。结果：腹腔注射ATRA可减轻CCl(4)诱导的肝纤维化，无ATRA组12周总生存率为26.5%（n=25），而治疗组为75.0%（n=24）（P=0.0187）。体外研究表明，ATRA 的施用可减少 (i) HSC 产生 TGF-β 1、IL-6 和胶原蛋白，(ii) TGF-β 依赖性细胞转分化和 IL-6 依赖性细胞增殖，以及 (iii) 核因子 kappa B p65 和 p38 丝裂原激活蛋白激酶的活性，刺激 TGF-β 1 和 IL-6 的产生，这可能是 ATRA 对肝脏预防作用的机制纤维化。结论：我们的研究结果表明 ATRA 可改善肝纤维化。由于口服给药具有良好的依从性，ATRA可能成为治疗肝纤维化的新方法。
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)-beta 1 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-beta 1, 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-kappa B p65 and p38mitogen-activated protein kinase, which stimulate the production of TGF-beta 1 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.