Development of new therapy for prevention of fibrosis in liver cirrhosis or chronic pancreatitis.

诱导型一氧化氮合酶(INOS)活性在病毒性肝炎、酒精性肝硬变和胆汁淤积症中显著升高。然而，关于iNOS与肝硬变关系的研究报道较少。在这里，我们研究了一种新的iNOS抑制剂，它已经被开发为口服给药，在一个实验性的大鼠肝硬变模型中的作用。采用长期注射硫代乙酰胺(TAA)的方法建立大鼠肝硬变模型。FR260330是一种新型的、设计合理的、选择性的iNOS抑制剂，可以口服。FR260330治疗12周后，大鼠的肝硬变、腹水和脾肿大的进展受到抑制，肝脏结缔组织的比例明显减少。FR260330治疗组硝基酪氨酸表达明显减少，表明过氧亚硝酸根的存在和核因子-kappaB的激活。免疫组织化学和免疫印迹分析显示，转化生长因子β1(TGFb1)在该组中的表达明显降低。本研究表明，FR260330通过抑制TGFb1减轻肝纤维化，延缓肝硬变的发展。这种口服诱导型一氧化氮合酶抑制剂将成为治疗肝硬变的新策略

Inducible nitric oxide synthase (iNOS) activity was significantly elevated in viral hepatitis, alcoholic cirrhosis, and cholestasis. however, there are few reports on the relationship between iNOS and cirrhosis. Here, we investigated the effects of a new iNOS inhibitor which has been developed for oral administration in an experimental rat liver cirrhosis model. A cirrhotic rat model was developed by long-term administration of thioacetamide (TAA) injections. FR260330, is a new, rationally designed, selective iNOS inhibitor that can be administered orally. After 12 weeks of treatment with FR260330, the rats showed inhibition of progressions of cirrhosis, ascites, and splenomegaly as well as a significant reduction in the proportions of connective tissue in the liver. The expression of nitrotyrosine, which indicates the existence of peroxynitrite and nuclear factor- kappa B (NFkB) activation, was remarkably decreased in the FR260330 treatment group. In addition, imnunohistochemical and western blot analyses showed that the expression of transforming growth factor beta-1 (TGFb1) was remarkably decreased in this group. The present study demonstrates that FR260330 reduces liver fibrosis by the inhibition of TGFb1 and retards the development of cirrhosis. This oral iNOS inhibitor will be a new strategy for the treatment of cirrhosis