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、酒精性肝硬化和胆汁淤积中显著升高。然而，关于iNOS与肝硬化的关系的报道较少。在这里，我们研究了一种新的iNOS抑制剂，已开发的口服给药在实验性大鼠肝硬化模型的影响。通过长期注射硫代乙酰胺（TAA）建立了大鼠癫痫模型。FR 260330是一种新型的、设计合理的、选择性的iNOS抑制剂，可以口服给药。在用FR 260330治疗12周后，大鼠显示出肝硬化、腹水和脾肿大的进展的抑制以及肝脏中结缔组织比例的显著降低。在FR 260330处理组中，硝基酪氨酸的表达显著降低，这表明存在过氧亚硝酸盐和核因子-κ B（NF κ B）活化.免疫组化和western blot分析显示，TGF β 1表达明显降低。本研究表明，FR 260330通过抑制TGF β 1减少肝纤维化，并延缓肝硬化的发展。这种口服iNOS抑制剂将成为治疗肝硬化的新策略

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