Chymase inhibition attenuates tetrachloride-induced liver fibrosis in hamsters
Chymase inhibition attenuates tetrachloride-induced liver fibrosis in hamsters
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DOI：
10.1111/j.1872-034x.2010.00672.x
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发表时间：
2010-08-01
影响因子：
4.2
通讯作者：
Miyazaki, Mizuo
中科院分区：
文献类型：
--
作者：
Komeda, Koji;Takai, Shinji;Miyazaki, Mizuo
目的：食糜酶将血管紧张素I转化为血管紧张素II，从而促进肝纤维化的发展。本研究探讨了食糜酶抑制剂TY-51469是否能减弱四氯化物(CCl4)诱导的肝纤维化。方法：通过皮下注射诱导肝纤维化。每周两次注射 1 mL/kg CCl4，持续 8 周，每只仓鼠给予 TY-51469（每天 1 mg/kg）或安慰剂。未治疗的仓鼠被用作对照组。结果：与对照组相比，安慰剂治疗组观察到血清丙氨酸氨基转移酶、总胆红素和透明质酸水平显着升高，但这些水平在TY-51469治疗组中显着减弱。安慰剂治疗组的肝糜酶活性显着高于对照组，而 TY51469 治疗组的活性则不然。安慰剂治疗组的肝脏中总血管紧张素 II 形成活性也显着高于对照组或 TY-51469 治疗组。安慰剂治疗组中纤维化面积与肝脏总面积的比率显着高于对照组，但 TY-51469 治疗组中该比率显着低于安慰剂治疗组。与安慰剂治疗组相比，TY-51469治疗组的α-平滑肌肌动蛋白（SMA）阳性细胞数量显着减少。结论：食糜酶阳性细胞数量与纤维化程度之间以及食糜酶阳性细胞数量与α-SMA阳性细胞数量之间存在显着相关性。因此，食糜酶抑制可能是预防肝纤维化的有效策略。
Aim:Chymase converts angiotensin I to angiotensin II, which may promote the development of liver fibrosis. In this study, whether a chymase inhibitor TY-51469 attenuated tetrachloride (CCl4)-induced liver fibrosis was examined.Methods:Liver fibrosis was induced by the s.c. injection of 1 mL/kg of CCl4 twice weekly for 8 weeks, and each hamster was given TY-51469 (1 mg/kg per day) or placebo. Untreated hamsters were used as a control group.Results:Significant increases of serum alanine aminotransferase, total bilirubin and hyaluronic acid levels were observed in the placebo-treated group compared with the control group, but these levels were significantly attenuated in the TY-51469-treated group. Liver chymase activity was significantly higher in the placebo-treated group than in the control group, whereas the activity in the TY51469-treated group was not. Total angiotensin II-forming activity in the liver was also significantly higher in the placebo-treatedgroup than in the control group or the TY-51469-treated group. The ratio of the fibrotic area to the total area in the liver was significantly higher in the placebo-treated group than in the control group, but the ratio was significantly lower in the TY-51469-treated group than in the placebo-treated group. A significant decrease in the number of alpha-smooth muscle actin (SMA)-positive cells was seen in the TY-51469-treated group compared to the placebo-treated group.Conclusion:Significant correlations between the number of chymase-positive cells and the degree of fibrosis and between the numbers of chymase-positive cells and alpha-SMA-positive cells were observed. Thus, chymase inhibition may be a useful strategy for preventing liver fibrosis.