Chymase inhibition attenuates tetrachloride-induced liver fibrosis in hamsters

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.