N-methyl-4-isoleucine cyclosporine attenuates CCl -induced liver fibrosis in rats by interacting with cyclophilin B and D

Background and Aim: N‐methyl‐4‐isoleucine cyclosporine (NIM811), a new analogue of cyclosporine A, can inhibit collagen deposition in vitro and reduce liver necrosis in a bile‐duct‐ligation animal model. However, whether NIM811 effects on CCl₄‐induced rat liver fibrosis, and the related mechanism has not been determined. Methods: A liver fibrosis model was induced in Wistar rats using CCl₄ for 6 weeks. Meanwhile, two different doses of NIM811 (low‐dose 10 mg/kg and high‐dose 20 mg/kg) were given to the CCl₄‐treated rats. Liver fibrosis was then evaluated according to histopathological scoring and liver hydroxyproline content. Serum alanine aminotransferase, aspartate aminotransferase and albumin levels, expression of matrix metalloproteinase‐13, tissue inhibitor of metalloproteinase‐1, α‐smooth muscle actin and cyclophilin B and D in liver tissue were determined. Cyclophilin B and D were also studied in an hepatic stellate cell line. Results: Hydroxyproline content was decreased in both NIM811 groups compared with the model (P < 0.05). Liver necrosis and fibrosis were also attenuated in the NIM811 groups. NIM811 suppressed the expression of tissue inhibitor of metalloproteinase‐1, transforming growth factor beta mRNA and α‐smooth muscle actin protein in liver tissue. Expression of cyclophilin B in the fibrosis model was increased compared with the normal group (P < 0.05), and was decreased significantly in the low‐dose NIM811 treatment group (P < 0.05), which indicated that cyclophilin B might have a profibrotic effect. In vitro studies revealed that cyclophilin B and/or D knockout were associated with collagen inhibition. Conclusions: NIM811 attenuates liver fibrosis in a CCl₄‐induced rat liver fibrosis model, which may be related to binding with cyclophilin B and D.