Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
J Gastroenterol Hepatol. 2011 Mar;26(3):558-67. doi: 10.1111/j.1440-1746.2010.06406.x.
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 CCl(4) -induced rat liver fibrosis, and the related mechanism has not been determined.
A liver fibrosis model was induced in Wistar rats using CCl(4) for 6 weeks. Meanwhile, two different doses of NIM811 (low-dose 10 mg/kg and high-dose 20 mg/kg) were given to the CCl(4) -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.
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.
NIM811 attenuates liver fibrosis in a CCl(4)-induced rat liver fibrosis model, which may be related to binding with cyclophilin B and D.
N-甲基-4-异亮氨酸环孢素（NIM811）是环孢素 A 的一种新型类似物，能够抑制体外胶原沉积，并减少胆管结扎动物模型中的肝坏死。然而，NIM811 是否对 CCl4 诱导的大鼠肝纤维化有作用，以及其相关机制尚未确定。
使用 CCl4 诱导 Wistar 大鼠肝纤维化模型 6 周，同时给予 CCl4 处理的大鼠两种不同剂量的 NIM811（低剂量 10mg/kg 和高剂量 20mg/kg）。根据组织学评分和肝羟脯氨酸含量评估肝纤维化。测定血清丙氨酸转氨酶、天冬氨酸转氨酶和白蛋白水平，肝组织基质金属蛋白酶-13、金属蛋白酶组织抑制剂-1、α-平滑肌肌动蛋白和亲环蛋白 B、D 的表达。还在肝星状细胞系中研究了亲环蛋白 B 和 D。
与模型组相比，NIM811 两组的羟脯氨酸含量均降低（P<0.05）。NIM811 还减轻了肝坏死和纤维化。NIM811 抑制了肝组织中金属蛋白酶组织抑制剂-1、转化生长因子β mRNA 和α-平滑肌肌动蛋白蛋白的表达。纤维化模型中亲环蛋白 B 的表达高于正常组（P<0.05），低剂量 NIM811 治疗组显著降低（P<0.05），表明亲环蛋白 B 可能具有促纤维化作用。体外研究表明，亲环蛋白 B 和/或 D 敲除与胶原抑制有关。
NIM811 可减轻 CCl4 诱导的大鼠肝纤维化模型中的肝纤维化，这可能与与亲环蛋白 B 和 D 结合有关。
