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

J Gastroenterol Hepatol. 2011 Mar;26(3):558-67. doi: 10.1111/j.1440-1746.2010.06406.x.

Abstract

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 CCl(4) -induced rat liver fibrosis, and the related mechanism has not been determined.

Methods: 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.

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 CCl(4)-induced rat liver fibrosis model, which may be related to binding with cyclophilin B and D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Alanine Transaminase / blood
  • Analysis of Variance
  • Animals
  • Aspartate Aminotransferases / blood
  • Carbon Tetrachloride
  • Cell Line
  • Collagen Type III / genetics
  • Cyclophilin D
  • Cyclophilins / genetics
  • Cyclophilins / metabolism*
  • Cyclosporine / pharmacology*
  • Cytoprotection
  • Dose-Response Relationship, Drug
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / enzymology
  • Hepatic Stellate Cells / pathology
  • Hydroxyproline / metabolism
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / pathology
  • Liver Cirrhosis, Experimental / chemically induced
  • Liver Cirrhosis, Experimental / enzymology
  • Liver Cirrhosis, Experimental / genetics
  • Liver Cirrhosis, Experimental / pathology
  • Liver Cirrhosis, Experimental / prevention & control*
  • Male
  • Matrix Metalloproteinase 13 / genetics
  • RNA Interference
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Serum Albumin / metabolism
  • Time Factors
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Actins
  • Collagen Type III
  • Cyclophilin D
  • RNA, Messenger
  • Serum Albumin
  • Tissue Inhibitor of Metalloproteinase-1
  • Transforming Growth Factor beta
  • smooth muscle actin, rat
  • cyclophilin B
  • Cyclosporine
  • (melle-4)cyclosporin
  • Carbon Tetrachloride
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Matrix Metalloproteinase 13
  • Mmp13 protein, rat
  • Cyclophilins
  • Hydroxyproline