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

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.

• Authors: Hui Wang, Yuguo Zhang, Tailing Wang, Hong You, Jidong Jia
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 26 Issue 3 Pg. 558-67 (Mar 2011) ISSN: 1440-1746 [Electronic] Australia
• PMID: 21332552 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Chemical References

• 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

Topics

• Actins (metabolism)
• Alanine Transaminase (blood)
• Analysis of Variance
• Animals
• Aspartate Aminotransferases (blood)
• Carbon Tetrachloride
• Cell Line
• Collagen Type III (genetics)
• Cyclophilin D
• Cyclophilins (genetics, metabolism)
• Cyclosporine (pharmacology)
• Cytoprotection
• Dose-Response Relationship, Drug
• Hepatic Stellate Cells (drug effects, enzymology, pathology)
• Hydroxyproline (metabolism)
• Liver (drug effects, enzymology, pathology)
• Liver Cirrhosis, Experimental (chemically induced, enzymology, genetics, pathology, 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)