Potent antifibrotic activity of mTOR inhibitors sirolimus and everolimus but not of cyclosporine A and tacrolimus in experimental liver fibrosis

Background & Aims: Recurrence of chronic hepatitis C and progressive fibrosis in liver transplants is frequent and impairs both graft and patient survival. Whether or not the choice of immunosuppression affects progression of fibrosis remains unclear. The aim of the present study was to compare the potential of the commonly used immunosuppressants to halt experimental liver fibrosis progression. Methods: To induce liver fibrosis, rats underwent bile duct ligation and treatment with sirolimus (2 mg/kg). everolimus (3 mg/kg), tacrolimus (1 mg/kg), and cyclosporin A (10 mg/kg) daily for 5 weeks. Fibrosis, inflammation, and portal pressure were evaluated by histology, hydroxyproline levels, morphometry, hemodynamics, and hepatic gene expression. Results: Sirolimus and everolimus decreased fibrosis up to 70%, improved portal pressure, reduced ascites, and showed potent down-regulation of pro-fibrogenic genes, paralleled by a strong increase in matrix degradation (collagenase) activity; in contrast, tacrolimus and cyclosporine A had no or even aggravating effects on liver fibrosis in rats. Conclusions: mTOR inhibition by sirolimus and everolimus in experimental liver fibrosis associates with significantly less fibrosis progression and portal hypertension than treatment with calcineurin inhibitors tacrolimus and cyclosporine A. These data suggest that the selection of the immunosuppressant could impact the recurrence of fibrosis in liver allografts. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.