Z Gastroenterol 2010; 48 - P3_12
DOI: 10.1055/s-0029-1246484

Potent antifibrotic activity of mTOR inhibitors Sirolimus and Everolimus but not of Cyclosporine A and Tacrolimus in experimental liver fibrosis

E Patsenker 1, M Ledermann 1, H Saegesser 1, V Schneider 1, F Stickel 1
  • 1Institut für Klinische Pharmakologie, Universität Bern, Schweiz, Bern, Schweiz

Aims: Recurrence of chronic hepatitis C (CHC) and progressive fibrosis in liver transplants impairs graft and patient survival. Recent evidence suggests that calcineurin inhibitors such as cyclosporine A exert antiviral effects, while others, such as sirolimus, may have antifibrotic properties. However, it is unclear whether the choice of immunosuppressant affects the course liver graft fibrosis. The aim of the present study was to compare established immunosuppressants regarding their potential to halt fibrosis progression in vivo.

Methods: To induce fibrosis, 50 male Wistar rats underwent bile duct ligation and treatment with sirolimus (SIR, 2mg/kg), everolimus (EVE, 3mg/kg), tacrolimus (TAC, 1mg/kg), cyclosporin A (CSA, 10mg/kg) or vehicle control for 5 weeks 1 week after BDL. Collagen deposition was evaluated by hydroxyproline (HYP) levels and liver morphometry. Liver enzymes were measured in serum and mRNA expression of fibrosis-associated genes quantified by TaqMan PCR.

Results: mTOR inhibitors SIR and EVE significantly reduced body, liver and spleen weights compared to calcineurin blockers TAC and CSA. Portal pressure was alleviated to baseline in rats treated with EVE, whereas TAC and CSA showed no effect. HYP and morphometry revealed significantly less fibrosis with mTOR inhibition, whereas calcineurin blockage was ineffective. Gene transcription including that of procollagen-a1(I), alpha-smooth muscle actin, transforming growth factor beta1/2, tissue inhibitor of metalloproteinase-1, connective tissue growth factor, and platelet-derived growth factor were significantly reduced by SIR and EVE treatment compared to CSA/TAC-treated animals and controls.

Conclusions: mTOR inhibition in experimental liver fibrosis is associated with significantly less fibrosis progression and portal hypertension than treatment with calcineurin inhibitors. These data suggest that the choice of immunosuppressant could impact fibrosis progression in liver allografts.

cyclosporin A - everolimus - immunosuppression - liver fibrosis - liver transplantation - sirolimus - tacrolimus