Potent antifibrotic activity of mTOR inhibitors sirolimus and everolimus but not of cyclosporine A and tacrolimus in experimental liver fibrosis
| Autor: | M. Ledermann, Felix Stickel, Christoph Dorn, Vreni Schneider, Eleonora Patsenker, Claus Hellerbrand, H. Saegesser |
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| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Portal venous pressure Calcineurin Inhibitors Liver transplantation Liver Cirrhosis Experimental Gastroenterology Tacrolimus Fibrosis Non-alcoholic Fatty Liver Disease Internal medicine Cyclosporin a medicine Animals Everolimus RNA Messenger Rats Wistar Ligation Triglycerides Sirolimus Hepatology business.industry TOR Serine-Threonine Kinases medicine.disease Portal Pressure Matrix Metalloproteinases Rats Calcineurin Fatty Liver surgical procedures operative Endocrinology Cyclosporine Disease Progression Bile Ducts business Immunosuppressive Agents medicine.drug |
| Zdroj: | Journal of hepatology. 55(2) |
| ISSN: | 1600-0641 |
| Popis: | 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 (2mg/kg), everolimus (3mg/kg), tacrolimus (1mg/kg), and cyclosporin A (10mg/kg) daily for 5weeks. 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. |
| Databáze: | OpenAIRE |
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