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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 15, 2005; DOI: 10.1124/jpet.104.079616

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Received for publication October 22, 2004.
Revised March 2, 2005.
Accepted for publication March 2, 2005.

Long-term treatment of bile duct ligated rats with (sirolimus) rapamycin significantly attenuates liver fibrosis: Analysis of the underlying mechanisms

Erwin Biecker 1, Andrea De Gottardi 2, Markus Neef 2, Matthias Unternahrer 2, Vreni Schneider 2, Monika Ledermann 2, Hans Sagesser 2, Sidney Shaw 3, Jurg Reichen 2*

1 Medizinische Klinik I 2 Department of Clinical Pharmacology, University of Berne 3 Department of Clinical Research

* Address correspondence to: E-mail: reichen{at}ikp.unibe.ch

Abstract

Background: Rapamycin is an immunosuppressant with anti-proliferative properties. We investigated whether rapamycin treatment of bile duct ligated (BDL) rats is capable to inhibit liver fibrosis and thereby affect hemodynamics. Methods: Following BDL, rats were treated for 28 days with rapamycin (BDL SIR). BDL animals without drug treatment (BDL CTR) and sham-operated animals served as controls. After 28days, hemodynamics were measured and livers were harvested for histology/immunohistochemistry. Liver mRNA levels of transforming growth factor (TGF)-{beta}1, connective tissue growth factor (CTGF), platelet derived growth factor (PDGF) beta, p27 and p21 were quantified by rtPCR. Liver protein levels of p27, p21, p70s6k, phospho-p70s6k, 4E-BP1, phospho-4E-BP1(Thr37/46) and phospho-4E-BP1(Ser65/Thr70) were determined by Western blotting. Results: Portal vein pressure was lower in BDL SIR than in BDL CTR animals. Volume fractions of connective tissue, bile duct epithelial, desmin-positive and actin-positive cells were lower in BDL SIR than in BDL CTR rats. On the mRNA level, TGF-{beta}1, CTGF and PDGF were decreased by rapamycin. p27 and p21 mRNA did not differ. On the protein level, rapamycin increased p27 and decreased p21 levels. Levels of non-phosphorylated p70s6k and 4E-BP1 did not vary between groups but levels of p-p70s6k were decreased by rapamycin. Rapamycin had no effect on p-4E-BP1(Thr37/46) and p-4E-BP1(Ser65/Thr70) levels. Conclusions: In BDL rats, rapamycin inhibits liver fibrosis and ameliorates portal hypertension. This is paralled by decreased levels of TGF-{beta}1, CTGF and PDGF. Rapamycin influences the cell cycle by upregulation of p27, downregulation of p21 and inhibition of p70s6k phosphorylation


Key words: bile duct ligation, cirrhosis, liver fibrosis, portal hypertension, rapamycin, signal transduction


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