期刊
JOURNAL OF HEPATOLOGY
卷 45, 期 6, 页码 786-796出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2006.07.030
关键词
bile duct-ligation; experimental liver cirrhosis; hepatic stellate cells; matrix metalloproteinase 2; mTOR; rapamycin; rat; thioacetamide; transforming growth factor-beta
Background/Aims: Mammalian target of rapamycin (mTOR) signalling is central in the activation of hepatic stellate cells (HSCs), the key source of extracellular matrix (ECM) in fibrotic liver. We tested the therapeutic potential of the mTOR inhibitor rapamycin in advanced cirrhosis. Methods: Cirrhosis was induced by bile duct-ligation (BDL) or thioacetamide injections (TAA). Rats received oral rapamycin (0.5 mg/kg/day) for either 14 or 28 days. Untreated BDL and TAA-rats served as controls. Liver function was quantified by aminopyrine breath test. ECM and ECM-producing cells were quantified by morphometry. MMP-2 activity was measured by zymography. mRNA expression of procollagen-alpha 1, transforming growth factor-beta 1 (TGF-beta 1) and beta 2 was quantified by RT-PCR. Results: Fourteen days of rapamycin improved liver function. Accumulation of ECM was decreased together with numbers of activated HSCs and MMP-2 activity in both animal models. TGF-beta 1 mRNA was downregulated in TAA, TGF-beta 2 mRNA was downregulated in BDL. 28 days of rapamycin treatment entailed a survival advantage of long-term treated BDL-rats. Conclusions: Low-dose rapamycin treatment is effectively antifibrotic and attenuates disease progression in advanced fibrosis. Our results warrant the clinical evaluation of rapamycin as an antifibrotic drug. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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