Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis
Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis
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DOI：
10.1016/j.jhep.2006.07.030
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发表时间：
2006-12-01
影响因子：
25.7
通讯作者：
Reichen, Juerg
中科院分区：
文献类型：
--
作者：
Neef, Markus;Ledermann, Monika;Reichen, Juerg
背景/目标：哺乳动物雷帕霉素靶蛋白（mTOR）信号传导在肝星状细胞（HSC）的活化中起中心作用，肝星状细胞是纤维化肝脏中细胞外基质（ECM）的关键来源。我们测试了mTOR抑制剂雷帕霉素在晚期肝硬变中的治疗潜力。方法：通过胆管结扎（BDL）或硫代乙酰胺注射（TAA）诱导肝硬变。大鼠接受口服雷帕霉素（0.5 mg/kg/天）14或28天。未处理的BDL和TAA大鼠作为对照。通过氨基比林呼气试验定量肝功能。ECM和ECM产生细胞通过形态测定法定量。酶谱法测定MMP-2活性。RT-PCR定量检测前胶原-α 1、转化生长因子-β 1（TGF-β 1）和β 2的mRNA表达。两种动物模型中ECM的积累与活化的HSC数量和MMP-2活性一起减少。TGF-β 1 mRNA在TAA中表达下调，TGF-β 2 mRNA在BDL中表达下调。28天的雷帕霉素治疗需要长期治疗的BDL-rats.Conclusions的生存优势：低剂量雷帕霉素治疗是有效的抗纤维化和衰减在晚期纤维化的疾病进展。我们的研究结果保证了雷帕霉素作为抗纤维化药物的临床评价。(c)2006年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
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.