The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen α1(I), TIMP-1 and MMP-2
The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen α1(I), TIMP-1 and MMP-2
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DOI：
10.1016/j.dld.2004.05.012
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发表时间：
2004-11-01
影响因子：
4.5
通讯作者：
Benedetti, A
中科院分区：
文献类型：
--
作者：
Di Sario, A;Bendia, E;Benedetti, A
背景。吡非尼酮（5甲基-1-苯基-2(1 H)-吡酮）是一种新型抗纤维化药物，在体内多种动物模型中已被证明可减少胶原沉积，最近在肝纤维化中也有应用。在细胞水平上，我们最近证明吡非尼酮能够抑制血小板源性生长因子诱导的肝星状细胞增殖，以及I型胶原积累和α - α(1)前胶原mRNA表达。评估吡非尼酮在诱导肝损伤后是否仍能保持其抗纤维化特性，并进一步研究导致吡非尼酮抗纤维化作用的分子机制。方法与结果。二甲基亚硝胺（10 mg/kg）治疗5周的大鼠，从第3周开始给予含0.5%吡非尼酮的液体饲料。根据丙氨酸转氨酶值和坏死炎症评分，吡非尼酮治疗降低了肝损伤程度，这与肝星状细胞增殖和胶原沉积减少有关。二甲基亚硝胺使转化生长因子（β 1）、前胶原α 1(I)、金属蛋白酶-1和基质金属蛋白酶-2的组织抑制剂的转录本水平分别提高了7倍、7倍、4倍和15倍。吡非尼酮将这些转录本的升高水平下调了50-60%，这与胶原沉积减少70%有关。(1)吡非尼酮在诱导肝损害后给药也有效；(2)吡非尼酮的抗纤维化作用主要是通过降低促纤维化前胶原α 1(I)和TIMP-1的表达，很可能是通过下调转化生长因子（beta1）、mRNA和基质金属蛋白酶-2的表达，这主要与正常细胞外基质的降解有关。(C) 2004年意大利胃肠病学主编，Elsevier Ltd.出版版权所有。
Background. Pirfenidone (5 methyl-1-phenyl-2(1 H)-pyridone) is a novel anti-fibrotic agent, which has been shown to decrease collagen deposition in a variety of animal models in vivo, and recently in hepatic fibrosis also. At cellular level, we have recently demonstrated that pirfenidone is able to inhibit proliferation of hepatic stellate cells induced by platelet-derived growth factor, as well as collagen type I accumulation and alphaI(1) procollagen mRNA expression.Aims. To evaluate if pirfenidone maintains its anti-fibrotic properties also when administered after the induction of hepatic damage and to further investigate the molecular mechanisms leading to the anti-fibrotic effect of pirfenidone.Methods and results. Rats treated with dimethylnitrosamine (10 mg/kg) for 5 weeks received a liquid diet containing 0.5% pirfenidone starting from the third week. Pirfenidone treatment reduced the degree of liver injury, as determined by alanine aminotransferase values and necro-inflammatory score, which was associated with reduced hepatic stellate cells proliferation and collagen deposition. Treatment with dimethylnitrosamine increased transcripts levels for transforming growth factor(beta1), procollagen alpha1(I), tissue inhibitors of metalloproteinase-1 and matrix metalloproteinase-2 by 7-, 7-, 4- and 15-fold, respectively. Pirfenidone administration downregulated elevated levels of those transcripts by 50-60%, and this was associated with a 70% reduction in collagen deposition.Conclusions. (1) Pirfenidone is effective also if administered after the induction of the hepatic damage; (2) the anti-fibrotic effect of pirfenidone is mainly due to the reduced expression of profibrogenic procollagen alpha1(I) and TIMP-1, most likely through the downregulation of transforming growth factor(beta1), mRNA, and of matrix metalloproteinase-2, which is mainly implicated in the degradation of the normal extracellular matrix. (C) 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.