Novel anti-fibrotic modalities for liver fibrosis: Molecular targeting and regenerative medicine in fibrosis therapy
Novel anti-fibrotic modalities for liver fibrosis: Molecular targeting and regenerative medicine in fibrosis therapy
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DOI：
10.1111/j.1440-1746.2011.07006.x
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发表时间：
2012-03-01
影响因子：
4.1
通讯作者：
Higashi, Kiyoshi
中科院分区：
文献类型：
--
作者：
Inagaki, Yutaka;Higashiyama, Reiichi;Higashi, Kiyoshi
基于肝纤维化形成的细胞和分子机制，人们提出了几种治疗肝纤维化的方法。在众多调节胶原代谢的生长因子和细胞因子中，转化生长因子-β是通过激活肝星状细胞、刺激胶原基因转录、抑制基质金属蛋白酶表达而加速肝纤维化的最有效的因子。因此，转化生长因子-β及其细胞内介质Smad蛋白可以成为治疗肝纤维化的潜在靶点。Smad3的结构性磷酸化和核积聚是激活的星状细胞的共同特征。我们合成了一种新的小分子化合物，它通过促进转录抑制因子YB-1的核输入来抑制Smad3依赖的胶原基因的转录。对抗纤维化策略的另一个见解是骨髓来源的细胞对肝纤维化消退的贡献。粒细胞集落刺激因子的应用促进了骨髓来源细胞向肝纤维化组织的迁移，加速了实验性肝纤维化的消退。我们最近发现了由骨髓来源的细胞表达的新的未知因子，这些因子不仅可以改善肝纤维化，还可以促进肝纤维化的再生。
Based on the cellular and molecular mechanisms underlying hepatic fibrogenesis, several kinds of approaches have been proposed to treat liver fibrosis. Among a number of growth factors and cytokines that regulate collagen metabolism, transforming growth factor (TGF)-beta is the most potent factor to accelerate liver fibrosis by activating hepatic stellate cells, stimulating collagen gene transcription, and suppressing matrix metalloproteinases expression. Thus, TGF-beta as well as its intracellular mediators, Smad proteins, can be potential therapeutic targets for liver fibrosis. Constitutive phosphorylation and nuclear accumulation of Smad3 is the common feature of activated stellate cells. We have synthesized a novel small compound that inhibits Smad3-dependent collagen gene transcription by promoting nuclear import of a transcriptional repressor, YB-1. Another insight into anti-fibrotic strategies is the contribution of bone marrow-derived cells to the regression of liver fibrosis. Administration of granulocyte-colony stimulating factor enhanced the migration of bone marrow-derived cells into fibrotic liver tissue and accelerated the regression of experimental liver fibrosis. We have recently identified novel unknown factors expressed by bone marrow-derived cells that not only ameliorate liver fibrosis but also accelerate regeneration of fibrotic liver.