Department of Regenerative Medicine, School of Medicine and Institute of Medical Sciences, Tokai University, Isehara, Japan.
J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:85-8. doi: 10.1111/j.1440-1746.2011.07006.x.
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)-β 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-β 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.
基于肝纤维化的细胞和分子机制，已经提出了几种方法来治疗肝纤维化。在调节胶原代谢的许多生长因子和细胞因子中，转化生长因子 (TGF)-β 是通过激活肝星状细胞、刺激胶原基因转录和抑制基质金属蛋白酶表达来加速肝纤维化的最有效因素。因此，TGF-β 及其细胞内介质 Smad 蛋白可以成为肝纤维化的潜在治疗靶点。Smad3 的组成性磷酸化和核积累是激活的星状细胞的共同特征。我们合成了一种新型小分子化合物，通过促进转录抑制剂 YB-1 的核输入来抑制 Smad3 依赖性胶原基因转录。抗纤维化策略的另一个新见解是骨髓源性细胞对肝纤维化消退的贡献。粒细胞集落刺激因子的给药增强了骨髓源性细胞向纤维性肝组织的迁移，并加速了实验性肝纤维化的消退。我们最近鉴定了骨髓源性细胞表达的新型未知因子，这些因子不仅改善肝纤维化，而且还加速纤维性肝的再生。
