Galectin-3 regulates myofibroblast activation and hepatic fibrosis
Galectin-3 regulates myofibroblast activation and hepatic fibrosis
复制标题
DOI：
10.1073/pnas.0511167103
复制
发表时间：
2006-03-28
影响因子：
11.1
通讯作者：
Sethi, T
中科院分区：
文献类型：
--
作者：
Henderson, NC;Mackinnon, AC;Sethi, T
纤维形成和器官瘢痕形成的核心是成纤维细胞活化成基质分泌肌成纤维细胞。我们证明，半乳糖凝集素-3表达上调，在建立人类纤维化肝病，是时间和空间相关的诱导和解决实验性肝纤维化。半乳糖凝集素-3基因的破坏在体外和体内阻断肌成纤维细胞活化和前胶原（1）表达，显著减轻肝纤维化。在体外添加外源性重组半乳糖凝集素-3逆转了这种异常。在半乳糖凝集素-3（-/-）小鼠中观察到的肝纤维化减少发生，尽管肝损伤和炎症相当，并且TGF-β的组织表达相似。与WT肝星状细胞相反，TGF-β不能反式激活半乳糖凝集素-3（-/-）肝星状细胞;然而，TGF-β刺激的Smad-2和Smad-3激活是等效的。这些数据表明，半乳糖凝集素-3对于TGF-β介导的肌成纤维细胞活化和基质产生是必需的。最后，半乳糖凝集素-3的体内siRNA敲低抑制了肝损伤后的肌成纤维细胞活化，因此可以提供预防和治疗肝纤维化的替代治疗方法。
Central to fibrogenesis and the scarring of organs is the activation of fibroblasts into matrix-secreting myofibroblasts. We demonstrate that Galectin-3 expression is up-regulated in established human fibrotic liver disease and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the Galectin-3 gene blocks myofibroblast activation and procollagen (1) expression in vitro and in vivo, markedly attenuating liver fibrosis. Addition of exogenous recombinant Galectin-3 in vitro reversed this abnormality. The reduction in hepatic fibrosis observed in the Galectin-3(-/-) mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-beta. TGF-beta failed to transactivate Galectin-3(-/-) hepatic stellate cells, in contrast with WT hepatic stellate cells; however, TGF-beta-stimulated Smad-2 and -3 activation was equivalent. These data suggest that Galectin-3 is required for TGF-beta mediated myofibroblast activation and matrix production. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation after hepatic injury and may therefore provide an alternative therapeutic approach to the prevention and treatment of liver fibrosis.