ACTIVATION OF HEPATIC STELLATE CELLS BY TGF-ALPHA AND COLLAGEN TYPE-I IS MEDIATED BY OXIDATIVE STRESS THROUGH C-MYB EXPRESSION
ACTIVATION OF HEPATIC STELLATE CELLS BY TGF-ALPHA AND COLLAGEN TYPE-I IS MEDIATED BY OXIDATIVE STRESS THROUGH C-MYB EXPRESSION
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DOI：
10.1172/jci118304
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发表时间：
1995-11-01
影响因子：
15.9
通讯作者：
CHOJKIER, M
中科院分区：
文献类型：
--
作者：
LEE, KS;BUCK, M;CHOJKIER, M
I型胶原蛋白的过度产生是肝纤维化的主要促成因素。活化的（成肌纤维细胞）但非静止的肝星状细胞（脂肪细胞）具有高水平的I型胶原蛋白和α-平滑肌肌动蛋白表达。因此，星状细胞活化是肝纤维化的关键步骤，在这里，我们表明，静止的星状细胞被激活的抗坏血酸/FeSO 4和丙二醛，脂质过氧化的产物的自由基的产生。此外，星状细胞激活的胶原蛋白I型基质和TGF α被阻断的抗氧化剂，如d-α-生育酚和丁基羟基甲苯。此外，氧化应激，TGF-α和I型胶原蛋白显着刺激星状细胞进入S期，NF-κ B活性和c-myb的表达，这是由抗氧化剂阻止。c-myb反义寡核苷酸阻断TGF α诱导的星状细胞活化和增殖。从活化的，但不是从静止的，星状细胞的核提取物与α-平滑肌肌动蛋白基因的关键启动子E盒形成复合物，其被c-myb和NFkB 65抗体破坏，并与c-myb和NFkB同源DNA竞争。c-Myb的表达在四氯化碳诱导的肝损伤和肝纤维化中的活化星状细胞中也被刺激。这项研究表明，氧化应激起着至关重要的作用，通过诱导c-myb和NF κ B，对星状细胞活化。
Excessive production of collagen type I is a major contributor to hepatic fibrosis, Activated (myofibroblastic), but not quiescent, hepatic stellate cells (lipocytes) have a high level of collagen type I and alpha-smooth muscle actin expression. Therefore, stellate cell activation is a critical step in hepatic fibrosis, Here we show that quiescent stellate cells were activated by the generation of free radicals with ascorbate/FeSO4 and by malondialdehyde, a product of lipid peroxidation, In addition, stellate cell activation by collagen type I matrix and TGF alpha was blocked by antioxidants, such as d-alpha-tocopherol and butylated hydroxytoluene. Moreover, oxidative stress, TGF alpha and collagen type I markedly stimulated stellate cell entry into S-phase, NFkB activity and c-myb expression, which were prevented by antioxidants. c-myb antisense oligonucleotide blocked the activation and proliferation of stellate cells induced by TGF alpha. Nuclear extracts from activated, but not from quiescent, stellate cells formed a complex with the critical promoter E box of the alpha-smooth muscle actin gene, which was disrupted by c-myb and NFkB65 antibodies, and competed by c-myb and NFkB cognate DNA. c-Myb expression was also stimulated in activated stellate cells in carbon tetrachloride-induced hepatic injury and fibrogenesis. This study indicates that oxidative stress plays an essential role, through the induction of c-myb and NFkB, on stellate cell activation.