Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in vivo.
Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in vivo.
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DOI：
10.1053/j.gastro.2010.05.074
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发表时间：
2010-10
期刊：
影响因子：
29.4
通讯作者：
Török NJ
中科院分区：
文献类型：
--
作者：
Jiang JX;Venugopal S;Serizawa N;Chen X;Scott F;Li Y;Adamson R;Devaraj S;Shah V;Gershwin ME;Friedman SL;Török NJ
肝细胞凋亡和肝星状细胞(HSC)激活是肝纤维化发生的关键事件。我们以前已经证明，HSC吞噬凋亡的肝细胞是促纤维化的。基于这一点，以及观察到NADPH氧化酶的诱导是纤维化形成的中心，我们的目的是研究吞噬细胞中的NADPH氧化酶NOX2。通过给野生型(Wt)或NOX2-/-小鼠注射含有肝细胞特异性启动子的慢病毒GFP和Ad-TRAIL，建立了体内吞噬模型。在胆管结扎(BDL)WT和NOX2-/-小鼠中，用或不用Gd治疗评估纤维化。研究了NOX2在人的肝脏样本和从纤维化肝脏分离的HSC中的表达。用胶原报告试剂盒检测NOX2的促纤维化活性。在吞噬模型中，可见绿色荧光蛋白标记的凋亡小体被吞噬，α-SMA和I型胶原的表达在wt组显著增加，而在nox2-/-小鼠中无明显变化。抑制细胞凋亡可降低促纤维化反应。NOX2-/-动物在BDL后表现出明显较少的纤维化。在wt bdl小鼠中灭活巨噬细胞并没有将胶原的产生降低到在NOX2-/-小鼠中观察到的水平，这表明表达NOX2的HSC在纤维化形成中起重要作用。肝纤维化HSC中NOX2表达上调，吞噬作用可诱导NOX2表达和活性。根据报道，NOX2介导的ROS直接诱导HSC的胶原启动子活性。肝细胞的凋亡和吞噬直接诱导HSC的激活和纤维化的发生。NOX2是一种吞噬细胞的NADPH氧化酶，在这一过程中发挥着关键作用，并在体内肝纤维化形成中发挥着关键作用。
Hepatocyte apoptosis and activation of hepatic stellate cells (HSC) are critical events in fibrogenesis. We previously demonstrated that phagocytosis of apoptotic hepatocytes by HSC is profibrogenic. Based on this, as well as the observation that NADPH oxidase induction is central to fibrogenesis, our aim was to study the phagocytic NADPH oxidase, NOX2. An in vivo phagocytosis model was developed by injecting wild type (wt) or NOX2-/- mice with lentiviral-GFP containing a hepatocyte-specific promoter, and ad-TRAIL. Fibrosis was evaluated in bile duct ligated (BDL) wt and NOX2-/- mice with or without gadolinium treatment. NOX2 expression was studied in human liver samples and in HSC isolated from fibrotic livers. The fibrogenic activity of NOX2 was assessed by collagen reporter assays. In the phagocytosis model engulfment of GFP-labeled apoptotic bodies was seen, and the expression of α-SMA and collagen I increased significantly in the wt, but not in the NOX2-/- mice. Inhibiting apoptosis decreased the profibrogenic response. NOX2-/- animals exhibited significantly less fibrosis following BDL. Inactivating macrophages in wt BDL mice did not lower collagen production to the level observed in NOX2-/- mice suggesting that NOX2-expressing HSC are important in fibrogenesis. NOX2 was upregulated in HSC from fibrotic livers, and phagocytosis-induced NOX2 expression and activity were demonstrated. Based on reporter assays, NOX2-mediated ROS directly induced collagen promoter activity in HSC. Apoptosis and phagocytosis of hepatocytes directly induce HSC activation and initiation of fibrosis. NOX2, the phagocytic NADPH oxidase plays a key role in this process and in liver fibrogenesis in vivo.
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影响因子：
13.5
作者：
Choi, Steve S.;Sicklick, Jason K.;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae
影响因子：
4.8
作者：
Reinehr, R;Becker, S;Häussinger, D
通讯作者：
Häussinger, D
影响因子：
15.9
作者：
Bataller, R;Schwabe, RF;Brenner, DA
通讯作者：
Brenner, DA
DOI：
10.1111/j.1440-1746.2006.04658.x
发表时间：
2007-06-01
影响因子：
4.1
作者：
Kisseleva, Tatiana;Brenner, David A.
通讯作者：
Brenner, David A.
影响因子：
4.8
作者：
Nieto, N;Friedman, SL;Cederbaum, AI
通讯作者：
Cederbaum, AI