Deficiency of nicotinamide adenine dinucleotide phosphate, reduced form oxidase enhances hepatocellular injury but attenuates fibrosis after chronic carbon tetrachloride administration.
Deficiency of nicotinamide adenine dinucleotide phosphate, reduced form oxidase enhances hepatocellular injury but attenuates fibrosis after chronic carbon tetrachloride administration.
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DOI：
10.1002/hep.22708
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发表时间：
2009-03
期刊：
影响因子：
13.5
通讯作者：
Mezey, Esteban
中科院分区：
文献类型：
--
作者：
Aram, Ghazaleh;Potter, James J.;Liu, Xiaopu;Wang, Lan;Torbenson, Michael S.;Mezey, Esteban
活性氧（ROS）激活肝星状细胞并增强纤维化。本研究确定了NAD（P）H氧化酶缺乏在肝细胞坏死、炎症和凋亡发展中的作用，这些发展与慢性CCl 4给药引起的纤维化有关。野生型（WT）小鼠或缺乏NAD（P）H复合物gp 91 phox亚基（gp 91 phox −/−）的小鼠在8周内接受每两周一次的CCl 4注射，而对照组接受橄榄油等容注射。与WT小鼠相比，gp 91 phox −/−小鼠在CCl 4给药后血清天冬氨酸转氨酶（AST）升高，这与肝组织学坏死增加相关。相比之下，在WT中发现CCl 4后的肝细胞凋亡多于gp 91 phox −/−小鼠，这与线粒体凋亡途径组分的变化有关，即WT中促凋亡BAX蛋白的增加，但在gp 91 phox −/−小鼠中没有，并且在gp 91 phox −/−小鼠中细胞色素c的降低。与WT小鼠相比，在gp 91 phox −/−中CCl 4后星状细胞和纤维化较少。然而，在gp 91 phox −/−小鼠中，CCl 4处理后α1（I）胶原mRNA的增加更大。CCl 4处理后，gp 91 phox-/-小鼠中基质金属蛋白酶-2（MMP-2）和MMP-9 mRNA的增加幅度大于WT小鼠。金属蛋白酶组织抑制剂1（TIMP-1）和TIMP-2增加后，四氯化碳仅在gp 91 phox −/−小鼠。在NAD（P）H氧化酶缺乏的小鼠中，慢性CCl 4给药后肝纤维化减少发生在坏死和炎症增加但凋亡减少的情况下。
Reactive oxygen species (ROS) activate hepatic stellate cells and enhance fibrogenesis. This study determine the role of NAD(P)H oxidase deficiency in the development of hepatocellular necrosis, inflammation and apoptosis in relation to fibrosis produced by chronic CCl4 administration. Wild-type (WT) mice or mice with deficiency of the gp91phox subunit of NAD(P)H complex (gp91phox−/−) were subjected to biweekly CCl4 injections over 8 weeks, while controls were given isovolumetric injections of olive oil. Serum aspartate aminotransferase (AST) was higher after CCl4 administration in gp91phox−/− than in WT mice, correlating with increased necrosis on liver histology. By contrast more hepatocyte apoptosis was found after CCl4 in the WT than in the gp91phox−/− mice, which was associated with changes in components of the mitochondrial pathway of apoptosis, namely an increase in the pro-apoptotic BAX protein in the WT, but not in the gp91phox−/− mice and also a lower cytosolic cytochrome c in the gp91phox−/− mice. There were fewer stellate cells and less fibrosis after CCl4 in the gp91phox−/− as compared to the WT mice. The increase in α1(I) collagen mRNA however was greater after CCl4 in the gp91phox−/− mice. Matrix metalloproteinase-2 (MMP-2) and MMP-9 mRNA increased more in the gp91phox−/− than in WT mice after CCl4. Tissue inhibitor of metalloproteinase 1 (TIMP-1) and TIMP-2 increased after CCl4 only in the gp91phox−/− mice. Decreased hepatic fibrosis after chronic CCl4 administration in mice with NAD(P)H oxidase deficiency occurs in the setting of greater necrosis and inflammation but decreased apoptosis.
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影响因子：
25.7
作者：
Krähenbühl, L;Ledermann, M;Krähenbühl, S
通讯作者：
Krähenbühl, S
影响因子：
13.5
作者：
Nieto, N;Friedman, SL;Cederbaum, AI
通讯作者：
Cederbaum, AI
DOI：
10.1124/jpet.103.060129
发表时间：
2004-03-01
影响因子：
3.5
作者：
Canbay, A;Feldstein, A;Gores, GJ
通讯作者：
Gores, GJ
影响因子：
15.9
作者：
Bataller, R;Schwabe, RF;Brenner, DA
通讯作者：
Brenner, DA
影响因子：
25.7
作者：
dela Pena, Aileen;Leclercq, Isabelle A.;Farrell, Geoffrey C.
通讯作者：
Farrell, Geoffrey C.