Deficiency of Nicotinamide Adenine Dinucleotide Phosphate, Reduced Form Oxidase Enhances Hepatocellular Injury But Attenuates Fibrosis After Chronic Carbon Tetrachloride Administration

作者：Aram Ghazaleh; Potter James J; Liu Xiaopu; Wang Lan; Torbenson Michael S; Mezey Esteban^*

来源：Hepatology, 2009, 49(3): 911-919.

DOI：10.1002/hep.22708

Reactive oxygen species (ROS) activate hepatic stellate cells and enhance fibrogenesis. This study determined the role of nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase deficiency in the development of hepatocellular necrosis, inflammation, and apoptosis in relation to fibrosis produced by chronic carbon tetrachloride (CCl(4)) administration. Wild-type (WT) mice or mice with deficiency of the gp91(phox) subunit of NADPH complex (gp91(phox-/-)) were subjected to biweekly CCl(4) injections over 8 weeks, whereas controls were given isovolumetric injections of olive oil. Serum aspartate aminotransferase (AST) was higher after CCl(4) administration in gp91(phox-/-) than in WT mice, correlating with increased necrosis on liver histology. By contrast, more hepatocyte apoptosis was found after CCl(4) in the WT than in the gp91(phox-/-) 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 NW, but not in the gp91(phox-/-) mice and also a lower cytosolic cytochrome c in the gp91(phox-/-) mice. There were fewer stellate cells and less fibrosis after CCl(4) in the gp91(phox-/-) as compared with the WT mice. The increase in alpha(1)(I) collagen messenger RNA (mRNA), however, was greater after CCl(4) in the gp91(phox-/-) mice. Matrix metalloproteinase-2 (MMP-2) and MMP-9 mRNA increased more in the gp91(phox-/-) than in WT mice after CCl(4). Tissue inhibitor of metalloproteinase 1 (TIMP-1) and TIMP-2 increased after CCl(4) only in the gp91(phox-/-) mice. Conclusion: Decreased hepatic fibrosis after chronic CCl(4) administration in mice with NADPH oxidase deficiency occurs in the setting of greater necrosis and inflammation but decreased apoptosis. (HEPATOLOGY 2009;49:911-919.)

• 出版日期2009-3