Deficiency of nicotinamide adenine dinucleotide phosphate, reduced form oxidase enhances hepatocellular injury but attenuates fibrosis after chronic carbon tetrachloride administration†

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Abstract
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 (CCl4) administration. Wild-type (WT) mice or mice with deficiency of the gp91phox subunit of NADPH complex (gp91) were subjected to biweekly CCl4 injections over 8 weeks, whereas controls were given isovolumetric injections of olive oil. Serum aspartate aminotransferase (AST) was higher after CCl4 administration in gp91 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 gp91 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 gp91 mice and also a lower cytosolic cytochrome c in the gp91 mice. There were fewer stellate cells and less fibrosis after CCl4 in the gp91 as compared with the WT mice. The increase in α1(I) collagen messenger RNA (mRNA), however, was greater after CCl4 in the gp91 mice. Matrix metalloproteinase-2 (MMP-2) and MMP-9 mRNA increased more in the gp91 than in WT mice after CCl4. Tissue inhibitor of metalloproteinase 1 (TIMP-1) and TIMP-2 increased after CCl4 only in the gp91 mice. Conclusion: Decreased hepatic fibrosis after chronic CCl4 administration in mice with NADPH oxidase deficiency occurs in the setting of greater necrosis and inflammation but decreased apoptosis. (HEPATOLOGY 2009.)