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

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 (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 WT, 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 α 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. (H EPATOLOGY 2009.)