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

✍ Scribed by Ghazaleh Aram; James J. Potter; Xiaopu Liu; Lan Wang; Michael S. Torbenson; Esteban Mezey

• Book ID: 102850246
• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 855 KB
• Volume: 49
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.22708

✦ Synopsis

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 ␣ 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.) R eactive oxygen species (ROS) activate stellate cells and stimulate fibrogenesis. 1 Lipid peroxidation products stimulate ␣ 1 (I) collagen expression and collagen synthesis by stellate cells in culture. 2,3 Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, which generates superoxide ion (O 2 ⅐ Ϫ) from oxygen (O 2 ), is a principal source of ROS. Platelet-derived growth factor-induced proliferation of hepatic stellate cells, which is mediated by ROS produced by NADPH oxidase, was abrogated by inhibition of NADPH with diphenylene iodonium pretreatment. 4 Furthermore, hepatic fibrosis produced in vivo by dimethylnitrosamine was eliminated by daily diphenylene iodonium administration. 4 Liver cell death attributable to necrosis or apoptosis results in inflammatory responses and in fibrogenesis. 5,6 Mice with deficiency of the p47 phox subunit of NADPH oxidase complex developed less hepatic necrosis and fibrosis after bile duct ligation than wild-type (WT) mice. 7 In another study, using a pan-