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

Ghazaleh Aram, James J. Potter, Xiaopu Liu, Lan Wang, Michael S. Torbenson, Esteban Mezey

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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 (gp91phox-/-) 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 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 with the WT mice. The increase in α1(I) collagen messenger RNA (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. 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.

Original languageEnglish (US)
Pages (from-to)911-919
Number of pages9
JournalHepatology
Volume49
Issue number3
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Hepatology

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