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

Full 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 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.

Author information

Author/s: Aram, Ghazaleh (G); Potter, James J (JJ); Liu, Xiaopu (X); Wang, Lan (L); Torbenson, Michael S (MS); Mezey, Esteban (E);

Affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Grants: 2 T32 AA07467 (Agency:NIAAA NIH HHS) ; 2464388 (Agency:PHS HHS) ; AA000626 (Agency:NIAAA NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Hepatology (Baltimore, Md.) (Hepatology), published in United States. (Language: eng)

Reference: 2009-Mar; vol 49 (issue 3) : pp 911-9

Dates: Created 2009/03/03; Completed 2009/04/01; Revised 2009/10/12;

PMID: 19072832, status: MEDLINE (last retrieved date: 10/13/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals
Apoptosis - drug effects
Carbon Tetrachloride - pharmacology; toxicity
Disease Models, Animal
Hepatocytes - drug effects; metabolism; pathology
Inflammation - metabolism; pathology
Liver Cirrhosis - chemically induced; pathology; prevention & control
Male
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 9 - metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Membrane Glycoproteins (0) ; Tissue Inhibitor of Metalloproteinase-1 (0) ; bcl-2-Associated X Protein (0) ; Tissue Inhibitor of Metalloproteinase-2 (127497-59-0) ; Carbon Tetrachloride (56-23-5) ; Cybb protein, mouse (EC 1.6.3.1) ; NADPH Oxidase (EC 1.6.3.1) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Matrix Metalloproteinase 9 (EC 3.4.24.35)

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