Influences of reactive oxygen species and nitric oxide on hepatic fibrogenesis.
OBJECTIVE
This study determined the roles of NAD(P)H oxidase, which generates reactive oxygen species (ROS), and of inducible nitric oxide synthase (iNOS), which generates nitric oxide (NO) on the development of hepatic fibrosis in mice.


METHODS
Hepatic fibrosis was produced by carbon tetrachloride administered for 12 weeks in wild-type (WT) mice and in mice with knockout of either the gp91phox subunit of the NAD(P)H complex (gp91phox-/-) or of iNOS (iNOS(-/-)).


RESULTS
Liver fibrosis and hydroxyproline after carbon tetrachloride was lower in gp91phox-/- and in iNOS(-/-) mice than in WT mice. The increase in alpha2(I) collagen mRNA was absent in the gp91phox-/- but not in the iNOS(-/-) mice. Transformation growth factor beta (TGF-beta) mRNA was increased more in the gp91phox-/- than in the WT mice, while in the iNOS(-/-) mice there was no increase in TGF-beta mRNA. 3-Nitrotyrosine was similarly increased by carbon tetrachloride in gp91phox-/- and WT mice, while there was no increase in the iNOS(-/-) mice.


CONCLUSIONS
Deficiencies in NAD(P)H oxidase and in iNOS separately reduce, but do not eliminate carbon tetrachloride-induced liver fibrosis. Likely causes for this inhibitory effects are decreases in the production of ROS in NAD(P)H deficiency and of peroxinitrite radicals in iNOS deficiency.
Novitskiy
Gennadiy
G
Department of Medicine, The Johns Hopkins University School of Medicine, The Johns Hopkins University, Baltimore 21205-2195, MD, USA.
Potter
James J
JJ
Wang
Lan
L
Mezey
Esteban
E
D000079:Acetaldehyde / Q000494:pharmacology; D000818:Animals; D008106:Liver Cirrhosis, Experimental / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009243:NAD / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D009243:NAD; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D000079:Acetaldehyde; D019331:NG-Nitroarginine Methyl Ester