Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice |
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| Authors: | McKim Stephen E Gäbele Erwin Isayama Fuyumi Lambert Jason C Tucker Lindsay M Wheeler Michael D Connor Henry D Mason Ronald P Doll Mark A Hein David W Arteel Gavin E |
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| Affiliation: | Department of Pharmacology, University of North Carolina, Chapel Hill, USA. |
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| Abstract: | ![]()
BACKGROUND & AIMS : Oxidative stress contributes to early alcohol-induced liver injury, and superoxide (O(2)*-) production from NADPH oxidase plays a key role. However, the production of the free radical nitric oxide (NO*) by inducible nitric oxide synthase (iNOS) could also be involved. METHODS : To test this hypothesis, iNOS knockout (B6.129P2-Nos2 (tm1 Lau)) and wild-type mice were fed high-fat control or ethanol-containing diets for 4 weeks. RESULTS : Mean body weight gains were not significantly different between treatment groups, and average urine ethanol concentrations were similar in wild-type and iNOS knockout mice. After 4 weeks, serum alanine aminotransferase (ALT) levels were increased significantly about 4-fold over control values (29 +/- IU/L) by enteral ethanol (113 +/- 20) in wild-type mice; this effect of ethanol was significantly blunted in iNOS knockout mice (50 +/- 9). Similar protective effects against liver damage were observed if wild-type mice were treated with the iNOS inhibitor N -(3-aminomethyl)benzyl-acetamindine (1400W). Enteral ethanol also caused severe fatty accumulation, mild inflammation, and necrosis in the liver in wild-type mice but had no effect in iNOS knockout mice. The accumulation of 4-hydroxynonenal (lipid peroxidation) and 3-nitrotyrosine (reactive nitrogen species formation) protein adducts caused by alcohol was completely blocked in iNOS knockout mice. CONCLUSIONS : These data strongly support the hypothesis that iNOS is required for the pathogenesis of early alcohol-induced hepatitis by production of nitric oxide-derived pro-oxidants (e.g., peroxynitrite). |
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| Keywords: | 1400W, N-(3-aminomethyl)benzyl-acetamindine CYP2E1, cytochrome P450 2E1 ESR, electron spin resonance HOCl−, hypochlorous acid l-NAME, N(G)-nitro-l-arginine methyl ester NF-κB, nuclear factor κB NOS, nitric oxide synthases NO·, nitric oxide O2·−, superoxide anion ·OH, hydroxyl radical ONOO−, peroxynitrite POBN, α-(4-pyridyl-N-oxide)-N-tert-butylnitrone ROS, reactive oxygen species RNS, reactive nitrogen species SOD, superoxide dismutases TNF-α, tumor necrosis factor-α TNFR1, tumor necrosis factor receptor 1 |
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