| First Author | McKim SE | Year | 2003 |
| Journal | Gastroenterology | Volume | 125 |
| Issue | 6 | Pages | 1834-44 |
| PubMed ID | 14724835 | Mgi Jnum | J:86852 |
| Mgi Id | MGI:2682169 | Doi | 10.1053/j.gastro.2003.08.030 |
| Citation | McKim SE, et al. (2003) Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice. Gastroenterology 125(6):1834-44 |
| abstractText | 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). |
