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Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice
Open accessAbstract
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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“For instance, NO-dependent inhibition of the mitochondrial respiration was monitored in both AFLD and NAFLD [86], [87], [88], [89], [90].”
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Metadata
- Authors
- McKim, S. E., Gäbele, E., Isayama, F., Lambert, J. C., Tucker, L. M., Wheeler, M. D., Connor, H. D., Mason, R. P., Doll, M. A., Hein, D. W., & Arteel, G. E.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Louisville (US)
- National Institutes of Health (US)
- Corresponding author
- Arteel, Gavin E
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2003-12
- Volume
- 125
- Issue
- 6
- Pages
- 1834-1844
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W1977679256
- Cited by
- 243
- References
- 55
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 6 · 2021: 11 · 2020: 8 · 2019: 10 · 2018: 8 · 2017: 17 · 2016: 17 · 2015: 13 · 2014: 16 · 2013: 9 · 2012: 11
- FWCI
- 7.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- inducible nitric oxide synthase, alcohol-induced liver injury, ethanol-induced hepatotoxicity, nitric oxide, oxidative stress, peroxynitrite, 4-hydroxynonenal, nitrotyrosine, lipid peroxidation, reactive nitrogen species, NOS2 knockout mice, 1400W, hepatic steatosis, liver necrosis
- MeSH terms
- Alanine Transaminase, Ethanol, Aldehydes, Animals, Aspartate Aminotransferases, Body Weight, Endotoxins, Free Radicals, Liver, Mice, Inbred C57BL, RNA, Messenger, Tumor Necrosis Factor-alpha, Tyrosine, Mice, Knockout, Nitric Oxide Synthase, Cytochrome P-450 CYP2E1, Mice, Nitric Oxide Synthase Type II
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