Nitric oxide mediates hepatocyte injury.
The degree of acute hepatic failure after severe trauma and sepsis is related to the extent of hepatocyte (HC) damage and cell death resulting from either necrosis or apoptosis. We have previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS) can directly lead to HC necrosis, but not apoptosis. To date, the reactive oxygen intermediates (ROI) and nitric oxide (NO) have been shown to play a potential role in the induction of cell apoptosis. However, it is unknown whether ROI and NO are involved in HC cell death. Therefore, in this study we tested the hypothesis that NO and ROI exert different effects on HC cell death. TNF-alpha and LPS alone failed to induce HC apoptosis but when combined with antioxidants resulted in HC apoptosis and DNA fragmentation, which is correlated with an increase in NO production. This effect was attenuated by the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Moreover, the NO donor sodium nitroprusside resulted in HC apoptosis and cell damage as represented by hepatocellular enzyme release. Antioxidants inhibited TNF-alpha- and LPS-mediated ROI generation and peroxynitrite formation in HC. TNF-alpha- and LPS-induced HC damage could be further reduced by the combination of antioxidants and L-NMMA. These results indicate that NO is involved in HC injury, primarily through the induction of HC apoptosis.
Wang
J H
JH
The Royal College of Surgeons in Ireland, Department of Surgery, Beaumont Hospital, Dublin 9, Ireland.
Redmond
H P
HP
Wu
Q D
QD
Bouchier-Hayes
D
D
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001219:Aspartate Aminotransferases / Q000032:analysis; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000502:physiology; D013482:Superoxide Dismutase / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000975:Antioxidants; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D001219:Aspartate Aminotransferases; D005978:Glutathione