Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury.
Corynebacterium parvum-treated mice produce large amounts of circulating nitrogen oxides and develop a severe liver injury in response to lipopolysaccharide (LPS). Concurrent administration of NG-monomethyl-L-arginine not only suppresses nitric oxide synthesis in these animals but also profoundly increases the hepatic damage following LPS. In this report, we present evidence that the increased hepatic damage from inhibition of nitric oxide synthesis is mediated in part by superoxide and hydroxyl radicals. The hepatic damage induced by suppressing nitric oxide production during endotoxemia could be reduced by treating mice with superoxide dismutase and deferoxamine, scavengers of superoxide and hydroxyl radicals, respectively. This damage could also be prevented by treating mice with the anticoagulant heparin sodium. The results suggest that nitric oxide synthesis during endotoxemia is important in preventing hepatic damage by reducing oxygen radical-mediated hepatic injury and preventing intravascular thrombosis.
Harbrecht
B G
BG
Department of Surgery, University of Pittsburgh, Pennsylvania.
Billiar
T R
TR
Stadler
J
J
Demetris
A J
AJ
Ochoa
J
J
Curran
R D
RD
Simmons
R L
RL
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D006502:Budd-Chiari Syndrome / Q000139:chemically induced* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D004731:Endotoxins / Q000097:blood*; D005260:Female; D016166:Free Radical Scavengers; D005609:Free Radicals / Q000378:metabolism; D016908:Gram-Positive Bacterial Infections / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D009569:Nitric Oxide / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010586:Phagocytes / Q000473:pathology; D011425:Propionibacterium acnes; D013481:Superoxides / Q000378:metabolism; D014115:Toxemia / Q000378:metabolism* / Q000382:microbiology; D019323:omega-N-Methylarginine
D004731:Endotoxins; D016166:Free Radical Scavengers; D005609:Free Radicals; D008070:Lipopolysaccharides; D013481:Superoxides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D010100:Oxygen