Nitric oxide ameliorates actinomycin D/endotoxin-induced apoptotic liver failure in mice.
Liver damage induced by lipopolysaccharide (LPS) in actinomycin D-sensitized mice was initiated by a Fas/CD95-independent apoptotic process that produced DNA fragmentation in hepatocytes followed by an increase of plasma ALT. The metabolic inhibitor actinomycin D blocked most of the LPS-induced increase of plasma nitrite/nitrate levels, as did administration of a nitric oxide synthase inhibitor, N(G)-monomethyl-l-arginine, which also promoted LPS-induced apoptotic liver damage. Administration of nitric oxide donors (hydroxylamine, S-nitroso-N-acetylpenicillamine or 2, 2'-(hydroxynitrosohydrazino)bis-ethanamine) resulted in elevation of the plasma nitrite/nitrate level and amelioration of actinomycin D/LPS-induced apoptotic liver damage. The protective effect of nitric oxide against apoptotic liver damage was partially reproduced by a membrane-permeable analog of cyclic GMP. On the other hand, treatment with the soluble guanylate cyclase inhibitor LY83583 overcame the protective effect of nitric oxide against apoptotic liver damage. These results suggest that nitric oxide may regulate programmed cell death in the mouse liver and that induction of genes, including inducible nitric oxide synthase, plays an important role in protecting the liver against LPS-induced apoptotic damage. This effect appears to be mediated, at least in part, via the soluble guanylate pathway.
Akahori
M
M
Department of Emergency and Critical Care Medicine, Kansai Medical University, Moriguchi, Osaka, 570-8507, Japan.
Yamada
S
S
Takeyama
N
N
Tanaka
T
T
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D053938:DNA Fragmentation / Q000187:drug effects; D003609:Dactinomycin; D003995:Dibutyryl Cyclic GMP / Q000494:pharmacology; D006501:Hepatic Encephalopathy / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D019811:Hydroxylamine / Q000494:pharmacology; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000502:physiology*; D009573:Nitrites / Q000097:blood; D009603:Nitroso Compounds / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000634:Aminoquinolines; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D009603:Nitroso Compounds; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D003609:Dactinomycin; D019323:omega-N-Methylarginine; D019811:Hydroxylamine; D009569:Nitric Oxide; D003995:Dibutyryl Cyclic GMP; C024942:S-nitrosopenicillamine; C041715:6-anilino-5,8-quinolinedione