Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury.
Induction of the heme-degrading enzyme heme oxygenase-1 (HO-1) has been shown to be beneficial in terms of improvement of liver allograft survival and prevention of CD95-mediated apoptosis in the liver. In the present study, we investigated the effects of HO-1, and its products carbon monoxide (CO), biliverdin (BV), and iron/ferritin, in a mouse model of inflammatory liver damage inducible by lipopolysaccharide (LPS) in mice sensitized with the hepatocyte-specific transcription inhibitor D-galactosamine (GalN). Our results show that HO-1 induction by cobalt-protoporphyrin-IX (CoPP) reduced cytokine expression, protected mice from liver injury, and prolonged survival. While in contrast to ferritin overexpression, single administration of the CO donor methylene chloride (MC) or of BV also protected mice from liver damage, only coadministration of both HO products prolonged survival and reduced the expression of cytokines, e.g., tumor necrosis factor (TNF) and interferon gamma (IFN-gamma). In conclusion, HO-1-induced prolongation of survival, but not the protection from liver damage, seems to be dependent on down-regulation of cytokine synthesis.
Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany.
Gabriele
G
Sass
Stefan
S
Seyfried
Miguel
M
Parreira Soares
Kenichiro
K
Yamashita
Elzbieta
E
Kaczmarek
Winfried L
WL
Neuhuber
Gisa
G
Tiegs
D000818:Animals; D001664:Biliverdine / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000503:physiopathology*; D016207:Cytokines / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D005293:Ferritins / Q000235:genetics / Q000494:pharmacology; D005688:Galactosamine / Q000276:immunology; D018014:Gene Transfer Techniques; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D051547:Heme Oxygenase-1; D007154:Immune System Diseases / Q000150:complications*; D007114:Immunization; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D016207:Cytokines; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D002248:Carbon Monoxide; D007371:Interferon-gamma; D005293:Ferritins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D001664:Biliverdine