title: Carbon monoxide liberated from carbon monoxide-releasing molecule CORM-2 attenuates inflammation in the liver of septic mice.
abstract: Recent studies suggest that exogenously administered CO is beneficial for the resolution of acute inflammation. In this study, we assessed the role of CO liberated from a systemically administered tricarbonyldichlororuthenium-(II)-dimer (CORM-2) on modulation of liver inflammation during sepsis. Polymicrobial sepsis in mice was induced by cecal ligation and perforation (CLP). CORM-2 (8 mg/kg iv) was administered immediately after CLP induction, and neutrophil [polymorphonuclear leukocyte (PMN)] tissue accumulation, activation of transcription factor, NF-kappaB, and changes in adhesion molecule ICAM-1 expression (inflammation-relevant markers) were assessed in murine liver 24 h later. In addition, the effects and potential mechanisms of CORM-2-released CO in modulation of vascular endothelial cell proinflammatory responses were assessed in vitro. To this end, human umbilical vein endothelial cells (HUVEC) were stimulated with LPS (1 microg/ml) in the presence or absence of CORM-2 (10-100 microM) and production of intracellular reactive oxygen species (ROS), (DHR123 oxidation) and NO (DAF-FM nitrosation) and subsequent activation of NF-kappaB were assessed 4 h later. In parallel, expression of ICAM-1 and inducible NO synthase (iNOS) proteins along with PMN adhesion to LPS-challenged HUVEC were also assessed. Induction of CLP resulted in increased PMN accumulation, ICAM-1 expression, and activation of NF-kappaB in the liver of septic mice. These effects were significantly attenuated by systemic administration of CORM-2. In in vitro experiments, CORM-2-released CO attenuated LPS-induced production of ROS and NO, activation of NF-kappaB, increase in ICAM-1 and iNOS protein expression and PMN adhesion to LPS-stimulated HUVEC. Taken together, these findings indicate that CO released from systemically administered CORM-2 provides anti-inflammatory effects by interfering with NF-kappaB activation and subsequent downregulation of proadhesive vascular endothelial cell phenotype in the liver of septic mice.
authors.affiliation: Centre for Critical Illness Research, Lawson Health Research Institute, London, Ontario, N6A 4G4, Canada. gcepinsk@uwo.ca
authors.forename: Gediminas
authors.initials: G
authors.lastname: Cepinskas
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Katada
authors.forename: Aurelia
authors.initials: A
authors.lastname: Bihari
authors.forename: Richard F
authors.initials: RF
authors.lastname: Potter
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002248:Carbon Monoxide / Q000378:metabolism*; D002432:Cecum / Q000601:surgery; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006505:Hepatitis / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007416:Intestinal Perforation / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C447082:tricarbonyldichlororuthenium (II) dimer; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D002248:Carbon Monoxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II