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1 Centre for Critical Illness Research, Lawson Health Research Institute, London, Canada
2 London, Canada; Centre for Critical Illness Research, Lawson Health Research Institute, London, Canada
* To whom correspondence should be addressed. E-mail: gcepinsk{at}uwo.ca.
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 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 (8mg/kg i.v.) was administered immediately after CLP induction, and neutrophil (PMN) tissue accumulation, activation of transcription factor, NF
B, and expression of adhesion molecule, ICAM-1 were assessed in murine liver 24 hrs later. In addition, the effects and potential mechanisms of CORM-2-released-CO in modulation of vascular endothelial cell pro-inflammatory responses were assessed in vitro. To this end, human umbilical vein endothelial cells (HUVEC) were stimulated with LPS (1µg/ml) in the presence or absence of CORM-2 (10-100µM). Production of intracellular ROS (DHR123 oxidation), NO (DAF-FM nitrosation) and activation of NFkB were assessed 4 hrs later. In parallel, expression of ICAM-1 and 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 NFB 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/NO, activation of NFB, 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 NFB activation and subsequent down-regulation of pro-adhesive vascular endothelial cell phenotype in the liver of septic mice.
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