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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/H920    most recent 00305.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Mizuguchi, S. Articles by Cepinskas, G. PubMed PubMed Citation Articles by Mizuguchi, S. Articles by Cepinskas, G.

CORM-3-derived CO modulates polymorphonuclear leukocyte migration across the vascular endothelium by reducing levels of cell surface-bound elastase

¹Centre for Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada; ²Department of Cardiovascular Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan; and ³Department of Chemistry, McMaster University, Hamilton, Ontario, Canada

Submitted 26 March 2009 ; accepted in final form 23 June 2009

Recently, it has been shown that carbon monoxide (CO)-releasing molecule (CORM)-released CO can suppress inflammation. In this study, we assessed the effects and potential mechanisms of a ruthenium-based water-soluble CO carrier [tricarbonylchloroglycinate-ruthenium(II) (CORM-3)] in the modulation of polymorphonuclear leukocyte (PMN) inflammatory responses in an experimental model of sepsis. Sepsis in mice was induced by cecal ligation and puncture. CORM-3 (3 mg/kg iv) was administered 15 min after the induction of cecal ligation and puncture. PMN accumulation in the lung (myeloperoxidase assay), bronchoalveolar lavage (BAL) fluid, and lung vascular permeability (protein content in BAL fluid) were assessed 6 h later. In in vitro experiments, human PMNs were primed with LPS (10 ng/ml) and subsequently stimulated with formyl-methionyl-leucylphenylalanine (fMLP; 100 nM). PMN production of ROS (L-012/dihydrorhodamine-123 oxidation), degranulation (release of elastase), and PMN rolling, adhesion, and migration to/across human umbilical vein endothelial cells (HUVECs) were assessed in the presence or absence of CORM-3 (1–100 µM). The obtained results indicated that systemically administered CORM-3 attenuates PMN accumulation and vascular permeability in the septic lung. Surprisingly, in in vitro experiments, treatment of PMNs with CORM-3 further augmented LPS/fMLP-induced ROS production and the release of elastase. The latter effects, however, were accompanied by an inability of PMNs to mobilize elastase to the cell surface (plasma membrane), an event required for efficient PMN transendothelial migration. The CORM-3-induced decrease in cell surface levels of elastase was followed by decreased PMN rolling/adhesion to HUVECs and complete prevention of PMN migration across HUVECs. In contrast, treatment of HUVECs with CORM-3 had no effect on PMN transendothelial migration. Taken together, these findings indicate that, in sepsis, CORM3-released CO, while further amplifying ROS production and degranulation of PMNs, concurrently reduces the levels of cell surface-bound elastase, which contributes to suppressed PMN transendothelial migration.

sepsis; systemic inflammation; oxidative stress; leukocyte adhesion/migration; proteolytic enzymes; carbon monoxide; carbon monoxide-releasing molecules; tricarbonylchloroglycinate-ruthenium(II)

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				V. C. Ganta and J. S. Alexander Focus on carbon monoxide: a modulator of neutrophil oxidants and elastase spatial localization? Am J Physiol Heart Circ Physiol, September 1, 2009; 297(3): H902 - H904. [Full Text] [PDF]