Opposing effects of carbon monoxide (CO) releasing molecule (CORM3) on activation of polymorphonuclear leukocytes (PMN) and endothelial cells (HUVEC) in sepsis.

Recently, it has been shown that CORM‐released CO can modulate inflammatory response. In this study we assessed the effects and potential mechanisms of water‐soluble CO‐releasing molecule, CORM3, in experimental model of sepsis. Sepsis in mice was induced by cecal ligation/puncture (CLP). CORM3 (3mg/kg; iv) was administered 15 min after CLP induction. PMN accumulation (MPO assay) in the lung was assessed 6 hr later. In in vitro experiments human PMN were primed with LPS (10ng/ml) and stimulated with fMLP (100nM). PMN production of ROS (oxidation of L‐012/DHR123 over 30 min period of time) and release of elastase (AAPV‐pNA; 1hr) were assessed. In parallel, HUVEC were stimulated with LPS (1µg/ml) and assessed for ROS production, E‐selectin/ICAM‐1 expression (RT‐PCR) and 51Cr‐PMN adhesion/migration. Some experiments were performed in the presence of CORM‐3 (1‐100 µM). The obtained results indicate that CORM3 significantly reduced PMN accumulation in the lung of septic mice. In parallel, LPS‐induced increase in HUVEC ROS production, E‐selectin/ICAM‐1 expression and PMN adhesion/migration were attenuated by CORM‐3. On the contrary, CORM3 markedly increased ROS production and potentiated release of elastase by LPS‐primed PMN. These data indicate that CORM3 reduces inflammation in the septic lung by differentially modulating PMN and endothelial cell activation (HSFO‐ NA6171 and MOP‐68848)