Carbon Monoxide-Releasing Molecules Modulate Leukocyte-Endothelial Interactions under Flow

Abstract

Carbon monoxide (CO) generated by the enzyme heme oxygenase during the breakdown of heme is known to mediate a number of biological effects. Here, we investigated whether CO liberated from a water-soluble CO-releasing molecule (CO-RM) is capable of modulating leukocyte-endothelial interactions. Tricarbonylchoro(glycinato)ruthenium (II) (CORM-3), a fast CO releaser, proved to be anti-inflammatory in two distinct models of acute inflammation in vivo. In both cases, a significant reduction in neutrophil extravasation was observed. Subsequent in vitro static experiments showed that CORM-3 produced a direct effect on neutrophil (polymorphonuclear neutrophil; PMN) adhesion molecule expression; dose-dependently inhibiting platelet-activating factor stimulated CD11b up-regulation and L-selectin shedding, whereas no effect was observed on up-regulation of human umbilical vein endothelial cell (HUVEC) adhesion molecules intercellular adhesion molecule-1 or E-selectin nor on interleukin-8 chemokine production. In addition, when PMN interaction with HUVECs was studied, an inhibitory effect of CORM-3 on cell capture and rolling was observed. The effect of CORM-3 on PMN CD11b expression was mimicked by the incubation of PMN with the selective large potassium channel opener 1,3-dihydro-1-(2-hydroxy-5-(trifluoromethyl)-phenyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619), which suggests that CORM-3 actions in this instance are mediated, at least in part, via opening of this channel. In conclusion, we have reported that CORM-3 possesses acute anti-inflammatory effects in vivo and that these are probably the result of targeting PMN activation and rolling upon the endothelium.