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.

• Authors: Paula Urquhart, Guglielmo Rosignoli, Dianne Cooper, Roberto Motterlini, Mauro Perretti
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 321 Issue 2 Pg. 656-62 (May 2007) ISSN: 0022-3565 [Print] United States
• PMID: 17289832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• CD11b Antigen
• Organometallic Compounds
• Platelet Endothelial Cell Adhesion Molecule-1
• tricarbonylchloro(glycinato)ruthenium(II)
• Carbon Monoxide

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• CD11b Antigen (analysis)
• Carbon Monoxide (metabolism)
• Cell Communication (drug effects)
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, physiology)
• Leukocyte Rolling (drug effects)
• Male
• Mice
• Neutrophil Activation (drug effects)
• Neutrophils (drug effects, physiology)
• Organometallic Compounds (pharmacology)
• Platelet Endothelial Cell Adhesion Molecule-1 (analysis)