Carbon monoxide-releasing molecules modulate leukocyte-endothelial interactions under flow.
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.
Urquhart
Paula
P
William Harvey Research Institute, London, UK.
Rosignoli
Guglielmo
G
Cooper
Dianne
D
Motterlini
Roberto
R
Perretti
Mauro
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D039481:CD11b Antigen / Q000032:analysis; D002248:Carbon Monoxide / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D036904:Leukocyte Rolling / Q000187:drug effects; D008297:Male; D051379:Mice; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D009942:Organometallic Compounds / Q000494:pharmacology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis
D000893:Anti-Inflammatory Agents; D039481:CD11b Antigen; D009942:Organometallic Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide