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.
Footnotes
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This work was supported by British Heart Foundation Grant PG/04/060/17166. Personal support to M.P. was from the Arthritis Research Campaign UK and to D.C. was from the Research Advisory Board of Barts and The London. R. M. has financial interest with hemoCORM Ltd. (London, UK).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.117218.
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ABBREVIATIONS: PMN, polymorphonuclear leukocyte(s); HO, heme oxygenase; BKCa, large-conductance Ca2+-activated K+ channel(s); CO-RM, CO-releasing molecule; HUVEC, human umbilical vein endothelial cell; CORM-3, tricarbonylchoro(glycinato)ruthenium (II); CORM-A1, sodium boranocarbonate; iCORM-3, inactive CORM-3; DPBS, Dulbecco's phosphate-buffered solution; ODQ, 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one; YC-1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole; NS-1619, 1,3-dihydro-1-(2-hydroxy-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one; PAF, platelet-activating factor; sGC, soluble guanylate cyclase; met-BSA, methylated bovine serum albumin; PSGL-1, P-selectin glycoprotein ligand-1; TNF, tumor necrosis factor; ICAM-1, intercellular adhesion molecule-1; PECAM-1, platelet endothelial cell adhesion molecule-1; IL, interleukin.
- Received November 17, 2006.
- Accepted February 6, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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