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* Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada;
Department of Experimental Pharmacology, University of Naples, Naples, Italy; and
Division of Gastroenterology and Hepatology, University of Perugia, Perugia, Italy
1Correspondence: Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, T2N 4N1, Canada. E-mail: wallacej{at}ucalgary.ca
ABSTRACT
Hydrogen sulfide (H2S) is increasingly recognized as an important signaling molecule in the cardiovascular and nervous systems. Recently, H2S donors were reported to induce neutrophil apoptosis and to suppress expression of some leukocyte and endothelial adhesion molecules. Using rats, we examined the possibility that H2S is an endogenous regulator of key inflammatory events at the leukocyte-endothelial interface. Via intravital microscopy, we observed that H2S donors (NaHS and Na2S) inhibited aspirin-induced leukocyte adherence in mesenteric venules (ED50 of 5.0 µmol/kg for Na2S), likely via activation of ATP-sensitive K+ (KATP) channels. Inhibition of endogenous H2S synthesis elicited leukocyte adherence. Leukocyte infiltration in an air pouch model was also suppressed by H2S donors (NaHS, Lawesson’s reagent, and N-acetylcysteine; ED50 of 42.7, 1.3, and 29.9 µmol/kg, respectively) and exacerbated by inhibition of endogenous H2S synthesis. Carrageenan-induced paw edema was suppressed by H2S donors (NaHS and Na2S; ED50s of 35 and 28 µmol/kg, respectively) to the same extent as by diclofenac and enhanced by an inhibitor of H2S synthesis. Suppression of edema formation by H2S donors was mimicked by a KATP channel agonist and reversed by an antagonist of this channel. These results suggest that endogenous H2S is an important mediator of acute inflammation, acting at the leukocyte-endothelium interface. These findings have important implications for anti-inflammatory drug development.—Zanardo, R. C. O., Brancaleone, V., Distrutti, E., Fiorucci, S., Cirino, G., Wallace, J. L. Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation.
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