Hydrogen sulfide is an endogenous modulator of leukocyte‐mediated inflammation

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 micromol/kg for Na2S), likely via activation of ATP-sensitive K+ (K(ATP)) 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 micromol/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 micromol/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 K(ATP) 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.

Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

“…30 Administration of the irritant carrageenan into the cavity induces a local inflammatory response that can be easily accessed to monitor changes in leukocyte recruitment and the cytokine network. [31][32][33] One percent carrageenan solution or PBS was administered into 6-day-old air pouches of 8-to 10-week-old male WT mice to induce an inflammatory response ( Figure 3A). As shown in Figure 3B, IL6 levels rapidly peaked at 4 hours after the administration of carrageenan and thereafter declined within 48 hours and 72 hours.…”

Selective fluorescent probes for live-cell monitoring of sulphide

“…H 2 S, or aqueous sulphide, elicits diverse physiological responses, including modulation of blood pressure and reduction of ischemia reperfusion injury [3][4][5] , exertion of anti-inflammatory effects 6 and reduction of metabolic rate 7 . The production of H 2 S is catalysed by the two pyridoxal 5′-phosphate-dependent enzymes, cystathionine β-synthase (CBS) 8 , and cystathionine γ-lyase 9 , and indirectly, via a pyridoxal 5′-phosphateindependent enzyme, 3-mercaptopyruvate sulphurtransferase 10 .…”

No facilitator required for membrane transport of hydrogen sulfide

“…H 2 S is engaged in regulation and modulation of physiological functions such as vasorelaxation, vasodilatation, blood pressure modulation, and inhibition of apoptosis in a number of cell types (2)(3)(4)(5). It is an important mediator of endotoxic shock (6) and acute inflammation, acting at the leukocyte-endothelium interface (7). Physiological concentrations of H 2 S selectively enhance NMDA receptor-mediated responses and may modulate synaptic activities regulated by steroid hormones and neurotransmitters, suggesting that endogenous H 2 S functions as a neuromodulator in the brain (8).…”