Zanardo Renata C O, Brancaleone Vincenzo, Distrutti Eleonora, Fiorucci Stefano, Cirino Giuseppe, Wallace John L
Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada.
FASEB J. 2006 Oct;20(12):2118-20. doi: 10.1096/fj.06-6270fje. Epub 2006 Aug 15.
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.
硫化氢（H₂S）日益被认为是心血管系统和神经系统中的一种重要信号分子。最近，有报道称H₂S供体可诱导中性粒细胞凋亡，并抑制某些白细胞和内皮黏附分子的表达。我们使用大鼠研究了H₂S是否为白细胞 - 内皮界面关键炎症事件的内源性调节因子。通过活体显微镜观察，我们发现H₂S供体（NaHS和Na₂S）抑制阿司匹林诱导的肠系膜小静脉中的白细胞黏附（Na₂S的半数有效剂量为5.0 μmol/kg），可能是通过激活ATP敏感性钾离子（K(ATP)）通道实现的。抑制内源性H₂S合成会引发白细胞黏附。H₂S供体（NaHS、劳森试剂和N - 乙酰半胱氨酸；半数有效剂量分别为42.7、1.3和29.9 μmol/kg）也抑制气袋模型中的白细胞浸润，而抑制内源性H₂S合成则会加剧这种浸润。角叉菜胶诱导的爪部水肿受到H₂S供体（NaHS和Na₂S；半数有效剂量分别为35和28 μmol/kg）的抑制，其程度与双氯芬酸相同，而H₂S合成抑制剂则会增强水肿。K(ATP)通道激动剂可模拟H₂S供体对水肿形成的抑制作用，而该通道的拮抗剂则可逆转这种作用。这些结果表明，内源性H₂S是急性炎症的重要介质，作用于白细胞 - 内皮界面。这些发现对抗炎药物的开发具有重要意义。
