Dal-Secco Daniela, Cunha Thiago M, Freitas Andressa, Alves-Filho José Carlos, Souto Fabrício O, Fukada Sandra Y, Grespan Renata, Alencar Nylane M N, Neto Alberto F, Rossi Marcos A, Ferreira Sérgio H, Hothersall John S, Cunha Fernando Q
Department of Pharmacology, School of Medicine of Ribeirão Preto, Ribeirão Preto, Brazil.
J Immunol. 2008 Sep 15;181(6):4287-98. doi: 10.4049/jimmunol.181.6.4287.
In this study, we have addressed the role of H(2)S in modulating neutrophil migration in either innate (LPS-challenged naive mice) or adaptive (methylated BSA (mBSA)-challenged immunized mice) immune responses. Treatment of mice with H(2)S synthesis inhibitors, dl-propargylglycine (PAG) or beta-cyanoalanine, reduced neutrophil migration induced by LPS or methylated BSA (mBSA) into the peritoneal cavity and by mBSA into the femur/tibial joint of immunized mice. This effect was associated with decreased leukocyte rolling, adhesion, and P-selectin and ICAM-1 expression on endothelium. Predictably, treatment of animals with the H(2)S donors, NaHS or Lawesson's reagent, enhanced these parameters. Moreover, the NaHS enhancement of neutrophil migration was not observed in ICAM-1-deficient mice. Neither PAG nor NaHS treatment changed LPS-induced CD18 expression on neutrophils, nor did the LPS- and mBSA-induced release of neutrophil chemoattractant mediators TNF-alpha, keratinocyte-derived chemokine, and LTB(4). Furthermore, in vitro MIP-2-induced neutrophil chemotaxis was inhibited by PAG and enhanced by NaHS treatments. Accordingly, MIP-2-induced CXCR2 internalization was enhanced by PAG and inhibited by NaHS treatments. Moreover, NaHS prevented MIP-2-induced CXCR2 desensitization. The PAG and NaHS effects correlated, respectively, with the enhancement and inhibition of MIP-2-induced G protein-coupled receptor kinase 2 expression. The effects of NaHS on neutrophil migration both in vivo and in vitro, together with CXCR2 internalization and G protein-coupled receptor kinase 2 expression were prevented by the ATP-sensitive potassium (K(ATP)(+)) channel blocker, glybenclamide. Conversely, diazoxide, a K(ATP)(+) channel opener, increased neutrophil migration in vivo. Together, our data suggest that during the inflammatory response, H(2)S augments neutrophil adhesion and locomotion, by a mechanism dependent on K(ATP)(+) channels.
在本研究中，我们探讨了硫化氢（H₂S）在先天免疫反应（脂多糖（LPS）刺激的未免疫小鼠）或适应性免疫反应（甲基化牛血清白蛋白（mBSA）刺激的免疫小鼠）中调节中性粒细胞迁移的作用。用H₂S合成抑制剂dl-炔丙基甘氨酸（PAG）或β-氰基丙氨酸处理小鼠，可减少LPS或mBSA诱导的中性粒细胞向腹腔的迁移，以及mBSA诱导的免疫小鼠股骨/胫骨关节中性粒细胞的迁移。这种作用与白细胞滚动、黏附减少以及内皮细胞上P-选择素和细胞间黏附分子-1（ICAM-1）表达降低有关。可以预见，用H₂S供体硫氢化钠（NaHS）或劳森试剂处理动物可增强这些参数。此外，在ICAM-1缺陷小鼠中未观察到NaHS对中性粒细胞迁移的增强作用。PAG和NaHS处理均未改变LPS诱导的中性粒细胞上CD18的表达，LPS和mBSA诱导的中性粒细胞趋化因子介质肿瘤坏死因子-α（TNF-α）、角质形成细胞衍生趋化因子和白三烯B₄（LTB₄）的释放也未改变。此外，体外巨噬细胞炎性蛋白-2（MIP-₂）诱导的中性粒细胞趋化作用被PAG抑制，被NaHS处理增强。因此，MIP-₂诱导的CXCR2内化被PAG增强，被NaHS处理抑制。此外，NaHS可防止MIP-₂诱导的CXCR2脱敏。PAG和NaHS的作用分别与MIP-₂诱导的G蛋白偶联受体激酶2表达的增强和抑制相关。NaHS对体内和体外中性粒细胞迁移的作用，以及CXCR2内化和G蛋白偶联受体激酶2表达，均被三磷酸腺苷敏感钾（KATP⁺）通道阻滞剂格列本脲阻断。相反，KATP⁺通道开放剂二氮嗪可增加体内中性粒细胞迁移。总之，我们的数据表明，在炎症反应过程中，H₂S通过一种依赖KATP⁺通道的机制增强中性粒细胞的黏附和运动。
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