title: Hydrogen sulfide augments neutrophil migration through enhancement of adhesion molecule expression and prevention of CXCR2 internalization: role of ATP-sensitive potassium channels.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, Ribeirão Preto, Brazil.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dal-Secco
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Andressa
authors.initials: A
authors.lastname: Freitas
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Alves-Filho
authors.forename: Fabrício O
authors.initials: FO
authors.lastname: Souto
authors.forename: Sandra Y
authors.initials: SY
authors.lastname: Fukada
authors.forename: Renata
authors.initials: R
authors.lastname: Grespan
authors.forename: Nylane M N
authors.initials: NM
authors.lastname: Alencar
authors.forename: Alberto F
authors.initials: AF
authors.lastname: Neto
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Rossi
authors.forename: Sérgio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: John S
authors.initials: JS
authors.lastname: Hothersall
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha