title: Hydrogen sulfide inhibits proliferation and release of IL-8 from human airway smooth muscle cells.
abstract: Hydrogen sulfide (H(2)S) is synthesized intracellularly by the enzymes cystathionine-γ-lyase and cystathionine-β-synthase (CBS), and is proposed to be a gasotransmitter with effects in modulating inflammation and cellular proliferation. We determined a role of H(2)S in airway smooth muscle (ASM) function. ASM were removed from resection or transplant donor lungs and were placed in culture. Proliferation of ASM was induced by FCS and the proinflammatory cytokine, IL-1β. Proliferation of ASM and IL-8 release were measured by bromodeoxyuridine incorporation and ELISA, respectively. Exposure of ASM to H(2)S "donors" inhibited this proliferation and IL-8 release. Methemoglobin, a scavenger of endogenous H(2)S, increased DNA synthesis induced by FCS and IL-1β. In addition, methemoglobin increased IL-8 release induced by FCS, but not by IL-1β, indicating a role for endogenous H(2)S in these systems. Inhibition of CBS, but not cystathionine-γ-lyase, reversed the inhibitory effect of H(2)S on proliferation and IL-8 release, indicating that this is dependent on CBS. CBS mRNA and protein expression were inhibited by H(2)S donors, and were increased by methemoglobin, indicating that CBS is the main enzyme responsible for endogenous H(2)S production. Finally, we found that exogenous H(2)S inhibited the phosphorylation of extracellular signal-regulated kinase-1/2 and p38, which could represent a mechanism by which H(2)S inhibited cellular proliferation and IL-8 release. In summary, H(2)S production provides a novel mechanism for regulation of ASM proliferation and IL-8 release. Therefore, regulation of H(2)S may represent a novel approach to controlling ASM proliferation and cytokine release that is found in patients with asthma.
authors.affiliation: Experimental Studies, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Perry
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Hui
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiteman
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wood
authors.forename: Ian
authors.initials: I
authors.lastname: Adcock
authors.forename: Paul
authors.initials: P
authors.lastname: Kirkham
authors.forename: Charalambos
authors.initials: C
authors.lastname: Michaeloudes
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
mesh_terms: D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003541:Cystathionine beta-Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D008706:Methemoglobin / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044967:Serum / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; C529376:GYY 4137; D053583:Interleukin-1beta; D016209:Interleukin-8; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D047428:Protein Kinase Inhibitors; D013440:Sulfides; D008706:Methemoglobin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; C025451:sodium bisulfide; D006862:Hydrogen Sulfide