Hydrogen sulfide (H2S) 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 H2S 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 H2S “donors” inhibited this proliferation and IL-8 release. Methemoglobin, a scavenger of endogenous H2S, 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 H2S in these systems. Inhibition of CBS, but not cystathionine-γ-lyase, reversed the inhibitory effect of H2S on proliferation and IL-8 release, indicating that this is dependent on CBS. CBS mRNA and protein expression were inhibited by H2S donors, and were increased by methemoglobin, indicating that CBS is the main enzyme responsible for endogenous H2S production. Finally, we found that exogenous H2S inhibited the phosphorylation of extracellular signal–regulated kinase–1/2 and p38, which could represent a mechanism by which H2S inhibited cellular proliferation and IL-8 release. In summary, H2S production provides a novel mechanism for regulation of ASM proliferation and IL-8 release. Therefore, regulation of H2S may represent a novel approach to controlling ASM proliferation and cytokine release that is found in patients with asthma.
|Journal||American Journal of Respiratory Cell and Molecular Biology|
|Publication status||Published - 1 Oct 2011|