Hydrogen Sulfide Inhibits Proliferation and Release of IL-8 from Human Airway Smooth Muscle Cells

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.