Hydrogen sulfide attenuates epithelial–mesenchymal transition of human alveolar epithelial cells

We previously reported that the endogenous cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway is implicated in the pathogenesis of bleomycin-induced pulmonary fibrosis in rats, but the exact cellular mechanisms are not well characterized. Epithelial–mesenchymal transition (EMT), induced by transforming growth factor β1 (TGF-β1) in alveolar epithelial cells, plays an important role in the pathogenesis of pulmonary fibrosis. We studied whether H2S could attenuate EMT in cultured alveolar epithelial cells and TGF-β1 treatment suppressed CSE expression in A549 cells. Inhibition of endogenous CSE by dl-propargylglycine led to spontaneous EMT, as manifested by decreased E-cadherin level, increased vimentin expression and fibroblast-like morphologic features. Exogenous H2S applied to TGF-β1-treated A549 cells decreased vimentin expression, increased E-cadherin level and retained epithelial morphologic features. In addition, preincubation with H2S decreased Smad2/3 phosphorylation in A549 cells stimulated by TGF-β1, and H2S-inhibited alveolar EMT was mimicked by treatment with SB505124, a Smad2/3 inhibitor, but not pinacidil, an ATP-sensitive K+ channel (KATP) opener. H2S serves a critical role in preserving an epithelial phenotype and in attenuating EMT in alveolar epithelial cells, mediated, at least in part, by decreased Smad2/3 phosphorylation and not dependent on KATP channel opening.