Hydrogen sulfide (H2S) is a colorless, toxic, asphyxiant gas. In recent years, industrial accidents involving H2S exposure have frequently resulted in fatalities and disabilities. Acute respiratory distress syndrome (ARDS) poses a substantial burden on healthcare systems worldwide. The syndrome's heterogeneity and multifaceted pathogenesis, combined with a paucity of effective treatments, contribute to a persistently high mortality rate, which currently stands at 30-35%. The present study utilized metabolomics, transcriptomics, and CUT&Tag sequencing to explore ARDS pathogenesis, providing insights into its mechanisms and therapeutic targets for its treatment. Serum metabolomics for individuals with H2S-induced ARDS identified lactate accumulation as a pivotal metabolic event that mediates changes in H2S-induced ARDS biomarkers. Lactate, a potential biomarker of H2S-induced ARDS, is associated with a poor prognosis. However, whether elevated lactate directly promotes H2S-induced ARDS and the mechanisms underlying this effect remain unclear. Here, we demonstrate that lactate disrupts the alveolar epithelial barrier, thereby facilitating the development of ARDS. Mechanistically, lactate promotes histone H3K18 lactylation at the promoter for ATG10, a gene involved in the process of autophagy, driving its transcription and upregulating autophagy in alveolar epithelial cells, which results in disruption of the epithelial barrier. For rats, the reduction of lactate generation by a glycolytic inhibitor mitigates H2S-induced ARDS, as evidenced by attenuated pulmonary edema. Our results show that the lactate-autophagy axis mediates H2S-induced ARDS. Therefore, targeting the regulation of lactate production and/or autophagy is a therapeutic strategy for patients with H2S-induced ARDS.
Keywords: Acute respiratory distress syndrome; Autophagy; H3K18 lactylation; Hydrogen sulfide; Lung epithelial barrier.
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