Endothelial endogenous CSE / H 2 S inhibits endothelial pyroptosis by activating sirtuin1 to attenuate LPS ‐induced acute lung injury

Abstract Endothelial pyroptosis, a pro‐inflammatory programmed cell death, promotes endothelial inflammation and is a pivotal process in the initial stage of acute lung injury (ALI). Hydrogen sulfide (H 2 S), a gasotransmitter primarily dependent on cystathionine γ‐lyase (CSE) in the cardiovascular and respiratory systems, plays a protective role during ALI. Nonetheless, the modulatory role and precise molecular mechanism of endothelial endogenous CSE/H 2 S in the pathogenesis of ALI remain elusive. Herein, we prepared an ALI mouse model using intratracheal administration of LPS (5 mg/kg), and lung injury was assessed by evaluating pulmonary edema, inflammatory response, and endothelial pyroptosis. In this model, H 2 S production from pulmonary tissues declined in a time‐dependent manner, accompanied by a compensatory elevation of CSE protein levels. Treatment with the H 2 S donor (NaHS) attenuated pulmonary edema, inflammatory cell infiltration, endothelial pyroptosis, and reduced serum levels of tumor necrosis factor‐alpha (TNF‐α), interleukin‐1β (IL‐1β), and interleukin‐6 (IL‐6). Meanwhile, the inducible deletion of CSE in endothelial cells exacerbated these changes. The blocking effect of CSE/H 2 S on endothelial pyroptosis (evidenced by caspase‐11 activation and GSDMD‐NT formation) was also confirmed in cultured pulmonary microvascular endothelial cells (PMECs). Mechanistically, H 2 S‐mediated regulation of sirtuin‐1 (SIRT1) expression and activation (via sulfhydration) contributed to the modulatory process. Collectively, we uncovered that endothelial endogenous CSE/H 2 S alleviates endothelial pyroptosis by activating SIRT1, thereby preventing LPS‐induced acute lung injury.