GSDMD‐mediated NETosis promotes the development of acute respiratory distress syndrome

Gasdermin D (GSDMD) is a classical molecule involved in pyroptosis. It has been reported to be cleaved into N‐terminal fragments to form pores in the neutrophil membrane and promote the release of neutrophil extracellular traps (NETs). However, it remains unclear if GSDMD is involved in neutrophil regulation and NET release during ARDS. The role of neutrophil GSDMD in the development of ARDS was investigated in a murine model of ARDS induced by lipopolysaccharide (LPS) using the neutrophil specific GSDMD‐deficient mice. The neutrophil GSDMD cleavage and its relationship with NETosis were also explored in ARDS patients. The cleavage of GSDMD in neutrophils from ARDS patients and mice was upregulated. Inhibition of GSDMD by genetic knockout or inhibitors resulted in reduced production of NET both in vivo and in vitro, and attenuation of LPS‐induced lung injury. Moreover, in vitro experiments showed that the inhibition of GSDMD attenuated endothelial injury co‐cultured with neutrophils from ARDS patients, while extrinsic NETs reversed the protective effect of GSDMD inhibition. Collectively, our data suggest that the neutrophil GSDMD cleavage is crucial in NET release during ARDS. The NET release maintained by cleaved GSDMD in neutrophils may be a key event in the development of ARDS. During ARDS, activated neutrophils prompt endothelial cell injury by releasing NET. GSDMD is cleaved into N‐GSDMD during NETosis and play a key role in the generation NET. Inhibition of neutrophil GSDMD abrogates NET formation, thus reducing the severity of ARDS.