Neutrophil extracellular traps promoted alveolar macrophages pyroptosis in LPS induced ALI/ARDS

Background: Systemic inflammation is the main feature in lipopolysaccharide(LPS)/severe infection-induced acute lung injury(ALI)/acute respiratory distress syndrome (ARDS), our previous study demonstrated alveolar macrophages pyroptosis confers a critical role in LPS-induced ALI. Furthermore, our another previous study show neutrophil extracellular traps also contribute to the pathogenesis of ALI/ARDS while NETs did not result in systemic inflammation directly. Then we hypothesize that NETs may upregulate alveolar macrophages pyroptosis resulted in aggravation of ALI/ARDS. Methods: the authors analyzed whether NETs are involved caspase-1 in the supernatant of bronchial aspiration and clinically involved in ARDS patients caused by severe bacterial infection. Then the authors used an LPS-induced ALI model to investigate whether targeting NETs can suppress alveolar macrophages pyroptosis and be protective in the mouse model. NETs degradation agents(DNase) and NETs inhibitor(PAD4) were administered to mice. Results: Analysis of supernatant of bronchial aspiration from ARDS patients (n = 20) showed elevated NETs and Caspase-1 were significantly correlated with the degree of ARDS and were higher in nonsurvivors (1865 ± 191.6, 35.7 ± 3.097, n=7) than in survivors (1300 ± 119.7, 26.94 ± 1.659, n=13). DNase and PAD4 inhibitor markedly attenuated the pyroptosis ratio of alveolar macrophages and the intensity of ARDS. Conclusion: NETs may play a contributory role to ARDS by promoting pyroptosis of alveolar macrophages and systemic inflammation, thus may become a marker reflecting disease activity. Targeting NETs may be a potential therapeutic strategy.