An Inhaled Neutrophil Elastase Inhibitor Alleviates Lipopolysaccharide-Mediated Neutrophil Extracellular Trap Formation in Acute Lung Injury via the MAPK/AKT/NLRP3 Pathway

Objective Neutrophil elastase (NE) plays a crucial role in the progression of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). AK0705 is a highly specific small molecule inhaled NE inhibitor. We investigated the protective effect of AK0705 on lipopolysaccharide (LPS)-induced ALI and the mechanism. Materials and methods The effect of AK0705 on ALI was evaluated by intratracheally administering LPS to a mouse model. The animals received saline, AK0705, and NET inhibitors. The mice were sacrificed 72 h after modeling. Lung pathological changes, inflammatory cell types, proinflammatory mediator protein levels, and the change of NETs were examined by H&E staining, immunochemistry, flow cytometry, ELISA, PicoGreen, immunofluorescence analysis, western blotting. Results AK0705 alleviated LPS-induced ALI in mice, as evidenced by reduced proinflammatory cytokine expression in the bronchoalveolar lavage fluid (BALF) and lung tissue samples, reduced NET production and reduced NE activity in the BALF, and reduced NET formation in vivo and in vitro. Mechanistically, AK0705 effectively inhibited LPS-induced pyroptosis by downregulating the MAPK/AKT/NLRP3 signaling pathway. Conclusion In summary, AK0705 significantly inhibited NET formation and pyroptosis in LPS-induced ALI. Our study indicated that targeting NETs or NE and early administration of AK0705 combined with NET inhibitors are novel strategies for treating ALI/ARDS.