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Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
An inhaled AK0705 modulates PI3K/AKT/MAPK/NF-κB signaling to alleviate LPS-NETs-induced inflammation and pyroptosis
Nurbiya Aji1, Bin Jia2, Zheng Cheng3
1Department of Respiratory and Critical Medicine, Zhongshan Hospital, Shanghai Key Laboratory of Lung Inflammation and Injury, Fudan University, Shanghai, China; Department of Respiratory and Critical Care Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China; Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Abstract:
Neutrophil elastase (NE) plays a crucial role in the progression of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). AK0705 is a potent small molecule inhaled NE inhibitor (IC50 = 0.015 nM). Herein, we investigated the protective effect of AK0705 on lipopolysaccharide (LPS)-induced ALI and the mechanism. We established LPS-induced ALI model and the effect of AK0705 on ALI was evaluated on ALI model in vivo and in vitro. Then, 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. We found that AK0705 alleviated LPS-induced ALI, as evidenced by reduced proinflammatory cytokine expression in the bronchoalveolar lavage fluid (BALF), lung tissue samples, and BMDNs, reduced NET productions and reduced NE activity in the BALF and cell supernatant, and reduced NET formation in vivo and in vitro. Mechanistically, the protective effect of AK0705 may be associated with modulation of the PI3K/AKT/MAPK/NF-κB signaling pathway. Our findings supported that AK0705 significantly inhibited NE, NET formation, and pyroptosis in LPS-induced ALI by suppressing inflammation and targeting NE with inhaled AK0705 is a novel strategy for treating ALI, with potential implications for ARDS.
