Knockdown of angiopoietin-like 4 suppresses sepsis-induced acute lung injury by blocking the NF-B pathway activation and hindering macrophage M1 polarization and pyroptosis

Objective: Sepsis -induced acute lung injury (ALI) is a life -threatening disease. Macrophage pyroptosis has been reported to exert function in ALI. We aimed to investigate the mechanisms of ANGPTL4-mediated cell pyroptosis in sepsis -induced ALI, thus providing new insights into the pathogenesis and prevention and treatment measures of sepsis -induced ALI. Methods: In vivo animal models and in vitro cell models were established by cecal ligation and puncture (CLP) method and lipopolysaccharide-induced macrophages RAW264.7. ANGPTL4 was silenced in CLP mice or macrophages, followed by the determination of ANGPTL4 expression in bronchoalveolar lavage fluid (BALF) or macrophages. Lung histopathology was observed by H&E staining, with pathological injury scores evaluated and lung wet and dry weight ratio recorded. M1/M2 macrophage marker levels (iNOS/CD86/Arg1), inflammatory factor (TNF-a/IL-6/IL-18/iNOS) expression in BALF, cell death and pyroptosis, NLRP3 inflammasome, cell pyroptosis-related protein (NLRP3/Cleaved-caspase-1/caspase-1/GSDMD-N) levels, NF-xB pathway activation were assessed by RT-qPCR/ELISA/flow cytometry/Western blot, respectively. Results: ANGPTL4 was highly expressed in mice with sepsis -induced ALI, and ANGPTL4 silencing ameliorated sepsis -induced ALI in mice. In vivo, ANGPTL4 silencing repressed M1 macrophage polarization and macrophage pyroptosis in mice with sepsis -induced ALI. In vitro, ANGPTL4 knockout impeded LPS-induced activation and pyroptosis of M1 macrophages and hindered LPS-induced activation of the NF-xB pathway in macrophages. Conclusion: Knockdown of ANGPTL4 blocks the NF-xB pathway activation, hinders macrophage M1 polarization and pyroptosis, thereby suppressing sepsis -induced ALI.