Apelin alleviates sepsis-induced acute lung injury in part by modulating the SIRT1/NLRP3 pathway to inhibit endothelial cell pyroptosis

Abstract

BackgroundSepsis, an intricate systemic inflammatory syndrome, gives rise to various life-threatening complications, with acute lung injury (ALI) being prominently encountered. ALI, clinically characterized by pulmonary infiltration, hypoxemia, and edema, stands as a prevailing consequence of sepsis. This work sought to elucidate the mechanism of Apelin in mitigating sepsis-induced ALI (siALI). MethodsA mouse sepsis model was constructed by cecal ligation and puncture surgery, followed utilizing histopathological analysis using HE staining. mRNA levels of inflammatory cytokines (IL-1β, IL-6, and TNF-α) were assessed utilizing qRT-PCR, while ELISA was employed to measure the levels of vWF, VEGF, IL-1β, and IL-18. Western blot was conducted to examine protein levels of NLRP3, Caspase-1 p20, GSDMD-N, and SIRT1. To evaluate the extent of endothelial cell (EC) pyroptosis, immunofluorescence co-staining of CD31, NLRP3, and Caspase-1 p20 was fulfilled. Furthermore, TUNEL staining was utilized to ascertain the degree of plasma membrane damage and cell death. ResultsApelin demonstrated its potential in ameliorating siALI in mice by diminishing mRNA expression levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) as well as expression levels of vWF and VEGF. Apelin inhibited protein expression of NLRP3, Caspase-1 p20, and GSDMD-N, indicating that EC pyroptosis was suppressed. Finally, Apelin could upregulate the protein expression of SIRT1. This upregulation led to the inhibition of protein expression of NLRP3, Caspase-1 p20, and GSDMD-N, consequently suppressing EC pyroptosis. As a result, a reduction in the expression of inflammatory cytokines IL-1β and IL-18 ultimately alleviated siALI. ConclusionApelin was confirmed to alleviate siALI partially by modulating SIRT1/NLRP3 pathway to inhibit EC pyroptosis, which dawned on the molecular mechanism of siALI and had important clinical significance for treating ALI effectively.