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

Background: Sepsis, 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).

Methods: A 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.

Results: Apelin 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.

Conclusion: Apelin 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.