High-density Lipoprotein Attenuates LPS-induced Acute Lung Injury Via SIRT1-mediated Inhibition of the NF-κB/NLRP3/IL-1β Pathway.

BACKGROUND:Acute lung injury (ALI) is a critical condition characterized by severe inflammatory responses. High-density lipoprotein (HDL) has been demonstrated to possess anti-inflammatory properties, yet its mechanistic role in ALI through the SIRT1/NF-κB/NLRP3 signaling axis remains to be elucidated. OBJECTIVE:This study aimed to investigate the role of HDL in ALI and to elucidate its underlying mechanisms, with a focus on modulation of the SIRT1/NF-κB/NLRP3 signaling pathway. METHODS:BEAS-2B cells were exposed to lipopolysaccharide (LPS) and treated with HDL (20-200 μg/mL). Cellular viability was assessed using CCK-8. In vivo, LPS-induced ALI mice received HDL treatment with or without the SIRT1 inhibitor EX-527. Lung pathology and edema were evaluated via H&E staining and wet-to-dry (W/D) ratios. Inflammatory markers and myeloperoxidase (MPO) activity were measured using qPCR and ELISA, while western blotting analyzed SIRT1, NF-κB, and NLRP3 inflammasome components. RESULTS:HDL at concentrations ≤100 μg/mL effectively mitigated LPS-induced cytotoxicity and inflammation in BEAS-2B cells (p<0.01). This protective effect was dose-dependent, evidenced by reductions in the expression of IL-6 (p<0.01), IL-1β, TNF-α (p<0.05), NLRP3, and caspase-1, alongside restoration of SIRT1 activity suppressed by LPS (p<0.01). In vivo, HDL (40 mg/kg) significantly improved pulmonary histopathology and reduced serum pro-inflammatory cytokine levels and MPO activity in ALI mice (p<0.01). Importantly, co-treatment with EX-527 abolished HDL´s protective effects, underscoring the pivotal role of SIRT1. Mechanistically, HDL upregulated SIRT1, which subsequently inhibited NF-κB signaling and suppressed NLRP3 inflammasome activation in a SIRT1-dependent manner (p<0.01). This sequential inhibition disrupted the NF-κB-driven cytokine amplification loop. CONCLUSION:HDL confers robust protection against LPS-induced ALI by upregulating SIRT1, thereby suppressing the NF-κB/NLRP3/IL-1β inflammasome signaling axis. These findings highlight the HDL-SIRT1 axis as a potential therapeutic target for ALI, supporting the development of HDL mimetics or SIRT1 activators.