Resveratrol Attenuates Sepsis-Induced Lung Injury by Suppressing NLRP3-Mediated Pyroptosis

BACKGROUND: Sepsis-induced acute lung injury (ALI) is a severe condition with a high mortality rate and limited treatment options. Although NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome-mediated pyroptosis is a key driver of ALI, the role of the natural anti-inflammatory polyphenol resveratrol (RSV) in this specific pathway remains unclear. Therefore, this study investigated the role of NLRP3-mediated pyroptosis in septic ALI and evaluated the therapeutic potential of RSV. METHODS: A murine sepsis model was established by intraperitoneal injection of allogeneic fecal filtrate, and RSV (30 mg/kg) was administered intramuscularly. Survival rates, Murine Sepsis Score, lung histopathology, wet-to-dry ratio, lung function, protein levels of pyroptosis-related markers (NLRP3, ASC, Caspase-1, Gasdermin D, interleukin-1β, interleukin-18), and barrier markers (E-cadherin and VE-cadherin) were measured. Subsequently, the effect of Nlrp3 knockout on these indices in septic mice was assessed. MLE-12 cells were incubated with septic serum to evaluate NLRP3 activation and pyroptosis in vitro . RESULTS: Sepsis-induced severe lung injury was characterized by elevated Murine Sepsis Score, impaired lung function, increased pyroptosis-related protein expression, and decreased barrier-related protein expression. RSV treatment significantly improved survival rates, attenuated lung injury and pyroptosis, and restored lung barrier function. Similar protective effects were observed in Nlrp3-/- mice. In vitro , septic serum reduced MLE-12 cell viability and triggered NLRP3-dependent pyroptosis, which was mitigated by serum obtained from RSV-treated or Nlrp3-/- mice. CONCLUSION: RSV alleviated sepsis-induced lung injury by inhibiting NLRP3-mediated pyroptosis and preserving pulmonary barrier integrity.