Resveratrol alleviates blast lung injury by modulating the epithelial sodium channel (ENaC) via the PI3K/AKT pathway

Blast lung injury (BLI) is a major cause of death in blast injuries, largely due to pulmonary edema. Effective clearance of alveolar fluid is critical for resolving pulmonary edema, with the epithelial sodium channel (ENaC) playing a key role in this process. Resveratrol (RES), a natural compound with known antioxidant and anti-inflammatory properties, has shown promise in treating respiratory diseases. However, its potential protective effects against BLI, particularly through ENaC modulation, remain unclear. In this study, complementary in vivo and in vitro models were used to investigate mechanisms underlying pulmonary edema following a gas explosion. We discovered that RES significantly alleviated BLI by decreasing pulmonary edema, pulmonary index, W/D ratio, oxidative stress, inflammatory cell infiltration, and TNF-α and IL-1β expression levels in rat lung tissue. RES upregulated the expression of ENaC and PI3K/AKT both in rats and in A549 cells. The knockout of the PI3K-p85 gene suppressed RES-induced upregulation of p-AKT and ENaC, reversing protein expression in A549 cells. Altogether, RES shows potential to attenuate blast-induced lung injury by upregulating ENaC, partly through the PI3K/AKT signaling pathway. This study highlights RES as a potential therapeutic agent for BLI and offers new insights into its mechanisms of action.