Ginsenoside alleviates sepsis related acute lung injury by inhibiting the destruction of alveolar epithelial barrier mediated by EVs secreted by alveolar macrophages.

Sepsis-associated acute lung injury (SALI) is a critical complication of sepsis, characterized by alveolar epithelial barrier disruption and excessive inflammation, which contributes substantially to morbidity and mortality. The present study investigates the protective effects of ginsenoside Rb1 on SALI and elucidates its underlying mechanisms involving alveolar macrophage-derived extracellular vesicles (EVs). Using a cecal ligation and puncture (CLP) murine model, LPS-stimulated alveolar macrophages, and EV isolation and characterization, we evaluated Rb1's influence on survival, lung histopathology, inflammatory cytokine levels, alveolar epithelial barrier proteins (ZO-1, Occludin, E-cadherin), and NF-κB signaling. Rb1 pretreatment significantly improved survival, reduced pulmonary edema and tissue injury, and decreased inflammatory cytokines in bronchoalveolar lavage fluid. Mechanistically, Rb1 suppressed the secretion of macrophage-derived EVs that mediate alveolar epithelial injury and restored barrier-associated protein expression both in vitro and in vivo. Bioinformatic analyses identified NF-κB signaling as a key pathway influenced by Rb1-modulated EVs, and experimental validation confirmed that Rb1 attenuated NF-κB activation in alveolar epithelial cells. Collectively, these findings demonstrate that Rb1 alleviates SALI by modulating macrophage-EV-mediated epithelial barrier disruption and inhibiting NF-κB-driven inflammation. This study highlights a novel intercellular mechanism underlying Rb1's protective effects and provides a mechanistic rationale for targeting EV-mediated communication as a therapeutic strategy in sepsis-induced lung injury.