EPA-Derived diHEPAs Attenuate Lipopolysaccharide-Induced Acute Lung Injury by Regulating Inflammation and Redox Homeostasis

Acute lung injury (ALI) is characterized by excessive inflammation, oxidative stress, and impaired resolution responses, partly driven by dysregulated macrophage activation. In this study, a defined mixture of eicosapentaenoic acid (EPA)-derived dihydroxyeicosapentaenoic acids (diHEPAs), comprising 5,15-diHEPA and 8,15-diHEPA at an equimolar ratio, was generated using soybean lipoxygenase and its protective effects on lipopolysaccharide (LPS)-induced ALI were investigated. Mice were orally administered 5,15-diHEPA (40 μg/kg), 8,15-diHEPA (40 μg/kg), or the diHEPA mixture (20 μg/kg each) for 7 days before LPS challenge. LPS exposure induced severe lung injury, as evidenced by an increased lung wet/dry ratio, inflammatory cell infiltration, and oxidative stress. Treatment with diHEPAs attenuated lung pathological damage, reduced proinflammatory cytokine production, and restored redox homeostasis. Consistently, in vitro studies in RAW264.7 macrophages showed that the diHEPA mixture suppressed LPS-induced inflammatory responses through the inhibition of NF-κB signaling and rebalanced oxidative stress via modulation of the NOX2/Nrf2/HO-1/ROS axis. Altogether, these results indicate that EPA-derived diHEPAs confer protection against ALI by suppressing inflammation and restoring redox balance, emphasizing their potential as therapeutic agents for ALI.