Sex dimorphism in lung ischemia-reperfusion injury reveals a protective role of 17β-estradiol via PI3K/AKT/GSK-3β pathway in male rats

Lung ischemia-reperfusion injury (LIRI) is a major perioperative challenge with considerable morbidity and limited therapeutic options, and sex‑related differences in LIRI remain poorly understood. This study investigated sex dimorphism in LIRI and determined whether 17β-estradiol (E2) pretreatment protects male rats through the PI3K/AKT/GSK-3β pathway. A total of 36 adult rats were assigned to six groups ( n = 6): female sham, male sham, female LIRI, male LIRI, male LIRI with E2 pretreatment, and male LIRI with E2 pretreatment plus PI3K inhibitor. LIRI groups underwent 60‑min left hilar occlusion and 120‑min reperfusion. Pulmonary gas exchange, wet-to-dry ratio, histopathological injury scores, serum and bronchoalveolar lavage fluid cytokines (IL-1β, IL-6, TGF-α), endothelial barrier proteins (ZO-1, VE-CAD, eNOS), apoptosis, and PI3K/AKT/GSK-3β pathway activation were comprehensively assessed. Male LIRI rats exhibited significantly worse hypoxemia, pulmonary edema, inflammation, endothelial disruption, and apoptosis than females. These alterations were accompanied by more severe suppression of PI3K/AKT/GSK‑3β phosphorylation and elevated levels of Cleaved Caspase-3. E2 pretreatment attenuated these injuries and reactivated the pathway, whereas the PI3K inhibitor LY294002 abolished E2-mediated protection. These findings establish sex dimorphism in LIRI and highlight PI3K/AKT/GSK-3β reactivation as a key mechanism underlying the protective effects of E2 on the lung in males.