Role of Akt/HO-1 pathway in estrogen-mediated attenuation of trauma-hemorrhage-induced lung injury

Abstract

BackgroundDespite advances in intensive care medicines, hemorrhagic shock leading to multiple organ failure remains the major causes of death in the injured host. Although studies have shown that 17β-estradiol (E2) prevents trauma-hemorrhage-induced lung damage, it remains unknown whether protein kinase B (Akt)/heme oxygenase (HO)-1 plays any role in E2-mediated lung protection after trauma-hemorrhage. Materials and methodsAfter a 5-cm midline laparotomy, male rats underwent hemorrhagic shock (mean blood pressure ∼40 mm Hg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E2 (1 kg/mg), E2 plus phosphoinositide 3-kinase inhibitor LY294002 (5 mg/kg), or LY294002. At 2 h after trauma-hemorrhage or sham operation, lung tissue myeloperoxidase activity, wet-to-dry-weight ratio, inflammatory mediators, and apoptosis were measured. Lung Akt, HO-1, and cleaved caspase-3 protein levels were also determined. ResultsE2 attenuated the trauma-hemorrhage-induced increase in lung myeloperoxidase activity, edema formation, inflammatory mediator levels, and apoptosis, which was blocked by co-administration of LY294002. Administration of E2 normalized lung Akt phosphorylation and further increased HO-1 expression and decreased cleaved caspase-3 levels after trauma-hemorrhage. Co-administration of LY294002 prevented the E2-mediated attenuation of shock-induced lung injury. ConclusionsOur results collectively suggest that Akt-dependent HO-1 upregulation may play a critical role in E2-meditated lung protection after trauma-hemorrhage.