Background: Despite 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 methods: After 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. Results: E2 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. Conclusions: Our results collectively suggest that Akt-dependent HO-1 upregulation may play a critical role in E2-meditated lung protection after trauma-hemorrhage. Crown Copyright © 2013 Published by Elsevier Inc. All rights reserved.