title: Role of Akt/HO-1 pathway in estrogen-mediated attenuation of trauma-hemorrhage-induced lung injury.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan. hsujt2813@adm.cgmh.org.tw
authors.forename: Jun-Te
authors.initials: JT
authors.lastname: Hsu
authors.forename: Huei-Chung
authors.initials: HC
authors.lastname: Yeh
authors.forename: Tsung-Hsing
authors.initials: TH
authors.lastname: Chen
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Chun-Jun
authors.initials: CJ
authors.lastname: Lin
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Hwang
authors.forename: Irshad I
authors.initials: II
authors.lastname: Chaudry
mesh_terms: D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004958:Estradiol / Q000627:therapeutic use*; D051547:Heme Oxygenase-1 / Q000502:physiology*; D055370:Lung Injury / Q000188:drug therapy*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000150:complications*; D015398:Signal Transduction / Q000502:physiology*; D014947:Wounds and Injuries / Q000150:complications*
chemical_list: D002867:Chromones; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004958:Estradiol; D009195:Peroxidase; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt