title: Role of p38 MAPK pathway in 17β-estradiol-mediated attenuation of hemorrhagic shock-induced hepatic injury.
abstract: Although 17β-estradiol (E2) treatment following hemorrhagic shock or ischemic reperfusion prevents organs from dysfunction and injury, the precise mechanism remains unknown. We hypothesize that the E2-mediated attenuation of liver injury following hemorrhagic shock and fluid resuscitation occurs via the p38 mitogen-activated protein kinase (MAPK)-dependent heme oxygenase (HO)-1 pathway. After a 5-cm midline laparotomy, male rats underwent hemorrhagic shock (mean blood pressure ∼40 mmHg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E2 (1 mg/kg) alone, or E2 plus p38 MAPK inhibitor SB-203580 (2 mg/kg), HO-1 inhibitor chromium mesoporphyrin-IX chloride (2.5 mg/kg) or estrogen receptor antagonist ICI 182,780 (3 mg/kg). At 2 h after hemorrhagic shock and fluid resuscitation, the liver injury markers were significantly increased compared with sham-operated control. Hemorrhagic shock resulted in a significant decrease in p38 MAPK phosphorylation compared with the shams. Administration of E2 following hemorrhagic shock normalized liver p38 MAPK phosphorylation, further increased HO-1 expression, and reduced cleaved caspase-3 levels. Coadministration of SB-203580 abolished the E2-mediated attenuation of the shock-induced liver injury markers. In addition, administration of chromium mesoporphyrin-IX chloride or ICI 182,780 abolished E2-mediated increases in liver HO-1 expression or p38 MAPK activation following hemorrhagic shock. Our results collectively suggest that the salutary effects of E2 on hepatic injury following hemorrhagic shock and resuscitation are in part mediated through an estrogen-receptor-related p38 MAPK-dependent HO-1 upregulation.
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.affiliation: Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; and.
authors.forename: Tsung-Hsing
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Department of Surgery, Chang Gung Memorial Hospital at Keelung, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.affiliation: Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; and.
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Kuo
authors.affiliation: Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; and.
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Lin
authors.affiliation: Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan;
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D004967:Estrogens / Q000494:pharmacology* / Q000627:therapeutic use; D051547:Heme Oxygenase-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C513297:Cxcl1 protein, rat; C513296:Cxcl2 protein, rat; D004967:Estrogens; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D009195:Peroxidase; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: HO-1; estrogen; estrogen receptor antagonist; hemorrhagic shock; liver injury; p38 MAPK