Role of p38 MAPK pathway in 17β-estradiol-mediated attenuation of hemorrhagic shock-induced hepatic injury

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.