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

Although 17 beta-estradiol (E-2) treatment following hemorrhagic shock or ischemic reperfusion prevents organs from dysfunction and injury, the precise mechanism remains unknown. We hypothesize that the E-2-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 similar to 40 mmHg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E-2 (1 mg/kg) alone, or E-2 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 E-2 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 E-2-mediated attenuation of the shock-induced liver injury markers. In addition, administration of chromium mesoporphyrin-IX chloride or ICI 182,780 abolished E-2-mediated increases in liver HO-1 expression or p38 MAPK activation following hemorrhagic shock. Our results collectively suggest that the salutary effects of E-2 on hepatic injury following hemorrhagic shock and resuscitation are in part mediated through an estrogen-receptor-related p38 MAPK-dependent HO-1 upregulation.