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.

Gender differences in trauma, shock and sepsis

“…Estradiol treatment following trauma-hemorrhage increased p38 phosphorylation and HO-1 induction and attenuated apoptosis. Conversely, administration of a p38 MAPK inhibitor prevented p38 phosphorylation and the increase in HO-1 induction [ 91 ].…”

Delay in post-ovariectomy estrogen replacement negates estrogen-induced augmentation of post-exercise muscle satellite cell proliferation

“…MAPK signalling, has also been found to be an important factor in signaling estrogen related post-ischemia neuro-protection and augmented neuro-regeneration (Azcoitia et al 2011). Similar interactions of estrogen and MAPK signalling have recently been reported in protection of hepatic tissues from hemorrhagic shock (Hsu et al 2015). Various other factors may also be involved as estrogen induces protective effects in vascular ischemia through a number of mechanisms including D r a f t 13 prevention of apoptosis and enhanced VEGF production (Lenfant et al 2011).…”

“…protective and/or regenerative benefits for vascular, neural, muscular and hepatic tissues following damage (Azcoitia et al 2011, Manson et al2007, Sipilä et al 2015, Hsu et al 2015. When circulating estrogen levels are diminished, as seen in post-menopausal females, many of the beneficial effects of estrogen on these tissues are also lost.…”

“…When circulating estrogen levels are diminished, as seen in post-menopausal females, many of the beneficial effects of estrogen on these tissues are also lost. However a number of studies using human and animal models, have demonstrated that with estrogen replacement the protective and regenerative effects of estrogen on skeletal muscle, vascular, hepatic and neural tissues can be restored (Ahtiainen et al 2012, Bourque et al 2009, Dieli-Conwright et al 2009, Pike et al 2009, Pöllänen et al 2010, Ronkainen et al 2009, Suzuki et al 2009, Velders and Diel, 2013, Hsu et al 2015. Specifically in skeletal muscle, estrogen replacement soon after ovariectomy in rodents will also restore post-atrophy muscle regenerative capacity and diminish post-exercise muscle inflammation and damage indices (McClung et al 2006).…”

Hepatic Shock Differential Diagnosis and Risk Factors: A Review Article

“…There is no specific treatment, but early resuscitation and treatment of underlying causes (such as sepsis) and intensive care would likely reduce the incidence and severity of outcomes ( 17 , 26 - 29 ). This can be achieved by stabilization of circulation parameters and cardiac output, control of infection, delicate control of mechanical ventilation and controlled administration of vasoactive drugs ( 9 , 30 - 34 ).…”