Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage: p38 MAPK-dependent upregulation of HO-1

Abstract

p38 MAPK has been reported to regulate the inflammatory response in various cell types via extracellular stimuli. p38 MAPK activation also results in the induction of heme oxygenase (HO)-1, which exerts potent anti-inflammatory effects. Although studies have shown that 17beta-estradiol (E(2)) prevented organ dysfunction following trauma-hemorrhage, it remains unknown whether p38 MAPK/HO-1 plays any role in E(2)-mediated attenuation of intestinal injury under those conditions. To study this, male rats underwent trauma-hemorrhage (mean blood pressure approximately 40 mmHg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E(2) (1 mg/kg body wt), the p38 MAPK inhibitor SB-203580 (2 mg/kg body wt) or E(2) plus SB-203580. Two hours thereafter, intestinal myeloperoxidase (MPO) activity and lactate, TNF-alpha, IL-6, ICAM-1, cytokine-induced neutrophil chemoattractant (CINC)-1, and macrophage inflammatory protein (MIP)-2 levels were measured. Intestinal p38 MAPK and HO-1 protein levels were also determined. Trauma-hemorrhage led to an increase in intestinal MPO activity and lactate, TNF-alpha, IL-6, ICAM-1, CINC-1, and MIP-2 levels. This was accompanied with a decrease in intestinal p38 MAPK activity and increase in HO-1 expression. Administration of E(2) normalized all the above parameters except HO-1, which was further increased following trauma-hemorrhage. Administration of SB-203580 with E(2) abolished the E(2)-mediated restoration of the above parameters as well as the increase in intestinal HO-1 expression following trauma-hemorrhage. These results suggest that the p38 MAPK/HO-1 pathway plays a critical role in mediating the salutary effects of E(2) on shock-induced intestinal injury.

High-Density Lipoproteins Inhibit Vascular Endothelial Inflammation by Increasing 3β-Hydroxysteroid-Δ24 Reductase Expression and Inducing Heme Oxygenase-1

“…26 Thyroid hormones 27 and estrogen 28 increase DHCR24 expression in human fetal neuroepithelial cells and also enhance HO-1 expression in the rat kidney 29 and intestine. 30 However, high dietary intake of the trace metal selenium reduces DHCR24 expression in the rat prostate, 31 whereas bovine aortic endothelial cells cultured in selenium-deficient medium have increased expression of HO-1. elements in the gene promoter region that can be stimulated by a range of transcription factors.…”

Sex steroids deficiency impairs glucose transporter 4 expression and its translocation through defective Akt phosphorylation in target tissues of adult male rat

“…It has been demonstrated that estradiol enhances phosphorylation of Akt through IRS/p85 of PI3K association in adipocytes [58] and cardiac muscle [59]. Enhanced Akt phosphorylation is associated with increased plasma membrane GLUT4 population but without increasing glucose uptake in adipose tissue.…”

Effect of Estrogen on Mitochondrial Function and Intracellular Stress Markers in Rat Liver and Kidney following Trauma-Hemorrhagic Shock and Prolonged Hypotension

“…It has been shown that T-H followed by resuscitation induces lipid peroxidation and protein nitrosylation (10), both of which subside after administration of the testosterone receptor antagonist, flutamide (10). T-H followed by resuscitation heightens the expression of heme oxygenase-1 (HO-1), a protective enzyme, and the administration of E2 further increases its expression (11). In addition, it has been shown that E2 facilitates accumulation of iron in iron storage (12), suggesting that E2 increases iron storage capacity in the tissues, which in turn may decrease the prooxidative capacity of the intracellular free-iron pool.…”