Mechanism of the nongenomic effects of estrogen on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of the PI-3K/Akt pathway.
As studies indicate that genomic and nongenomic pathways are involved in mediating the salutary effects of 17beta-estradiol (E2) following trauma-hemorrhage, we examined if the nongenomic effects of E2 on attenuation of intestinal injury after trauma-hemorrhage involve the PI-3K/Akt pathway. Male Sprague-Dawley rats ( approximately 300 g body weight) underwent trauma-hemorrhage (mean blood pressure 40 mmHg for 90 min), followed by resuscitation. E2 conjugated to BSA (E2-BSA; 1 mg/Kg E2), with or without an estrogen receptor antagonist (ICI 182,780), a PI-3K inhibitor (Wortmannin), or vehicle, was injected i.v. during resuscitation. At 2 h after trauma-hemorrhage or sham operation, intestinal myeloperoxidase (MPO) activity, ICAM-1, cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-3, and IL-6 levels were measured (n=6 rats/group). Intestinal PI-3K, phosphorylation of Akt (p-Akt), and Akt protein expressions were also determined. One-way ANOVA and Tukey's test were used for statistical analysis. The results indicated that trauma-hemorrhage increased intestinal MPO activity and ICAM-1, CINC-1, CINC-3, and IL-6 levels. These parameters were improved significantly in the E2- or E2-BSA-treated rats subjected to trauma-hemorrhage. Although trauma-hemorrhage decreased intestinal PI-3K and p-Akt protein expressions, E2 or E2-BSA treatment following trauma-hemorrhage prevented such decreases in intestinal PI-3K and p-Akt protein expressions. Coadministration of ICI 182,780 or Wortmannin abolished the beneficial effects of E2-BSA on attenuation of intestinal injury following trauma-hemorrhage. Thus, the PI-3K/Akt pathway plays a critical role in mediating the nongenomic, salutary effects of E2 on attenuation of shock-induced intestinal tissue damage.
Yu
Huang-Ping
HP
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall, Room G094, Birmingham, AL 35294-0019, USA.
Hsieh
Ya-Ching
YC
Suzuki
Takao
T
Choudhry
Mashkoor A
MA
Schwacha
Martin G
MG
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D000077267:Fulvestrant; D016678:Genome; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000188:drug therapy / Q000378:metabolism*; D015854:Up-Regulation; D000077191:Wortmannin; D014947:Wounds and Injuries / Q000188:drug therapy / Q000378:metabolism*
D000730:Androstadienes; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D004958:Estradiol; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D000077267:Fulvestrant; D018799:Intercellular Adhesion Molecule-1; D015850:Interleukin-6; D009195:Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen; D000077191:Wortmannin; C513297:Cxcl1 protein, rat