Mechanism of the nongenomic effects of estrogen on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of the PI-3K/Akt pathway.

Abstract

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.

• Authors: Huang-Ping Yu, Ya-Ching Hsieh, Takao Suzuki, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H Chaudry
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 82 Issue 3 Pg. 774-80 (Sep 2007) ISSN: 0741-5400 [Print] United States
• PMID: 17586659 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Androstadienes
• Chemokine CXCL1
• Chemokines, CXC
• Cxcl1 protein, rat
• Estrogen Antagonists
• Estrogen Receptor Modulators
• Interleukin-6
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Receptors, Estrogen
• Intercellular Adhesion Molecule-1
• Fulvestrant
• Estradiol
• Peroxidase
• Proto-Oncogene Proteins c-akt
• Wortmannin

Topics

• Androstadienes (pharmacology)
• Animals
• Blotting, Western
• Chemokine CXCL1
• Chemokines, CXC (metabolism)
• Estradiol (analogs & derivatives, pharmacology)
• Estrogen Antagonists (pharmacology)
• Estrogen Receptor Modulators (pharmacology)
• Fulvestrant
• Genome
• Intercellular Adhesion Molecule-1 (metabolism)
• Interleukin-6 (metabolism)
• Intestine, Small (drug effects, enzymology)
• Male
• Peroxidase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Estrogen (antagonists & inhibitors, metabolism)
• Shock, Hemorrhagic (drug therapy, metabolism)
• Up-Regulation
• Wortmannin
• Wounds and Injuries (drug therapy, metabolism)