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Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 up-regulation.

Abstract
Protein kinase B (Akt) is known to be involved in proinflammatory and chemotactic events in response to injury. Akt activation also leads to the induction of heme oxygenase (HO)-1. Up-regulation of HO-1 mediates potent, anti-inflammatory effects and attenuates organ injury. Although studies have shown that 17beta-estradiol (E2) prevents organ damage following trauma-hemorrhage, it remains unknown whether Akt/HO-1 plays any role in E2-mediated attenuation of hepatic injury following trauma-hemorrhage. 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, E2 (1 mg/kg body weight), E2 plus the PI-3K inhibitor (Wortmannin), or the estrogen receptor (ER) antagonist (ICI 182,780). At 2 h after sham operation or trauma-hemorrhage, plasma alpha-GST and hepatic tissue myeloperoxidase (MPO) activity, IL-6, TNF-alpha, ICAM-1, cytokine-induced neutrophil chemoattractant-1, and MIP-2 levels were measured. Hepatic Akt and HO-1 protein levels were also determined. Trauma-hemorrhage increased hepatic injury markers (alpha-GST and MPO activity), cytokines, ICAM-1, and chemokine levels. These parameters were markedly improved in the E2-treated rats following trauma-hemorrhage. E2 treatment also increased hepatic Akt activation and HO-1 expression compared with vehicle-treated, trauma-hemorrhage rats, which were abolished by coadministration of Wortmannin or ICI 182,780. These results suggest that the salutary effects of E2 on hepatic injury following trauma-hemorrhage are in part mediated via an ER-related, Akt-dependent up-regulation of HO-1.
AuthorsJun-Te Hsu, Wen-Hong Kan, Chi-Hsun Hsieh, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H Chaudry
JournalJournal of leukocyte biology (J Leukoc Biol) Vol. 82 Issue 4 Pg. 1019-26 (Oct 2007) ISSN: 0741-5400 [Print] United States
PMID17656650 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Androstadienes
  • Chemokine CXCL1
  • Chemokine CXCL2
  • Cxcl1 protein, rat
  • Cxcl2 protein, rat
  • Estrogen Antagonists
  • Estrogens
  • Interleukin-6
  • Protein Kinase Inhibitors
  • Receptors, Estrogen
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • fulvestrant
  • Estradiol
  • Peroxidase
  • Heme Oxygenase-1
  • Glutathione Transferase
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • wortmannin
Topics
  • Androstadienes (pharmacology)
  • Animals
  • Blood Pressure (drug effects)
  • Chemokine CXCL1 (biosynthesis)
  • Chemokine CXCL2 (biosynthesis)
  • Estradiol (analogs & derivatives, pharmacology)
  • Estrogen Antagonists (pharmacology)
  • Estrogens (pharmacology)
  • Gene Expression Regulation, Enzymologic (drug effects)
  • Glutathione Transferase (metabolism)
  • Heme Oxygenase-1 (biosynthesis)
  • Hemorrhage (enzymology, pathology)
  • Intercellular Adhesion Molecule-1 (biosynthesis)
  • Interleukin-6 (biosynthesis)
  • Liver (enzymology, injuries, pathology)
  • Male
  • Peroxidase (biosynthesis)
  • Phosphatidylinositol 3-Kinases (antagonists & inhibitors, metabolism)
  • Protein Kinase Inhibitors (pharmacology)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen (metabolism)
  • Resuscitation
  • Tumor Necrosis Factor-alpha (biosynthesis)
  • Up-Regulation (drug effects)
  • Wounds and Injuries (enzymology, pathology)

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