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

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
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: