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.

• Authors: Jun-Te Hsu, Wen-Hong Kan, Chi-Hsun Hsieh, Mashkoor A Choudhry, Martin G Schwacha, Kirby I Bland, Irshad H Chaudry
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 82 Issue 4 Pg. 1019-26 (Oct 2007) ISSN: 0741-5400 [Print] United States
• PMID: 17656650 (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
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Receptors, Estrogen
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• Fulvestrant
• Estradiol
• Peroxidase
• Heme Oxygenase-1
• Glutathione Transferase
• 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)
• Fulvestrant
• 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 (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• 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)
• Wortmannin
• Wounds and Injuries (enzymology, pathology)