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Mechanism of estrogen‐mediated attenuation of hepatic injury following trauma‐hemorrhage: Akt‐dependent HO‐1 up‐regulation
Author(s) -
Hsu Junte,
Kan WenHong,
Hsieh ChiHsun,
Choudhry Mashkoor A.,
Schwacha Martin G.,
Bland Kirby I.,
Chaudry Irshad H.
Publication year - 2007
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0607355
Subject(s) - wortmannin , protein kinase b , proinflammatory cytokine , medicine , endocrinology , liver injury , resuscitation , myeloperoxidase , pharmacology , biology , inflammation , anesthesia , signal transduction , biochemistry
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 17β‐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, ∼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 α‐GST and hepatic tissue myeloperoxidase (MPO) activity, IL‐6, TNF‐α, 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 (α‐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.