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Published online before print December 5, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0705363

Received for publication July 5, 2005.
Revised August 21, 2005.
Accepted for publication October 20, 2005.

Article

Mechanism of the salutary effects of flutamide on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of estrogen receptor--dependent HO-1

Huang-Ping Yu ^*, Mashkoor A. Choudhry ^*, Tomoharu Shimizu ^*, Ya-Ching Hsieh ^*, Martin G. Schwacha ^*, Shaolong Yang ^*, and Irshad H. Chaudry ^*@

*Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham; and Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan

^@ To whom correspondence should be addressed. E-mail: Irshad.Chaudry{at}ccc.uab.edu.

	Abstract

Hemeoxygenase (HO)-1 induction following adverse circulatory conditions is known to be protective, and precastrated males have less intestinal damage than sham-operated males following trauma-hemorrhage (T-H). Previous studies have also shown that administration of flutamide up-regulated estrogen receptor (ER) expression in males following T-H. We hypothesized that flutamide administration in males following T-H up-regulates HO-1 via an ER-dependent pathway and protects against intestinal injury. Male Sprague-Dawley rats underwent T-H (mean basic protein 40 mmHg for 90 min and then resuscitation). A single dose of flutamide (25 mg/kg body weight), with or without an ER antagonist (ICI 182,780), a HO enzyme inhibitor [chromium-mesoporphyrin (CrMP)], or vehicle, was administered subcutaneously during resuscitation. At 2 h after T-H or sham operation, intestinal myeloperoxidase (MPO) activity, intercellular adhesion molecule (ICAM)-1, cytokine-induced neutrophil chemoattractant (CINC)-1, and CINC-3 levels were measured. Intestinal ER-, ER-, androgen receptor, and HO-1 mRNA/protein levels were also determined. Results showed that T-H increased intestinal MPO activity, ICAM-1, CINC-1, and CINC-3 levels. These parameters were improved significantly in the flutamide-treated rats subjected to T-H. Flutamide treatment increased intestinal HO-1 and ER- mRNA/protein levels as compared with vehicle-treated T-H rats. Administration of the ER antagonist ICI 182,780 or the HO inhibitor CrMP prevented the flutamide-induced attenuation of shock-induced intestinal damage. Thus, the salutary effects of flutamide administration on attenuation of intestinal injury following T-H are mediated via up-regulation of ER--dependent HO-1 expression.

Key Words: chromium-mesoporphyrin • hemorrhagic shock • ICAM-1 • CINC-1 • CINC-3

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