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

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

Research output: Contribution to journalArticle

42 Scopus citations

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 blood pressure (MBP) 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-α, ER-β, 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-β 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-β-dependent HO-1 expression.

Original languageEnglish (US)
Pages (from-to)277-284
Number of pages8
JournalJournal of Leukocyte Biology
Volume79
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

Keywords

  • CINC-1
  • CINC-3
  • Chromium-mesoporphyrin
  • Hemorrhagic shock
  • ICAM-1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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