Mechanism of the salutary effects of flutamide on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of estrogen receptor-{beta}-dependent HO-1.
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-alpha, ER-beta, 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-beta 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-beta-dependent HO-1 expression.
Yu
Huang-Ping
HP
University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall, Room G094, Birmingham, AL 35294-0019, USA.
Choudhry
Mashkoor A
MA
Shimizu
Tomoharu
T
Hsieh
Ya-Ching
YC
Schwacha
Martin G
MG
Yang
Shaolong
S
Chaudry
Irshad H
IH
D000818:Animals; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005485:Flutamide / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D000077267:Fulvestrant; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006470:Hemorrhage / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000201:enzymology* / Q000293:injuries*; D008297:Male; D008652:Mesoporphyrins / Q000494:pharmacology; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008652:Mesoporphyrins; D012333:RNA, Messenger; C427471:chromium mesoporphyrin; D018799:Intercellular Adhesion Molecule-1; D000077267:Fulvestrant; D004958:Estradiol; D005485:Flutamide; D009195:Peroxidase; D051547:Heme Oxygenase-1