title: Flutamide attenuates pro-inflammatory cytokine production and hepatic injury following trauma-hemorrhage via estrogen receptor-related pathway.
abstract: OBJECTIVE
  To determine the mechanism by which flutamide administration following trauma-hemorrhage (T-H) decreases cytokine production and hepatic injury under those conditions.
  
  
  BACKGROUND
  Although studies have demonstrated that flutamide administration following T-H improves hepatic and immune functions, the mechanism by which flutamide produces the salutary effects remains unknown.
  
  
  METHODS
  Male Sprague-Dawley rats underwent a 5-cm laparotomy and hemorrhagic shock (40 mm Hg for approximately 90 minutes), followed by resuscitation with 4 times the shed blood volume in the form of Ringer's lactate. Flutamide (25 mg/kg body weight, sc) was administered at the middle of resuscitation and animals were killed 2 hours thereafter. To block estrogen receptor (ER), ER antagonist ICI 182,780 was administrated with flutamide.
  
  
  RESULTS
  Hepatic injury, myeloperoxidase activity, nuclear factor-kappaB (NF-kappaB) DNA binding activity and protein expression of intercellular adhesion molecule-1, and cytokine-induced neutrophil chemoattractant (CINC-1 and CINC-3) markedly increased following T-H. Hepatic mRNA and plasma IL-6 levels were also elevated following T-H. The alterations in these parameters induced by T-H were significantly attenuated by flutamide administration. The decreased plasma estradiol levels following T-H were restored to sham levels in the flutamide-treated T-H animals. Coadministration of ICI 182,780 prevented those salutary effects of flutamide administration on pro-inflammatory responses and hepatic injury following T-H.
  
  
  CONCLUSIONS
  These findings suggest that the reduction in the production of pro-inflammatory mediators and hepatic injury produced by flutamide administration following T-H is likely due to the down-regulation in hepatic NF-kappaB DNA binding activity. Moreover, the salutary effects of flutamide administration appear to be mediated at least in part via ER-related pathway.
authors.affiliation: Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, 35294-0019, USA.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Shimizu
authors.forename: Huang-Ping
authors.initials: HP
authors.lastname: Yu
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Mashkoor A
authors.initials: MA
authors.lastname: Choudhry
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kirby I
authors.initials: KI
authors.lastname: Bland
authors.forename: Irshad H
authors.initials: IH
authors.lastname: Chaudry
mesh_terms: D000007:Abdominal Injuries / Q000150:complications* / Q000378:metabolism; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000096:biosynthesis; D004195:Disease Models, Animal; D004586:Electrophoresis; D004797:Enzyme-Linked Immunosorbent Assay; D005485:Flutamide / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D007813:Laparotomy / Q000009:adverse effects; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009195:Peroxidase / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D018799:Intercellular Adhesion Molecule-1; D005485:Flutamide; D009195:Peroxidase