Flutamide protects against trauma-hemorrhage-induced liver injury via attenuation of the inflammatory response, oxidative stress, and apopotosis.
Although studies have shown that administration of testosterone receptor antagonist, flutamide, following trauma-hemorrhage, improves hepatic, cardiovascular, and immune functions, the precise cellular/molecular mechanisms responsible for producing these salutary effects remain largely unknown. To study this, male C3H/HeN mice were subjected to a midline laparotomy and hemorrhagic shock (35+/-5 mmHg for approximately 90 min), followed by resuscitation with Ringer lactate. Flutamide (25 mg/kg) or vehicle was administered subcutaneously at the onset of resuscitation, and animals were killed 2 h thereafter. Hepatic injury was assessed by plasma alpha-glutathione S-transferase concentration, liver myeloperoxidase activity, and nitrotyrosine formation. Hepatic malondialdehyde and 4-hydroxyalkenals (lipid peroxidation indicators), cellular DNA fragmentation, and the expression of inducible nitric oxide synthase and hypoxia-inducible factor-1alpha were also evaluated. Cytokines (TNF-alpha, IL-6) and chemokines (keratinocyte-derived chemokine and monocyte chemoattractant protein-1) levels were determined by cytometric bead array. The results indicate that flutamide administration after trauma-hemorrhage reduced liver injury, which was associated with decreased levels of alpha-glutathione S-transferase, myeloperoxidase activity, nitrotyrosine formation, lipid peroxidation, and cytokines/chemokines (systemic, liver tissue, and intracellular cytokines/chemokines). Cellular apoptosis, hepatocyte hypoxia-inducible factor-1alpha, and inducible nitric oxide synthase expression were also decreased under such conditions. Thus administration of flutamide following trauma-hemorrhage protects against liver injury via reduced inflammation, cellular oxidative stress, and apoptosis.
Center for Surgical Research, Department of Surgery, University of Alabama at Birmingham, G094 Volker Hall, 1670 Univ. Blvd., Birmingham, AL 35294-0019, USA.
Wen-Hong
WH
Kan
Chi-Hsun
CH
Hsieh
Martin G
MG
Schwacha
Mashkoor A
MA
Choudhry
Raghavan
R
Raju
Kirby I
KI
Bland
Irshad H
IH
Chaudry
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002469:Cell Separation; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D005485:Flutamide / Q000627:therapeutic use*; D005982:Glutathione Transferase / Q000378:metabolism; D006470:Hemorrhage / Q000517:prevention & control*; D006505:Hepatitis / Q000473:pathology / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects; D008099:Liver / Q000293:injuries*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000726:Androgen Antagonists; D018925:Chemokines; D016207:Cytokines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C002744:3-nitrotyrosine; D014443:Tyrosine; D005485:Flutamide; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D005982:Glutathione Transferase