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.
Kan
Wen-Hong
WH
Center for Surgical Research, Department of Surgery, University of Alabama at Birmingham, G094 Volker Hall, 1670 Univ. Blvd., Birmingham, AL 35294-0019, USA.
Hsieh
Chi-Hsun
CH
Schwacha
Martin G
MG
Choudhry
Mashkoor A
MA
Raju
Raghavan
R
Bland
Kirby I
KI
Chaudry
Irshad H
IH
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