Flutamide protects against trauma-hemorrhage-induced liver injury via attenuation of the inflammatory response, oxidative stress, and apopotosis

Wen Hong Kan, Chi Hsun Hsieh, Martin G. Schwacha, Mashkoor A. Choudhry, Raghavan Raju, Kirby I. Bland, Irshad H. Chaudry

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27 Scopus citations

Abstract

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 ∼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 α-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-1α were also evaluated. Cytokines (TNF-α, 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 α-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-1α, 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.

Original languageEnglish (US)
Pages (from-to)595-602
Number of pages8
JournalJournal of Applied Physiology
Volume105
Issue number2
DOIs
Publication statusPublished - Aug 1 2008
Externally publishedYes

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Keywords

  • Hypoxia-inducible factor-1α
  • Inflammation
  • Inflammatory cytokines
  • Kupffer cells

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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