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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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
StatePublished - Aug 2008
Externally publishedYes

Fingerprint

Flutamide
Oxidative Stress
Hemorrhage
Liver
Wounds and Injuries
Chemokines
Hypoxia-Inducible Factor 1
Nitric Oxide Synthase Type II
Cytokines
Glutathione Transferase
Resuscitation
Lipid Peroxidation
Peroxidase
Apoptosis
Hemorrhagic Shock
Inbred C3H Mouse
Chemokine CCL2
Androgen Receptors
DNA Fragmentation
Malondialdehyde

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Flutamide protects against trauma-hemorrhage-induced liver injury via attenuation of the inflammatory response, oxidative stress, and apopotosis. / Kan, Wen Hong; Hsieh, Chi Hsun; Schwacha, Martin G; Choudhry, Mashkoor A.; Raju, Raghavan; Bland, Kirby I.; Chaudry, Irshad H.

In: Journal of Applied Physiology, Vol. 105, No. 2, 08.2008, p. 595-602.

Research output: Contribution to journalArticle

Kan, Wen Hong ; Hsieh, Chi Hsun ; Schwacha, Martin G ; Choudhry, Mashkoor A. ; Raju, Raghavan ; Bland, Kirby I. ; Chaudry, Irshad H. / Flutamide protects against trauma-hemorrhage-induced liver injury via attenuation of the inflammatory response, oxidative stress, and apopotosis. In: Journal of Applied Physiology. 2008 ; Vol. 105, No. 2. pp. 595-602.
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T1 - Flutamide protects against trauma-hemorrhage-induced liver injury via attenuation of the inflammatory response, oxidative stress, and apopotosis

AU - Kan, Wen Hong

AU - Hsieh, Chi Hsun

AU - Schwacha, Martin G

AU - Choudhry, Mashkoor A.

AU - Raju, Raghavan

AU - Bland, Kirby I.

AU - Chaudry, Irshad H.

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N2 - 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.

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KW - Hypoxia-inducible factor-1α

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KW - Kupffer cells

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