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

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 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.

Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1

“…Simultaneous with improvement in cardiac function, RSV treatment resulted in decreased systemic TNF-α level and elevated cardiac ATP content (Figures 3 and 5). An exacerbated proinflammatory response following T-H is well documented (39)(40)(41). Our experiments clearly show improved cardiac function in RSV recipients, although the salutary effect of RSV is likely due to its effect on multiple organs and systemic inflammatory pathways.…”

Time dependent influence of host factors on outcome after trauma

“…The impact of gender on mortality and post-injury complications has been debated [29]. Whilst experimental studies indicate superior survival for female subjects, an effect suggested to be linked to female versus male sex steroids, [6][7][8] clinical studies have shown varying findings. Even though several studies have reported that male gender constitutes an independent risk factor for trauma-related mortality other studies have been unable to show this relationship [27,[30][31][32].…”

“…Gender differences among patients surviving severe trauma have been studied both experimentally and in clinical settings. Whilst experimental studies [6][7][8] point to better survival for fertile females, clinical studies have shown somewhat contradictory findings [9][10][11][12][13]. Co-morbidity has been advocated as an important risk factor for post-injury morbidity and mortality but the strength of this association seems to vary depending on injury severity, age and time since admission [3,4].…”

Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock

“…The hypoxic condition following hemorrhage as well as tissue reperfusion following resuscitation are conducive to the production of oxidative damage in most organs (12)(13)(14)(15). Mitochondria is likely to be a major focal point for the generation of reactive oxygen species (16)(17)(18)(19).…”