Resveratrol Attenuates Hepatic Injury After Trauma-Hemorrhage via Estrogen Receptor-Related Pathway

Abstract

Resveratrol administration after adverse circulatory conditions is known to be protective, however, the mechanism by which resveratrol produces the salutary effects remains unknown. Recently, it was shown that resveratrol activates estrogen receptor (ER) in endothelial cells. We hypothesized that resveratrol administration in males after trauma-hemorrhage decreases cytokine production and protects against hepatic injury through an ER-dependent pathway. To study this, male Sprague-Dawley rats were subjected to trauma-hemorrhage (mean blood pressure, 40 mmHg for 90 min) then resuscitation. A single dose of resveratrol (30 mg/kg of body weight) with or without an ER antagonist (ICI 182,780), ICI 182,780, or vehicle was administered i.v. during resuscitation. Tissue myeloperoxidase activity (a marker of neutrophil sequestration), cytokine-induced neutrophil chemoattractant 1 (CINC-1), CINC-3, intercellular adhesion molecule 1, and interleukin 6 (IL-6) levels in the liver and plasma aspartate aminotransferase and alanine aminotransferase concentrations were measured at 2 and 24 h postresuscitation (n = 6 rats per group). One-way ANOVA and Tukey test were used for statistical analysis. Results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, CINC-1, CINC-3, intercellular adhesion molecule 1, and IL-6 levels and plasma aspartate aminotransferase and alanine aminotransferase concentrations. These parameters were significantly improved in the resveratrol-treated rats at both 2 and 24 h postresuscitation. Coadministration of the ER antagonist ICI 182,780 prevented the beneficial effects of resveratrol administration on postresuscitation proinflammatory responses and hepatic injury. Thus, resveratrol administration after trauma-hemorrhage attenuated hepatic injury, likely through reduction of proinflammatory mediators. Resveratrol-mediated hepatic preservation seemed to progress via an ER-related pathway.

Role of Akt-Dependent Pathway in Resveratrol-Mediated Cardioprotection after Trauma-Hemorrhage

“…Resveratrol has been shown to have cardioprotective effects during ischemia reperfusion [10], and our studies have shown that resveratrol can attenuate hepatic injury after trauma-hemorrhage [9]. The PI3K/Akt pathway is known to be an endogenous negative feedback or compensatory mechanism, which serves to limit proinflammatory and chemotactic events in response to injury [11][12][13].…”

“…The time required for maximum hemorrhage was about 45 min, the volume of maximum hemorrhage was about 60% of the calculated circulating blood volume, and the total hemorrhage time was about 90 min [20]. Thirty minutes before the end of the resuscitation period, the rats received resveratrol (30 mg/kg, intravenously) [9], resveratrol plus the PI3K inhibitor wortmannin (1 mg/kg, intravenously at the beginning of resuscitation), wortmannin or an equal volume of the vehicle (w0.2 mL, 10% DMSO; Sigma, St. Louis, MO, USA) [8]. The catheters were then removed, the vessels ligated, and the skin incisions closed with sutures.…”

“…Studies have also shown that activation of the PI3K pathway protects organs or cells against ischemia-reperfusion injury and hypoxia through suppression of the apoptosis machinery [17]. Resveratrol has been shown to be protective in male rats after experimental induction of shock-like states [9,18]. Nevertheless, it remains unclear whether Akt plays a role in resveratrol-mediated cardioprotection following trauma-hemorrhage.…”

“…Intercellular adhesion molecule (ICAM)-1 is known to play a major role in the firm adhesion of neutrophils to the vascular endothelium and is markedly up-regulated following trauma-hemorrhagic shock [7]. Furthermore, there is convincing evidence that interleukin (IL)-6 plays a significant role in organ injury and is required for the expression of adhesion molecules [8,9].…”

Estrogens, inflammation and obesity: an overview

“…As mentioned previously, because the α subtype is widely expressed, many of the anti-obesity effects of these compounds may be due to estrogen receptor-independent signaling. Interestingly though, a recent study demonstrated an estrogen receptor-dependent effect of resveratrol to reduce hepatic IL-6 in a trauma-hemorrhage model (Yu et al, 2008). Additionally, both genistein and daidzein have also been shown to prevent endoplasmic reticulum stress activation in neuroblastoma cells .…”