Ringer's ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats

Harvard University, Cambridge, Massachusetts, United States
Critical Care Medicine (Impact Factor: 6.31). 09/2001; 29(8):1513-8. DOI: 10.1097/00003246-200108000-00003
Source: PubMed


Pyruvate has been shown to be protective in numerous in vitro and in vivo models of oxidant-mediated cellular or organ system injury. Unfortunately, the usefulness of pyruvate as a therapeutic agent is abrogated by its very poor stability in solution. In an effort to take advantage of the ability of pyruvate to scavenge reactive oxygen species while avoiding the problems associated with the instability of pyruvate in solution, we sought to determine whether a simple derivative, ethyl pyruvate, would be protective in an animal model of reactive oxygen species-mediated tissue injury, namely mesenteric ischemia and reperfusion in rats.
Prospective, randomized trial.
Animal research center.
Male Sprague-Dawley rats.
Under general anesthesia, rats were subjected to 60 mins of mesenteric ischemia followed by 60 mins of reperfusion. Controls (n = 6) received intravenous lactated Ringer's solution according this dosing schedule: 1.5 mL/kg bolus before ischemia, 3.0 mL/kg bolus before resuscitation, and 1.5 by continuous infusion. Two experimental groups received similar volumes of either pyruvate (n = 6 each) or ethyl pyruvate (n = 9) solution made up exactly like lactated Ringer's solution except for the substitution of either pyruvate or ethyl pyruvate for lactate, respectively.
To obtain tissues for assessing mucosal permeability and histology, five 10-cm long segments of small intestine were obtained at the following time points: baseline, after 30 and 60 mins of ischemia, and after 30 and 60 mins of reperfusion. Mucosal permeability to fluorescein isothiocyanate dextran (molecular weight 4000 Da) was assessed ex vivo by using an everted gut sac method. Compared with controls, treatment of rats with either pyruvate solution or ethyl pyruvate solution significantly ameliorated the development of intestinal mucosal hyperpermeability during the reperfusion. Treatment with ethyl pyruvate solution also significantly decreased the extent of histologic mucosal damage after mesenteric reperfusion.
Treatment with Ringer's ethyl pyruvate solution ameliorated structural and functional damage to the intestinal mucosa in a rat model of mesenteric ischemia/reperfusion. Ethyl pyruvate solution warrants further evaluation as a novel therapeutic agent for preventing oxidant-mediated injury in various disease states.

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    • "Inflammation was characterized by airway neutrophilia and eosinophilia, along with elevated BAL cytokines, raised levels of IL-4 and IFN-γ in supernatant of cultured lymphocytes, and increased total serum IgE, accompanied by airway epithelial goblet cell hyperplasia. EP has been shown to be an effective anti-inflammatory agent in a wide variety of in vivo and in vitro models of inflammation-mediated cellular or tissue injury, including severe sepsis, hemorrhagic shock, ischemia/reperfusion-induced intestinal mucosal injury and ileus induced by bowel manipulation in mice [21] [22] [23] [24] [25] [26]. However, EP used for treatment in TDI-induced asthma has not been studied yet. "
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    ABSTRACT: Diisocyanates are one of the leading causes of occupational asthma, which is dominated by granulocytic inflammation in the airway. In this study, we intended to explore the role of ethyl pyruvate (EP) on neutrophil infiltration in a toluene-2,4-diisocyanate (TDI)-induced murine asthma model. The experimental mice were first dermally sensitized and then challenged with TDI via oropharyngeal aspiration. The mice were treated intraperitoneally with 100, 50 or 10mg/kg EP 1h before each challenge. One day after the last challenge, airway reactivity to methacholine was measured by a barometric plethysmographic chamber. Total and differential cell counts, along with levels of macrophage inflammatory protein-2 (MIP-2), TNF-α in bronchoalveolar lavage (BAL) fluid and mRNA expression of CXCR2 in the lung were assessed. To depict neutrophils, a naphthol AS-D chloroacetate esterase kit was used. High mobility group box 1 (HMGB1) was determined by western blot and immunohistochemistry. Treatment with EP dramatically decreased airway hyperresponsiveness in TDI-challenged mice, as well as numbers of neutrophils in BAL fluid and peribronchovascular regions. Both the TDI-induced raised protein level and abnormal distribution of HMGB1 were significantly recovered by EP in a dose-dependent manner. The concentration of MIP-2 in TDI-induced asthma mice was significantly higher than that of the control ones, while EP had few effects on MIP-2. The mRNA expression of CXCR2 didn't change significantly, and TNF-α was not detected in BAL fluids. EP reduces airway neutrophil infiltration partly through downregulating HMGB1 in a chemical-induced murine asthma model.
    International immunopharmacology 05/2014; 21(1). DOI:10.1016/j.intimp.2014.04.024 · 2.47 Impact Factor
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    • "Ethyl pyruvate (EP) is a stable and lipophilic ester derived from the endogenous metabolite pyruvic acid [13]. The pharmacological effects of EP include downregulation of the secretion of proinflammatory cytokines, amelioration of redox-mediated damage to cells and tissues, and inhibition of apoptosis [14]. "
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    ABSTRACT: Ethyl pyruvate (EP) has demonstrated neuroprotective effects against acute brain injury through its anti-inflammatory action. The nuclear protein high-mobility group box 1 (HMGB1) can activate inflammatory pathways when released from dying cells. This study was designed to investigate the protective effects of EP against secondary brain injury in rats after Traumatic Brain Injury (TBI). Adult male rats were randomly divided into three groups: (1) Sham + vehicle group, (2) TBI + vehicle group, and (3) TBI + EP group (n = 30 per group). Right parietal cortical contusion was made by using a weight-dropping TBI method. In TBI + EP group, EP was administered intraperitoneally at a dosage of 75 mg/kg at 5 min, 1 and 6 h after TBI. Brain samples were harvested at 24 h after TBI. We found that EP treatment markedly inhibited the expressions of HMGB1 and TLR4, NF-κB DNA binding activity and inflammatory mediators, such as IL-1β, TNF-α and IL-6. Also, EP treatment significantly ameliorated beam walking performance, brain edema, and cortical apoptotic cell death. These results suggest that the protective effects of EP may be mediated by the reduction of HMGB1/TLR4/NF-κB-mediated inflammatory response in the injured rat brain.
    Mediators of Inflammation 06/2011; 2011(5):807142. DOI:10.1155/2011/807142 · 3.24 Impact Factor
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    • "Following these seminal experiments, ethyl pyruvate has been tested extensively in multiple disease models and species. It improved survival as well as organ function in preclinical models of severe sepsis and endotoxaemia, acute respiratory distress syndrome, haemorrhagic shock and stroke when it was administered within 12–24 h of disease induction in rodents (Sims et al. 2001; Tawadrous et al. 2002; Ulloa et al. 2002; Venkataraman et al. 2002; Yang et al. 2002; Kim et al. 2005; Su et al. 2007; van Zoelen et al. 2007; Karabeyogˇlu et al. 2008; Cai et al. 2009a,b; Cruz et al. 2009) and haemorrhagic shock in swine (Dong et al. 2009). Ethyl pyruvate failed to improve haemodyanic indices in patients during cardiopulmonary bypass in a phase II clinical trial (Bennett-Guerrero et al. 2009). "
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    ABSTRACT: Endotoxaemia causes substantial morbidity and mortality in horses with colic and sepsis. Ethyl pyruvate is a novel anti-inflammatory medication that improved survival in preclinical models of severe sepsis endotoxaemia and intestinal ischaemia and reperfusion in rodents, swine, sheep and dogs and may be a useful medication in horses. Ethyl pyruvate has no adverse effects in normal horses and is biologically active based on suppression of proinflammatory gene expression in endotoxin stimulated whole blood, in vitro. Physical and neurological examinations, behaviour scores, electrocardiograms and clinicopathological tests were performed on 5 normal healthy horses receiving 4 different doses of ethyl pyruvate. Doses included 0, 50, 100 and 150 mg/kg bwt administered in a randomised crossover design with a 2 week washout period between doses. Biological efficacy was assessed by stimulating whole blood with endotoxin from the horses that received ethyl pyruvate prior to and 1 and 6 h after drug infusion. Gene expression for TNFα, IL-1β and IL-6 was assessed. There were no effects of drug or dose (0, 50, 100 or 150 mg/kg bwt) on any of the physical or neurological examination, behaviour factors, electrocardiogram or clinical pathological results collected from any of the horses. All parameters measured remained within the normal reference range. There was a significant reduction in TNFα, IL-1β and IL-6 gene expression in endotoxin stimulated whole blood from horses 6 h after receiving 150 mg/kg bwt ethyl pyruvate. There were no detectable effects on gene expression of any of the other doses of ethyl pyruvate tested. We were unable to detect any detrimental effects of ethyl pyruvate administration in normal horses. Ethyl pyruvate significantly decreased proinflammatory gene expression in endotoxin stimulated blood 6 h after drug administration. Ethyl pyruvate may be a safe, effective medication in endotoxaemic horses.
    Equine Veterinary Journal 05/2011; 43(3):341-7. DOI:10.1111/j.2042-3306.2010.00214.x · 2.37 Impact Factor
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