Ethyl pyruvate ameliorates distant organ injury in a murine model of acute necrotizing pancreatitis*

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Abstract

Objective:

Ethyl pyruvate has been shown to be an effective anti-inflammatory agent in a variety of in vitro and in vivo model systems. Herein, we used a murine model of acute pancreatitis to compare the effects of treatment with either Ringer’s lactate solution or ethyl pyruvate solution on several physiologic and biochemical variables related to disease severity.

Design:

Experimental animal study.

Setting:

University laboratory.

Subjects:

C57Bl/6 mice.

Interventions:

Pancreatitis was induced by feeding the animals a choline-deficient diet supplemented with 0.5% ethionine for 24 hrs and then challenging the animals with seven hourly 50 μg/kg intraperitoneal injections of cerulein and a single intraperitoneal injection of Escherichia coli lipopolysaccharide (4 mg/kg).

Measurements and Main Results:

When mice were treated with ethyl pyruvate (40 mg/kg intraperitoneally every 6 hrs for 48 hrs) instead of Ringer’s lactate solution starting 2 hrs after the injection of lipopolysaccharide, long-term survival was improved from one of ten to six of ten (p = .057). When mice were treated with a 40 mg/kg dose of ethyl pyruvate just before the first dose of cerulein and then injected with a second 40 mg/kg dose 6 hrs later, serum concentrations of alanine aminotransferase measured 10 hrs after the first cerulein dose were significantly lower than in mice with pancreatitis treated with Ringer’s lactate solution. In this model of acute pancreatitis, the same dosing regimen for ethyl pyruvate also ameliorated bacterial translocation to mesenteric lymph nodes and leakage of fluorescein isothiocyanate-labeled albumin from blood into bronchoalveolar lavage fluid. Treatment with ethyl pyruvate decreased pancreatic expression of tumor necrosis factor and interleukin-6 messenger RNA and nuclear factor-κB DNA binding in nuclear extracts prepared from pancreatic tissue.

Conclusion:

Treatment with ethyl pyruvate ameliorated the local inflammatory response and decreased local and distant organ injury in a murine model of necrotizing pancreatitis.

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