The liberation of endotoxin from gram negative bacteria plays a critical role in stimulating mononuclear cells. This leads to the cleavage of the inhibitory protein I&kappaB from the cytosolic protein NF&kappaB resulting in the translocation of NF&kappaB into the nucleus of the cell culminating in up regulation of both transcription and translation of protein. The protein from the nucleus is transformed by the endoplasmic reticulum to form both pro-inflammatory and anti-inflammatory cytokines and eicosanoids (leukotreines and prostaglandins). Mortality from sepsis in people approaches 40%. Endotoxemia causes significant morbidity in horses, including laminitis, ileus and coagulopathy. Despite current medications and fluid therapy, horses and people succumb to sepsis and endotoxemia. The search for new therapies to treat sepsis led to investigations using pyruvate derivatives. Ethyl pyruvate mitigated the cardiovascular effects of sepsis in multiple preclinical models including rodents, sheep, and swine. Ethyl pyruvate may be a novel treatment for endotoxin induced sepsis in the horse. The goal of this thesis is to provide a review of the current literature relevant to the use of ethyl pyruvate in preclinical models of sepsis and gastrointestinal ischemia and to present the data supporting ethyl pyruvate as both a safe and biologically active drug in normal adult horses.
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