Ethyl Pyruvate: A Novel Treatment for Sepsis

Mitchell   P.   Fink

Abstract

Pyruvic acid is a three-carbon α-ketocarboxylic acid that plays a central role in intermediary metabolism, being the final product of glycolysis and the starting substrate for the tricarboxylic acid cycle. Ethyl pyruvate, which is a simple aliphatic ester derived from pyruvic acid, has been shown to improve survival and ameliorate organ system dysfunction in mice with peritonitis induced by cecal ligation and perforation, even when treatment is started as late as 12-24 hours after the onset of sepsis. In studies using lipopolysaccharidestimulated RAW 264.7 murine macrophage-like cells, ethyl pyruvate inhibits activation of the pro-inflammatory transcription factor, NF-κB, and down-regulates secretion of a number of pro-inflammatory cytokines, such as TNF. In this reductionist in vitro system, ethyl pyruvate also blocks secretion of the late-appearing pro-inflammatory cytokine-like molecule, high mobility group B1 (HMGB1). In murine models of endotoxemia or sepsis, treatment with ethyl pyruvate decreases circulating levels of TNF and HMGB1. While the molecular events responsible for the salutary effects of ethyl pyruvate remain to be elucidated, one mechanism may involve covalent modification of a critical thiol residue in the p65 component of NF-κB. Ethyl pyruvate warrants evaluation as a therapeutic agent for the treatment of sepsis in humans.

Keywords: NF-kappaB, lipopolysaccharide, LPS, endotoxin, pyruvic acid, reactive oxygen species, signal transduction, acute renal failure