Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation

Abstract

Sepsis, a potentially fatal clinical syndrome, is mediated by an early (e.g., tumor necrosis factor and IL-1) and late [e.g., high mobility group B-1 (HMGB1)] proinflammatory cytokine response to infection. Specifically targeting early mediators has not been effective clinically, in part because peak mediator activity often has passed before therapy can be initiated. Late-acting downstream effectors, such as HMGB1, that mediate sepsis lethality may be more relevant therapeutic targets. Ethyl pyruvate (EP) recently was identified as an experimental therapeutic that significantly protects against lethal hemorrhagic shock. Here, we report that EP attenuates lethal systemic inflammation caused by either endotoxemia or sepsis even if treatment begins after the early tumor necrosis factor response. Treatment with EP initiated 24 h after cecal puncture significantly increased survival (vehicle survival ‫؍‬ 30% vs. EP survival ‫؍‬ 88%, P < 0.005). EP treatment significantly reduced circulating levels of HMGB1 in animals with established endotoxemia or sepsis. In macrophage cultures, EP specifically inhibited activation of p38 mitogen-activated protein kinase and NF-B, two signaling pathways that are critical for cytokine release. This report describes a new strategy to pharmacologically inhibit HMGB1 release with a small molecule that is effective at clinically achievable concentrations. EP now warrants further evaluation as an experimental ''rescue'' therapeutic for sepsis and other potentially fatal systemic inflammatory disorders.tumor necrosis factor ͉ NF-B ͉ lipopolysaccharide

The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll‐like receptor‐mediated inflammatory signals

“…They induce proinflammatory mediators by promoting MAPK, such as ERK, JNK, and p38 MAPK, and NF-jB [29][30][31][32][33]. Unfortunately, we experienced difficulties in measuring the protein levels in several visceral compartments in septic mice; therefore, we used an in vitro setting to evaluate the efficacy of ginsan to act on TLR and MAPK signaling transduction pathways.…”

“…Nuclear extracts of PM that had been pretreated with ginsan (0.1 lg/mL) for 6 h and then co-cultured with heat-killed S. aureus for 40 min were prepared as described previously [29]. The double-stranded oligonucleotide probes containing NF-jB binding sequences (5 0 -GGGGACTTTCCC-3 0 ) were end-labeled with [c-32 P]ATP using T4 polynucleotide kinase.…”

High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis

“…Addition of ethyl pyruvate to macrophage cultures significantly inhibited HMGB-1 release following stimulation with endotoxin. Ethyl pyruvate conferred significant protection against lethality even when the first dose was administered 24 hours after the onset of cecal perforation (19). Thus, in vivo studies using either anti-HMGB-1 antibodies or ethyl pyruvate suggest an important role for HMGB-1 as a therapeutic target in acute systemic inflammatory syndromes.…”

“…Recent evidence now indicates that an experimental therapeutic agent, ethyl pyruvate, which attenuates serum HMGB-1 levels, is significantly protective against the lethality of sepsis (19). Ethyl pyruvate was administered to mice with established sepsis caused by cecal ligation and puncture, a standardized and widely used preclinical model of sepsis (19).…”

“…Ethyl pyruvate was administered to mice with established sepsis caused by cecal ligation and puncture, a standardized and widely used preclinical model of sepsis (19). Administration of ethyl pyruvate significantly reduced serum HMGB-1 levels and conferred a significant survival advantage to mice with established sepsis.…”