Ethyl pyruvate decreased early nuclear factor-κB levels but worsened survival in lipopolysaccharide-challenged mice*

Abstract

Ethyl pyruvate (EP) treatment inhibits nuclear factor (NF)-kappaB-mediated inflammation and has been considered for sepsis. However, NF-kappaB is also protective, and its inhibition may have adverse effects. We studied EP in lipopolysaccharide-challenged mice and systematically analyzed its efficacy in published sepsis models. After lipopolysaccharide, compared with placebo (n = 68), each of six doses of EP (0.01-100 mg/kg, n = 204) increased the hazards ratio of death. Although these increases were individually not significant (p = .13 to .37), when combined, they were (log mean +/- SEM, 0.26 +/- 0.13; p = .01). At 3 and 9 hrs after challenge, lipopolysaccharide increased lung NF-kappaB and 12 serum cytokines (p < or = .05 vs. phosphate-buffered saline challenge, except for interleukin-4 at 9 hrs). With lipopolysaccharide, although EP (100 mg/kg) decreased NF-kappaB and 11 of 12 cytokines at 3 hrs, it increased NF-kappaB and 11 of 12 cytokines at 9 hrs in patterns that differed (p < or = .05) across time points. In 14 published comparisons, EP's effects on the odds ratio of death varied (I2 = 85% [95% confidence interval, 74-91%], p < .0001), decreasing it significantly in five of the studies but not the other nine. In three of the latter, it increased time to death. Although EP has had promising effects in some preclinical sepsis models, it has not in others, and in the present model, it worsened outcome. Based on the complex role NF-kappaB has regulating both maladaptive and protective host responses, further defining factors that influence EP's effects is important if this agent is considered for patients with or at risk of sepsis.