Su Junwu, Li Xuemei, Cui Xizhong, Li Yan, Fitz Yvonne, Hsu Lewis, Mani Haresh, Quezado Martha, Eichacker Peter Q
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Crit Care Med. 2008 Apr;36(4):1059-67. doi: 10.1097/CCM.0B013E318164403B.
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.
丙酮酸乙酯（EP）治疗可抑制核因子（NF）-κB介导的炎症反应，已被用于脓毒症的治疗。然而，NF-κB也具有保护作用，抑制它可能会产生不良影响。
我们在脂多糖攻击的小鼠中研究了EP，并系统分析了其在已发表的脓毒症模型中的疗效。
脂多糖攻击后，与安慰剂组（n = 68）相比，六种剂量的EP（0.01 - 100 mg/kg，n = 204）中的每一种都增加了死亡风险比。虽然这些增加单独来看并不显著（p = 0.13至0.37），但合并起来则具有显著性（对数均值±SEM，0.26±0.13；p = 0.01）。在攻击后3小时和9小时，脂多糖增加了肺组织中的NF-κB和12种血清细胞因子（与磷酸盐缓冲盐水攻击相比，p≤0.05，9小时时的白细胞介素-4除外）。使用脂多糖时，虽然EP（100 mg/kg）在3小时时降低了NF-κB和12种细胞因子中的11种，但在9小时时却增加了NF-κB和12种细胞因子中的11种，且不同时间点的变化模式不同（p≤0.05）。在14项已发表的比较中，EP对死亡比值比的影响各不相同（I² = 85%[95%置信区间，74 - 91%]，p < 0.0001），在其中五项研究中显著降低了死亡比值比，但在其他九项研究中则没有。在后者中的三项研究中，它延长了死亡时间。
虽然EP在一些临床前脓毒症模型中显示出有前景的效果，但在其他模型中并非如此，并且在本模型中，它恶化了预后。鉴于NF-κB在调节适应性和保护性宿主反应中具有复杂作用，如果考虑将该药物用于脓毒症患者或有脓毒症风险的患者，进一步确定影响EP效果的因素很重要。
