Reduced peroxisome proliferator-activated receptor α expression is associated with decreased survival and increased tissue bacterial load in sepsis.
Reduced peroxisome proliferator-activated receptor α expression is associated with decreased survival and increased tissue bacterial load in sepsis.
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DOI：
10.1097/shk.0b013e31823f1a00
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Wong HR
中科院分区：
文献类型：
--
作者：
Standage SW;Caldwell CC;Zingarelli B;Wong HR
过氧化物酶体增殖物激活受体α(PPARα)是核受体家族中的一员，在代谢和炎症过程中发挥着重要的生理作用。先前对感染性休克儿童患者的研究显示，在患有更严重疾病的儿童中，与PPARα信号通路相对应的基因显著下调。在这项研究中，利用全血来源的核糖核酸分析了PPARα的表达，发现感染性休克患者PPARα的表达降低，并且这种下降的幅度与疾病的严重程度有关。在盲肠结扎和穿孔诱导的脓毒症小鼠模型中，与野生型动物相比，缺乏PPARα的基因敲除小鼠的存活率降低。血浆细胞因子分析显示，IL-1β、IL-6、IL-17、KC、单核细胞趋化蛋白-1、巨噬细胞趋化蛋白-2和肿瘤坏死因子α在PPARα基因敲除动物的24小时内显著降低。PPARα缺失组小鼠脾树突状细胞、巨噬细胞和CD8T细胞表面活化标志物减少，肺和脾组织细菌载量增加。这些数据表明，在脓毒症中，PPARα的表达减少或缺失是一种生存劣势，PPARα在脓毒症反应过程中发挥着维持适当免疫功能的作用。
The peroxisome-proliferator activated receptor alpha (PPARα) is a member of the nuclear receptor family with many important physiologic roles related to metabolism and inflammation. Previous research in pediatric patients with septic shock revealed that genes corresponding to the PPARα signaling pathway are significantly downregulated in a subgroup of children with more severe disease. In this study, PPARα expression analysis using whole blood derived RNA revealed that PPARα expression was decreased in patients with septic shock and that the magnitude of that decrement correlated with the severity of disease. In a mouse model of sepsis, induced by cecal ligation and puncture (CLP), knockout mice lacking PPARα had decreased survival compared to wild type animals. Plasma cytokine analysis demonstrated decreased levels of IL-1β, IL-6, IL-17, KC, MCP-1, MIP-2, and TNFα at 24 hours in PPARα knockout animals. Cell surface markers of activation on splenic dendritic cells, macrophages, and CD8 T-cells were reduced in PPARα null animals and the bacterial load in lung and splenic tissues was increased. These data indicate that reduced or absent PPARα expression confers a survival disadvantage in sepsis and that PPARα plays a role in maintaining appropriate immune functions during the sepsis response.