Impact of plasma histones in human sepsis and their contribution to cellular injury and inflammation.
Impact of plasma histones in human sepsis and their contribution to cellular injury and inflammation.
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DOI：
10.1186/s13054-014-0543-8
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发表时间：
2014-09-24
期刊：
影响因子：
--
通讯作者：
Claus RA
中科院分区：
文献类型：
--
作者：
Ekaney ML;Otto GP;Sossdorf M;Sponholz C;Boehringer M;Loesche W;Rittirsch D;Wilharm A;Kurzai O;Bauer M;Claus RA
在脓毒症动物模型和创伤相关肺损伤患者中，循环组蛋白已被确定为损伤的介质。尽管组蛋白的实际浓度、临床意义和在不同疾病条件下的作用机制仍存在争议，但组蛋白在人类脓毒症中的水平、与疾病进展的关系以及对内皮细胞和免疫细胞的中介作用仍未见报道。本研究旨在确定脓毒症患者的组蛋白水平及其临床意义，并阐明组蛋白在体外的作用。组蛋白水平、内源性活化蛋白C(APC)水平和来自两个独立的脓毒症患者队列的临床数据被获得。将组蛋白水平与不同对照组进行比较，包括健康人、无脓毒症的重症监护病房(ICU)患者、有多器官衰竭的ICU患者和无感染的轻伤或多发伤患者。用组蛋白刺激内皮细胞和单核细胞。对细胞完整性和脓毒症典型细胞因子进行评估。用功能阻断抗体研究了组蛋白通过Toll样受体4(TLR4)的作用机制。免疫印迹法检测血浆中组蛋白的降解情况。组蛋白H4水平在脓毒症患者(队列I；n = 15和队列II；n = 19)与重症监护病房对照组(n = 12)、多器官衰竭患者(n = 12)或轻微创伤患者(n = 7)相比显著升高，这与需要肾脏替代治疗和疾病进展过程中血小板计数减少有关，并与脓毒症患者死亡率显著相关(ICU-，28天和90天死亡率)。血浆组蛋白与内源性APC水平呈负相关。组蛋白刺激诱导脓毒症原型细胞因子的释放，细胞完整性降低，乳酸脱氢酶(LDH)和碘化丙啶(PI)染色显着增加。阻断TLR4可降低细胞对内皮细胞的细胞毒作用。计算出组蛋白在添加血浆中的半衰期为4.6分钟。脓毒症患者组蛋白水平显著升高，可能通过TLR4信号介导细胞损伤和炎症，从而可能导致多器官衰竭和致命结局。
Circulating histones have been identified as mediators of damage in animal models of sepsis and in patients with trauma-associated lung injury. Despite existing controversies on actual histone concentrations, clinical implications and mechanism of action in various disease conditions, histone levels in human sepsis, association with disease progression and mediated effects on endothelial and immune cells remain unreported. This study aimed to determine histone levels and its clinical implication in septic patients and to elucidate histone-mediated effects ex-vivo. Histone levels, endogenous activated protein C (APC) levels and clinical data from two independent cohorts of septic patients were obtained. Histone levels were compared with various control groups including healthy individuals, intensive care unit (ICU) patients without sepsis, ICU patients with multiple organ failure and patients with minor or multiple trauma, all without infection. Endothelial and monocytic cells were stimulated with histones. Cellular integrity and sepsis prototypical cytokines were evaluated. The mechanism of action of histones via Toll-like receptor 4 (TLR4) was evaluated using a function blocking antibody. Histone degradation in plasma was studied by immunoblotting. Histone H4 levels were significantly elevated in patients with sepsis (cohort I; n = 15 and cohort II; n = 19) versus ICU controls (n = 12), patients with multiple organ failure (n = 12) or minor trauma (n = 7), associated with need for renal replacement therapy and decrease in platelet count during disease progression, and remarkably were significantly associated with increased mortality rates in septic patients (ICU-, 28 day- and 90 day mortality rates). There was an inverse correlation between plasma histones and endogenous APC levels. Histone stimulation induced the release of sepsis prototypic cytokines and decreased cell integrity indicated by a significant increase of lactate dehydrogenase (LDH) and propidium iodide (PI) staining. Blocking of TLR4 decreased cellular cytotoxicity on endothelial cells. The calculated half-life of histones in spiked plasma was 4.6 minutes. Histone levels in septic patients are significantly increased and might mediate disease aggravation by cellular injury and inflammation via TLR4 signaling, which potentially results in multiple organ failure and fatal outcome.
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细胞外组蛋白是败血症死亡的主要介体。
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1111/j.1538-7836.2011.04544.x
发表时间：
2012-01
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Brill A;Fuchs TA;Savchenko AS;Thomas GM;Martinod K;De Meyer SF;Bhandari AA;Wagner DD
通讯作者：
Wagner DD
影响因子：
3.1
作者：
Filiponi, Thiago Corsi;Durao, Marcelino de Souza, Jr.
通讯作者：
Durao, Marcelino de Souza, Jr.
影响因子：
8.8
作者：
MARSHALL, JC;COOK, DJ;SIBBALD, WJ
通讯作者：
SIBBALD, WJ
影响因子：
8.8
作者：
Vanderschueren, S;De Weerdt, A;Bobbaers, H
通讯作者：
Bobbaers, H