Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis.
Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis.
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DOI：
10.1186/cc7866
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Zijlstra JG
中科院分区：
文献类型：
--
作者：
Kümpers P;van Meurs M;David S;Molema G;Bijzet J;Lukasz A;Biertz F;Haller H;Zijlstra JG
血管内皮细胞激活导致血管屏障破坏表明败血症是一种破坏性事件。血管生成素(Ang)-2是血管内皮细胞特异性Tie2受体的一种循环拮抗配体，可迅速从Webel-Palade释放，并已被确认为内皮激活的非冗余守门人。本研究旨在研究血管紧张素-2在人体实验性内毒素血症中释放的时程；血管紧张素-2与可溶性黏附分子和炎性细胞因子的关系；以及危重病人脓毒症时血管紧张素-2释放的早期时程。22名健康志愿者单次静脉注射脂多糖(LPS；4 ng/kg)后24小时内，采用免疫发光法(ILMA)、酶联免疫吸附试验(ELISA)和微珠复合技术检测循环Ang-1、Ang-2、可溶性Tie2受体、炎症分子TNF-α、IL-6、IL-8和C反应蛋白，以及可溶性内皮细胞黏附分子细胞间黏附分子-1(ICAM-1)、E-选择素和P-选择素。在内毒素注射前30分钟，单剂量口服安慰剂或p38丝裂原激活蛋白(MAP)激酶抑制剂药物RWJ-67657。另外，分析了21例脓毒症患者入院时、入院24小时和72小时后循环血管紧张素转换酶-2的变化。在内毒素血症期间，循环Ang-2水平显著升高，在注射内毒素后4.5h达到峰值。Ang-2表现出与早期促炎细胞因子TNF-α、IL-6和IL-8相似的动力学特征。血管紧张素转换酶-2水平在可溶性内皮细胞特异性黏附分子之前达到峰值。血管紧张素-2水平与肿瘤坏死因子-α水平(r=0.61，P=0.003)、可溶性E-选择素水平(r=0.64，P<0.002)、心率/平均动脉压指数(r=0.75，P<0.0001)呈正相关。在败血症患者中，Ang-2仅在死亡患者中升高，并且在基线、24小时和72小时显著高于存活患者。脂蛋白是男性Ang-2释放的触发因素。在实验性人类内毒素血症期间，循环Ang-2以独特的时间顺序出现在体循环中，并与肿瘤坏死因子-α和E-选择素水平相关。此外，不仅基线Ang-2浓度较高，而且在早期病程中Ang-2持续升高也可识别预后不良的脓毒症患者。
Endothelial activation leading to vascular barrier breakdown denotes a devastating event in sepsis. Angiopoietin (Ang)-2, a circulating antagonistic ligand of the endothelial specific Tie2 receptor, is rapidly released from Weibel-Palade and has been identified as a non-redundant gatekeeper of endothelial activation. We aimed to study: the time course of Ang-2 release during human experimental endotoxemia; the association of Ang-2 with soluble adhesion molecules and inflammatory cytokines; and the early time course of Ang-2 release during sepsis in critically ill patients. In 22 healthy volunteers during a 24-hour period after a single intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) the following measurement were taken by immuno luminometric assay (ILMA), ELISA, and bead-based multiplex technology: circulating Ang-1, Ang-2, soluble Tie2 receptor, the inflammatory molecules TNF-alpha, IL-6, IL-8 and C-reactive protein, and the soluble endothelial adhesion molecules inter-cellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin. A single oral dose of placebo or the p38 mitogen activated protein (MAP) kinase inhibitor drug, RWJ-67657, was administered 30 minutes before the endotoxin infusion. In addition, the course of circulating Ang-2 was analyzed in 21 septic patients at intensive care unit (ICU) admission and after 24 and 72 hours, respectively. During endotoxemia, circulating Ang-2 levels were significantly elevated, reaching peak levels 4.5 hours after LPS infusion. Ang-2 exhibited a kinetic profile similar to early pro-inflammatory cytokines TNF-alpha, IL-6, and IL-8. Ang-2 levels peaked prior to soluble endothelial-specific adhesion molecules. Finally, Ang-2 correlated with TNF-alpha levels (r = 0.61, P = 0.003), soluble E-selectin levels (r = 0.64, P < 0.002), and the heart rate/mean arterial pressure index (r = 0.75, P < 0.0001). In septic patients, Ang-2 increased in non-survivors only, and was significantly higher compared with survivors at baseline, 24 hours, and 72 hours. LPS is a triggering factor for Ang-2 release in men. Circulating Ang-2 appears in the systemic circulation during experimental human endotoxemia in a distinctive temporal sequence and correlates with TNF-alpha and E-selectin levels. In addition, not only higher baseline Ang-2 concentrations, but also a persistent increase in Ang-2 during the early course identifies septic patients with unfavorable outcome.
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影响因子：
15.8
作者：
Parikh SM;Mammoto T;Schultz A;Yuan HT;Christiani D;Karumanchi SA;Sukhatme VP
通讯作者：
Sukhatme VP
影响因子：
8.8
作者：
Orfanos, Stylianos E.;Kotanidou, Anastasia;Roussos, Charis
通讯作者：
Roussos, Charis
DOI：
10.1124/jpet.105.086553
发表时间：
2005-08-01
影响因子：
3.5
作者：
Roviezzo, F;Tsigkos, S;Papapetropoulos, A
通讯作者：
Papapetropoulos, A
DOI：
10.1164/ajrccm.159.3.9805087
发表时间：
1999-03-01
影响因子：
24.7
作者：
Jilma, B;Blann, A;Wagner, OF
通讯作者：
Wagner, OF
影响因子：
4.6
作者：
Fijen, JW;Zijlstra, JG;Tulleken, JE
通讯作者：
Tulleken, JE