Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
PLoS Negl Trop Dis. 2013 Jul 11;7(7):e2306. doi: 10.1371/journal.pntd.0002306. Print 2013.
The endothelial protein C receptor (EPCR) enhances anticoagulation by accelerating activation of protein C to activated protein C (APC) and mediates anti-inflammatory effects by facilitating APC-mediated signaling via protease activated receptor-1. We studied the role of EPCR in the host response during pneumonia-derived sepsis instigated by Burkholderia (B.) pseudomallei, the causative agent of melioidosis, a common form of community-acquired Gram-negative (pneumo)sepsis in South-East Asia.
METHODOLOGY/PRINCIPAL FINDINGS: Soluble EPCR was measured in plasma of patients with septic culture-proven melioidosis and healthy controls. Experimental melioidosis was induced by intranasal inoculation of B. pseudomallei in wild-type (WT) mice and mice with either EPCR-overexpression (Tie2-EPCR) or EPCR-deficiency (EPCR(-/-)). Mice were sacrificed after 24, 48 or 72 hours. Organs and plasma were harvested to measure colony forming units, cellular influxes, cytokine levels and coagulation parameters. Plasma EPCR-levels were higher in melioidosis patients than in healthy controls and associated with an increased mortality. Tie2-EPCR mice demonstrated enhanced bacterial growth and dissemination to distant organs during experimental melioidosis, accompanied by increased lung damage, neutrophil influx and cytokine production, and attenuated coagulation activation. EPCR(-/-) mice had an unremarkable response to B. pseudomallei infection as compared to WT mice, except for a difference in coagulation activation in plasma.
CONCLUSION/SIGNIFICANCE: Increased EPCR-levels correlate with accelerated mortality in patients with melioidosis. In mice, transgenic overexpression of EPCR aggravates outcome during Gram-negative pneumonia-derived sepsis caused by B. pseudomallei, while endogenous EPCR does not impact on the host response. These results add to a better understanding of the regulation of coagulation during severe (pneumo)sepsis.
内皮蛋白 C 受体（EPCR）通过加速蛋白 C 向活化蛋白 C（APC）的激活来增强抗凝作用，并通过促进 APC 介导的蛋白酶激活受体-1 信号转导来发挥抗炎作用。我们研究了 EPCR 在伯克霍尔德菌（B.）假单胞菌引发的肺炎相关性脓毒症宿主反应中的作用，B.假单胞菌是类鼻疽的病原体，也是东南亚常见的社区获得性革兰氏阴性（肺炎）脓毒症的一种形式。
方法/主要发现：检测了脓毒症培养阳性类鼻疽患者和健康对照者的血浆可溶性 EPCR 水平。通过鼻内接种 B.假单胞菌在野生型（WT）小鼠和 EPCR 过表达（Tie2-EPCR）或 EPCR 缺陷（EPCR(-/-)）小鼠中诱导实验性类鼻疽。在 24、48 或 72 小时后处死小鼠。采集器官和血浆以测量菌落形成单位、细胞浸润、细胞因子水平和凝血参数。类鼻疽患者的血浆 EPCR 水平高于健康对照者，且与死亡率增加相关。Tie2-EPCR 小鼠在实验性类鼻疽中表现出细菌生长和向远处器官扩散的增强，伴有肺损伤、中性粒细胞浸润和细胞因子产生的增加以及凝血激活的减弱。与 WT 小鼠相比，EPCR(-/-) 小鼠对 B.假单胞菌感染的反应无明显差异，除了血浆凝血激活的差异。
结论/意义：EPCR 水平升高与类鼻疽患者死亡率的加快相关。在小鼠中，EPCR 的转基因过表达加剧了由 B.假单胞菌引起的革兰氏阴性肺炎相关性脓毒症的结局，而内源性 EPCR 对宿主反应没有影响。这些结果有助于更好地了解严重（肺炎）脓毒症期间凝血的调节。
