Schouten Marcel, de Boer J Daan, Kager Liesbeth M, Roelofs Joris J T H, Meijers Joost C M, Esmon Charles T, Levi Marcel, van 't Veer Cornelis, van der Poll Tom
Marcel Schouten, MD, Center for Experimental and Molecular Medicine (CEMM), Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room G2-130, 1105 AZ Amsterdam, The Netherlands, Tel.: +31 20 566 5910, Fax: +31 20 697 7192, E-mail:
Thromb Haemost. 2014 May 5;111(5):970-80. doi: 10.1160/TH13-10-0859. Epub 2014 Jan 9.
Pneumococcal pneumonia is a frequent cause of gram-positive sepsis and has a high mortality. The endothelial protein C receptor (EPCR) has been implicated in both the activation of protein C (PC) and the anti-inflammatory actions of activated (A)PC. The aim of this study was to determine the role of the EPCR in murine pneumococcal pneumonia and sepsis. Wild-type (WT), EPCR knockout (KO) and Tie2-EPCR mice, which overexpress EPCR on the endothelium, were infected intranasally (pneumonia) or intravenously (sepsis) with viable Streptococcus pneumoniae and euthanised at 24 or 48 hours after initiation of the infection for analyses. Pneumonia did not alter constitutive EPCR expression on pulmonary endothelium but was associated with an influx of EPCR positive neutrophils into lung tissue. In pneumococcal pneumonia EPCR KO mice demonstrated diminished bacterial growth in the lungs and dissemination to spleen and liver, reduced neutrophil recruitment to the lungs and a mitigated inflammatory response. Moreover, EPCR KO mice displayed enhanced activation of coagulation in the early phase of disease. Correspondingly, in pneumococcal sepsis EPCR KO mice showed reduced bacterial growth in lung and liver and attenuated cytokine release. Conversely, EPCR-overexpressing mice displayed higher bacterial outgrowth in lung, blood, spleen and liver in pneumococcal sepsis. In conclusion, EPCR impairs antibacterial defense in both pneumococcal pneumonia and sepsis, which is associated with an enhanced pro-inflammatory response.
肺炎球菌肺炎是革兰氏阳性菌败血症的常见病因，死亡率很高。内皮蛋白C受体（EPCR）与蛋白C（PC）的激活以及活化蛋白C（APC）的抗炎作用均有关联。本研究的目的是确定EPCR在小鼠肺炎球菌肺炎和败血症中的作用。野生型（WT）、EPCR基因敲除（KO）小鼠以及在内皮细胞上过表达EPCR的Tie2-EPCR小鼠，通过鼻内（肺炎）或静脉内（败血症）感染活的肺炎链球菌，并在感染开始后24或48小时实施安乐死以进行分析。肺炎并未改变肺内皮细胞上EPCR的组成性表达，但与EPCR阳性中性粒细胞流入肺组织有关。在肺炎球菌肺炎中，EPCR基因敲除小鼠肺部细菌生长减少，向脾脏和肝脏的扩散减少，肺内中性粒细胞募集减少，炎症反应减轻。此外，EPCR基因敲除小鼠在疾病早期凝血激活增强。相应地，在肺炎球菌败血症中，EPCR基因敲除小鼠肺和肝脏中的细菌生长减少，细胞因子释放减弱。相反，在肺炎球菌败血症中，过表达EPCR的小鼠在肺、血液、脾脏和肝脏中的细菌生长更高。总之，EPCR在肺炎球菌肺炎和败血症中均损害抗菌防御，这与促炎反应增强有关。
