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Thromb Haemost 2014; 111(05): 970-980
DOI: 10.1160/TH13-10-0859
Animal Models
Schattauer GmbH

The endothelial protein C receptor impairs the antibacterial response in murine pneumococcal pneumonia and sepsis

Marcel Schouten
1   Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
J. Daan de Boer
1   Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Liesbeth M. Kager
1   Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3   Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Joris J. T. H. Roelofs
4   Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Joost C. M. Meijers
5   Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Charles T. Esmon
6   Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
,
Marcel Levi
3   Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Cornelis van ’t Veer
1   Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Tom van der Poll
1   Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3   Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
› Author Affiliations Financial support: Marcel Schouten is supported by a research grant of the Dutch Thrombosis Foundation [grant number TSN 2005–1]. J. Daan de Boer is supported by a research grant of the Netherlands Asthma Foundation (project 3.2.08.009). L.M. Kager is supported by research grants of ZonMW (grant number 92003504), the Stichting BeGeTu and the Mr. Willem Bakhuys Roozeboom Stichting.
Further Information

Publication History

Received: 19 October 2013

Accepted after minor revision: 10 January 2013

Publication Date:
01 December 2017 (online)

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Summary

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.

Keywords

Coagulation - endothelial protein C receptor - pneumonia - sepsis - Streptococcus pneumoniae

 

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