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Thromb Haemost 2015; 114(01): 115-122
DOI: 10.1160/TH14-12-1053
Blood Cells, Inflammation and Infection
Schattauer GmbH

Endogenous tissue factor pathway inhibitor has a limited effect on host defence in murine pneumococcal pneumonia

Florry E. van den Boogaard
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   Laboratory of Experimental Intensive Care and Anaesthesiology (LEICA), 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
,
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
,
Marcus J. Schultz
3   Laboratory of Experimental Intensive Care and Anaesthesiology (LEICA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
6   Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
George Broze Jr
7   Division of Infectious Diseases, 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
8   Division of Haematology, Washington University School of Medicine, St. Louis, Missouri, USA
› Author Affiliations
Further Information

Publication History

Received: 17 December 2014

Accepted after major revision: 22 April 2015

Publication Date:
22 November 2017 (online)

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Summary

Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Coagulation and inflammation interact in the host response to infection. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant protein that inhibits tissue factor (TF), the main activator of inflammation-induced coagulation. It was the objective of this study to investigate the effect of endogenous TFPI levels on coagulation, inflammation and bacterial growth during S. pneumoniae pneumonia in mice. The effect of low endogenous TFPI levels was studied by administration of a neutralising anti-TFPI antibody to wild-type mice, and by using genetically modified mice expressing low levels of TFPI, due to a genetic deletion of the first Kunitz domain of TFPI (TFPIK1(-/-)) rescued with a human TFPI transgene. Pneumonia was induced by intranasal inoculation with S. pneumoniae and samples were obtained at 6, 24 and 48 hours after infection. Anti-TFPI reduced TFPI activity by ~50 %. Homozygous lowTFPI mice and heterozygous controls had ~10 % and ~50 % of normal TFPI activity, respectively. TFPI levels did not influence bacterial growth or dissemination. Whereas lung pathology was unaffected in all groups, mice with ~10 % (but not with ~50 %) of TFPI levels displayed elevated lung cytokine and chemokine concentrations 24 hours after infection. None of the groups with low TFPI levels showed an altered procoagulant response in lungs or plasma during pneumonia. These data argue against an important role for endogenous TFPI in the antibacterial, inflammatory and procoagulant response during pneumococcal pneumonia.

Keywords

Coagulation inhibitors - inflammation - lung - bacterial infection - Streptococcus pneumoniae

 

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