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

Florry E. van den Boogaard; Cornelis van ’t Veer; Joris J. T. H. Roelofs; Joost C. M. Meijers; Marcus J. Schultz; George Broze Jr; Tom van der Poll

doi:10.1160/TH14-12-1053

Thrombosis and Haemostasis, Table of Contents

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

Authors

Florry E. van den Boogaard

¹Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

²Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

³Laboratory of Experimental Intensive Care and Anaesthesiology (LEICA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Cornelis van ’t Veer

¹Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

²Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Joris J. T. H. Roelofs

⁴Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Joost C. M. Meijers

⁵Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Marcus J. Schultz

³Laboratory of Experimental Intensive Care and Anaesthesiology (LEICA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

⁶Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
George Broze Jr

⁷Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Tom van der Poll

¹Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

²Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

⁸Division of Haematology, Washington University School of Medicine, St. Louis, Missouri, USA

Abstract

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

Full Text

References

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