title: Endogenous tissue factor pathway inhibitor has a limited effect on host defence in murine pneumococcal pneumonia.
abstract: 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.
authors.affiliation: Floor van den Boogaard, MD, Academic Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine, G2-130, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands, Tel: +31 20 566 5910, Fax: +31 20 566 7192, E-mail: f.e.vandenboogaard@amc.uva.nl.
authors.forename: Florry E
authors.initials: FE
authors.lastname: van den Boogaard
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.forename: George J
authors.initials: GJ
authors.lastname: Broze
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D058491:Bacterial Load; D001777:Blood Coagulation; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005838:Genotype; D054884:Host-Pathogen Interactions; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008074:Lipoproteins / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011018:Pneumonia, Pneumococcal / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D013997:Time Factors
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor
keywords: Coagulation inhibitors; Streptococcus pneumoniae; bacterial infection; inflammation; lung
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