Recombinant human tissue factor pathway inhibitor exerts anticoagulant, anti‐inflammatory and antimicrobial effects in murine pneumococcal pneumonia

See also Maroney SA, Mast AE. Tissue factor pathway inhibitor and bacterial infection. This issue, pp 119–21. Summary.  Background: Streptococcus (S.) pneumoniae is the most common causative pathogen in community‐acquired pneumonia and a major cause of sepsis. Recombinant human tissue factor pathway...

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Published in:Journal of thrombosis and haemostasis Vol. 9; no. 1; pp. 122 - 132
Main Authors: VAN DEN BOOGAARD, F. E., BRANDS, X., SCHULTZ, M. J., LEVI, M., ROELOFS, J. J. T. H., VAN 'T VEER, C., VAN DER POLL, T.
Format: Journal Article
Language:English
Published: Oxford, UK Blackwell Publishing Ltd 01.01.2011
Subjects:
Animals
Anti-Infective Agents - administration & dosage
Anti-Infective Agents - pharmacokinetics
Anti-Infective Agents - pharmacology
Anti-Inflammatory Agents - administration & dosage
Anti-Inflammatory Agents - pharmacokinetics
Anti-Inflammatory Agents - pharmacology
Antibiotics
Anticoagulants
Anticoagulants - administration & dosage
Anticoagulants - pharmacokinetics
Anticoagulants - pharmacology
Antimicrobial agents
Blood Coagulation - drug effects
Ceftriaxone
Ceftriaxone - pharmacology
Chemokines
Clinical trials
Coagulation
Cytokines
Disease Models, Animal
Drug Therapy, Combination
Female
Humans
Infection
Inflammation
Inflammation Mediators - metabolism
Injections, Intraperitoneal
Inoculation
Leukocytes (neutrophilic)
Lipoproteins - administration & dosage
Lipoproteins - pharmacokinetics
Lipoproteins - pharmacology
Lung
Mice
Mice, Inbred C57BL
Pathogens
Pneumonia
Pneumonia, Pneumococcal - blood
Pneumonia, Pneumococcal - drug therapy
Pneumonia, Pneumococcal - immunology
Pneumonia, Pneumococcal - microbiology
Recombinant Proteins - pharmacology
Sepsis
Streptococcus pneumoniae
Streptococcus pneumoniae - drug effects
Streptococcus pneumoniae - growth & development
Thrombosis
Time Factors
Tissue factor
tissue factor pathway inhibitor
ISSN:1538-7933, 1538-7836, 1538-7836
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Summary:See also Maroney SA, Mast AE. Tissue factor pathway inhibitor and bacterial infection. This issue, pp 119–21. Summary.  Background: Streptococcus (S.) pneumoniae is the most common causative pathogen in community‐acquired pneumonia and a major cause of sepsis. Recombinant human tissue factor pathway inhibitor (rh‐TFPI) attenuates sepsis‐induced coagulation and has been evaluated in clinical trials involving patients with sepsis and community‐acquired pneumonia. Objective: To examine the effect of rh‐TFPI on coagulation, inflammation and bacterial outgrowth in S. pneumoniae pneumonia in mice, with or without concurrent antibiotic treatment. Methods: Pneumonia was induced by intranasal inoculation with S. pneumoniae. Mice were treated with placebo, rh‐TFPI, ceftriaxone or rh‐TFPI combined with ceftriaxone. Early (8 h) and late (24 h) initiated treatments were evaluated. Samples were obtained 24 or 48 h after infection, for early and late initiated treatment, respectively. In vitro, placebo or rh‐TFPI was added to a suspension of S. pneumoniae. Results: Rh‐TFPI reduced pneumonia‐induced coagulation; rh‐TFPI with ceftriaxone further attenuated coagulation relative to ceftriaxone alone. Rh‐TFPI inhibited accumulation of neutrophils in lung tissue and reduced the levels of several cytokines and chemokines in lungs and plasma in mice not treated with antibiotics; in these animals, rh‐TFPI initiated 24 h after infection decreased pulmonary bacterial loads. In vitro, rh‐TFPI also inhibited growth of S. pneumoniae. Conclusions: Therapeutic rh‐TFPI attenuates coagulation, inflammation and bacterial growth during pneumococcal pneumonia, whereby the latter two effects only become apparent in the absence of concurrent antibiotic treatment.
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ISSN:1538-7933
1538-7836
1538-7836
DOI:10.1111/j.1538-7836.2010.04089.x