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Published on: February 23, 2014
Endogenous tissue factor pathway inhibitor has a limited effect on host defence in murine pneumococcal pneumonia
Florry E van den Boogaard1, Cornelis van 't Veer, Joris J T H Roelofs
1Floor 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,
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.
Insights
Lowering tissue factor pathway inhibitor (TFPI) levels in mice with Streptococcus pneumoniae pneumonia did not affect bacterial growth or coagulation. However, significantly reduced TFPI levels increased lung inflammation.
Area of Science:
- Infectious Diseases
- Hematology
- Immunology
Background:
- Streptococcus pneumoniae is a leading cause of community-acquired pneumonia.
- Coagulation and inflammation are key components of the host response to infection.
- Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant that regulates the tissue factor (TF)-initiated coagulation cascade.
Purpose of the Study:
- To investigate the impact of endogenous TFPI levels on coagulation, inflammation, and bacterial growth during S. pneumoniae pneumonia in a mouse model.
- To assess the role of TFPI in the host's response to pneumococcal infection.
Main Methods:
- Pneumonia was induced in mice via intranasal inoculation with S. pneumoniae.
- Reduced endogenous TFPI levels were achieved using a neutralizing anti-TFPI antibody in wild-type mice and genetically modified mice (TFPIK1(-/-)) expressing low TFPI levels.
- Samples were collected at 6, 24, and 48 hours post-infection for analysis.
Main Results:
- TFPI levels did not influence bacterial growth or dissemination.
- Lung pathology remained unaffected across all experimental groups.
- Mice with approximately 10% of normal TFPI levels exhibited elevated lung cytokine and chemokine concentrations at 24 hours post-infection, unlike those with 50% TFPI levels.
- No altered procoagulant response was observed in the lungs or plasma of mice with low TFPI levels.
Conclusions:
- Endogenous TFPI does not appear to play a significant role in the antibacterial or procoagulant response during pneumococcal pneumonia.
- Significantly reduced TFPI levels may contribute to increased lung inflammation in response to S. pneumoniae infection.
