Recombinant human tissue factor pathway inhibitor exerts anticoagulant, anti-inflammatory and antibacterial effects in murine pneumococcal pneumonia
© BioMed Central Ltd 2009
Published: 11 November 2009
Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia and a major cause of sepsis. Pneumonia elicits a procoagulant state in the lung resulting from activation of coagulation, downregulation of anticoagulant pathways and concurrent inhibition of fibrinolysis. Tissue factor is the main initiator of coagulation. 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.
To examine the effect of rh-TFPI on coagulation, inflammation and bacterial outgrowth in S. pneumoniae pneumonia in mice, either alone or with concurrent antibiotic treatment.
Pneumonia was induced by intranasal inoculation with S. pneumoniae. Four groups of mice (n = 8) were treated intra-peritoneally with (1) placebo, (2) rh-TFPI every 8 hours, (3) ceftriaxone twice daily or (4) rh-TFPI in combination with ceftriaxone. Early (8 hours) and late (24 hours) initiated treatments were evaluated. Bronchoalveolar lavage fluid (BALF), lungs and plasma were obtained 24 hours (for groups in which treatment was started after 8 hours) or 48 hours (treatment started after 24 hours) after infection. Statistical analysis was performed by Mann-Whitney U test.
Pneumonia resulted in local and systemic activation of coagulation (as reflected by increased thrombin-antithrombin complexes) and inhibition of fibrinolysis (as reflected by increased plasminogen activator inhibitor-1 and decreased plasminogen activator activity). Both early and late treatment with rh-TFPI reduced pneumonia-induced coagulation in lungs and plasma; rh-TFPI given with ceftriaxone further attenuated coagulation relative to ceftriaxone only. No effects of rh-TFPI on pneumonia-inhibited fibrinolysis were observed. Cell recruitment in BALF did not differ between groups. Remarkably, rh-TFPI reduced levels of several cytokines and chemokines not only in lung homogenates, but also in BALF (IL-6, IFNγ, MCP-1, LIX) and plasma (IL-6, TNFα, IFNγ). The attenuated host inflammatory response was not reflected by differences in total histopathology scores between treatment groups. In mice not treated with ceftriaxone, rh-TFPI decreased bacterial loads in lung homogenates ~10-fold (P < 0.01 vs. placebo) at 48 hours, while leaving bacterial loads in BALF and the systemic compartment unaltered.
rh-TFPI attenuates local and systemic coagulopathy, the local and systemic inflammatory response and pulmonary bacterial growth during S. pneumoniae pneumonia in mice.