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

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.