Inhibition of Pulmonary Coagulopathy by Nebulized Natural Anticoagulants during Streptococcus Pneumoniae Pneumonia in Rats

Abstract

RATIONALE: Alveolar fibrin deposition is intrinsic to pneumonia and acute lung injury. Activation of coagulation during pulmonary inflammation is primarily mediated by the tissue factor–factor VIIa pathway. Tissue factor levels in the lungs increase during pulmonary inflammation due to disruption of endothelial–epithelial barrier and expression of tissue factor on alveolar macrophages. Intravenous infusion of the natural anticoagulants activated protein C (APC) or antithrombin (AT) has been shown to have lung–protective effects in critically ill patients, but increases the risk of severe bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized tissue factor pathway inhibitor (TFPI), APC or AT on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia.DESIGN: Randomized controlled in vivo study in a rat model of S. pneumoniae pneumonia. Twenty–eight male Sprague–Dawley rats were challenged intratracheally with S. pneumoniae (serotype 3, 106 colony forming units), inducing pneumonia. Rats were randomized to nebulization with TFPI, APC, AT or normal saline.RESULTS: Rats infected with S. pneumoniae had increased pulmonary and systemic levels of thrombin–antithrombin complexes (TATc) and fibrin degradation products (FDP), indicating increased coagulation. Simultaneously, pulmonary plasminogen activator inhibitor 1 (PAI–1) activity was increased and plasminogen activator activity (PAA) was reduced, indicating inhibition of endogenous fibrinolysis. Treatment with any nebulized natural anticoagulant significantly attenuated the rise in bronchoalveolar TATc (3.5 ± 0.9 ng/mL (TFPI), 3.6 ± 0.6 ng/mL (APC) and 4.6 ± 0.6 ng/mL (AT) versus 9.1 ± 0.75 ng/mL in saline treated rats, P<.01) and FDP (290 ± 92 ng/mL (TFPI), 310 ± 90 ng/mL (APC) and 158 ± 44 ng/mL (AT) versus 559 ± 116 ng/mL in saline treated rats, P<.01). TFPI and APC also significantly reduced systemic TATc levels while AT did not have any effect on systemic coagulopathy (17 ng/mL ± 3.4 (TFPI) and 13.8 ± 2.3 ng/mL (APC) versus 19.7 ± 1.6 ng/mL in saline treated rats, P<.05 and P<.01 respectively). While TFPI and APC did not affect host defense to S. pneumoniae, treatment with AT resulted in a reduction of bacterial outgrowth from the lungs, a reduction of neutrophil influx into the pulmonary compartment and less histopathologic lung injury.CONCLUSIONS: Nebulization of natural anticoagulants attenuates pulmonary coagulopathy during S. pneumoniae pneumonia. While APC and TFPI leaves local inflammation and host defense unaltered, AT exerts significant lung–protective effects in pneumococcal pneumonia in rats.