TY - JOUR
T1 - Recombinant human activated protein C inhibits local and systemic activation of coagulation without influencing inflammation during Pseudomonas aeruginosa pneumonia in rats
AU - Choi, Goda
AU - Hofstra, Jorrit-Jan H.
AU - Roelofs, Joris J. T. H.
AU - Florquin, Sandrine
AU - Bresser, Paul
AU - Levi, Marcel
AU - van der Poll, Tom
AU - Schultz, Marcus J.
PY - 2007
Y1 - 2007
N2 - OBJECTIVE: Alveolar fibrin deposition is a hallmark of pneumonia. It has been proposed that recombinant human activated protein C exerts lung-protective effects via anticoagulant and anti-inflammatory pathways. We investigated the role of the protein C system in pneumonia caused by Pseudomonas aeruginosa, the organism that is predominantly involved in ventilator-associated pneumonia. DESIGN: An observational clinical study and a controlled, in vivo laboratory study. SETTING: Multidisciplinary intensive care unit and a research laboratory of a university hospital. PATIENTS AND SUBJECTS: Patients with unilateral ventilator-associated pneumonia and male Sprague-Dawley rats. INTERVENTIONS: Bilateral bronchoalveolar lavage was performed in five patients with unilateral ventilator-associated pneumonia. A total of 62 rats were challenged with intratracheal P. aeruginosa (10 colony-forming units), inducing pneumonia. Rats were randomized to treatment with normal saline, recombinant human activated protein C, heparin, or recombinant tissue plasminogen activator. MEASUREMENTS AND MAIN RESULTS: Patients with pneumonia demonstrated suppressed levels of protein C and activated protein C in bronchoalveolar lavage fluid obtained from the infected site compared with the contralateral uninfected site. Intravenous administration of recombinant human activated protein C in rats with P. aeruginosa pneumonia limited bronchoalveolar generation of thrombin-antithrombin complexes, largely preserving local antithrombin activity. However, recombinant human activated protein C did not have effects on neutrophil influx and activity, expression of pulmonary cytokines, or bacterial clearance. CONCLUSIONS: In patients with ventilator-associated pneumonia, the pulmonary protein C pathway is impaired at the site of infection, and local anticoagulant activity may be insufficient. Recombinant human activated protein C prevents procoagulant changes in the lung; however, it does not seem to alter the pulmonary host defense against P. aeruginosa pneumonia
AB - OBJECTIVE: Alveolar fibrin deposition is a hallmark of pneumonia. It has been proposed that recombinant human activated protein C exerts lung-protective effects via anticoagulant and anti-inflammatory pathways. We investigated the role of the protein C system in pneumonia caused by Pseudomonas aeruginosa, the organism that is predominantly involved in ventilator-associated pneumonia. DESIGN: An observational clinical study and a controlled, in vivo laboratory study. SETTING: Multidisciplinary intensive care unit and a research laboratory of a university hospital. PATIENTS AND SUBJECTS: Patients with unilateral ventilator-associated pneumonia and male Sprague-Dawley rats. INTERVENTIONS: Bilateral bronchoalveolar lavage was performed in five patients with unilateral ventilator-associated pneumonia. A total of 62 rats were challenged with intratracheal P. aeruginosa (10 colony-forming units), inducing pneumonia. Rats were randomized to treatment with normal saline, recombinant human activated protein C, heparin, or recombinant tissue plasminogen activator. MEASUREMENTS AND MAIN RESULTS: Patients with pneumonia demonstrated suppressed levels of protein C and activated protein C in bronchoalveolar lavage fluid obtained from the infected site compared with the contralateral uninfected site. Intravenous administration of recombinant human activated protein C in rats with P. aeruginosa pneumonia limited bronchoalveolar generation of thrombin-antithrombin complexes, largely preserving local antithrombin activity. However, recombinant human activated protein C did not have effects on neutrophil influx and activity, expression of pulmonary cytokines, or bacterial clearance. CONCLUSIONS: In patients with ventilator-associated pneumonia, the pulmonary protein C pathway is impaired at the site of infection, and local anticoagulant activity may be insufficient. Recombinant human activated protein C prevents procoagulant changes in the lung; however, it does not seem to alter the pulmonary host defense against P. aeruginosa pneumonia
U2 - https://doi.org/10.1097/01.CCM.0000261888.32654.6D
DO - https://doi.org/10.1097/01.CCM.0000261888.32654.6D
M3 - Article
C2 - 17414732
SN - 0090-3493
VL - 35
SP - 1362
EP - 1368
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 5
ER -