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.
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.
Authors: Antonio Artigas; Marta Camprubí-Rimblas; Neus Tantinyà; Josep Bringué; Raquel Guillamat-Prats; Michael A Matthay Journal: Ann Transl Med Date: 2017-07
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Authors: Akanksha Gupta; Bruce Gerlitz; Mark A Richardson; Christopher Bull; David T Berg; Samreen Syed; Elizabeth J Galbreath; Barbara A Swanson; Bryan E Jones; Brian W Grinnell Journal: J Am Soc Nephrol Date: 2008-12-17 Impact factor: 10.121
Authors: Jorrit J Hofstra; Alexander D Cornet; Paul J Declerck; Barry Dixon; Hamid Aslami; Alexander P J Vlaar; Joris J Roelofs; Tom van der Poll; Marcel Levi; Marcus J Schultz Journal: PLoS One Date: 2013-02-07 Impact factor: 3.240