Recombinant human activated protein C inhibits local and systemic activation of coagulation without influencing inflammation during Pseudomonas aeruginosa pneumonia in rats

Goda Choi, Jorrit-Jan H Hofstra, Joris J T H Roelofs, Sandrine Florquin, Paul Bresser, Marcel Levi, Tom van der Poll, Marcus J Schultz

    OnderzoeksoutputAcademicpeer review

    44 Citaten (Scopus)

    Samenvatting

    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.

    Originele taal-2English
    Pagina's (van-tot)1362-1368
    Aantal pagina's7
    TijdschriftCritical Care Medicine
    Volume35
    Nummer van het tijdschrift5
    DOI's
    StatusPublished - mei-2007

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