Publication

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

Choi, G., Hofstra, J-J. H., Roelofs, J. J. T. H., Florquin, S., Bresser, P., Levi, M., van der Poll, T. & Schultz, M. J., May-2007, In : Critical Care Medicine. 35, 5, p. 1362-1368 7 p.

Research output: Contribution to journalArticleAcademicpeer-review

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

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.

Original languageEnglish
Pages (from-to)1362-1368
Number of pages7
JournalCritical Care Medicine
Volume35
Issue number5
Publication statusPublished - May-2007

    Keywords

  • Animals, Anti-Infective Agents, Antithrombins, Blood Coagulation, Bronchoalveolar Lavage Fluid, Fibrinolytic Agents, Heparin, Humans, Inflammation, Male, Neutrophils, Pneumonia, Ventilator-Associated, Protein C, Pseudomonas Infections, Random Allocation, Rats, Rats, Sprague-Dawley, Recombinant Proteins, Thrombin, Thrombomodulin, Tissue Plasminogen Activator

ID: 29061472