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


METHODS
An observational clinical study and a controlled, in vivo laboratory study.


METHODS
Multidisciplinary intensive care unit and a research laboratory of a university hospital.


METHODS
Patients with unilateral ventilator-associated pneumonia and male Sprague-Dawley rats.


METHODS
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.


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.
Choi
Goda
G
Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. godachoi@mail.com
Hofstra
Jorrit-Jan H
JJ
Roelofs
Joris J T H
JJ
Florquin
Sandrine
S
Bresser
Paul
P
Levi
Marcel
M
van der Poll
Tom
T
Schultz
Marcus J
MJ
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage*; D000991:Antithrombins / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy / Q000378:metabolism*; D011486:Protein C / Q000008:administration & dosage* / Q000378:metabolism; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage; D000077785:Tenecteplase; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage
D000890:Anti-Infective Agents; D000991:Antithrombins; D005343:Fibrinolytic Agents; D011486:Protein C; D011994:Recombinant Proteins; D018180:Thrombomodulin; D006493:Heparin; D013917:Thrombin; D010959:Tissue Plasminogen Activator; C421124:drotrecogin alfa activated; D000077785:Tenecteplase