Recombinant activated protein C attenuates coagulopathy and inflammation when administered early in murine pneumococcal pneumonia

Recombinant human activated protein C (APC), which has both anticoagulant and anti-inflammatory properties, improves survival of patients with severe sepsis. This beneficial effect is especially apparent in patients with pneumococcal pneumonia. Earlier treatment with APC in sepsis has been associate...

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Published in:Thrombosis and haemostasis Vol. 106; no. 6; p. 1189
Main Authors: Schouten, Marcel, van 't Veer, Cornelis, Roelofs, Joris J T H, Gerlitz, Bruce, Grinnell, Brian W, Levi, Marcel, van der Poll, Tom
Format: Journal Article
Language:English
Published: Germany 01.12.2011
Subjects:
Animals
Anti-Inflammatory Agents - administration & dosage
Antithrombin III - metabolism
Biomarkers - metabolism
Blood Coagulation - drug effects
Cytokines - metabolism
Disease Models, Animal
Down-Regulation
Fibrin Fibrinogen Degradation Products - metabolism
Humans
Lung - drug effects
Lung - metabolism
Lung - pathology
Male
Mice
Mice, Inbred C57BL
Peptide Hydrolases - metabolism
Pneumonia, Pneumococcal - blood
Pneumonia, Pneumococcal - immunology
Protein C - administration & dosage
Recombinant Proteins - administration & dosage
Streptococcus pneumoniae - growth & development
Streptococcus pneumoniae - immunology
Streptococcus pneumoniae - pathogenicity
ISSN:0340-6245, 2567-689X, 2567-689X
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Summary:Recombinant human activated protein C (APC), which has both anticoagulant and anti-inflammatory properties, improves survival of patients with severe sepsis. This beneficial effect is especially apparent in patients with pneumococcal pneumonia. Earlier treatment with APC in sepsis has been associated with a better therapeutic response as compared to later treatment. In a mouse model it was recently confirmed that recombinant murine (rm-)APC decreases coagulation activation and improves survival in pneumococcal pneumonia; however, APC did not impact on the inflammatory response. The aim of this study was to determine the effect of APC treatment instigated early in infection on activation of coagulation and inflammation after induction of pneumococcal pneumonia. Mice were infected intranasally with viable S. pneumoniae . Mice were treated with rm-APC (125 μg) or vehicle intraperitoneally 12 hours after infection and were sacrificed after 20 hours, after which blood and organs were harvested for determination of bacterial outgrowth, coagulation activation and inflammatory markers. In this early treatment model, rm-APC treatment inhibited pulmonary and systemic activation of coagulation as reflected by lower levels of thrombin-antithrombin complexes and D-dimer. Moreover, rm-APC reduced the levels of a large number of cytokines and chemokines in the lung. When administered early in pneumococcal pneumonia, rm-APC inhibits systemic and pulmonary activation of coagulation and moreover exerts various anti-inflammatory effects in the lung.
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ISSN:0340-6245
2567-689X
2567-689X
DOI:10.1160/TH11-06-0438