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

Marcel Schouten; Cornelis van ’t Veer; Joris J. T. H. Roelofs; Bruce Gerlitz; Brian W. Grinnell; Marcel Levi; Tom van der Poll

doi:10.1160/TH11-06-0438

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 106(06): 1189-1196
DOI: 10.1160/TH11-06-0438

Animal Models

Schattauer GmbH

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

Authors

Marcel Schouten

¹Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, The Netherlands

²Center for Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Amsterdam, The Netherlands
Cornelis van ’t Veer

¹Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, The Netherlands

²Center for Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Amsterdam, The Netherlands
Joris J. T. H. Roelofs

³Department of Pathology; Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Bruce Gerlitz

⁴Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USA
Brian W. Grinnell

⁴Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USA
Marcel Levi

⁵Department of Internal Medicine; Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Tom van der Poll

¹Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, The Netherlands

²Center for Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, Amsterdam, The Netherlands

⁴Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USA

Abstract

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 throm-bin-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.

Keywords

Protein C/S pathway - infectious diseases - bacteria - sepsis - animal models

Full Text

References

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