Overexpression of activated protein C hampers bacterial dissemination during pneumococcal pneumonia.

Johannes Daan De Boer,Joost Cm Meijers,Liesbeth M Kager,Tom Van Der Poll,Cornelis Van ’T Veer,Berend Isermann,Hartmut Weiler,Joris Jth Roelofs,Onno J De Boer

doi:10.1186/s12879-014-0559-3

Abstract

BackgroundDuring pneumonia, inflammation and coagulation are activated as part of anti-bacterial host defense. Activated protein C (APC) has anticoagulant and anti-inflammatory properties and until recently was a registered drug for the treatment of severe sepsis. Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia.MethodsWe aimed to investigate the effect of high APC levels during experimental pneumococcal pneumonia. Wild type (WT) and APC overexpressing (APChigh)-mice were intranasally infected with S. pneumoniae and sacrificed after 6, 24 or 48 hours, or followed in a survival study.ResultsIn comparison to WT mice, APChigh-mice showed decreased bacterial dissemination to liver and spleen, while no differences in bacterial loads were detected at the primary site of infection. Although no differences in the extent of lung histopathology were seen, APChigh-mice showed a significantly decreased recruitment of neutrophils into lung tissue and bronchoalveolar lavage fluid. Activation of coagulation was not altered in APChigh-mice. No differences in survival were observed between WT and APChigh-mice (P =0.06).ConclusionAPC overexpression improves host defense during experimental pneumococcal pneumonia. This knowledge may add to a better understanding of the regulation of the inflammatory and procoagulant responses during severe Gram-positive pneumonia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-014-0559-3) contains supplementary material, which is available to authorized users.

Highlights

During pneumonia, inflammation and coagulation are activated as part of anti-bacterial host defense
To investigate whether overexpression of Activated protein C (APC) would impact on bacterial growth, we infected Wild type (WT) and APChigh-mice with 5*104 colony forming units (CFU) of S. pneumoniae and sacrificed them after 6, 24 or 48 hours to determine bacterial loads in lungs, blood, liver and spleen homogenates (Figure 1)
Relative to WT mice, APChigh-mice showed markedly decreased bacterial loads 24 and 48 hours after infection in both liver (Figure 1C; P

Summary

Introduction

Inflammation and coagulation are activated as part of anti-bacterial host defense. In the PROWESS study treatment of severe sepsis patients with intravenous recombinant human APC (rhAPC) reduced mortality [13] and patients with sepsis caused by S. pneumoniae pneumonia were among those with the largest benefit from rhAPC treatment [14,15]. Despite these positive results, post-marketing studies failed to show similar protective effects of APC [16] and a recently completed confirmatory trial in septic shock patients did not show any benefit from APC treatment [17], leading to the withdrawal of this compound from the market [18]

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