title: Overexpression of activated protein C hampers bacterial dissemination during pneumococcal pneumonia.
abstract: BACKGROUND
  During 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.
  
  
  METHODS
  We aimed to investigate the effect of high APC levels during experimental pneumococcal pneumonia. Wild type (WT) and APC overexpressing (APC(high))-mice were intranasally infected with S. pneumoniae and sacrificed after 6, 24 or 48 hours, or followed in a survival study.
  
  
  RESULTS
  In comparison to WT mice, APC(high)-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, APC(high)-mice showed a significantly decreased recruitment of neutrophils into lung tissue and bronchoalveolar lavage fluid. Activation of coagulation was not altered in APC(high)-mice. No differences in survival were observed between WT and APC(high)-mice (P =0.06).
  
  
  CONCLUSIONS
  APC 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.
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands. j.d.deboer@amc.uva.nl.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands. j.d.deboer@amc.uva.nl.
authors.forename: Johannes Daan
authors.initials: JD
authors.lastname: de Boer
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands. l.m.kager@amc.uva.nl.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands. l.m.kager@amc.uva.nl.|Center for Experimental and Molecular Medicine (CEMM), Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room G2-130, 1105 AZ, Amsterdam, The Netherlands. l.m.kager@amc.uva.nl.
authors.forename: Liesbeth M
authors.initials: LM
authors.lastname: Kager
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. j.j.roelofs@amc.uva.nl.
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. j.c.meijers@amc.uva.nl.|Department Plasma Proteins, Sanquin, Amsterdam, The Netherlands. j.c.meijers@amc.uva.nl.
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. o.j.deboer@amc.uva.nl.
authors.forename: Onno J
authors.initials: OJ
authors.lastname: de Boer
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI, USA. hartmut.weiler@bcw.edu.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University, Magdeburg, Germany. berend.isermann@med.ovgu.de.
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands. c.vantveer@amc.uva.nl.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands. c.vantveer@amc.uva.nl.
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands. tvanderpoll@amc.uva.nl.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands. tvanderpoll@amc.uva.nl.|Division of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. tvanderpoll@amc.uva.nl.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D058491:Bacterial Load; D004195:Disease Models, Animal; D005260:Female; D008099:Liver / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000382:microbiology*; D011486:Protein C / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000472:pathogenicity*
chemical_list: D011486:Protein C