title: The cytoprotective effects of endogenous activated protein C reduce activation of coagulation during murine pneumococcal pneumonia and sepsis.
abstract: BACKGROUND
  Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and sepsis. Activated protein C (APC) has been implicated as an important anticoagulant and anti-inflammatory mediator. We here sought to determine the role of the anticoagulant and cytoprotective functions of endogenous APC during pneumonia and sepsis caused by S. pneumoniae.
  
  
  METHODS
  Mice were treated intraperitoneally with monoclonal antibody (mAb) 1609 (which inhibits both anticoagulant and cytoprotective effects of APC), mAb 1591 (which inhibits only the anticoagulant effects of APC) or a control antibody mAb prior to infection with viable S. pneumoniae via the airways (to induce pneumonia) or via the tail vein (to induce primary sepsis). Mice were analyzed at 24 or 48 hours after infection.
  
  
  RESULTS
  mAb 1609, but not mAb 1591, enhanced the procoagulant response to pneumococcal pneumonia and sepsis, as indicated by elevated levels of thrombin-antithrombin complexes and D-dimer in plasma and lungs. mAb 1609 only modestly affected the fibrinolytic response (elevated plasma and lung levels of the fibrinolysis inhibitor plasminogen activator inhibitor type I during sepsis) and cytokine release (elevated plasma interleukin-6 concentrations during pneumonia).
  
  
  CONCLUSIONS
  The cytoprotective effects of endogenous APC reduce activation of coagulation during murine pneumococcal pneumonia and sepsis.
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands; Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. Electronic address: narcels@yahoo.com.
authors.forename: Marcel
authors.initials: M
authors.lastname: Schouten
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands; Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. Electronic address: c.vantveer@amc.uva.nl.
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands; Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. Electronic address: nadiachm1987@hotmail.com.
authors.forename: Nadia
authors.initials: N
authors.lastname: Poulussen
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. Electronic address: j.c.meijers@amc.uva.nl.
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.affiliation: Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. Electronic address: m.m.levi@amc.uva.nl.
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
authors.affiliation: Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, 825 NE 13th St Oklahoma City, OK 73104, OK, USA. Electronic address: esmonc@omrf.org.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands; Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands; Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. Electronic address: t.vanderpoll@amc.uva.nl.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000378:metabolism*; D001777:Blood Coagulation; D003451:Cryoprotective Agents / Q000378:metabolism*; D004789:Enzyme Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D011486:Protein C / Q000378:metabolism*; D018805:Sepsis / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000302:isolation & purification
chemical_list: D000925:Anticoagulants; D003451:Cryoprotective Agents; D011486:Protein C
keywords: S. pneumoniae; coagulation; inflammation; pneumonia; protein C; sepsis