The cytoprotective effects of endogenous activated protein C reduce activation of coagulation during murine pneumococcal pneumonia and sepsis

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 fun...

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Veröffentlicht in:	Thrombosis research Jg. 135; H. 3; S. 537 - 543
Hauptverfasser:	Schouten, Marcel, van ‘t Veer, Cornelis, Poulussen, Nadia, Meijers, Joost C.M., Levi, Marcel, Esmon, Charles T., van der Poll, Tom
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Elsevier Ltd 01.03.2015
Schlagworte:	Animals Anticoagulants - metabolism Blood Coagulation coagulation Cryoprotective Agents - metabolism Enzyme Activation Hematology, Oncology and Palliative Medicine inflammation Male Mice Mice, Inbred C57BL pneumonia Pneumonia, Pneumococcal - blood Pneumonia, Pneumococcal - complications Pneumonia, Pneumococcal - diagnosis Pneumonia, Pneumococcal - metabolism protein C Protein C - metabolism S. pneumoniae sepsis Sepsis - blood Sepsis - complications Sepsis - diagnosis Sepsis - metabolism Streptococcus pneumoniae - isolation & purification S. pneumoniae protein C pneumonia inflammation coagulation sepsis
ISSN:	0049-3848, 1879-2472, 1879-2472
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Abstract	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. 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 48hours after infection. 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). The cytoprotective effects of endogenous APC reduce activation of coagulation during murine pneumococcal pneumonia and sepsis. •Endogenous PC inhibits pulmonary and systemic coagulation in pneumococcal infection.•The cytoprotective effects of APC inhibit coagulation in pneumococcal infection.•Endogenous APC has small impact on fibrinolysis in pneumococcal infection.•Endogenous APC has small impact on inflammation in pneumococcal infection.
AbstractList	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. 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 48hours after infection. 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). The cytoprotective effects of endogenous APC reduce activation of coagulation during murine pneumococcal pneumonia and sepsis. •Endogenous PC inhibits pulmonary and systemic coagulation in pneumococcal infection.•The cytoprotective effects of APC inhibit coagulation in pneumococcal infection.•Endogenous APC has small impact on fibrinolysis in pneumococcal infection.•Endogenous APC has small impact on inflammation in pneumococcal infection. Abstract Introduction 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. Materials & 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). Conclusion The cytoprotective effects of endogenous APC reduce activation of coagulation during murine pneumococcal pneumonia and sepsis. 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. 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. 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). The cytoprotective effects of endogenous APC reduce activation of coagulation during murine pneumococcal pneumonia and sepsis. 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.INTRODUCTIONStreptococcus (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.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.MATERIALS & METHODSMice 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.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).RESULTSmAb 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).The cytoprotective effects of endogenous APC reduce activation of coagulation during murine pneumococcal pneumonia and sepsis.CONCLUSIONThe cytoprotective effects of endogenous APC reduce activation of coagulation during murine pneumococcal pneumonia and sepsis.
Author	Schouten, Marcel Poulussen, Nadia Levi, Marcel Esmon, Charles T. van der Poll, Tom Meijers, Joost C.M. van ‘t Veer, Cornelis
Author_xml	– sequence: 1 givenname: Marcel surname: Schouten fullname: Schouten, Marcel email: narcels@yahoo.com organization: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands – sequence: 2 givenname: Cornelis surname: van ‘t Veer fullname: van ‘t Veer, Cornelis email: c.vantveer@amc.uva.nl organization: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands – sequence: 3 givenname: Nadia surname: Poulussen fullname: Poulussen, Nadia email: nadiachm1987@hotmail.com organization: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands – sequence: 4 givenname: Joost C.M. surname: Meijers fullname: Meijers, Joost C.M. email: j.c.meijers@amc.uva.nl organization: Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands – sequence: 5 givenname: Marcel surname: Levi fullname: Levi, Marcel email: m.m.levi@amc.uva.nl organization: Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands – sequence: 6 givenname: Charles T. surname: Esmon fullname: Esmon, Charles T. email: esmonc@omrf.org organization: Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, 825 NE 13th St Oklahoma City, OK 73104, OK, USA – sequence: 7 givenname: Tom surname: van der Poll fullname: van der Poll, Tom email: t.vanderpoll@amc.uva.nl organization: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
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Keywords	S. pneumoniae protein C pneumonia inflammation coagulation sepsis
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Snippet	Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and sepsis. Activated protein C (APC) has been implicated... Abstract Introduction Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and sepsis. Activated protein C (APC)...
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SubjectTerms	Animals Anticoagulants - metabolism Blood Coagulation coagulation Cryoprotective Agents - metabolism Enzyme Activation Hematology, Oncology and Palliative Medicine inflammation Male Mice Mice, Inbred C57BL pneumonia Pneumonia, Pneumococcal - blood Pneumonia, Pneumococcal - complications Pneumonia, Pneumococcal - diagnosis Pneumonia, Pneumococcal - metabolism protein C Protein C - metabolism S. pneumoniae sepsis Sepsis - blood Sepsis - complications Sepsis - diagnosis Sepsis - metabolism Streptococcus pneumoniae - isolation & purification
Title	The cytoprotective effects of endogenous activated protein C reduce activation of coagulation during murine pneumococcal pneumonia and sepsis
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