The endothelial protein C receptor impairs the antibacterial response in murine pneumococcal pneumonia and sepsis

Pneumococcal pneumonia is a frequent cause of gram-positive sepsis and has a high mortality. The endothelial protein C receptor (EPCR) has been implicated in both the activation of protein C (PC) and the anti-inflammatory actions of activated (A)PC. The aim of this study was to determine the role of...

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Vydáno v:Thrombosis and haemostasis Ročník 111; číslo 5; s. 970
Hlavní autoři: Schouten, Marcel, de Boer, J Daan, Kager, Liesbeth M, Roelofs, Joris J T H, Meijers, Joost C M, Esmon, Charles T, Levi, Marcel, van 't Veer, Cornelis, van der Poll, Tom
Médium: Journal Article
Jazyk:angličtina
Vydáno: Germany 2014
Témata:
Animals
Bacterial Load - genetics
Cell Movement - genetics
Cells, Cultured
Disease Models, Animal
Endothelial Protein C Receptor
Endothelium - immunology
Endothelium - metabolism
Endothelium - microbiology
Female
Humans
Immunity, Innate - genetics
Inflammation - genetics
Lung - pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Mice, Transgenic
Neutrophils - immunology
Neutrophils - metabolism
Neutrophils - microbiology
Pneumonia, Pneumococcal - immunology
Pneumonia, Pneumococcal - microbiology
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Sepsis - immunology
Streptococcus pneumoniae - growth & development
Streptococcus pneumoniae - immunology
pneumonia
endothelial protein C receptor
sepsis
Coagulation
Streptococcus pneumoniae
ISSN:0340-6245, 2567-689X, 2567-689X
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Shrnutí:Pneumococcal pneumonia is a frequent cause of gram-positive sepsis and has a high mortality. The endothelial protein C receptor (EPCR) has been implicated in both the activation of protein C (PC) and the anti-inflammatory actions of activated (A)PC. The aim of this study was to determine the role of the EPCR in murine pneumococcal pneumonia and sepsis. Wild-type (WT), EPCR knockout (KO) and Tie2-EPCR mice, which overexpress EPCR on the endothelium, were infected intranasally (pneumonia) or intravenously (sepsis) with viable Streptococcus pneumoniae and euthanised at 24 or 48 hours after initiation of the infection for analyses. Pneumonia did not alter constitutive EPCR expression on pulmonary endothelium but was associated with an influx of EPCR positive neutrophils into lung tissue. In pneumococcal pneumonia EPCR KO mice demonstrated diminished bacterial growth in the lungs and dissemination to spleen and liver, reduced neutrophil recruitment to the lungs and a mitigated inflammatory response. Moreover, EPCR KO mice displayed enhanced activation of coagulation in the early phase of disease. Correspondingly, in pneumococcal sepsis EPCR KO mice showed reduced bacterial growth in lung and liver and attenuated cytokine release. Conversely, EPCR-overexpressing mice displayed higher bacterial outgrowth in lung, blood, spleen and liver in pneumococcal sepsis. In conclusion, EPCR impairs antibacterial defense in both pneumococcal pneumonia and sepsis, which is associated with an enhanced pro-inflammatory response.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0340-6245
2567-689X
2567-689X
DOI:10.1160/TH13-10-0859