Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 5, Issue 7, Pages 1394-1400Publisher
BLACKWELL PUBLISHING
DOI: 10.1111/j.1538-7836.2007.02592.x
Keywords
coagulation; endotoxin; endothelial protein C receptor
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Funding
- NHLBI NIH HHS [P50 HL54502] Funding Source: Medline
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Background: Activated protein C (APC) protects the host from severe sepsis. Endothelial protein C receptor (EPCR) is expressed on both hematopoietic leukocytes and non-hematopoietic endothelium, and plays a key role in protein C activation. Objectives: We explore the influence of EPCR deletion on the responses to lipopolysaccharide (LPS) and then determine whether the observed differences are due to loss of hematopoietic or non-hematopoietic EPCR. Methods and results: After LPS challenge, EPCR null (Procr(-/-)) mice exhibited more thrombin and cytokine generation, neutrophil sequestration in the lung and a higher mortality rate than Procr(+/-) mice. Procr(+/-) BM/Procr(-/-) (non-hematopoietic Procr(-/-)) and Procr(-/-) BM/Procr(+/-) (hematopoietic Procr(-/-)) chimeric mice were generated by bone marrow (BM) transplantation. Compared with control Procr(+/-) mice, non-hematopoietic Procr(-/-) mice exhibited reduced protein C activation by thrombin and exaggerated responses to LPS challenge, whereas Procr(+/-) mice and hematopoietic Procr(-/-) mice exhibited similar protein C activation by thrombin and similar responses to LPS challenge. Conclusions: EPCR deletion exaggerates the host responses to LPS primarily due to deficiency of EPCR on the non-hematopoietic cells.
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