Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia.
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.


OBJECTIVE
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.


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.
Zheng
X
X
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Li
W
W
Song
Y
Y
Hu
Y
Y
Ferrell
G L
GL
Esmon
N L
NL
Esmon
C T
CT
D000818:Animals; D001777:Blood Coagulation; D016207:Cytokines / Q000096:biosynthesis; D000074283:Endothelial Protein C Receptor; D004730:Endothelium, Vascular / Q000378:metabolism; D019446:Endotoxemia / Q000097:blood* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000097:blood / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011486:Protein C / Q000378:metabolism*; D011956:Receptors, Cell Surface; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology
D016207:Cytokines; D000074283:Endothelial Protein C Receptor; D006023:Glycoproteins; D008070:Lipopolysaccharides; C080248:Procr protein, mouse; D011486:Protein C; D011956:Receptors, Cell Surface; D013917:Thrombin