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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1680-1686
The endothelial cell protein C receptor aids in host defense
against Escherichia coli sepsis
F. B. Taylor Jr,
D. J. Stearns-Kurosawa,
S. Kurosawa,
G. Ferrell,
A. C. K. Chang,
Z. Laszik,
S. Kosanke,
G. Peer, and
C. T. Esmon
From the Oklahoma Medical Research Foundation (OMRF); University of
Oklahoma Health Sciences Center (OUHSC); Departments of Pathology, and
Biochemistry and Molecular Biology, University of Oklahoma, OUHSC;
Howard Hughes Medical Institute (HHMI), Oklahoma City, OK.
The influence of the endothelial protein C receptor (EPCR) on the
host response to Escherichia coli was studied. Animals
were treated with 4 separate protocols for survival studies and
analysis of physiologic and biochemical parameters: (1) monoclonal
antibody (mAb) that blocks protein C/activated protein C binding to
EPCR plus sublethal numbers of E coli (SLEC)
(n = 4); (2) mAb to EPCR that does not block binding plus SLEC
(n = 3); (3) SLEC alone (n = 4); and (4) blocking mAB alone
(n = 1). Those animals receiving blocking mAb to EPCR plus
sublethal E coli died 7 to 54 hours after challenge,
whereas all animals treated with the other protocols were permanent
survivors. Histopathologic studies of tissues from animals receiving
blocking mAb plus SLEC removed at postmortem were compared with those
animals receiving SLEC alone killed at T+24 hours. The animals
receiving the blocking mAb exhibited consumption of fibrinogen,
microvascular thrombosis with hemorrhage of both the adrenal and renal
cortex, and an intense influx of neutrophils into the adrenal, renal,
and hepatic microvasculature, whereas the tissues from animals
receiving only sublethal E coli exhibited none of these
abnormal histopathologic changes. Compared with the control animals,
the animals receiving the blocking mAb exhibited significantly elevated
serum glutamic pyruvic transaminase, anion gap, thrombin-antithrombin
complex, IL-6, IL-8, and soluble thrombomodulin. The levels of
circulating activated protein C varied too widely to allow a clear
determination of whether the extent of protein C activation was altered
in vivo by blocking protein C binding to EPCR. We conclude that protein
C/activated protein C binding to EPCR contributes to the negative
regulation of the coagulopathic and inflammatory response to E
coli and that EPCR provides an additional critical step in the
host defense against E coli.
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