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C4b-binding protein exacerbates the host response to Escherichia coli
F Taylor, A Chang, G Ferrell, T Mather, R Catlett, K Blick and CT Esmon
Oklahoma Medical Research Foundation, University of Oklahoma Health
Sciences Center, Oklahoma City.
Activated protein C is a plasma anticoagulant. For activated protein C to
function as an anticoagulant, it must form a complex with protein S.
Protein S anticoagulant activity is neutralized by formation of a
reversible complex with C4b binding protein (C4bBP). C4bBP is an acute-
phase plasma protein. When C4bBP levels increase, mass action forces the
level of free protein S to decrease, giving rise to an acquired functional
protein S deficiency. It has been proposed that these elevated C4bBP levels
and the resultant acquired deficiency of protein S that occurs in
inflammation could contribute to a hypercoagulable state. An experimental
model to test this hypothesis was suggested by our previous studies that
demonstrated that inhibition of protein C activation rendered baboons
hypercoagulable in response to sublethal Escherichia coli infusion (J Clin
Invest 79:918, 1987). We have extended these studies to examine the effect
of inhibition of protein S activity with C4bBP in the host (baboon)
response to infusion of sublethal concentrations of E coli organisms. Five
sets of animals were studied: (1) those challenged with sublethal
concentrations of E coli alone (0.4 x 10(10)/kg); (2) those supplemented
only with C4bBP (20 mg/kg); (3) those challenged with the same level of E
coli but supplemented with C4bBP (20 mg/kg); (4) those challenged with
sublethal E coli and supplemented with C4bBP (20 mg/kg) and sufficient
protein S (2.3 mg/kg) to fill the protein S binding sites on C4bBP; and (5)
those challenged with lethal concentrations of E coli. Sublethal E coli
infusion (group 1 animals) caused only an acute-phase response with no
consumption of fibrinogen, detectable organ damage, or detectable tumor
necrosis factor (TNF) in the plasma. C4bBP infusion (group 2 animals)
resulted in no significant physiologic changes, no detectable plasma TNF,
and little change in fibrinogen level. The group 3 animals, receiving both
sublethal E coli and C4bBP, exhibited rapid consumption of fibrinogen,
systemic organ damage, and detectable circulating TNF ultimately leading to
death. The overall response of this group was very similar to the response
of the group 5 animals receiving an LD100 dose of E coli. The group 4
animals, which were treated exactly as above except that C4bBP was
supplemented with a slight excess of protein S, responded essentially like
those that received sublethal E coli alone. These studies suggest that the
elevation of C4bBP during an inflammatory response can contribute to
fibrinogen consumption and vascular damage. This vascular damage may be
associated with enhanced elaboration of cytokines like TNF.(ABSTRACT
TRUNCATED AT 400 WORDS)
Volume 78,
Issue 2,
pp. 357-363,
07/15/1991
Copyright © 1991 by The American Society of Hematology
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