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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1680-1686
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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.
 |
Abstract |
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.
(Blood. 2000;95:1680-1686)
© 2000 by The American Society of Hematology.
| |
Introduction |
The protein C anticoagulant pathway serves as an "on
demand" anticoagulant system.1 Thrombin binding to
thrombomodulin (TM) results in a complex that rapidly converts protein
C to the active anticoagulant serine protease, activated protein C
(APC). TM also increases the rate of thrombin activation of a
procarboxypeptidase B, referred to as thrombin activatable fibrinolysis
inhibitor.2 APC in complex with protein S functions as an
anticoagulant by inactivating factors Va and VIIIa by limited proteolysis.
Defects in this pathway are the most common basis for hereditary
thrombophilia3,4 and infants born with homozygous protein C
deficiency usually develop microvascular thrombosis of the skin (purpura fulminans).5 Clinical studies have shown that
protein C and protein S levels often decrease dramatically in septic
shock patients6 and in meningococcemia, in particular. The
extent of the decrease is correlated with risk of mortality and the
development of purpura fulminans7 reminiscent of that seen
in homozygous protein C-deficient infants. In addition to protein C
consumption, several mechanisms impair the function of the pathway.
These include inhibition of TM function by cytokine-mediated
down-regulation8-12 and proteolysis of TM by neutrophil
elastase13 or of protein S by thrombin and other
proteases.6
Previous studies have shown that infusion of APC protects baboons from
a lethal response to LD100 Escherichia coli and
that inhibition of protein C activation exacerbates the response to sublethal numbers of E coli resulting in a lethal
coagulant and inflammatory response.14 Modulation of the
pathway by inhibition of protein S function results in a similar
exacerbation of the septic response that can be reversed by increasing
the protein S levels to near normal.15 In rodent models of
septic shock, infusion of TM has been shown to prevent
disseminated intravascular coagulation (DIC) and organ
failure16-20 and to suppress tumor necrosis factor
elaboration.21,22 Initial clinical results have suggested
that protein C infusion may be beneficial in meningococcemia and other
forms of septic shock.23-25 Taken together, these results suggest that the pathway is both a target of inflammatory injury that occurs in sepsis and that this down-regulation of function contributes to the morbidity and mortality associated with at least
some forms of sepsis.
Recently, an endothelial cell protein C receptor (EPCR) was
identified.26 EPCR is a type 1 transmembrane protein that
is expressed primarily by endothelial cells of the large blood
vessels.26,27 It is homologous to the major
histocompatibility class 1/CD1 family of proteins involved in the
immune response.28 Human endothelium exposed to tumor
necrosis factor  (TNF) in culture exhibits a time-dependent
decrease in EPCR expression and mRNA levels. In vitro studies
demonstrated that cellular EPCR augments the activation of protein C on
endothelium,29,30 whereas soluble EPCR inhibits APC
anticoagulant activity.31 Soluble EPCR is released
constitutively and the levels of soluble EPCR rise in patients with
gram negative sepsis and lupus erythematosus.32,33 These
observations raise 2 broad questions: does endogenous EPCR play a role
in the host response to E coli, and if so, is this protection related solely to its role in protein C activation?
In this study, we challenged baboons with sublethal E coli and
blocked protein C binding to EPCR with an anti-EPCR mAb to determine
whether EPCR plays a critical role in the host response to
E coli.
| |
Methods |
Reagents and monoclonal antibodies B 2 IgG1 mAbs against
human EPCR that cross react with baboon EPCR, 1494 (blocking) and 1510 (nonblocking), were prepared as described by Laszik et
al.27 Fab fragments of these mAbs were prepared as
described by Xu et al.29 E coli organisms
(33 985 Type B7-86a:K1; American Type Culture Collection, Rockville,
MD) used in the infusion study were isolated from a stool specimen at
Children's Memorial Hospital (Oklahoma City, OK). They were stored in
the lyophilized state at 4°C after growth in tryptic soybean agar
and reconstituted and characterized as described
previously.34 To eliminate differences due to E
coli strain variations, all animals were infused with E
coli from this single isolate.
Preexperimentation and experimentation procedures
The study protocol received prior approval by the Institutional
Animal Care and Use Committees of both the Oklahoma Medical Research
Foundation and the University of Oklahoma Health Sciences Center
(OUHSC). Papio cyanocephalus cynocephalus or Papio cyanocephalus anubis
baboons were purchased from either a breeding colony maintained at
OUHSC or the Biomedical Research Foundation, Inc (Houston, TX). Animals
weighed 4.3 to 13.6 kg, had leukocyte counts of 5000 to 10 000/µL,
and hematocrits exceeding 36%. They were free of tuberculosis. The
animals were held for 30 days at the OUHSC animal facility, where the
infusion studies were performed. All animals were observed continuously
during the first 8 hours after infusion of the test materials. Only
animals with a negative blood culture before experimentation were
included in the study. This led to exclusion of 1 control female who
subsequently was found to have a positive blood culture before
E coli infusion.
Infusion procedures
Experiments were performed on 16 baboons. Animals were fasted
overnight before each experiment, but were allowed water ad libitum.
Each animal was sedated with ketamine hydrochloride (14 mg/kg,
intramuscularly) on the morning of the study, and then, using a
percutaneous catheter in the cephalic vein, anesthetized with sodium
pentobarbital (2 mg/kg initially and with additional amounts
approximately every 20 minutes for 8 hours to maintain a light level of
surgical anesthesia).35 Animals were intubated orally and
allowed to breathe spontaneously. The femoral artery and vein were
cannulated aseptically and used for measuring arterial pressure and
obtaining blood samples, respectively. A percutaneous catheter was
placed in the saphenous vein and used to infuse the E
coli.35 Each anesthetized baboon was positioned on
its side in contact with controlled temperature heating pads.
Experimental groups
Table 1 shows the 4 groups of animals
studied: group 1 was infused with an anti-EPCR mAb that blocked protein
C/APC binding plus sublethal E coli; group 2 was
infused with anti-EPCR mAb that binds EPCR but does not block protein
C/APC binding plus sublethal E coli; group 3 was
infused with sublethal E coli; group 4 was infused with
blocking anti-EPCR mAb alone. One animal from group 4 was humanely
killed at 24 hours for histology and the other was a permanent (7 day)
survivor. Animals number 9 (nonblocking group 2) and number 10 (blocking group 1) received Fab fragments of their respective anti-EPCR
mAbs, while the remaining animals in these 2 groups received intact
anti EPCR mAbs.
After the initial 8 hours, those animals that were still alive were
returned to their cages and observed until they either exhibited signs
of irreversible organ failure at which time they were killed or until
they survived for a full 168 hours of observation (permanent
survivors). Those that survived were returned to the colony. Three
animals infused with sublethal E coli alone were killed
at T+24 hours to enable histopathologic comparison of tissues collected
from animals infused with blocking mAb plus sublethal E
coli (group 1).
The mAbs against EPCR were infused at a concentration of 5 mg/kg as a
bolus at T-0.5 hours in all groups in which they were given. The peak
mAb concentrations of groups 1, 2, and 4 were 39 ± 2.7,
45 ± 3.1, and 57 ± 1 µg/mL, respectively. The rate of decline of plasma concentrations were similar (T2 = 5.6
hours). The sublethal E coli infusions were begun at T-0 hours.
These infusions were carried out over a 2-hour period at the end of which time colony counts were performed on blood taken at that time.
Sublethal E coli doses administered ranged from 4.73 to 6.0 × 109 CFU/kg with mean values of 5.3, 5.4, and
5.5 in groups 1, 2, and 3, respectively. The mean blood concentrations
of E coli at T+2 hours in 1, 2, and 3 were 0.9 ± 0.2,
2.1 ± 0.6, and 0.6 ± 0.2 × 106 CFU/mL, respectively.
Sampling
Mean systemic arterial pressure (MSAP) and heart rate were monitored
with a Stathem pressure transducer and Hewlett Packard (Avondale, PA)
recorder. Rectal temperature was measured with a telethermometer
(Yellow Springs Instrument Co, Yellow Springs, OH). The above
measurements were made, and blood samples were collected, at
T = -0.5, 0, +1, +2, +3, +4, +6, +8, and +24 hours where T = 0
designates when the infusion of E coli was begun. Less than
10% of the animals' calculated blood volume (70 mL/kg) was withdrawn
over the 8-hour monitoring period. At the time of death, tissue
specimens were collected from the animal's lungs, kidneys, liver,
adrenal glands, heart, spleen, and brain for light microscopic
examination and the gross pathologic findings were recorded.
Assays
The levels of circulating tumor necrosis factor (TNF),36 interleukin-6 (IL-6),36
interleukin-8 (IL-8),36 thrombin-antithrombin complex
(TAT),37 monoclonal Ab to EPCR,37
elastase-1-antitrypsin,38 tPA,39 and soluble
TM40,41 were determined by enzyme-linked immunosorbent
assay (ELISA). Plasma APC levels were measured by a minor modification
of the enzyme capture assay described by Gruber and
Griffin.42 The modification involved using a different mAb
(HPC 1241) to trap the APC in the baboon plasma. Fibrin degradation products (FDP) were measured by latex agglutination
assay.43 Fibrinogen concentration was determined based on
the thrombin clotting time.44 Platelet and white cell
counts were determined in a Coulter counter. Serum creatinine
(CR),45 blood urea nitrogen (BUN),46 anion
gap,46 and glutamic pyruvic transaminase
(SGPT)47 were measured by automated methods. A PTAH
(phosphotungstic acid and hematoxylin) stain was used to estimate the
extent of thrombosis.
Statistical analysis and scoring of tissue histopathology B
The clinical chemistry data were analyzed using analysis of variance
with Duncan's multicomparison test to determine significant differences for a given variable between groups at given times. An
analysis of variance was also used to determine significant differences
(P < .05) between time 0 (T-0) and baseline and subsequent times for a given variable and a given group. The adrenal glands, kidneys and lungs were examined for polymorphonuclear (PMN) cell influx, congestion, hemorrhage, thrombosis, and necrosis. The tissues
were rated according to the severity of the histopathologic lesions.
The scale ranged from 0 to +4, with 4 being the most severe. All
microscopic sections were read by Dr Kosanke, who was blinded as to
which study was being analyzed. The Kruskal-Wallis test, a
nonparametric test, was used to determine significant differences
(P < .05) between groups for a given pathologic lesion.
| |
Results |
The survival time of animals receiving sublethal E coli plus
blocking mAb to EPCR (group 1) ranged from 7 to 54 hours, whereas 4 of
4 receiving sublethal E coli plus saline (group3) and 3 of 3 receiving sublethal E coli plus nonblocking mAb to EPCR (group 2) were permanent (7 day) survivors (Table 1). The dosage of E
coli infused ranged from 4.7 to 6.0 × 109
CFU/kg. The animal infused with the blocking mAb alone showed no signs
of organ injury, no increase in markers of coagulation or inflammation,
and survived for the 7-day period of observation.
The responses among groups with respect to coagulation, hemodynamics,
vascular injury, and inflammation were monitored by determining
fibrinogen levels, fibrin degradation products, blood pressure, soluble
TM, IL-6 and IL-8 (Figure 1). In the
blocking mAb group, fibrinogen (Figure 1A) dropped significantly more
than in either of the control groups. Conversely, FDPs were higher in
the blocking mAb group than in either of the control groups (Figure
1B). The blood pressure decreased more in the blocking group than in
either control group (Figure 1C). Similarly, soluble TM levels, a
marker of endothelial cell injury, were significantly higher in the
blocking than in either of the control groups (Figure 1D). Unlike the
control groups in which soluble TM concentrations remained essentially
constant after 4 hours, the soluble TM levels continued to rise over
the initial 24 hours in the group receiving the blocking mAb,
suggesting ongoing vascular injury. IL-6 (Figure 1E) and IL-8 (Figure
1F) reached significantly higher concentrations in the blocking mAb
group than in the other 2 groups, indicating an increased inflammatory
response.
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| Fig 1.
The blocking mAB to EPCR induces changes in fibrinogen
consumption, fibrin degradation products, blood pressure, soluble TM,
IL-6, and IL-8 levels.
(A) Fibrinogen levels were determined as a function of time after
infusion of sublethal E coli and (1) the blocking mAb ( ) (2)
the control mAb ( ), and (3) saline ( ). The same symbols are used
to identify the experimental groups throughout this figure; (B) Fibrin
degradation products; (C) Blood pressure (MSAP); (D) Soluble TM; (E)
IL-6; and (F) IL-8. All assays were performed at least in triplicate
and the error bar represents the standard error of the mean from all
animals in the group. When error bars are not shown in this and other
figures, the error was smaller than the data point on the graph.
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The scoring of the histopathologic lesions of the adrenal glands,
liver, and kidneys is shown in Figure 2.
The lesions of the blocking mAb group, with the exception of congestion
of the adrenal sinusoids, were significantly more severe than those of animals in the saline group. The influx of neutrophils in the liver,
and thrombosis of adrenal and renal parenchyma were severe in the
blocking mAb group. In addition to these histopathologic changes, in
the animals receiving the blocking mAb and sublethal E coli,
petechial hemorrhagic lesions were observed in the stomach, all mucosal
membranes, and skin. Such lesions were never seen in animals receiving
sublethal E coli alone.
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| Fig 2.
Comparison of the histochemical changes in organs from
animals with or without the EPCR blocking mAb.
The histopathologic responses of the animals given the blocking mAb
plus sublethal E coli are compared with those given sublethal
E coli alone. The tissues from animals in the E coli
alone group were recovered after death at T + 24 hours, whereas those
from the blocking mAb group were recovered at the time of impending
death (7 to 54 hours). No histopathologic studies of tissues from
animals in the nonblocking mAb group were performed because we wished
to compare survival time and biochemical parameters between the
blocking and nonblocking groups. Evaluations of the parameters were
performed in a blinded fashion. PMN influx, congestion, hemorrhage,
necrosis, and thrombosis were graded on a scale from 0 to 4, with 0 being normal and 4 being severe. The histopathologic changes of the
tissues recovered from the blocking mAb group are significantly more
severe than those of the sublethal E coli control group
P < .001, with the exception of the adrenal and hepatic
congestion.
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Because inhibition of protein C activation was one of the key potential
mechanisms to explain the deleterious effects of EPCR-protein C
interaction blockade, we examined the circulating plasma APC in the
groups infused with the blocking or nonblocking mAbs. Unfortunately, these levels varied widely among individuals within each group. Because
APC formation is dependent on thrombin generation, we examined the TAT
complex levels as a surrogate marker for thrombin generation. These
levels also varied widely between animals in each group. The levels of
plasma APC in the control and blocking mAb groups were similar and
varied too widely to allow a determination of the extent of inhibition
of protein C activation in this model. It is clear, however, that
protein C activation can occur relatively well even in the presence of
the blocking mAB.
Time-dependent changes in markers of organ and cardiovascular function,
as well as inflammatory responses, are compared among the groups in
Table 2. The creatinine is significantly
higher in blocking mAb group than in either of the control groups
(P  .05), indicating significantly greater renal damage in
the group where EPCR-protein C binding is blocked. The anion gap and
SGPT were also elevated, but did not reach statistical significance. In
contrast, the white blood cells, tumor necrosis factor, tissue plasminogen activator, and platelet responses did not differ among any
of the groups receiving E coli.
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Table 2.
Summary of clinical laboratory and markers of hemostatic
and inflammatory system responses to sublethal Escherichia
coli plus blocking or nonblocking mAb to EPCR, or saline
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|
The histologic appearance of adrenal, liver, kidney, and lung tissues
collected at 24 hours after the infusion of sublethal E coli
plus saline revealed no evidence of abnormal neutrophil influx,
congestion, hemorrhage, necrosis, or thrombosis and, with the exception
of the significant congestion of the adrenals and minor
congestion of the liver, the tissues appeared normal (data not shown).
This is in marked contrast to the histologic appearance of the adrenals
(Figure 3A and B) and kidneys (Figure 3C
and D) in baboons infused with sublethal E coli plus blocking
anti-EPCR mAb. In the adrenal gland, 2 types of pathology were
observed: one dominated by microthrombus formation (Figure 3A, arrow)
and hemorrhage and the other dominated by leukocyte infiltration
(Figure 3B) with little thrombosis or hemorrhage present. The
thrombosis was observed in the 2 animals that died earliest and the
leukocyte infiltration was seen in the other 2 animals. Thrombosis
(arrow) involving 90% of the glomeruli of the kidney was also seen in the 2 animals that died the earliest (Figure 3C). This was accompanied in the kidney by karyopyknosis of 75% of the proximal tubular cells
(arrow), indicating early ischemia. In contrast, severe acute necrosis
of the proximal tubular epithelial cells of the kidney is seen in the 2 animals that died the latest (Figure 3D).
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| Fig 3.
Photographs of sections of adrenal and kidneys from
baboons injected with sublethal doses of E coli and blocking
anti-EPCR mAbs.
The organs were harvested at the time of impending death. The
"early" changes (ie, changes in animals with relatively short
survival) consist of prominent microthrombus formation in the
subcapsular vessels (arrows) of the adrenals (A) and also in the renal
glomeruli (arrow) (C). Note the extensive cortical hemorrhage in the
adrenal gland (A) and the early ischemic/necrobiotic changes
(karyopyknosis) in the proximal tubular epithelial cells (triangle)
of the kidney (C). In B and D, the animals that had relatively long
survival, widespread necrotic foci were apparent with associated
polymorphonuclear leukocyte infiltrates in the adrenal cortex (B) and
severe acute tubular necrosis involving the proximal tubules (P) of the
kidney (D). The distal tubules (D) were well-preserved. Occasional
mitotic figures of the proximal tubular epithelial cells are also seen
as features of regeneration (arrow) (D). Note the lack of thrombi and
hemorrhage in the "late" group (B and D).
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Treatment with the blocking mAb plus sublethal E coli resulted
in significant pathologic changes in the liver (Figure
4), compared with the animals treated with
sublethal E coli alone. Both the portal and centrilobular zones
of the animals that died early (Figure 4A and C) are characterized by
well-preserved architecture. The centrilobular region, however,
exhibits an intense polymorphonuclear leukocyte infiltrate in
association with some necrobiotic/necrotic changes of scattered
hepatocytes. In contrast, the histopathology of the portal and
centrilobular zones of the animals that died later (Figure 4B and D) is
dominated by "open" nuclei (pale chromatin pattern) with
prominent nucleoli and vacuolar degeneration, which is most prominent
in the centrilobular region, indicating hepatocellular degeneration.
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| Fig 4.
Photographs of sections of the liver from baboons
injected with sublethal doses of E coli and blocking anti-EPCR
mAbs.
In the "early" animals (ie, animals with relatively short
survival) the portal areas of the liver (A) are quite unremarkable with
well-preserved architecture showing the bile duct (B), portal vein (P),
hepatic artery, and numerous hepatocytes. The centrilobular regions (C)
of the liver from the "early" animals exhibit prominent PMN
infiltrate in association with necrobiotic/necrotic changes of
scattered hepatocytes. The "late" changes (ie, changes in animals
with relatively long survival) consist of "open" nuclei (ie,
nuclei with pale chromatin pattern) and prominent nucleoli in the
hepatocytes both in the portal (B) and centrilobular (D) regions and
vacuolar degeneration of the hepatocytes more severe in the
centrilobular area (D). Note (B) the well-preserved portal structures
with bile duct (B), hepatic artery, and portal vein (P). Note also the
lack of PMN infiltrate in the centrilobular area (D).
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| |
Discussion |
This study demonstrates that inhibition of protein C binding to EPCR
converts the response to sublethal concentrations of E coli
into a lethal response. These animals exhibit DIC, intense neutrophil influx into the tissues, and elevation of some
of the inflammatory cytokines. These responses are not due to
nonspecific effects as the mAb because Fab fragments, which cannot fix
complement, caused a similar response, and a class similar mAb to EPCR
that does not block protein C-EPCR interaction was without significant effects on survival, inflammatory cytokine levels, or markers of organ
damage. Furthermore, in the absence of a challenge to the system, the
infusion of the blocking mAb elicited neither a change in organ
morphology nor death. This study provides the first evidence that EPCR
plays an important physiological role. It will be of considerable
interest to compare the results of these studies with the murine EPCR
gene deletion model currently in progress.
There are several possible mechanisms by which EPCR might protect
against E coli sepsis. The first, and most obvious, mechanism is that animals receiving the blocking mAb might activate less protein
C than the controls. It is clear, however, that protein C activation
occurs relatively well even in the presence of the blocking mAb. This
is consistent with the majority of the TM being in small vessels and
the majority of the EPCR being in large vessels.27,28 Because the coagulant response to E coli varies among animals whether or not EPCR mAbs are present48 and the blocking mAb elicits vascular damage in this model, the model is not well suited for
investigations of the role of EPCR in protein C activation in vivo.
This question is being approached using thrombin infusion in the
presence and absence of blocking antibodies following the procedures
described by Lentz's group.49
A second mechanism of protection could involve regulation of the
inflammatory response. Consistent with this possibility, compared with
controls, animals receiving the blocking mAb exhibited increased
leukocyte infiltration into the tissues. The molecular basis for this
response is not known. However, soluble EPCR has been shown to interact
with leukocytes,50 a process mediated in part by proteinase
3, the autoantigen of Wegener's granulomatosis. The soluble TM levels
in the blocking mAb group continued to rise for 24 hours or until
death. This latter observation probably reflects progressive injury to
the vascular endothelium,13,51 possibly mediated by the
adherent leukocytes.51
IL-6 and IL-8 levels are increased in the blocking mAb group compared
with the controls. Both cytokines appear early and remain elevated
until death instead of returning to baseline as occurs in the controls.
These results imply that inhibition of the protein C-EPCR interaction
results in an increased inflammatory response that fails to be
regulated normally. Whether this is a direct or indirect response is unclear.
Protein C and APC are currently in clinical trials for septic shock.
The observation that EPCR plays an important role in the host defense
against sepsis may be quite relevant in terms of evaluating patients
capable of responding to either therapy. It is known that cytokines
such as TNF can down-regulate EPCR expression in cell
culture26 suggesting that in some patients the levels of
EPCR may be too low for the protein C/APC to be effective. Consistent
with this possibility, histopathologic studies of skin biopsy specimens
of patients with meningococcemia have shown markedly reduced levels of
EPCR expression in the thrombosed vasculature compared with biopsy
specimens from adjacent skin.52 Analysis of samples from
these trials will not only test this hypothesis, but may provide
insights into appropriate therapeutic regimens.50,52
| |
Footnotes |
Submitted June 2, 1999; accepted October 28, 1999.
Funded by: Grant # P01 HL54804 (C.T.E.) (C.T.E. is an investigator of
the Howard Hughes Medical Institute); NIH Grant #2R01GMHL37704-12 (F.B.T.).
Reprints: Fletcher B. Taylor Jr, Cardiovascular Biology
Research Program, Oklahoma Medical Research Foundation, 825 NE 13th St,
Oklahoma City, OK 73104; e-mail: marie-brewer{at}omrf.ouhsc.edu.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction