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Next Article 
Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1113-1116
FOCUS ON HEMATOLOGY
Introduction: are natural anticoagulants candidates for
modulating the inflammatory response to endotoxin?
Charles T. Esmon
From the Cardiovascular Biology Research Program, Oklahoma Medical
Research Foundation; Departments of Pathology and Biochemistry and
Molecular Biology, University of Oklahoma Health Science Center; and
Howard Hughes Medical Institute, Oklahoma City, OK.
 |
Article |
Recent studies have focused on the potential role
of natural anticoagulants in modulating host responses to endotoxin.
The natural anticoagulants that have drawn the greatest attention are
antithrombin, protein C, and tissue factor pathway inhibitor (TFPI).
Interest in this area is spurred by clinical and basic observations. On
the clinical side, there is a correlation between low levels of protein
C and antithrombin and a negative clinical outcome. The situation with
TFPI is much more difficult to interpret because the majority of TFPI
is associated with the blood vessel1 and changes in plasma
levels can reflect altered distribution between the vessel wall and
plasma. On the basic side, animal models of septic shock employing
either endotoxin or Escherichia coli, usually performed by
intravenous infusion of these agents, have shown that
antithrombin,2 protein C/activated protein C,3
or TFPI4 can reduce the frequency of lethal responses in
nonhuman primates and other animals. In general, these studies have
found that, in addition to dampening the disseminated intravascular coagulation (DIC) associated with the endotoxin challenge, elevation of
the natural anticoagulant levels also decreases the inflammatory response including IL-6 and IL-8 levels in the case of TFPI (see Creasey et al4) and antithrombin (see Minnema et al, this issue).
Contrasting these reports are studies of human volunteers administered
low doses of endotoxin: there was an increase in their coagulation
response, but the administration of TFPI failed to alter
the IL-6 levels or those of other markers of inflammation (see de Jonge
et al, this issue). This discrepancy between the response of human
volunteers and experimental animals to endotoxin infusion raises
several questions that warrant some discussion. For instance, are the
differences simply a matter of species, or are there
differences in experimental design that could account for the different
outcomes? Before dealing with this issue, it is worth reviewing a
rapidly growing literature on the role of coagulation factors in
activating cells and eliciting inflammatory responses. It is in this
context that the potential role of natural anticoagulants in modulating
these responses is most easily understood. When considering any in vivo
results, it is important to bear in mind that altering the
concentration of antithrombin or TFPI will diminish thrombin formation
in response to endotoxin and that this will diminish the activation of
protein C. Thus if activated protein C has antiinflammatory functions
not replicated by the other inhibitors, elevation of the other natural
anticoagulants could have unexpected negative effects on the regulation
of both the coagulation and inflammation processes.
How the natural anticoagulants might impact the inflammatory system
remains an active area of investigation, but several observations help
provide a framework by which this might be accomplished. In part, the
answer may lie in the recent observations that factor VIIa, factor Xa,
and thrombin can all activate cells directly, probably mediated in
large part by the cleavage of cell surface protease activated receptors
(PARs). The mechanism of activation of PARs is reviewed in
Coughlin.5 Briefly, cleavage of these receptors generates a
new N terminus that serves as a "tethered" ligand to activate
these 7 transmembrane G protein-coupled receptors. Because each of the
above coagulation enzymes appears to accomplish cell activation by
different mechanisms, their mechanisms of cell signaling will be
discussed separately.
Recently, several studies have shown that the tissue factor-factor
VIIa complex can activate cells,6-8 causing a
Ca2+ influx resulting in the activation of map kinase,
c-Jun N terminal kinase, and the early growth response gene-1
(egr-1).9 This process potentially contributes to
inflammatory mediator release from cells. Cell activation requires the
factor VIIa to be proteolytically active;8 hence cell
activation is not mediated by direct binding of factor VIIa to tissue
factor. Instead, the cell activation appears to be mediated in part by
activation of a protease activated receptor, either PAR 2 or a closely
related receptor.9
Other unidentified factors apparently play a role in signaling since
cellular signaling could not be reconstituted by cotransfection of
cells with tissue factor and PAR 2 alone. Signaling through PAR 2 has
particular relevance to a potential role in inflammation because PAR 2 is induced by TNF  and IL-1 in endothelial cells,10 potentially augmenting the ability of the tissue factor-factor VIIa
complex to activate the endothelium either through endothelial cell
tissue factor or tissue factor on adherent monocytes. The relevance of
tissue-factor-mediated signaling to monocyte/macrophage activation and
the potential for augmenting cytokine elaboration have recently been
demonstrated by showing that the tissue factor-factor VIIa complex
could elicit a variety of proinflammatory responses in macrophages,
including reactive oxygen species, and induction of MHC class II and
adhesion receptors.7 The macrophage activation required
both the active site of factor VIIa and the cytoplasmic tail of tissue factor.
Inhibitors that block factor VIIa proteolytic activity, as TFPI does,
would be expected to block cell activation in this system. Thus, by
increasing the rate of tissue factor-factor VIIa inhibition on the
cell surface, it may be possible to limit some of the cellular activation mechanisms that could contribute to the inflammatory response. It is worth noting that signaling requires relatively high
levels of surface tissue factor expression and factor VIIa. These
levels correspond to complete activation of the factor VII,7,
9 a point that may be important when considering the observation by de Jonge et al that they failed to see an impact of TFPI on cytokine
elaboration in human volunteers challenged with low levels of
endotoxin. Under these conditions, one would expect most of the factor
VII to remain in the zymogen form, and hence the factor VIIa
concentration might be too low to signal effectively. In the more
severe cases of endotoxin challenge when overt DIC is occurring, it is
likely that most of the factor VII at or near the endothelial or
monocyte/macrophage cell surface may become activated.
Tissue-factor signaling seems to be more complex than simply
facilitating factor VIIa cleavage of a PAR on the cell surface. As
mentioned above, tissue-factor-mediated macrophage activation requires
the presence of the cytoplasmic tail of tissue factor. Potential
signaling involvement through the cytoplasmic tail is suggested by the
observation that it is a substrate for phosphorylation on 3 serine
residues.11 One aspect of tissue factor that has drawn
considerable attention is its participation in tumor metastasis. Like
the situation in macrophage activation, the cytoplasmic tail of tissue
factor is required to potentiate metastasis.12 The cytoplasmic tail of tissue factor also interacts actin binding protein
280.13 The tissue factor-factor VIIa complex can interact with TFPI bound to the matrix or presumably to the endothelial cell
surface proteoglycans where it can work in concert with intergrins to
tighten cell-cell interaction and, in the case of monocytes, potentially augment the inflammatory response by facilitating cell extravisation.
In addition to these roles of tissue factor in cell activation and
tumor-cell migration, reverse migration of monocytes from the basal to
apical surface of the endothelium was shown recently to involve tissue
factor or, specifically, to be blocked by antibodies to tissue
factor.14 Whether this process is dependent on factor VIIa,
requires the cytoplasmic tail of tissue factor, or is modulated by TFPI
or other factor VIIa inhibitors is unclear. While the cytoplasmic tail
of tissue factor seems to play an important role in some of these
aspects of cell migration and signaling, it is not critical for
survival because tissue factor with the cytoplasmic domain truncated
can rescue tissue-factor-null mice.15
Factor Xa is another candidate enzyme for augmenting inflammation.
Importantly in the current context, both TFPI and antithrombin are
effective inhibitors of factor Xa at the concentrations employed in the
studies presented in this issue. Recently a receptor for factor Xa,
effector protease receptor 1 (EPR-1), was identified and
cloned.16 The receptor is expressed on a wide variety of cells, including leukocytes,17 endothelium,18
and smooth muscle cells.19 Current evidence suggests that
EPR-1 signals via 2 mechanisms, one mediated by factor Xa
binding20, 21 and the other requiring the active
site.18, 19 Factor Xa can also activate cells in an
apparently EPR-1-independent fashion.9 On endothelium,
factor Xa elicits synthesis and release of IL-6, IL-8, and monocyte
chemotactic protein-1 by an active site-dependent reaction
independent of EPR-1.
EPR-1-dependent inflammatory events that are apparently factor
Xa-active-site independent, and hence presumably insensitive to factor
Xa inhibitors, include augmentation of IL-1 mediated lymphocyte
proliferation22 and edema.21 Edema could be
blocked by peptides that prevent factor Xa binding to EPR-1. In vivo in mice, EPR-1 has been implicated in CD3/T-cell-receptor-dependent lymphocyte proliferation. Blocking receptor synthesis or function eliminated among other things graft-versus-host
disease.23 It is unfortunate that, with regard to
factor Xa mediated signaling involving EPR-1, it is unclear whether the
natural protease inhibitors, antithrombin and TFPI, will prevent the
factor Xa-EPR-1 complex from forming. In several cases of protease
receptor interactions in the coagulation system, the complex can
form with low-molecular-weight inhibitors in the active site,
but antithrombin inhibition results in the loss of affinity
for the receptor.24
Thrombin is the most frequently recognized clotting enzyme to be
implicated in cell activation and inflammation. Thrombin triggers cell
activation through PAR 1, 3-4.25 Activation results in a Ca2+ flux and generation of a host of second
messengers.5 In the case of endothelium, thrombin
facilitates leukocyte adhesion through elaboration of adhesion
molecules and stimulates platelet activating factor formation, a potent
agonist for neutrophils.26 Thrombin induced IL-8 release in
clotting blood and CD14+ monocytes. Thrombin also caused
IL-6 and IL-8 production from endothelial cells in
culture.27 Antithrombin would be anticipated to shorten the
half-life of thrombin in the circulation and, hence, to decrease
thrombin mediated augmentation of the inflammatory events. In addition,
cells containing thrombomodulin at high concentrations, such as those
in the endothelium, are less sensitive to thrombin than cells lacking
thrombomodulin,28 probably because thrombomodulin binds
thrombin with high affinity and masks the thrombin receptor recognition
site.24 Because thrombomodulin can be down-regulated by
cytokines29 and proteolytically released from endothelium by netrophil elastase,30 it is possible that the
endothelial-cell PARs become more susceptible to thrombin activation as
the inflammatory process in sepsis proceeds.
Not all coagulation inhibitors are equal in their ability to protect
animals from endotoxin shock. Heparin blocks endotoxin initiated
clotting but is ineffective in preventing organ failure and death in
baboons.31 Likewise, factor Xa blocked with a small molecule in the active site effectively inhibits coagulation induced by
E coli in baboons but does not protect from organ failure or prevent death.32 It is possible that failure of these
compounds to protect may have to do with some of their nonanticoagulant functions. In the case of heparin, it can bind growth factors and
facilitate cell signaling.33 In addition, heparin displaces TFPI from the endothelium,1 the impact of which is
uncertain with regard to protection of the endothelium, especially the
microvascular endothelium during sepsis. In the case of the
active-site-blocked factor Xa, it is possible that failure to protect
the animals was linked to the fact that the modified factor Xa would
still interact with EPR-1, possibly eliciting some of the inflammatory responses reviewed above. The alternative interpretation is that the
natural anticoagulants initiate other functions distinct from their
role in coagulation.
The third major natural anticoagulant candidate being considered for
modulation in sepsis is protein C/activated protein C. Protein C is
activated when thrombin binds to thrombomodulin, primarily on the
surface of the endothelium.24 Because activation is
dependent on thrombin generation, potent anticoagulants can prevent
activation. Activated protein C, however, has been shown to inhibit
monocyte activation by LPS,34 and inhibition of the pathway
has resulted in increased levels of inflammatory cytokines in baboons
challenged with E coli.35 These effects are thought to be mediated by an as yet uncharacterized receptor for APC on the
monocyte.36 In septic patients receiving activated protein C, the IL-6 levels were reduced substantially.37 Therefore, at least with this natural anticoagulant, in vivo studies in primates and humans indicate that modulating the activated-protein-C levels results in decreases in the inflammatory response. In considering how
the system is actually regulated, however, it is important to recall
the multiple sites of interaction. A telling example of the complexity
are studies with 1-antitrypsin Pittsburgh, a mutation of
the normal inhibitor that results in a very potent thrombin inhibitor
that is also a potent activated protein C inhibitor. Infusion of this
inhibitor into baboons challenged with E coli actually
decreased survival time relative to controls,38 suggesting that despite controlling coagulation there was an exacerbated inflammatory response.
Particularly relevant to the issue of coagulation factor induction of
inflammatory mediators, in many settings the coagulation enzymes are
either ineffective or require high concentrations to induce cytokine
elaboration. In many of these settings, however, the coagulation
factors work synergistically with other agonists, such as endotoxin, to
stimulate cytokine elaboration. As an example, thrombin and factor Xa
failed to elicit IL-1 production from macrophages alone but increased
IL-1 production up to 200-fold in the presence of suboptimal levels of
endotoxin.39
Given the myriad of mechanisms by which the coagulation system can
interact to modulate the inflammatory response, how can one explain the
failure of TFPI to modulate inflammation in human volunteers when the
same agent did modulate inflammation in baboons? There are several
differences in the studies. In the baboons E coli were used
rather than endotoxin. The bacteria may elicit greater complement
activation and may interact in other ways distinct from endotoxin. The
physiology of the response in the baboons was different with the E
coli than endotoxin and the response to E coli was much
more reproducible than to endotoxin (Dr. Lerner Hinshaw, personal
communication, 1980). Second and perhaps more importantly, the
nonhuman-primate and other sepsis models in which natural
anticoagulants have been effective in preventing death and in dampening
the inflammatory response have all used lethal or near lethal levels of
endotoxin or E coli as the challenge to which the
inflammatory mediators are compared in the presence or absence of
natural anticoagulant supplementation. Under these conditions, vascular
integrity is compromised, allowing coagulation factors to contact
extravascular cells where receptors for coagulation factors are
abundant.5 Activation of these cells could potentially augment the inflammatory response. Natural anticoagulant
supplementation could, among other things, diminish loss of vascular
integrity and thereby diminish the inflammatory response simply by
maintaining the response to the intravascular space. In addition, in
the in vitro systems, signaling by both factor Xa and factor VIIa
requires relatively high levels of these enzymes.7, 22, 40
These levels may be reached in severe sepsis but are not obtained with
the human volunteers given endotoxin. Although it remains possible that
humans differ dramatically from nonhuman primates and other animals in
the linkage between coagulation and inflammation, given that at least
with some natural anticoagulants inhibition of inflammation has been
observed in septic patients with these agents, the difference is more
likely related to dose. In severely challenged animals, coagulation
almost certainly amplifies to an acute inflammatory response, but at
low levels of endotoxin the monocyte-driven inflammatory response is
probably largely coagulation independent, in part because the
coagulation factors may not reach the critical levels to further
stimulate the cells. The dramatic differences between the models of
sepsis can be seen by the remarkable differences in the levels of
markers measured in the following 2 papers. In the human volunteers
IL-6 reached 3-5 ng/mL, whereas in the baboon it was approximately 1000 ng/mL. Likewise, the levels of the thrombin-antithrombin complex, a
surrogate for the circulating thrombin levels, were approximately 100 ng/mL in the human volunteers and 30 times that level in the baboons.
Because it is obviously not ethical to subject the human volunteers to
lethal levels of endotoxin, it would be of interest to examine whether
these natural anticoagulants fail to prevent the elevation of
inflammatory mediators in experimental animals given the low doses of
endotoxin. This would at least argue against the idea that the apparent
discrepancies are related to species differences.
Clinical studies to date have suggested a trend toward improved
survival of septic patients given antithrombin 41 or
protein C/activated protein C.37, 40, 42 But either these
were uncontrolled studies or the numbers of patients enrolled were too
few to provide a definitive answer about the impact of these agents on
mortality. The efficacy of these agents in treating sepsis/septic shock
should be resolved in the near future with the completion of phase 3 clinical trials now in progress. Regardless of the outcome of these
trials, it will be important to gain a better understanding of the
unique mechanisms by which different natural anticoagulants function in
the regulation of the inflammatory response. This information should
prove useful in providing better guidelines for the use of natural
anticoagulants or combinations of these agents in the treatment of
sepsis or trauma patients.
| |
Footnotes |
Submitted December 14, 1999; accepted December 14, 1999.
Reprints: Charles T. Esmon, Cardiovascular Biology Research
Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma
City, OK 73104; e-mail: charles-esmon{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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