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reverse transcriptase–polymerase chain reaction, Sturn and colleagues showed that neutrophils synthesize EPCR mRNA and, based
on flow cytometric analysis, express EPCR
on their surface. These findings raise the
possibility that EPCR-mediated ligation of
protein C or APC retards neutrophil migration in response to the types of inflammatory mediators that might be generated in
sepsis. This inhibitory activity would be lost
as protein C is consumed and would be restored by infusion of protein C or APC, a
phenomenon that may contribute to the beneficial effects of APC in sepsis patients.
How do these findings build on previous
investigations into the anti-inflammatory
properties of protein C? APC infusion protects baboons from the lethal effects of
Escherichia coli, and the levels of inflammatory cytokines rise when APC is inhibited (Taylor et al, J Clin Invest. 1987;79:
918-925). When administered to patients
with severe sepsis, APC reduces IL-6 levels
(Bernard et al, N Engl J Med. 2001;344:
699-709). Finally, in endotoxin-treated rats,
APC decreases vascular permeability and
leukocyte accumulation in the lungs. By
contrast, neither heparin plus antithrombin
nor active site-blocked factor Xa has activity in this model, suggesting that the beneficial effects of APC are independent of its
anticoagulant properties (Murakami et al,
Blood. 1996;87:642-647).
How does APC modulate the inflammatory response? In addition to augmenting
protein C activation, EPCR shuttles APC
from the endothelial cell surface into the
nucleus where the APC/EPCR complex
alters gene expression (Esmon, Ann Med.
2002;34:598-605). Gene expression profiling
demonstrates that APC down-regulates functional NF kappa B expression in endothelial
cells. This, in turn, suppresses expression of
adhesion molecules in response to tumor
necrosis factor, a phenomenon that could
limit vascular injury by attenuating leukocyte attachment to the vessel wall (Joyce et
al, J Biol Chem. 2001;276:11199-11203).
APC also inhibits staurosporine-induced
endothelial cell apoptosis, an effect dependent on EPCR and protease activated
receptor-1 (Cheng et al, Nat Med. 2003;
9:338-342), and reduces the release of
proinflammatory cytokines by monocytes,
cells that also express EPCR (Esmon, Ann
Med. 2002;34:598-605).
As a cost-effective and life-saving treatment for selected sepsis patients (Bernard et
al, N Engl J Med. 2001;344:699-709), APC
modulates coagulation and inflammation.
The work of Sturn and colleagues adds to
our understanding of the anti-inflammatory
properties of protein C.
—Jeffrey I. Weitz
McMaster University and Henderson
Research Centre
PlGF: a link between
inflammation and
angiogenesis in sickle
disease
In recent years considerable evidence has
accumulated that sickle cell disease is an
inflammatory state. For example, sickle patients have elevated white blood counts, activated granulocytes, monocytes, and endothelial cells, enhanced expression of
endothelial cell adhesion molecules, elevated cytokine levels, and elevated acute
phase reactants. Neovascularization of the
retina secondary to concomitant angiogenesis is a common feature of the disease.
What has been puzzling is where this exuberant inflammatory response is coming
from. It is unclear whether inflammation is
a primary response of the polymerization of
sickle hemoglobin or a secondary response
to tissue injury or infection. For example, a
host of speculative mechanisms for activating inflammation have been proposed,
including spontaneous oxygen radical formation in the sickle red cell, reperfusion
tissue injury through transient vaso-occlusion and reperfusion, activation of leukocytes by red blood cells, etc. Stated another
way, how does a mutation in the beta globin
BLOOD, 15 AUGUST 2003 䡠 VOLUME 102, NUMBER 4
gene that promotes anemia and enhanced
erythropoiesis lead to an inflammatory phenotype that is proangiogenic? Two papers in
this issue of Blood posit that placenta
growth factor, PlGF, an angiogenic factor
belonging to the vascular endothelial growth
factor (VEGF) family, can be the tie that
binds enhanced erythropoiesis, inflammation, and angiogenesis together in sickle cell
disease. Perelman and colleagues (page
1506) demonstrate that PlGF activates
monocytes, while serum levels correlate
with sickle cell disease severity. Remarkably, PlGF could be induced in bone
marrow CD34 progenitor cells in the presence of erythropoietin. Thus, enhanced
erythropoiesis increases PlGF. In addition,
PlGF increases mRNA of proinflammatory
cytokines such as interleukin-1 (IL-1) and
IL-8 as well as VEGF itself. In a companion manuscript by Selvaraj and colleagues on page 1515 in this issue, the
mechanism of monocyte activation by PGIF
is dissected. Specifically, activation of
monocytes by PlGF occurs via activation of
flt-1, which results in activation of PI3 kinase/AKT and ERK-1/2 pathways. PlGF
levels are elevated in sickle cell disease,
possibly related to chronic hypoxia. This is
not surprising, since PlGF belongs to the
same gene family as VEGF. This paper
demonstrates that PlGF, like VEGF, signals
through the flt-1 (VEGFR-1), confirming
other reports. Potentially, inhibitors of flt-1
may be excellent anti-inflammatory agents
for patients with sickle cell disease. There is
no unifying hypothesis on how inflammation, hemoglobin polymerization, vaso-occlusion, and angiogenesis are all tied together. Is this marriage of enhanced
erythropoiesis, PlGF, inflammation, and angiogenesis destined for the long term, or
will it be a brief honeymoon? Studies in
other hemolytic diseases and anemias and
verification in animal models seem warranted.
—Gregory M. Vercellotti
University of Minnesota
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