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needed for erythropoiesis were consistently required for tissue
protection.
The diametrically opposed pharmacodynamics of renal EPO-
hematopoiesis compared to hypoEPO-tissue protection suggested
that systemic use of hypoEPO could provide tissue protection, but
would not trigger effective erythropoiesis. To test this hypothesis,
renal EPO was fully desialyted (asialoEPO), which was shown
using a variety of tissue injury models to be a potent protective
agent but totally devoid of hematopoietic effects (
7
).
The structure of the EPO receptor that controls the survival of
erythrocyte precursors was defined in the 1990s. Similar to the
structure of other members of the type I cytokine family, the EPO
receptor was found to consist of subunits, in this case a dimer of
two identical subunits, (EPOR)
2
(
1
). The EPO molecule has two
regions localized on opposite sides of the molecule (one of high
affinity and the other lower) that recognize docking sites within
each of the subunit receptor proteins. When EPO binds to this
receptor, occupancy of these binding sites leads to a conforma-
tional change that triggers phosphorylation of Janus kinase 2
(Jak-2), which then subsequently phosphorylates multiple other
molecules downstream and activates a constellation of biological
hematopoietic responses (
1
).
Although it was originally believed that erythrocyte precursors
were the only cells that expressed the hematopoietic homodimer,
accumulated evidence revealed a variety of other cell types also
express this receptor. In a general way, other cells that express
(EPOR)
2
are also involved in maintaining adequate circulating
numbers of red cells. Specifically, these are cell types that are
involved in limiting blood loss during hemorrhage by promoting
thrombosis (platelets and endothelial cells) or maintaining ade-
quate circulating pressure and blood volume (via vascular smooth
muscle) (
8
). In the subacute time frame, EPOR is also expressed
by hepatocytes that secrete hepcidin, the major modulator of iron
absorption (
9
). In the setting of red cell losses and attendant rela-
tive hypoxia, EPO serum levels become elevated from the normal
range of 1-20 mIU/ml to as high as 200-300 mIU/ml.
3
Alternative EPO Signaling
The endogenous tissue protective system is one aspect of an evolu-
tionarily ancient innate immune response to injury or infection
(reviewed in ref.
10
). The “logic” of this system is simple: danger
from the invasion of pathogens and parasites or damage caused by
diverse injuries is sensed by surveillance cells in the vicinity. A vari-
ety of molecular signatures, some representative of the foreign
organism, others endogenous molecules expressed and released
from damaged cells, quickly activates a proinflammatory reaction.
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