Biology Reference
In-Depth Information
6
Regeneration and Repair
One of the earliest studies that identified a non-erythropoietic
activity for EPO showed that EPO was trophic for cholinergic neu-
rons in vitro and in vivo (
23
). Shortly thereafter, a widespread
presence of EPO and EPO receptor was reported for the brain (
2
)
and neuroprotective effects of EPO discovered (
5
). Much of the
subsequent study has evaluated the importance of EPO in the pro-
tection of tissue from damage/insults. However, this focus is too
restricted, as much work has also shown that EPO and non-eryth-
ropoietic tissue protective derivatives play a critical role in repair of
damaged tissues. For example, tissue protective derivatives of EPO
have been shown to play a significant role in the improvement of
function when administered following experimental brain injury,
even when given with a significant temporal delay (
24
). A major
role has also been documented for EPO-induced endothelial cell
growth of new blood vessels into damaged tissues, allowing for an
accelerated healing phase, e.g., within infarcted myocardium (
25
),
and for wounds in general (
26
). Endothelial nitric oxide synthase
plays a critical role in the healing response and the
CR-EPOR has
been shown to be the receptor mediating this effect (
27
). Recently,
vascular endothelial growth factor receptor 2 (VEGFR2) has also
been shown to be a component of the receptor complex as well
(
28
). These observations illustrate the multiple ways the
β
CR can
associate with different receptor subunits to provide specific physi-
ological functions (reviewed in ref.
19
).
β
7
Looking Forward
Organisms respond to tissue injury by activating an inflammatory
cascade that typically results in amplified damage that extends far
beyond the locus of the initial injury. Therapeutics that target
specific components of the inflammatory cascade, e.g., anti-TNF
α
therapy, have been spectacularly successful in a number of chronic
inflammatory diseases. However, as successful as these approaches
have been, they target only a component of the damage cascade
and further, do not specifically activate endogenous repair mecha-
nisms. Work performed by many investigators over the last 20 years
have uncovered the critical role the EPO plays in counteracting
injury at a level higher than individual proinflammatory cytokines,
as well as effects that occur at multiple lower levels that involve
attenuating the damaging effects of otherwise self-amplifying
proinflammatory cytokines, reversing programmed cell death, and
stimulating repair mechanisms (Fig.
4
). In this sense, endogenous
hypoglycosylated-EPO activates a molecular switch that shuts off
inflammation, as well as activates healing and regenerative processes.
Search WWH ::
Custom Search