Biology Reference
In-Depth Information
Chapter 1
Erythropoietin and Engineered Innate Repair Activators
Michael Brines and Anthony Cerami
Abstract
Erythropoietin (EPO) is a pleiotropic type I cytokine that has been identified as a major endogenous tissue
protective molecule. In response to injury, EPO and a distinct receptor are expressed with a characteristic
temporal and spatial expression pattern. Together, these serve to limit injury and to initiate repair.
Administration of EPO in the setting of injury has been shown to be beneficial in a multitude of preclinical
models. However, translation into the clinic has been hampered by EPO's adverse effects, including pro-
motion of thrombosis. Recently, engineered molecules based on EPO's structure-activity relationships
have been developed that are devoid of hematopoietic effects. These compounds are promising candidates
for treatment of a wide variety of acute and chronic diseases.
Key words Innate immune response, Inflammation, Tissue damage, Tissue protection, Healing,
Drug design, Type 1 cytokine
1
Erythropoietin
Erythropoietin (EPO) is a 165-amino-acid protein (MW ~ 30.4 kDa)
and a member of the type I cytokine superfamily (reviewed in ref. 1 ).
The molecule contains four alpha helices that self-associate to
form a relatively compact, globular shape. For many years it was
thought that the sole function of EPO is to maintain an adequate
number of erythrocytes within the circulation. This physiological
process operates as a classical hormonal negative feedback system
that is activated by relative hypoxia that is detected by the kidney.
If red cell number significantly declines, oxygenation also falls,
and EPO is produced by medullary tubular interstitial cells. The
plasma concentrations of EPO required to maintain normal red
cell numbers is in the picomolar range. When secreted into the
circulation, EPO targets colony forming units erythroid within
the bone marrow to mature into erythrocytes. The principal effect
of EPO in its erythropoietic role is to function as a molecular
switch that turns off programmed cell death in developing eryth-
rocyte precursors. Since erythrocytes are constantly lost due to
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