Temporal and Spatial Expression of Erythropoietin, Erythropoietin Receptor, and Common β Receptor in Wound Fluid and Granulation
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Recombinant human Epo is therapeutically utilized for stimulation of the erythroid lineage to treat the anemia associated with chronic renal failure, HIV infection, cancer chemotherapy, and to reduce allogenic blood transfusion in burn and surgery patients.19
However, in the last decade Epo has emerged as an important cytoprotective cytokine that possesses the ability to protect tissues including brain, heart, and kidney against ischemia and reperfusion injury.20–22 Epo receptors have been identified and appear to be widely distributed not only in erythroid precursor cells but also in numerous adult tissues, including most renal cell types, endothelial and smooth muscle cells, cardiomyocytes, and astrocytes, suggesting that Epo may exert autocrine and paracrine functions other than promoting erythropoiesis.5–7
The GM-CSF, IL-3, and IL-5 receptors are all comprised of unique α chains that bind their specific ligands with low-affinity, and a shared β chain that alone does not bind ligand, but is essential for high-affinity binding.23 Current research has demonstrated that the β chain functionally and physically associates with EpoR. This suggests that these cytokine receptors exist as a large supercomplex and offers a molecular explanation for the synergistic effects of IL-3 and GM-CSF with Epo during erythropoiesis.24
Recently, investigators have shown that the cytoprotective effects of Epo are mediated through its binding to heterodimers containing EpoR and βcR.25 Interestingly, carbamylated Epo binds to these heteroreceptors and exerts tissue protective effects, while it does not bind to the classical EpoR and does not stimulate erythropoiesis.26 This is the first evidence suggesting that erythropoietin receptors expressed in different tissues are not identical.
Recombinant human Epo is receiving increasing attention as a potential therapy for prevention of injury and restoration of function in nonhematopoietic tissues. However, the minimum effective dose required to mimic and augment these normal paracrine functions of Epo in some organs is higher than for treatment of anemia. Notably, in high-risk groups, a dose-dependant risk of adverse effects has been associated with recombinant human Epo administration including polycythemia-hyperviscosity syndrome, hypertension, and vascular thrombosis.26
The development of compounds that lack the erythropoietic features of Epo but maintain its tissue protective effects, such as carbamylated Epo, may have therapeutic application in wound healing by binding to a heteroreceptor complex composed of EpoR and βcR present in granulation tissue.
This study was supported by an American Heart Association Southeast Affiliate Grant (T.R.H.).
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