Temporal and Spatial Expression of Erythropoietin, Erythropoietin Receptor, and Common β Receptor in Wound Fluid and Granulation
- 0 Comments
- 7230 reads
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.).
1. Bunn HF. New agents that stimulate erythropoiesis. Blood. 2007;109(3):868–873.
2. Parganas E, Wang D, Stravopodis D, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998;93(3):385–395.
3. Kertesz N, Wu J, Chen TH, Sucov HM, Wu H. The role of erythropoietin in regulating angiogenesis. Dev Biol. 2004;276(1):101–110.
4. Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML. Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development. 1999;126(16):3597–3605.
5. Parsa CJ, Kim J, Riel RU, et al. Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts. J Biol Chem. 2004;279(20):20655–20662.
6. Nagai A, Nakagawa E, Choi HB, Hatori K, Kobayashi S, Kim SU. Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. J Neuropathol Exp Neurol. 2001;60(4):386–392.
7. Westenfelder C, Biddle DL, Baranowski RL. Human, rat, and mouse kidney cells express functional erythropoietin receptors. Kidney Int. 1999;55(3):808–820.
8. Fiordaliso F, Chimenti S, Staszewsky L, et al. A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2005;102(6):2046–2051.
9. Haroon ZA, Amin K, Jiang X, Arcasoy MO. A novel role for erythropoietin during fibrin-induced wound-healing response. Am J Pathol. 2003;163(3):993–1000.
10. Buemi M, Galeano M, Sturiale A, et al. Recombinant human erythropoietin stimulates angiogenesis and healing of ischemic skin wounds. Shock. 2004;22(2):169–173.
11. Buemi M, Vaccaro M, Sturiale A, et al. Recombinant human erythropoietin influences revascularization and healing in a rat model of random ischaemic flaps. Acta Derm Venereol. 2002;82(6):411–417.
12. Galeano M, Altavilla D, Bitto A, et al. Recombinant human erythropoietin improves angiogenesis and wound healing in experimental burn wounds. Crit Care Med. 2006;34(4):1139–1146.
13. Howdieshell TR, Riegner C, Gupta V, et al. Normoxic wound fluid contains high levels of vascular endothelial growth factor. Ann Surg. 1998;228(5):707–715.
14. Howdieshell TR, Webb WL, Sathyanarayana, McNeil PL. Inhibition of inducible nitric oxide synthase results in reductions in wound vascular endothelial growth factor expression, granulation tissue formation, and local perfusion. Surgery. 2003;133(5):528–537.
15. Clark RA. Cutaneous tissue repair: basic biologic consideration. I. J Am Acad Dermatol. 1985;13(5 Pt 1):701–725.
16. Stadelmann WK, Digenis AG, Tobin GR. Impediments to wound healing. Am J Surg. 1998;176(2A Suppl):39S–47S.
17. Brem H, Balledux J, Bloom T, Kerstein MD, Hollier L. Healing of diabetic foot ulcers and pressure ulcers with human skin equivalent, a new paradigm in wound healing. Arch Surg. 2000;135(6):627–634.
18. Höckel M, Schlenger K, Doctrow S, Kissel T, Vaupel P. Therapeutic angiogenesis. Arch Surg. 1993;128(4):423–429.
19. Eckardt KU. The potential of erythropoietin and related strategies to stimulate erythropoiesis. Curr Opin Investig Drugs. 2001;2(8):1081–1085.
20. Grasso G, Sfacteria A, Cerami A, Brines M. Erythropoietin as a tissue-protective cytokine in brain injury: what do we know and where do we go? Neuroscientist. 2004;10(2):93–98.
21. Hanlon PR, Fu P, Wright GL, Steenbergen C, Arcasoy MO, Murphy E. Mechanisms of erythropoietin-mediated cardioprotection during ischemia-reperfusion injury: role of protein kinase C and phosphatidylinositol 3-kinase signaling. FASEB J. 2005;19(10):1323–1325.
22. Vesey DA, Cheung C, Pat B, Endre Z, Gobé G, Johnson DW. Erythropoietin protects against ischemic acute renal injury. Nephrol Dial Transplant. 2004;19(2):348–355.
23. Hayashida K, Kitamura T, Gorman DM, Arai K, Yokota T, Miyajima A. Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF): reconstitution of a high-affinity GM-CSF receptor. Proc Natl Acad Sci U S A. 1990;87(24):9655–9660.
24. Jubinsky PT, Krijanovski OI, Nathan DG, Tavernier J, Sieff CA. The beta chain of the interleukin-3 receptor functionally associates with the erythropoietin receptor. Blood. 1997;90(5):1867–1873.
25. Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A. 2004;101(41):14907–14912.
26. Coleman TR, Westernfelder C, Tögel FE, et al. Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc Natl Acad Sci U S A. 2006;103(15):5965–5970.