A novel role for erythropoietin during fibrin-induced wound-healing response.
In this study, we investigated the role of the hematopoietic cytokine erythropoietin (EPO) during wound healing, the physiological response to tissue injury. We used an in vivo wound-healing assay (fibrin Z-chambers) consisting of fibrin-filled chambers implanted subcutaneously in rats. The fibrin inside the chambers is replaced by granulation tissue consisting of new blood vessels, macrophages and fibroblasts as part of the wound-healing response. Local, exogenous recombinant EPO administration into the fibrin matrix significantly increased granulation tissue formation in a dose-dependent manner. To investigate the physiological role of endogenous EPO during wound healing, we used soluble EPO receptor or anti-EPO monoclonal antibodies to neutralize EPO and observed dose-dependent inhibition of granulation tissue formation, consistent with an important role for EPO in the wound-healing cascade. The ability of recombinant EPO to promote wound healing was associated with a proangiogenic effect during granulation tissue formation. We also found abundant expression of EPO receptor protein in macrophages, cells that play a pivotal role during wound healing. Modulation of wound healing because of administration of recombinant EPO or inhibition of endogenous EPO-EPO receptor correlated with changes in levels of inducible nitric oxide synthase protein in granulation tissue. These data demonstrate a novel function for EPO by providing in vivo evidence for a physiological role during fibrin-induced wound healing.
Haroon
Zishan A
ZA
Synergenics, San Francisco, California, USA.
Amin
Khalid
K
Jiang
Xiaohong
X
Arcasoy
Murat O
MO
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004921:Erythropoietin / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005337:Fibrin / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D018919:Neovascularization, Physiologic; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011916:Rats, Inbred F344; D017467:Receptors, Erythropoietin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000293:injuries* / Q000503:physiopathology; D012995:Solubility; D014945:Wound Healing / Q000187:drug effects*; D014947:Wounds and Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D000906:Antibodies; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D005337:Fibrin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat