Topical Erythropoietin Treatment Accelerates the Healing of Cutaneous Burn Wounds in Diabetic Pigs Through an Aquaporin-3-Dependent Mechanism

• Published in: Diabetes (New York, N.Y.) Vol. 66; no. 8; pp. 2254 - 2265
• Main Authors: Hamed, Saher, Ullmann, Yehuda, Egozi, Dana, Keren, Aviad, Daod, Essam, Anis, Omer, Kabha, Hoda, Belokopytov, Mark, Ashkar, Manal, Shofti, Rona, Zaretsky, Asaph, Schlesinger, Michal, Teot, Luc, Liu, Paul Y
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.08.2017
• Subjects: Administration, Topical; Angiogenesis; Angiogenesis Inducing Agents - administration & dosage; Animals; Apoptosis; Aquaporin 3; Aquaporin 3 - metabolism; Burns; Burns - drug therapy; Burns - genetics; Cell adhesion & migration; Cell migration; Collagen; Collagen - genetics; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Type 1 - genetics; Erythropoietin; Erythropoietin - administration & dosage; Extracellular matrix; Extracellular Matrix - genetics; Fibronectin; Fibronectins - administration & dosage; Glycerol; Hemostasis; Hogs; Hyaluronic acid; Hyaluronic Acid - biosynthesis; Inflammation; Keratinocytes; Keratinocytes - metabolism; Membrane proteins; Neovascularization, Physiologic; Re-Epithelialization - genetics; Rodents; Skin; Skin - metabolism; Swine; Topical application; Wound healing; Wound Healing - drug effects; Wound Healing - genetics
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db16-1205

We have previously reported that the topical application of erythropoietin (EPO) to cutaneous wounds in rats and mice with experimentally induced diabetes accelerates their healing by stimulating angiogenesis, reepithelialization, and collagen deposition, and by suppressing the inflammatory response and apoptosis. Aquaporins (AQPs) are integral membrane proteins whose function is to regulate intracellular fluid hemostasis by enabling the transport of water and glycerol. AQP3 is the AQP that is expressed in the skin where it facilitates cell migration and proliferation and re-epithelialization during wound healing. In this report, we provide the results of an investigation that examined the contribution of AQP3 to the mechanism of EPO action on the healing of burn wounds in the skin of pigs with experimentally induced type 1 diabetes. We found that topical EPO treatment of the burns accelerated their healing through an AQP3-dependent mechanism that activates angiogenesis, triggers collagen and hyaluronic acid synthesis and the formation of the extracellular matrix (ECM), and stimulates reepithelialization by keratinocytes. We also found that incorporating fibronectin, a crucial constituent of the ECM, into the topical EPO-containing gel, can potentiate the accelerating action of EPO on the healing of the burn injury.