Erythropoietin Restores C-Fiber Function and Prevents Pressure Ulcer Formation in Diabetic Mice

Abstract

Pressure-induced vasodilatation (PIV), a cutaneous physiological neurovascular (C-fiber/endothelium) mechanism, is altered in diabetes and could possibly contribute to pressure ulcer development. We wanted to determine whether recombinant human erythropoietin (rhEPO), which has protective neurovascular effects, could prevent PIV alteration and pressure ulcer formation. We developed a skin pressure ulcer model in mice by applying two magnetic plates to the dorsal skin. This induced significant stage 2 ulcers (assessed visually and histologically) in streptozotocin-treated mice with 8 weeks of diabetes compared with very few in controls. Control and streptozotocin mice received either no treatment or systematic rhEPO (3,000 UI kg(-1) intraperitoneally, twice a week) during the last 2 weeks of diabetes. After 8 weeks of diabetes, we assessed ulcer development, PIV, endothelium-dependent vasodilation, C-fiber-mediated nociception threshold, and skin innervation density. Pretreatment with rhEPO fully prevented ulcer development in streptozotocin mice and also fully restored C-fiber nociception, skin innervation density, and significantly improved PIV, but had no effect on endothelium-dependent vasodilation. Our finding that rhEPO treatment protects the skin against pressure-induced ulcers in diabetic mice encourages evaluation of the therapeutic potential for non-hematopoietic analogs of EPO in preventing neuropathic diabetic ulcers.

Deep Tissue Injury in Development of Pressure Ulcers: A Decrease of Inflammasome Activation and Changes in Human Skin Morphology in Response to Aging and Mechanical Load

“…However, models that utilize application of compressive load to skin to study development of DTI are very scarce. Current animal models include use of magnetic devices [15], [66] or spinal cord injury models [67]. Although important knowledge was gained from these studies, the correlation to human condition is limited, mostly because of anatomical difference between rodents and humans and limitations in precise control of the applied load/pressure.…”

Adipose Stromal Cells Repair Pressure Ulcers in Both Young and Elderly Mice: Potential Role of Adipogenesis in Skin Repair

“…Studies suggest that repeated cycles of ischemia reperfusion, impairing blood and lymph flow locally, lead to cell necrosis in the epidermis, dermis, subcutaneous adipose, and skeletal muscle tissues [10][11][12]. Prior preclinical pressure ulcer studies have used a variety of rodent models including the diabetic mouse [13][14][15][16][17][18][19], and only two murine studies have examined the effect of age on healing outcomes [16,20]. In one study, chitosan scaffolds with or without fibroblast growth factor 2 were found to accelerate the closure of pressure ulcer wounds in old (20)(21)(22) months old [mo]) mice [16].…”

Biological Responses of Three-Dimensional Cultured Fibroblasts by Sustained Compressive Loading Include Apoptosis and Survival Activity

“…In fact, there are some animal models of chronic wounds [38]–[41]. However, these animal models employed two magnetic plates to dorsal skin for making PUs [38], [39] or treated with drugs to induce diabetic conditions before making full thickness wound [40], [41] to create the chronic wounds, therefore cannot be used for assessing the effect of pressure applied to the existing wounds on its healing process.…”