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C.N. Tchanque‐Fossuo, S.E. Dahle, S.R. Buchman, R. Rivkah Isseroff, Deferoxamine: potential novel topical therapeutic for chronic wounds, British Journal of Dermatology, Volume 176, Issue 4, 1 April 2017, Pages 1056–1059, https://doi.org/10.1111/bjd.14956
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Although chronic wounds have multifactorial aetiologies, they share a common characteristic of compromise of the local vasculature leading to diminished oxygen tension.1 In pressure ulcers (PU), the obstruction of capillary blood flow and lymphatics from the local shear pressure results in ischaemia. The subsequent reperfusion causes hyperaemia and oedema, further reducing the regional oxygen level.1 Similarly, in venous leg ulcers (VLU), vascular permeability and increase in venous hypertension generate local oedema. In diabetic foot ulcers (DFU), hypoxia results from local pressure and high metabolic stress on the wound bed. During the initial phase of healing for all three wound types, the local and acute hypoxic climate results in the release of numerous growth factors by endothelial cells, fibroblasts and macrophages.1 One of those essential factors is the hypoxia inducible factor‐1 (HIF‐1). The regulation of HIF‐1 activity resides in its oxygen‐dependent degradation, by prolyl 4‐hydroxylase (PHD) enzymes that require iron (Fe2+) as a cofactor. Under hypoxic conditions, HIF‐1α is stabilized against PHD enzymatic degradation and moves to the nucleus, where it dimerizes with HIF‐1β and binds to a hypoxia response element. For its transcriptional activity, HIF‐1α also needs to bind to the coactivators p300/cyclic adenosine monophosphate response element binding protein (CREB) binding protein (CBP).1 This results in the upregulation and the activation of more than 60 HIF‐1α target genes for tissue repair, cell growth and proliferation, and important angiogenic factors such as vascular endothelial growth factor (VEGF; Fig. 1).1 Although VEGF induces angiogenesis, studies have shown that prolonged hypoxia results in increased acidosis, decrease adenosine triphosphate production and inhibition of neovascularization that cannot be reversed by VEGF.1 This explains the need for a therapeutic agent that would maintain the multitarget activity of HIF‐1α within the chronic wound environment (Fig. 1).
