The soluble urokinase plasminogen activator receptor and its fragments in venous ulcers

ObjectiveActivation of proteolytic mechanisms at the cell surface through the activity of urokinase-type plasminogen activator (uPA) bound to its receptor, uPAR, is an important process in wound healing. The soluble forms of uPAR (suPAR and its fragments I, II, and III) have nonproteolytic functions that include chemotaxis, adhesion, and proliferation, which also have a role in wound healing. The aim of this study was to determine whether suPAR and its cleaved fragments are present in venous ulcers and whether their levels are associated with healing.MethodsUlcer exudates were collected from patients with venous leg ulcers (n = 30). Healing was defined as complete re-epithelialization within 6 months of compression therapy. Time-resolved fluorescence immunoassays were validated for quantification of suPAR and its fragments in ulcer exudates. The effect of exudates on keratinocyte migration was analyzed by an in vitro scratch assay.ResultsUlcer exudates from patients who healed (n = 9) had approximately threefold higher levels of intact suPAR (P = .005), twofold higher levels of suPARI (P = .03), and approximately threefold higher levels suPARII-III (P < .0001) compared with nonhealers (n = 21). Exudate from healing ulcers stimulated keratinocyte migration (P = .02), whereas depletion of suPAR from exudates resulted in cell apoptosis.ConclusionsWe conclude that suPAR and its fragments are present in the environs of venous ulcers and may act as indicators of the propensity of venous ulcers to heal, with suPARII-III being the best discriminator. We speculate that suPAR and its fragments may have a role in the maintenance of an optimal ulcer-healing environment.

Clinical RelevanceThe mechanisms that regulate venous ulcer healing are still not clear, and this may be reflected in lack of ulcer healing in a significant proportion of patients treated with conventional compression therapy. Urokinase plasminogen activator (uPA) and its receptor (uPAR) are present in environs of venous ulcers, and the soluble forms of uPAR are thought to be important in wound healing. Little is known with regard to the presence of these soluble forms in the environs of venous ulcers. This study examines the levels of the soluble uPAR fragments in ulcer exudates and their potential role in ulcer healing.