Nrf2-activating Therapy Accelerates Wound Healing in a Model of Cutaneous Chronic Venous Insufficiency

BACKGROUND: Chronic venous insufficiency (CVI) stems from venous hypertension, extravasation of blood, and iron-rich skin deposits. The latter is central to ulcer development through generating reactive oxygen species (ROS) that drive persistent local inflammation and the development of lipodermatosclerosis. The ability to study CVI cutaneous inflammation is fundamental to advancing therapies. To address this end, a novel protocol was adapted to investigate cutaneous wound healing in iron-induced inflammation. METHODS: Mice were injected subcutaneously or intraperitoneally with iron-dextran, and excisional wounding was performed. Histologic and biomolecular analysis was performed. RESULTS: Iron loading was associated with dense iron deposits similar to those in chronic venous stasis. Subcutaneous but not intraperitoneal loading resulted in dermal collagen expansion. Iron overload was associated with atypical antioxidant expression as compared to vehicle controls (p < 0.0001) as well as delayed wound healing by 3-4 days. A potent activator of Nuclear factor erythroid 2-related factor 2 (Nrf2), a major transcriptional regulator of redox status, was applied to establish therapeutic efficacy. Nrf2 activation in the wound resulted in significant reduction of closure times across all experimental arms. Antioxidant expression following topical treatment was significantly increased for intraperitoneally iron-loaded mice (p < 0.0001) but did not achieve significance for the subcutaneously-loaded animals. CONCLUSIONS: We have characterized a novel model of cutaneous iron-overload designed to advance our understanding of dysfunctional wound healing in CVI. Cutaneous changes of iron overload coincide with redox imbalance and delayed wound healing. By activating Nrf2, we demonstrate the regenerative potential of pro-antioxidant mediators in treating CVI related wound complications.