Uric acid and xanthine oxidoreductase in wound healing.

Chronic wounds are an important health problem because they are difficult to heal and treatment is often complicated, lengthy and expensive. For a majority of sufferers the most common outcomes are long-term immobility, infection and prolonged hospitalisation. There is therefore an urgent need for effective therapeutics that will enhance ulcer healing and patient quality of life, and will reduce healthcare costs. Studies in our laboratory have revealed elevated levels of purine catabolites in wound fluid from patients with venous leg ulcers. In particular, we have discovered that uric acid is elevated in wound fluid, with higher concentrations correlating with increased wound severity. We have also revealed a corresponding depletion in uric acid precursors, including adenosine. Further, we have revealed that xanthine oxidoreductase, the enzyme that catalyses the production of uric acid, is present at elevated levels in wound fluid. Taken together, these findings provide evidence that xanthine oxidoreductase may have a function in the formation or persistence of chronic wounds. Here we describe the potential function of xanthine oxidoreductase and uric acid accumulation in the wound site, and the effect of xanthine oxidoreductase in potentiating the inflammatory response.

Elevated uric acid correlates with wound severity.

Chronic venous leg ulcers are a major health issue and represent an often overlooked area of biomedical research. Nevertheless, it is becoming increasingly evident that new approaches to enhance healing outcomes may arise through better understanding the processes involved in the formation of chronic wounds. We have for the first time shown that the terminal purine catabolite uric acid (UA) is elevated in wound fluid (WF) from chronic venous leg ulcers with relative concentrations correlating with wound chronicity. We have also shown a corresponding depletion in UA precursors, including adenosine, with increased wound severity. Further, we have shown that xanthine oxidase, the only enzyme in humans that catalyses the production of UA in conjunction with a burst of free radicals, is active in chronic WF. Taken together, this provides compelling evidence that xanthine oxidase may play a critical role in the formation of chronic wounds by prolonging the inflammatory process.

Xanthine Oxidoreductase: A Novel Therapeutic Target for the Treatment of Chronic Wounds?

Significance: Chronic wounds are a major burden to patients and to healthcare systems worldwide. These wounds are difficult to heal and treatment is often lengthy and expensive. This has led to research efforts focussed on the wound environment attempting to understand the underlying pathological mechanisms of impaired wound healing. While some of this research has translated to advancements in wound therapies and implementation of new treatment options, chronic wounds remain a significant challenge to treat. Thus, identification of effective, low-cost, advanced wound therapies that enhance healing rates of these problematic wounds is still essential. Recent Advances and Critical Issues: Xanthine oxidoreductase (XOR), a molybdoflavin enzyme, is emerging as an important source of reactive oxygen species (ROS) in various pathologies, including diabetes and chronic wounds. XOR has recently been shown to be upregulated in chronic wounds, stimulating the overproduction of ROS during dysfunctional wound healing. XOR-induced ROS can amplify and potentiate inflammation in the wound environment further delaying wound closure. Future Directions: The detrimental role of XOR in impaired healing indicates it may be a therapeutic target. Targeted inhibition of XOR has been shown to reduce the expression and activity of this enzyme in diabetic wound models. In turn, this resulted in a significant decrease in ROS levels in the wound environment and improved wound healing. Therefore, repurposing existing XOR inhibitors that are approved for human use may be able to restore homeostasis at the wound site and enable damaged tissue to return to normal healing.