Diabetes and its complications are a significant burden on the healthcare system in the United States with nearly $250 billion spent on the care of these patients in 2012. This is even more significant in the VA Healthcare System where the incidence of diabetes is three times as high. Diabetic patients are prone to develop foot and leg ulcers resulting from neuropathy, susceptibility to infection, and microvascular disease. Unfortunately, diabetics have a significantly impaired ability to heal these ulcers and often go on to minor or major limb amputations. These events lead to loss of productivity and associated morbidity and mortality. One of the deficits associated with impaired wound healing in diabetic patients is the excessive production of reactive oxygen species (ROS) and insufficient nitric oxide (NO) production. It has been demonstrated that reduction of ROS or delivery of NO to diabetic wounds can improve healing rates and reduce infection. However, NO delivery is hampered by the short half-life of the molecule and its highly reactive state. Xanthine oxidoreductase (XOR) is an enzyme known for its ability to produce ROSs and we identified that it is highly expressed in skin and wounds. XOR has attracted a great deal of attention in the past few years because it can convert the stable compound nitrite back to NO. XOR has been shown to utilize dietary nitrite to mediate the beneficial effects of NO in a variety of disease models. In the wound, preliminary data indicate that XOR plays an essential role in normal wound repair but its role in diabetic wounds remains uncertain. The systemic inhibition of XOR in diabetes appears to improve wound healing while local inhibition further delays healing. In addition, the administration of systemic or topical nitite also improves wound repair. An attractive property of XOR is that it favors the production of NO when nitrite is provided in the setting of hypoxia. When producing NO, XOR mediated ROS production is reduced. These properties are extremely favorable in the setting of chronic wounds where vascularity is diminished with resulting ischemia. In such a setting, administering nitrite may not only induce XOR to generate NO but it may also reduce ROS production. The goal of this proposal is to investigate the precise role of XOR and its products in the diabetic wound repair process. Studies will examine the function of XOR generated NO and ROS in diabetic wounds. The role of XOR in wound neovascularization will be examined to define the importance of the source of the XOR function. These studies will be aided by the use of endothelial cell specific XOR knockout mice. The proposal will culminate in examination of human wounds of different etiologies to quantify XOR activity, the ability to augment local NO production through nitrite supplementation, and the impact of other nitrite reductases in this NO production. The ultimate goal of this proposal is to establish the foundation for developing topical nitrite as a treatment for impaired diabetic wound healing. The extremely attractive aspect of such a therapy is its simplicity, low cost, and the ability to harness the body's own machinery to produce the therapeutic agent. If effective, topical nitrite therapy may also be applied to wounds of other etiologies such as venous stasis and ischemic wounds.

Public Health Relevance

Diabetes affects over 25 million people in the US, ~8% of the population. Complications from diabetic wounds cost over $1.5 billion annually. The progression to major amputation is extremely high in diabetics with ~84% of all amputations being preceded by a nonhealing diabetic ulcer. In the VA population, the incidence of diabetes is 3 fold higher and, with a combination of poor social support and self-care, the incidence of major limb amputation is excessive. Despite decades of research, very little impact has been made on improving healing in these patients. The goal of our proposal is to investigate the role of an enzyme called xanthine oxidoreductase that is abundant in wounds and can produce nitric oxide from a stable compound called nitrite. We will determine if XOR can be harnessed to deliver nitric oxide to improve diabetic wound healing. We will characterize XOR expression in human wound tissues from different wound etiologies that may also be amenable to nitrite therapy. Such a therapy would be very inexpensive and safe.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Surgery (SURG)
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Veterans Health Administration
United States
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