Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing

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The present study is designed to understand the contribution of peripheral vascular disease and peripheral neuropathy to the wound-healing impairment associated with diabetes. Using a rabbit model of diabetic neuroischemic wound healing, we investigated rate of healing, leukocyte infiltration, and expression of cytokines, interleukin-8 and interleukin-6, and neuropeptides, substance P, and neuropeptide Y.


Diabetes was induced in New Zealand White rabbits by administering alloxan while control rabbits received saline. Ten days later, animals in both groups underwent surgery. One ear served as a sham, and the other was made ischemic (ligation of central+rostral arteries) or neuroischemic (ischemia+ resection of central+rostral nerves). Four 6-mm punch biopsy wounds were created in both ears and wound healing was followed for 10 days using computerized planimetry.


Nondiabetic sham and ischemic wounds healed significantly more rapidly than diabetic sham and ischemic wounds. Healing was slowest in neuroischemic wounds, irrespective of diabetic status. A high M1/M2 macrophage ratio and a high proinflammatory cytokine expression, both indicators of chronic proinflammatory state, and low neuropeptide expression were seen in preinjury diabetic skin. Postinjury, in diabetic wounds, the M1/M2 ratio remained high, the reactive increase in cytokine expression was low, and neuropeptide expression was further decreased in neuroischemic wounds.


This rabbit model illustrates how a combination of a high M1/M2 ratio, a failure to mount postinjury cytokine response as well as a diminished neuropeptide expression, contribute to wound-healing impairment in diabetes. The addition of neuropathy to ischemia leads to equivalently severe impaired wound-healing irrespective of diabetes status, suggesting that in the presence of ischemia, loss of neuropeptide function contributes to the impaired healing associated with diabetes.

Clinical Relevance:

Although, diabetic foot ulceration is a major clinical problem and the most common cause for hospital admissions in diabetic patients, there is limited basic and translational research. One of the main reasons is the lack of appropriate animal models that control for factors related to the major complications of diabetes, namely, neuropathy and ischemia. The aim of this study was to use a clinically relevant animal model of neuroischemic wound healing that is representative of human diabetic foot ulceration and to examine the contribution of neuropeptides and inflammation. These data, showing a link between neuropeptide and cytokine function, diabetes, and neuroischemia, provide both a basis and a model for studies of wound-healing therapies.

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