Cutaneous sensory nerves mediate
inflammation and wound healing by releasing
neuropeptides, such as
substance P, which stimulates pro-inflammatory responses by keratinocytes, fibroblasts, and endothelial cells. The cell surface
enzyme,
neutral endopeptidase, degrades
substance P, thereby regulating its biologic actions. We hypothesized that
neutral endopeptidase enzymatic activity is increased in chronic
wounds and skin from subjects with diabetes. We compared cutaneous
neutral endopeptidase expression and enzymatic activity between normal controls and diabetic subjects with neuropathy and chronic
wounds. Skin samples from subjects with diabetes were taken at the time of
amputation for nonhealing
ulcers. Skin taken from the
ulcer margin, 1 cm from the
ulcer (adjacent), and from the most proximal region of the amputated leg were studied. Skin biopsies from the leg of healthy control subjects were also studied.
Neutral endopeptidase was localized by immunohistochemistry in all tissue sections.
Neutral endopeptidase activity was measured using a fluorimetric assay. The median
neutral endopeptidase activity of the
ulcer margin was 1.21 x higher (p>0.2) than adjacent skin, 5.26 (p<0.001) than proximal skin, and 15.22 x higher (p<0.001) than control skin. Adjacent skin had a median
neutral endopeptidase activity 4.34 x higher (p<0.001) than proximal skin and 12.58 x higher (p<0.001) than control skin. The median
neutral endopeptidase activity of proximal skin was 2.90 x higher (p<0.001) than control skin. This elevated
neutral endopeptidase activity in the skin and chronic
ulcers of subjects with diabetes combined with
peripheral neuropathy may contribute to deficient neuroinflammatory signaling and may impair wound healing in subjects with diabetes.