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Neutral endopeptidase inhibition in diabetic wound repair
Author(s) -
Spenny Michelle L.,
Muangman Pornprom,
Sullivan Stephen R.,
Bunnett Nigel W.,
Ansel John C.,
Olerud John E.,
Gibran Nicole S.
Publication year - 2002
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1046/j.1524-475x.2002.10504.x
Subject(s) - thiorphan , substance p , neprilysin , saline , endocrinology , proinflammatory cytokine , wound healing , medicine , chemistry , inflammation , neuropeptide , enzyme , surgery , biochemistry , receptor
In response to cutaneous injury, sensory nerves release substance P, a proinflammatory neuropeptide. Substance P stimulates mitogenesis and migration of keratinocytes, fibroblasts, and endothelial cells. Neutral endopeptidase (NEP), a cell surface metallopeptidase, degrades substance P. Chronic nonhealing wounds and skin from patients with diabetes mellitus show increased NEP localization and activity. We hypothesized that increased NEP may retard wound healing and that NEP inhibition would improve closure kinetics in an excisional murine wound model. NEP enzyme activity was measured in skin samples from mutant diabetic mice (db/db) and nondiabetic (db/–) littermates by degradation of glutaryl‐ala‐ala‐phe‐4‐methoxy‐2‐naphthylamine. Full‐thickness 6‐mm dorsal excisional wounds treated with normal saline or the NEP inhibitor thiorphan (10 µM or 25 µM) for 7 days were followed until closure. Histological examination and NEP activity were evaluated in a subset of wounds. NEP activity in unwounded db/db skin (20.6 pmol MNA/hr/µg) significantly exceeded activity in db/–skin (7.9 pmol MNA/hr/µg; p = 0.02). In db/db mice, 25 µM thiorphan shortened time to closure (18.0 days; p < 0.05) compared to normal saline (23.5 days). NEP inhibition did not alter closure kinetics in db/–mice. While the inflammatory response appeared enhanced in early wounds treated with thiorphan, blinded histological scoring of healed wounds using a semiquantitative scale showed no difference in inflammation. Unwounded skin from diabetic mice shows increased NEP activity and NEP inhibition improved wound closure kinetics without affecting contraction, suggesting that its principal effect was to augment epithelialization. (WOUND REP REG 2002;10:295–301)