Neutral endopeptidase inhibition in diabetic wound repair.

Abstract

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 microM or 25 microM) 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/ microg) significantly exceeded activity in db/-skin (7.9 pmol MNA/hr/ microg; p = 0.02). In db/db mice, 25 microM 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.

• Authors: Michelle L Spenny, Pornprom Muangman, Stephen R Sullivan, Nigel W Bunnett, John C Ansel, John E Olerud, Nicole S Gibran
• Journal: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society (Wound Repair Regen) 2002 Sep-Oct Vol. 10 Issue 5 Pg. 295-301 ISSN: 1067-1927 [Print] United States
• PMID: 12406165 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Protease Inhibitors
• Thiorphan
• Neprilysin

Topics

• Animals
• Diabetes Mellitus, Experimental (enzymology)
• Male
• Mice
• Mice, Inbred C57BL
• Neprilysin (antagonists & inhibitors, metabolism)
• Occlusive Dressings
• Protease Inhibitors (pharmacology)
• Skin (enzymology, injuries)
• Thiorphan (pharmacology)
• Wound Healing (drug effects, physiology)