Neutral endopeptidase inhibition in diabetic wound repair

Spenny, Michelle L.; Muangman, Pornprom; Sullivan, Stephen R.; Bunnett, Nigel W.; Ansel, John C.; Olerud, John E.; Gibran, Nicole S.

doi:10.1046/j.1524-475x.2002.10504.x

Cited by 68 publications

(54 citation statements)

References 32 publications

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“…NEP inhibitors have been proposed as possible treatments, but their use is hampered by the fact that they result in hydrolysis of a large number of peptides and are associated with serious adverse effects, such as angioedema. 41,42 However, local treatment with SP or SP analogs has the potential not only to promote diabetic foot ulceration healing but also to reverse the chronic proinflammatory state present in diabetic skin without major adverse effects expected.…”

Section: Discussionmentioning

confidence: 99%

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

Leal

Carvalho

Tellechea

et al. 2015

The American Journal of Pathology

179

155

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Diabetic foot ulceration is a major complication of diabetes. Substance P (SP) is involved in wound healing, but its effect in diabetic skin wounds is unclear. We examined the effect of exogenous SP delivery on diabetic mouse and rabbit wounds. We also studied the impact of deficiency in SP or its receptor, neurokinin-1 receptor, on wound healing in mouse models. SP treatment improved wound healing in mice and rabbits, whereas the absence of SP or its receptor impaired wound progression in mice. Moreover, SP bioavailability in diabetic skin was reduced as SP gene expression was decreased, whereas the gene expression and protein levels of the enzyme that degrades SP, neutral endopeptidase, were increased. Diabetes and SP deficiency were associated with absence of an acute inflammatory response important for wound healing progression and instead revealed a persistent inflammation throughout the healing process. SP treatment induced an acute inflammatory response, which enabled the progression to the proliferative phase and modulated macrophage activation toward the M2 phenotype that promotes wound healing. In conclusion, SP treatment reverses the chronic proinflammatory state in diabetic skin and promotes healing of diabetic wounds. (Am J Pathol 2015 http://dx

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Section: Discussionmentioning

confidence: 99%

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

Leal

Carvalho

Tellechea

et al. 2015

The American Journal of Pathology

179

155

View full text Add to dashboard Cite

show abstract

“…Dermal healing was assessed in hematoxylin-and eosinstained sections of wounds with a maturity scoring system introduced by Greenhalgh et al (1990) as modified by Spenny et al (2002). The amount and type of cell accumulation, the type of granulation tissue, and scarring are assessed in this model, with a score ranging from 1 to 15.…”

Section: Assessment Of Wound Healingmentioning

confidence: 99%

SPARC-thrombospondin-2-double-null Mice Exhibit Enhanced Cutaneous Wound Healing and Increased Fibrovascular Invasion of Subcutaneous Polyvinyl Alcohol Sponges

Puolakkainen

Bradshaw

Brekken

et al. 2005

J Histochem Cytochem.

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S U M M A R YSecreted protein acidic and rich in cysteine (SPARC) and thrombospondin-2 (TSP-2) are structurally unrelated matricellular proteins that have important roles in cellextracellular matrix (ECM) interactions and tissue repair. SPARC-null mice exhibit accelerated wound closure, and TSP-2-null mice show an overall enhancement in wound healing. To assess potential compensation of one protein for the other, we examined cutaneous wound healing and fibrovascular invasion of subcutaneous sponges in SPARC-TSP-2 (ST) double-null and wild-type (WT) mice. Epidermal closure of cutaneous wounds was found to occur significantly faster in ST-double-null mice, compared with WT animals: histological analysis of dermal wound repair revealed significantly more mature phases of healing at 1, 4, 7, 10, and 14 days after wounding, and electron microscopy showed disrupted ECM at 14 days in these mice. ST-double-null dermal fibroblasts displayed accelerated migration, relative to WT fibroblasts, in a wounding assay in vitro, as well as enhanced contraction of native collagen gels. Zymography indicated that fibroblasts from ST-double-null mice also produced higher levels of matrix metalloproteinase (MMP)-2. These data are consistent with the increased fibrovascular invasion of subcutaneous sponge implants seen in the double-null mice. The generally accelerated wound healing of ST-double-null mice reflects that described for the single-null animals. Importantly, the absence of both proteins results in elevated MMP-2 levels. SPARC and TSP-2 therefore perform similar functions in the regulation of cutaneous wound healing, but fine-tuning with respect to ECM production and remodeling could account for the enhanced response seen in ST-double-null mice.

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“…Inhibition of NEP accelerates reepithelialization, suggesting that impaired KC migration in diabetic wounds may be due, in part, to decreased motogenic signaling from neuropeptides such as SP. 101 Cholinergic receptor agonists. KCs express both nicotinic and muscarinic acetylcholine (ACh) receptors (nAChR and mAChR respectively), and synthesize ACh.…”

mentioning

confidence: 99%