Cited by 223Wound Healing and TreatmentsDiabetic Foot Ulcer Assessment and ManagementPain Mechanisms and Treatments

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

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Leal, Ermelindo C., Carvalho, Eugénia, Tellechea, Ana, Kafanas, Antonios, Tecilazich, Francesco, Kearney, Cathal, Kuchibhotla, Sarada, Auster, Michael E. +5 more·2015·The American Journal of Pathology

Abstract

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.

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Crossref · 10.1016/j.ajpath.2015.02.011

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Authors
Leal, E. C., Carvalho, E., Tellechea, A., Kafanas, A., Tecilazich, F., Kearney, C., Kuchibhotla, S., Auster, M. E., Kokkotou, E., Mooney, D. J., LoGerfo, F. W., Pradhan-Nabzdyk, L., & Veves, A.
Affiliations
  • Beth Israel Deaconess Medical Center (US)
  • Harvard University (US)
Corresponding author
Veves, Aristidis
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2015-06
Volume
185
Issue
6
Pages
1638-1648
ISSN
0002-9440 (ISSN-L)
OpenAlex
W2017787550
Cited by
223
References
45
Citations by year
2026: 15 · 2025: 19 · 2024: 16 · 2023: 21 · 2022: 26 · 2021: 32 · 2020: 28 · 2019: 20 · 2018: 17 · 2017: 13 · 2016: 14 · 2015: 1
FWCI
15.13
Type
journal article
Language
en
Open access
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
Funders
  • European Foundation for the Study of Diabetes (SFRH/BPD/46341/2008, PTDC/SAU-FAR/121109/2010, SFRH/BD/48624/2008, 1R01NS066205, 1R24DK091210-01, 1R01DK076937, 1R01NS046710)
  • Juvenile Diabetes Research Foundation International (SFRH/BPD/46341/2008, PTDC/SAU-FAR/121109/2010, SFRH/BD/48624/2008, 1R01NS066205, 1R24DK091210-01, 1R01DK076937, 1R01NS046710)
  • National Institutes of Health (SFRH/BPD/46341/2008, PTDC/SAU-FAR/121109/2010, SFRH/BD/48624/2008, 1R01NS066205, 1R24DK091210-01, 1R01DK076937, 1R01NS046710)
  • Fundação para a Ciência e a Tecnologia (SFRH/BPD/46341/2008, PTDC/SAU-FAR/121109/2010, SFRH/BD/48624/2008, 1R01NS066205, 1R24DK091210-01, 1R01DK076937, 1R01NS046710)
Topics
  • Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetic Foot Ulcer Assessment and Management
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Keywords
substance P, wound healing, diabetes mellitus, diabetic foot ulcer, neurokinin-1 receptor, macrophage polarization, M2 macrophages, chronic inflammation, acute inflammatory response, neutral endopeptidase, skin wounds
MeSH terms
Animals, Diabetes Mellitus, Experimental, Diabetic Neuropathies, Inflammation, Macrophages, Rabbits, Skin, Substance P, Wound Healing, Receptors, Neurokinin-1, Mice

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