Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype
Open accessAbstract
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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SP accelerates normal acute and chronic wound healing processes.
“SP accelerates the normal acute and chronic wound healing processes54–56.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [55]
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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
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 185
- Issue
- 6
- Pages
- 1638-1648
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC4450333
- 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
- bronze
- doi.org
- Licence
- 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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