Impaired cutaneous wound healing after sensory denervation in developing rats: effects on cell proliferation and apoptosis
Abstract
The role of sensory nociceptor nerves in cutaneous wound healing was investigated following full-thickness 4-mm diameter dorsal cutaneous excision wounding of rats on postnatal day 12. In rats with intact innervation, wounds at 3 days contained large numbers of TUNEL- and BRDU-labeled nuclei, consistent with inflammatory cell death and granulation cell proliferation. Wound area and volume decreased through 11 days in concert with a transient appearance of alpha-smooth muscle actin-immunoreactive myofibroblasts, declining rates of cell division, and increased occurrence of apoptotic cells. Sensory denervation by capsaicin injections on postnatal days 2 and 9 reduced calcitonin gene-related peptide-immunoreactive wound innervation persistently by up to 43%. This was associated with increased wound surface area and volume, and delays in scab loss and re-epithelialization. Relative to control wounds, granulation tissue showed increased myofibroblast content at 5-7 days. Capsaicin-treated rats had more BRDU-labeled cells, including myofibroblasts, through day 7. Numbers of TUNEL apoptotic cells per unit area of tissue section were reduced by denervation in both early and late stages of healing. We conclude that partial loss of sensory innervation impairs cutaneous wound healing in developing rats, as manifested by delayed re-epithelialization and failure of the wound area to decrease normally through at least 21 days. This is associated with an abnormally enlarged wound tissue volume resulting from increased granulation cell proliferation without proportionate increases in apoptosis. These findings suggest that nociceptor innervation plays a critical role in wound healing by regulating wound cellularity.
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Sensory denervation impairs cutaneous wound healing through increased apoptosis and reduced proliferation.
“It is well documented that sensory denervation impairs cutaneous wound healing through increased apoptosis and reduced proliferation50,51.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [50]
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- Authors
- Smith, P., & Liu, M.
- Affiliations
- University of Kansas Medical Center (US)
- Corresponding author
- Smith, Peter
- Venue
- Cell and Tissue Research
- Published
- 2002-03-01
- Volume
- 307
- Issue
- 3
- Pages
- 281-291
- ISSN
- 0302-766X (ISSN-L)
- 1432-0878
- OpenAlex
- W2059396066
- Cited by
- 102
- References
- 71
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 2 · 2021: 8 · 2020: 5 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 7 · 2012: 1
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell and Tissue Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns023502-12)
- National Institute of Neurological Disorders and Stroke (NS 23502)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-02528)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- skin wound healing, sensory denervation, nociceptors, capsaicin, calcitonin gene-related peptide, myofibroblasts, apoptosis, cell proliferation, re-epithelialization, granulation tissue, postnatal development, inflammatory cell death
- MeSH terms
- Actins, Animals, Animals, Newborn, Bromodeoxyuridine, Capsaicin, Cell Nucleus, Denervation, Nociceptors, Random Allocation, Skin, Wound Healing, Calcitonin Gene-Related Peptide, Rats, Sprague-Dawley, Apoptosis, In Situ Nick-End Labeling, Rats
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