The mast cell stabilizer ketotifen prevents development of excessive skin wound contraction and fibrosis in red Duroc pigs
Open accessAbstract
Skin wound healing in Yorkshire pigs closely approximates human wound healing. Conversely, red Duroc pigs form fibroproliferative, hypercontractile scars. As mast cells have been implicated in several fibrotic conditions, the present study used these models to evaluate the potential role of mast cells in wound contraction and fibrosis. Immediately following the creation of full‐thickness excisional wounds, the mast cell stabilizer ketotifen was used to treat both Yorkshire and red Durocs. Control red Durocs showed significantly more wound contraction than Yorkshires, both before and after reepithelialization. Ketotifen treatment significantly reduced the first phase of contraction in red Duroc wounds to a level equivalent to Yorkshire wounds, but had no detectable effect on the postepithelialization phase of contraction. Cessation of drug treatment after 10 weeks did not lead to resumption of excessive contraction in red Durocs, indicating that ketotifen blocked rather than delayed such contraction during a critical phase of healing. Ketotifen treatment also reduced the deposition of collagen within the red Duroc wounds, but did not affect Yorkshire wound contraction or collagen deposition. These results suggest that ketotifen may be an effective treatment for the reduction of excessive wound contraction and fibrosis in human cutaneous injuries, without affecting the normal healing process.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Activated mast cells are more abundant in hypertrophic scars than normal scars, release cytokines, histamine, and serotonin, and are required for myofibroblast proliferation, wound contracture, and hypertrophic scarring.
“Notably, activated mast cells are more abundant in hypertrophic scars than in normal scars; they release cytokines, histamine, and serotonin, and they are required for myofibroblast proliferation, wound contracture, and the hypertrophic scarring (262–264).”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [264]
The Abstract and Discussion report increased mast-cell numbers in hypertrophic scars, histamine and cytokine release, and a possible role in excessive wound contraction and scarring. They do not establish that activated mast cells are more abundant than in normal scars, mention serotonin release, or show that mast cells are required for myofibroblast proliferation or hypertrophic scarring. The Discussion explicitly says mast cells are not absolutely required for normal wound contraction. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Junqueira, L. C. U., Bignolas, G., & Brentani, H. (1979) · The Histochemical Journal · doi:10.1007/bf01002772 · Cited by 2,570 · see citing works
HYPERTROPHIC SCARS, KELOIDS, AND CONTRACTURES
Tredget, E. E., Nedelec, B., Scott, P. G., & Ghahary, A. (1997) · Surgical Clinics of North America · doi:10.1016/s0039-6109(05)70576-4 · Cited by 392 · see citing works
Repetitive Motion Disorders of the Upper Extremity
Gordon, S. L., Blair, S. J., Fine, L. J., et al. (1995) · Medical Entomology and Zoology · Cited by 240 · see citing works
Garbuzenko, E., Nagler, A., Pickholtz, D., Gillery, P., Reich, R., Maquart, F., & Levi‐Schaffer, F. (2002) · Clinical & Experimental Allergy · doi:10.1046/j.1365-2222.2002.01293.x · Cited by 225 · see citing works
Use of Dermal Regeneration Template in Contracture Release Procedures: A Multicenter Evaluation
Frame, J. D., Still, J. M., Lakhel-LeCoadou, A., et al. (2004) · Plastic & Reconstructive Surgery · doi:10.1097/01.prs.0000111883.93604.85 · Cited by 184 · see citing works
Mast cells modulate the inflammatory but not the proliferative response in healing wounds
Egozi, E. I., Ferreira, A. M., Burns, A. L., Gamelli, R. L., & DiPietro, L. A. (2003) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.2003.11108.x · Cited by 176 · see citing works
Compendium of Pharmaceuticals and Specialties
Hartleib, C. J. (1974) · American Journal of Health-System Pharmacy · doi:10.1093/ajhp/31.11.1085a · Cited by 170 · see citing works
Nedelec, B., Ghahary, A., Scott, P. G., & Tredget, E. E. (2000) · Hand Clinics · doi:10.1016/s0749-0712(21)00204-3 · Cited by 169 · see citing works
Hiromatsu, Y., & Toda, S. (2002) · Microscopy Research and Technique · doi:10.1002/jemt.10244 · Cited by 167 · see citing works
Control of wound contraction. Basic and clinical features.
Nedelec, B., Ghahary, A., Scott, P. G., & Tredget, E. E. (2000) · PubMed · Cited by 160 · see citing works
Mechanical Forces Induce Scar Remodeling
Monte‐Alto‐Costa, A., Peyrol, S., Pôrto, L. C., Comparin, J.-P., Foyatier, J.-L., & Desmoulière, A. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65482-x · Cited by 136 · see citing works
Iba, Y., Shibata, A., Kato, M., & Masukawa, T. (2004) · International Immunopharmacology · doi:10.1016/j.intimp.2004.08.009 · Cited by 135 · see citing works
Molecular and Cell Biology of Skin Wound Healing in a Pig Model
Wang, J. F., Olson, M. E., Reno, C. R., Kulyk, W. M., Wright, J. B., & Hart, D. A. (2000) · Connective Tissue Research · doi:10.3109/03008200009005290 · Cited by 111 · see citing works
Self-citationThe Effect of Myofibroblast on Contracture of Hypertrophic Scar
Shin, D., & Minn, K. W. (2004) · Plastic & Reconstructive Surgery · doi:10.1097/01.prs.0000101530.33096.5b · Cited by 107 · see citing works
Gender and Neurogenic Variables in Tendon Biology and Repetitive Motion Disorders
Hart, D. A., Archambault, J. M., Kydd, A. S., et al. (1998) · Clinical Orthopaedics and Related Research · doi:10.1097/00003086-199806000-00007 · Cited by 105 · see citing works
Self-citationGallant, C. L., Olson, M. E., & Hart, D. A. (2004) · Wound Repair and Regeneration · doi:10.1111/j.1067-1927.2004.012311.x · Cited by 100 · see citing works
Self-citation(2001) · PubMed · Cited by 93 · see citing works
Hostophotometric estimation of volume density of collagen as an indication of fibrosis in rat liver
James, J., Bosch, K. S., Zuyderhoudt, F. M. J., Houtkooper, J. M., & Gool, J. V. (1986) · Histochemistry and Cell Biology · doi:10.1007/bf00491759 · Cited by 91 · see citing works
Alving, K., Sundstr�m, C., Matran, R., et al. (1991) · Cell and Tissue Research · doi:10.1007/bf00319042 · Cited by 88 · see citing works
Histamine in Human Epidermal Cells is Induced by Ultraviolet Light Injury
Malaviya, R., Morrison, A. R., & Pentland, A. P. (1996) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12346356 · Cited by 82 · see citing works
Ketotifen: Current Views on Its Mechanism of Action and Their Therapeutic Implications
Craps, L. P., & Ney, U. M. (2009) · Respiration · doi:10.1159/000194648 · Cited by 72 · see citing works
Vanadate and the Absence of Myofibroblasts in Wound Contraction
Ehrlich, H. P. (1999) · Archives of Surgery · doi:10.1001/archsurg.134.5.494 · Cited by 67 · see citing works
Moyer, K. E., Saggers, G. C., & Ehrlich, H. P. (2004) · Wound Repair and Regeneration · doi:10.1111/j.1067-1927.2004.012310.x · Cited by 66 · see citing works
Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children
Bassler, D., Mitra, A. A., Ducharme, F. M., Förster, J., & Schwarzer, G. (2004) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001384.pub2 · Cited by 63 · see citing works
Reconstruction of axillary scar contractures—retrospective study of 124 cases over 25 years
Ogawa, R., Hyakusoku, H., Murakami, M., et al. (2003) · British Journal of Plastic Surgery · doi:10.1016/s0007-1226(03)00035-3 · Cited by 62 · see citing works
Genetic analysis of skin wound healing and scarring in a porcine model
Gallant‐Behm, C. L., & Hart, D. A. (2006) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2005.00087.x · Cited by 50 · see citing works
Self-citationKetotifen prevents skin fibrosis in the tight skin mouse.
Walker, M., Harley, R. A., & LeRoy, E. C. (1990) · PubMed · Cited by 48 · see citing works
Mast cells and fibrosis. The relevance to scleroderma.
Claman, H. N. (1990) · PubMed · Cited by 47 · see citing works
The mast cell in hypertrophic scars.
Cw, K., & Jf, B. (1972) · PubMed · Cited by 46 · see citing works
Inoue, K., Ogawa, K., Okada, J., et al. (2005) · Journal of Controlled Release · doi:10.1016/j.jconrel.2005.08.008 · Cited by 40 · see citing works
Lee, Y., & Vijayasingam, S. (1995) · PubMed · Cited by 39 · see citing works
Apoptosis of hair follicle cells in the second-degree burn wound unders hypernatremic conditions
Harada, T., Izaki, S., Tsutsumi, H., et al. (1998) · Burns · doi:10.1016/s0305-4179(98)00034-5 · Cited by 33 · see citing works
Gallant‐Behm, C. L., Olson, M. E., & Hart, D. A. (2005) · Journal of Cutaneous Medicine and Surgery · doi:10.1007/s10227-005-0105-4 · Cited by 28 · see citing works
Self-citationAnimal models of wound contraction.
Hayward, P. G., & Mc, R. (1991) · PubMed · Cited by 26 · see citing works
Co-Cultured Human Mast Cells Stimulate Fibroblast-Mediated Contraction of Collagen Gels
Sköld, C. M., Ohkuni, Y., Liu, X. D., et al. (2001) · Inflammation · doi:10.1023/a:1007075628316 · Cited by 24 · see citing works
Tredget, E. E., Iwashina, T., Scott, P. G., & Ghahary, A. (1997) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(97)00122-9 · Cited by 22 · see citing works
Hart, D. A., Frank, C. B., Kydd, A. S., et al. (2005) · Springer eBooks · doi:10.1007/1-84628-050-8_6 · Cited by 21 · see citing works
Self-citationTherapeutic Effect and Pharmacokinetics of Ketotifen Transdermal Delivery System
Chiang, C., Chen, J.-L., Liu, Y., et al. (1998) · Drug Development and Industrial Pharmacy · doi:10.3109/03639049809085612 · Cited by 20 · see citing works
Beare, A. H. M., Krane, S. M., & Ferguson, M. W. J. (2005) · Wound Repair and Regeneration · doi:10.1111/j.1067-1927.2005.130105.x · Cited by 11 · see citing works
Bhattacharya, A., & Sk, G. (2001) · PubMed · Cited by 9 · see citing works
Fibreless diet and diverticulosis.
O'Grady, T. T. (1977) · PubMed · Cited by 6 · see citing works
Harunari, N., Engrav, L. H., Armendariz, R. T., et al. (2008) · Wound Repair and Regeneration · doi:10.1111/j.1067-1927.2005.130215cq.x · Cited by 1 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Hildebrand KA, Zhang M, Salo PT, Hart DA. Post-trau- matic elbow contractures are associated with elevations in mast cells and neuropeptides in the joint capsule. Wound Repair Regen 2007; 15: A20.
Cited by
Sorted by citations
Are mast cells instrumental for fibrotic diseases?
Overed-Sayer, C., Rapley, L., Mustelin, T., & Clarke, D. L. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2013.00174 · Cited by 105 · see citing works
The Importance of Mast Cells in Dermal Scarring
Wilgus, T. A., & Wulff, B. C. (2014) · Advances in Wound Care · doi:10.1089/wound.2013.0457 · Cited by 105 · see citing works
Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup>
Brash, D. E., & Goncalves, L. C. P. (2023) · Photochemistry and Photobiology · doi:10.1111/php.13781 · Cited by 16 · see citing works
- Authors
- Gallant‐Behm, C. L., Hildebrand, K. A., & Hart, D. A.
- Affiliations
- Northwestern University (US)
- University of Calgary (CA)
- Corresponding author
- Hart, David A.
- Venue
- Wound Repair and Regeneration
- Publisher
- Wiley
- Published
- 2008-03
- Volume
- 16
- Issue
- 2
- Pages
- 226-233
- ISSN
- 1067-1927 (ISSN-L)
- 1524-475X
- OpenAlex
- W2070167505
- Cited by
- 98
- References
- 42
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 5 · 2020: 13 · 2019: 1 · 2018: 7 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 9 · 2013: 11 · 2012: 1
- FWCI
- 6.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Wound Repair and Regeneration (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Calgary Foundation
- National Institutes of Health
- Canadian Institutes of Health Research
- Institute of Gender and Health
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Dermatology › Dermatologic Treatments and Research
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Keywords
- ketotifen, mast cell stabilizers, wound contraction, scar fibrosis, Large White pigs, full-thickness excisional wounds, re-epithelialization, collagen deposition, skin wound healing, mast cells
- MeSH terms
- Administration, Oral, Animals, Female, Fibrosis, Ketotifen, Mast Cells, Skin, Wound Healing, Sus scrofa
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
