Morphometric Changes in Rat Periwound Skin During Healing of Excisional Wounds After Exposure to Chronic Social Stress
DOI:
https://doi.org/10.20535/ibb.2025.9.1.310092Keywords:
wound healing, chronic social stress, periwound, epidermis, dermis, subcutaneous tissueAbstract
Background. Chronic stress is the most common systemic factor that negatively affects the body's overall resistance, including wound healing. While many aspects of skin recovery after a surgical wound are well defined, the involvement of cells in the periwound rarea emains unsufficiently studied.
Objective. To determine the morphological features of the periwound skin at different stages of the healing process after exposure to chronic social stress.
Methods. Chronic social stress was modeled through long-term psychoemotional exposure in Wistar laboratory rats of the experimental group. Animals in both control and experimental groups were wounded in the interscapular area by skin excision. The material of the periwounds was collected on the 1st, 3rd, 7th, 14th and 30th days of wound healing and processed according to standard histological methods.
Results. Exposure to chronic social stress led to thinning of the skin layers even before wounding. Visual wound healing was delayed. The main reparative processes by phases (inflammation, proliferation, and remodulation) also occurred with significant delays.
Conclusions. Aggressive-dominant social stress is a rather strong damaging factor for susceptible animals, leading to impaired physiological skin regeneration. This was evident in the thinning of skin layers observed in histological samples even before wound application, resulting from reduced proliferation and differentiation processes. The negative consequences of chronic social stress were further manifested in the healing of a surgical wound: the repair processes during the main phases, in particular inflammation and proliferation, were delayed, which ultimately led to the chronicity of reparative regeneration.
References
Delavary BM, van der Veer WM, van Egmond M, Niessen FB, Beelen RHJ. Macrophages in skin injury and repair. Immunobiology. 2011;216(7):753-62. DOI: 10.1016/j.imbio.2011.01.001
Mostafavi Yazdi SJ, Baqersad J. Mechanical modeling and characterization of human skin: A review. Journal of Biomechanics. 2022;130:110864. DOI: 10.1016/j.jbiomech.2021.110864
Mansfield K, Naik S. Unraveling immune-epithelial interactions in skin homeostasis and injury. Yale Journal of Biology and Medicine. 2020;93(1):133-43.
Jiao Q, Zhi L, You B, Wang G, Wu N, Jia Y. Skin homeostasis: Mechanism and influencing factors. Journal of Cosmetic Dermatology. 2024;23(5):1518-26. DOI: 10.1111/jocd.16155
Broughton G, Janis JE, Attinger CE. Wound healing: An overview. Plastic and Reconstructive Surgery. 2006;117(7 Suppl):1e-S-32e-S. DOI: 10.1097/01.prs.0000222562.60260.f9
Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nature Reviews Molecular Cell Biology. 2024;25(8):599-616. DOI: 10.1038/s41580-024-00715-1
de Oliveira Gonzalez AC, Costa TF, de Araújo Andrade Z, Peixoto Medrado ARA. Wound healing - A literature review. Anais Brasileiros de Dermatologia. 2016;91(5):614-20. DOI: 10.1590/abd1806-4841.20164741
Baum CL, Arpey CJ. Normal cutaneous wound healing: Clinical correlation with cellular and molecular events. Dermatologic Surgery. 2005;31(6):674-86. DOI: 10.1111/j.1524-4725.2005.31612
Guo S, DiPietro LA. Factors affecting wound healing. Journal of Dental Research. 2010;89(3):219-29. DOI: 10.1177/0022034509359125
Godbout JP, Glaser R. Stress-induced immune dysregulation: implications for wound healing, infectious disease and cancer. Journal of Neuroimmune Pharmacology. 2006;1(4):421-7. DOI: 10.1007/s11481-006-9036-0
Wynn M, Holloway S. The impact of psychological stress on wound healing: a theoretical and clinical perspective. Wounds UK. 2019;15(3):20-7.
Gouin J-P. Chronic stress, immune dysregulation, and health. American Journal of Lifestyle Medicine. 2011;5(6):476-85. DOI: 10.1177/1559827610395467
Grigorieva SM, Starosyla DB, Rybalko SL, Motronenko VV, Lutsenko TM, Galkin OYu. Effect of recombinant human interleukin-7 on Pseudomonas aeruginosa wound infection. The Ukrainian Biochemical Journal. 2019;91(5):7-15. DOI: 10.15407/ubj91.05.007
Stress in America 2022: Concerned for the future, beset by inflation, 2022. American Psychological Association. Available from: https://www.apa.org/news/press/releases/stress/2022/concerned-future-inflation
Stress in America 2023: A nation recovering from collective trauma, 2023. American Psychological Association. Available from: https://www.apa.org/news/press/releases/stress/2023/collective-trauma-recovery
Theoharides TC. The impact of psychological stress on mast cells. Annals of Allergy, Asthma & Immunology. 2020;125(4):388-92. DOI: 10.1016/j.anai.2020.07.007
Komi DEA, Khomtchouk K, Santa Maria PL. A review of the contribution of mast cells in wound healing: Involved molecular and cellular mechanisms. Clinical Reviews in Allergy & Immunology. 2020;58(3):298-312. DOI: 10.1007/s12016-019-08729-w
Virtanen MI, Brinchmann MF, Patel DM, Iversen MH. Chronic stress negatively impacts wound healing, welfare, and stress regulation in internally tagged Atlantic salmon (Salmo salar). Frontiers in Physiology. 2023;14:1147235. DOI: 10.3389/fphys.2023.1147235
Maassen S, Coenen B, Ioannidis M, Harber K, Grijpstra P, Van den Bossche J, van den Bogaart G. Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages. Redox Biology. 2023;59:102591. DOI: 10.1016/j.redox.2022.102591
Dorsett-Martin WA. Rat models of skin wound healing: A review. Wound Repair and Regeneration. 2004;12(6):591-9. DOI: 10.1111/j.1067-1927.2004.12601.x
Rippon MG, Rogers AA, Ousey K, Atkin L, Williams K. The importance of periwound skin in wound healing: An overview of the evidence. Journal of Wound Care. 2022;31(8):648-59. DOI: 10.12968/jowc.2022.31.8.648
Avci P, Sadasivam M, Gupta A, De Melo WC, Huang Y-Y, Yin R, et al. Animal models of skin disease for drug discovery. Expert Opinion on Drug Discovery. 2013;8(3):331-55. DOI: 10.1517/17460441.2013.761202
Ben-Ami Bartal I, Rodgers DA, Bernardez Sarria MS, Decety J, Mason P. Pro-social behavior in rats is modulated by social experience. eLife. 2014;3:e01385. DOI: 10.7554/eLife.01385
Rygula R, Abumaria N, Flügge G, Fuchs E, Rüther E, Havemann-Reinecke U. Anhedonia and motivational deficits in rats: Impact of chronic social stress. Behavioural Brain Research. 2005;162(1):127-34. DOI: 10.1016/j.bbr.2005.03.009
Masis-Calvo M, Schmidtner AK, de Moura Oliveira VE, Grossmann CP, de Jong TR, Neumann ID. Animal models of social stress: the dark side of social interactions. Stress. 2018;21(5):417-32. DOI: 10.1080/10253890.2018.1462327
Nakano Y. Stress-induced modulation of skin immune function: two types of antigen-presenting cells in the epidermis are differentially regulated by chronic stress. British Journal of Dermatology. 2004;151(1):50-64. DOI: 10.1111/j.1365-2133.2004.05980.x
Webster Marketon JI, Glaser R. Stress hormones and immune function. Cellular Immunology. 2008;252(1-2):16-26. DOI: 10.1016/j.cellimm.2007.09.006
Vileikyte L. Stress and wound healing. Clinics in Dermatology. 2007;25(1):49-55. DOI: 10.1016/j.clindermatol.2006.09.005
Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Frontiers in Neuroendocrinology. 2003;24(3):151-80. DOI: 10.1016/j.yfrne.2003.07.001
Sandig H, McDonald J, Gilmour J, Arno M, Lee TH, Cousins DJ. Fibronectin is a TH1-specific molecule in human subjects. Journal of Allergy and Clinical Immunology. 2009;124(3):528-535.e5. DOI: 10.1016/j.jaci.2009.04.036
Shastri M, Sharma M, Sharma K, Sharma A, Minz RW, Dogra S, Chhabra S. Cutaneous-immuno-neuro-endocrine (CINE) system: A complex enterprise transforming skin into a super organ. Experimental Dermatology. 2024;33(3):e15029. DOI: 10.1111/exd.15029
Parker GA, Picut CA (ed.). Atlas of histology of the juvenile rat. Amsterdam, Netherlands: Academic Press, 2016, 462 p.
Dhabhar FS. Acute stress enhances while chronic stress suppresses skin immunity: The role of stress hormones and leukocyte trafficking. Annals of the New York Academy of Sciences. 2000;917(1):876-93. DOI: 10.1111/j.1749-6632.2000.tb05454.x
Passeron T, Zouboulis CC, Tan J, Andersen ML, Katta R, Lyu X, et al. Adult skin acute stress responses to short-term environmental and internal aggression from exposome factors. Journal of the European Academy of Dermatology and Venereology. 2021;35(10):1963-75. DOI: 10.1111/jdv.17432
Raziyeva K, Kim Y, Zharkinbekov Z, Kassymbek K, Jimi S, Saparov A. Immunology of acute and chronic wound healing. Biomolecules. 2021;11(5):700. DOI: 10.3390/biom11050700
Chapman CR, Tuckett RP, Song CW. Pain and stress in a systems perspective: Reciprocal neural, endocrine, and immune interactions. The Journal of Pain. 2008;9(2):122-45. DOI: 10.1016/j.jpain.2007.09.006
Picard K, St-Pierre M-K, Vecchiarelli HA, Bordeleau M, Tremblay M-E. Neuroendocrine, neuroinflammatory, and pathological outcomes of chronic stress: A story of microglial remodeling. Neurochemistry International. 2021;145:104987. DOI: 10.1016/j.neuint.2021.104987
Sengupta P. The Laboratory Rat: Relating Its Age With Human's. International Journal of Preventive Medicine. 2013;4(6):624-30.
Andreollo NA, dos Santos EF, Araújo MR, Lopes LR. Rat's age versus human's age: what is the relationship? ABCD. Arquivos Brasileiros de Cirurgia Digestiva. 2012;25(1):49–51. DOI: 10.1590/S0102-67202012000100011
Pereira VH, Campos I, Sousa N. The role of autonomic nervous system in susceptibility and resilience to stress. Current Opinion in Behavioral Sciences. 2017;14:102-7. DOI: 10.1016/j.cobeha.2017.01.003
Kyrou I, Tsigos C. Stress mechanisms and metabolic complications. Hormone and Metabolic Research. 2007;39(6):430-8. DOI: 10.1055/s-2007-981462
Makyeyeva LV, Aliyeva OG, Frolov OK. Quantitative characteristics of mast cells in the course of wound healing in rats with chronic social stress. Acta Biologica Ukrainica. 2021;(1):34-40. DOI: 10.26661/2410-0943-2021-1-03
Makyeyeva L, Frolov O, Aliyeva O. Functional changes in skin mast cells during surgical wound healing in rats after the influence of chronic social stress. Fitoterapia. 2024;(2):36-46. DOI: 10.32782/2522-9680-2024-2-36
Forsythe P. Mast cells in neuroimmune interactions. Trends in Neurosciences. 2019;42(1):43-55. DOI: 10.1016/j.tins.2018.09.006
Oskeritzian CA. Mast cells and wound healing. Advances in Wound Care. 2012;1(1):23-8. DOI: 10.1089/wound.2011.0357
Romana-Souza B, Chen L, DiPietro LA. Repeated stress-induced crosstalk between the sympathetic nervous system and mast cells contributes to delayed cutaneous wound healing in mice. Journal of Neuroimmunology. 2023;379:578104. DOI: 10.1016/j.jneuroim.2023.578104
Shimba A, Ikuta K. Control of immunity by glucocorticoids in health and disease. Seminars in Immunopathology. 2020;42(6):669-80. DOI: 10.1007/s00281-020-00827-8
de Almeida TF, de Castro Pires T, Monte-Alto-Costa A. Blockade of glucocorticoid receptors improves cutaneous wound healing in stressed mice. Experimental Biology and Medicine. 2016;241(4):353-8. DOI: 10.1177/1535370215612940
Bielefeld KA, Amini-Nik S, Alman BA. Cutaneous wound healing: recruiting developmental pathways for regeneration. Cellular and Molecular Life Sciences. 2013;70(12):2059-81. DOI: 10.1007/s00018-012-1152-9
Jiang D, Scharffetter-Kochanek K. Mesenchymal stem cells adaptively respond to environmental cues thereby improving granulation tissue formation and wound healing. Frontiers in Cell and Developmental Biology. 2020;8:697. DOI: 10.3389/fcell.2020.00697
Taves MD, Ashwell JD. Glucocorticoids in T cell development, differentiation, and function. Nature Reviews Immunology. 2021;21(4):233-43. DOI: 10.1038/s41577-020-00464-0
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 The Author(s)
This work is licensed under a Creative Commons Attribution 4.0 International License.
The ownership of copyright remains with the Authors.
Authors may use their own material in other publications provided that the Journal is acknowledged as the original place of publication and National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute” as the Publisher.
Authors are reminded that it is their responsibility to comply with copyright laws. It is essential to ensure that no part of the text or illustrations have appeared or are due to appear in other publications, without prior permission from the copyright holder.
IBB articles are published under Creative Commons licence:- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under CC BY 4.0 that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.
