PATHOPHYSIOLOGICAL ASPECTS OF WOUND HEALING IN NORMAL AND DIABETIC FOOT

Cover Page

Abstract


The main cause of long-term healing of ulcers in patients with diabetic foot is considered to be direct mechanical damage when walking due to reduced sensitivity to due to neuropathy, hyperglycemia, infection and peripheral artery disease. These factors determine the standard approaches to the treatment of diabetic foot, which include: offloading, glycemic control, debridement of ulcers, antibiotic therapy and revascularization. Recently, however, disturbances in the healing process of the skin in diabetes recognized an additional factor affecting the timing of healing patients with diabetic foot. Improved understanding and correction of cellular, molecular and biochemical abnormalities in chronic wound in combination with standard of care for diabetic foot gives new hope to solve the problem of ulcer healing in diabetes.

 


About the authors

N. V. Maksimova

Sechenov First Moscow State Medical University, Russian Federation

Author for correspondence.
Email: maximova.nadezhda@gmail.com

Russian Federation кандидат медицинских наук, ассистент кафедры эндокринологии лечебного факультета Первого МГМУ им. И.М. Сеченова Адрес: 119992, Москва, ул. Трубецкая, д. 8, стр. 2, тел.: +7 (495) 530-32-16

A. V. Lyundup

Sechenov First Moscow State Medical University, Russian Federation

Email: lyundup@gmail.com

Russian Federation кандидат медицинских наук, заведующий отделом биомедицинских исследований НИИ молекулярной медицины Первого МГМУ им. И.М. Сеченова Адрес: 119992, Москва, ул. Трубецкая, д. 8, стр. 2, тел.: +7 (495) 609-14-00

R. O. Lyubimov

Sechenov First Moscow State Medical University, Russian Federation

Email: lubimov@onet.ru

Russian Federation аспирант Первого МГМУ им. И.М. Сеченова Адрес: 119992, Москва, ул. Трубецкая, д. 8, стр. 2, тел.: +7 (495) 530-32-16

G. A. Mel'nichenko

Sechenov First Moscow State Medical University, Russian Federation

Email: teofrast2000@mail.ru

Russian Federation академик РАН, доктор медицинских наук, профессор кафедры эндокринологии лечебного факультета Первого МГМУ им. И.М. Сеченова Адрес: 119992, Москва, ул. Трубецкая, д. 8, стр. 2, тел.: +7 (495) 609-14-00

V. N. Nikolenko

Sechenov First Moscow State Medical University, Russian Federation
M.V. Lomonosov Moscow State University, Russian Federation

Email: nikolenko@mma.ru

Russian Federation доктор медицинских наук, профессор кафедры анатомии человека Первого МГМУ им. И.М. Сеченова, заведующий кафедрой нормальной и топографической анатомии факультета фундаментальной медицины МГУ им. М.В. Ломоносова Адрес: 119992, Москва, ул. Трубецкая, д. 8, стр. 2, тел.: +7 (495) 609-14-00

References

  1. Галстян Г.Р., Дедов И.И. Организация помощи больным с синдромом диабетической стопы в Российской Федерации. Сахарный диабет. 2009; 1: 4–7.
  2. Margolis D.J., Kantor J., Berlin J.A. Healing of diabetic neuropathic foot ulcers receiving standard treatment. Diabetes Care. 1999; 22 (5): 692–695.
  3. Prompers L., Huijberts M., Schaper N., Apelqvist J., Bakker K., Edmonds M., Holstein P., Jude E., Jirkovska A., Mauricio D., Piaggesi A., Reike H., Spraul M., Van Acker K., Van Baal S., Van Merode F., Uccioli L., Urbancic V., Ragnarson Tennval G. Resource utilisation and costs associated with the treatment of diabetic foot ulcers. Prospective data from the Eurodiale Study. Diabetologia. 2008; 51: 1826–1834.
  4. Vamos E.P., Bottle A., Majeed A., Millett C. Trends in lower extremity amputations in people with and without diabetes in England, 1996-2005. Diabetes Res Clin Pract. 2010; 87: 275–282.
  5. Singer A.J., Clark R.A. Cutaneous wound healing. N. Engl. J. Med. 1999; 341: 738–746;
  6. Enoch S., Price P.E. Cellular, molecular and biochemical differences in the pathophysiology of healing between acute wounds, chronic wounds and wounds in the aged. World Wide Wounds. 2004. URL: http:// www.worldwidewounds.com (available: 27.11.2014).
  7. Leibovich S.J., Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am. J. Pathol. 1975; 78 (1): 71–100.
  8. Schreml S., Szeimies R.M., Prantl L., Landthaler M., Babilas P. Wound healing in the 21st century. J. Am. Acad. Dermatol. 2010; 63 (5): 866–881.
  9. Оболенский В.Н. Хроническая рана: обзор современных методов лечения. РМЖ. 2013; 5: 282–289.
  10. Kane C.J., Hebda P.A., Mansbridge J.N., Hanawalt P.C. Direct evidence for spatial and temporal regulation of transforming growth factor beta 1 expression during cutaneous wound healing. J. Cell. Physiol. 1991; 148 (1): 157–173.
  11. Igarashi A., Okochi H., Bradham D.M., Grotendorst G.R. Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair. Mol. Biol. Cell. 1993; 4 (6): 637–645.
  12. Marchese C., Felici A., Visco V., Lucania G., Igarashi M., Picardo M., Frati L., Torrisi M.R. Fibroblast growth factor 10 induces proliferation and differentiation of human primary cultured keratinocytes. J. Invest. Dermatol. 2001; 116 (4): 623–628.
  13. Werner S., Beer H.D., Mauch C., Lüscher B., Werner S. The Mad1 transcription factor is a novel target of activin and TGF-beta action in keratinocytes: possible role of Mad1 in wound repair and psoriasis. Oncogene. 2001; 20 (51): 7494–7504.
  14. Sorrell J.M., Baber M.A., Caplan A.I. Site matched papillary and reticular human dermal fibroblasts differ in their release of specific growth factors/cytokines and in their interaction with keratinocytes. J. Cell. Physiol. 2004; 200 (1): 134–145.
  15. Grinnell F. Fibroblasts, myofibroblasts and wound contraction. J. Cell. Biol. 1994; 124 (4): 401–404.
  16. Blomme E.A., Sugimoto Y., Lin Y.C., Capen C.C., Rosol T.J. Parathyroid hormone-related protein is a positive regulator of keratinocyte growth factor expression by normal dermal fibroblasts. Mol. Cell. Endocrinol. 1999; 152 (1–2): 189–197.
  17. Tonnesen M.G., Feng X., Clark R.A. Angiogenesis in wound healing. J. Investig. Dermatol. Symp. Proc. 2000; 5 (1): 40–46.
  18. Lauer G., Sollberg S., Cole M., Flamme I., Stürzebecher J., Mann K., Krieg T., Eming S.A. Expression and proteolysis of vascular endothelial growth factor is increased in chronic wounds. J. Invest. Dermatol. 2000; 115 (1): 12–18.
  19. Clark R.A., Fitzpatrick T.B., Eisen A.Z., Wolff K. Mechanisms of cutaneous wound repair. Dermatology in General Medicine. New York: McGraw-Hill. 1993; 1: 473–486.
  20. Wilgus T.A., Matthies M.A., DiPietro L.A. Novel Function for Vascular Endothelial Growth Factor Receptor-1 on Epidermal Keratinocytes. Am. J. Pathol. 2005; 167 (5): 1257–1266.
  21. Clark R.A., Nielsen L.D., Welch M.P., McPherson J.M. Collagen matrices attenuate the collagen-synthetic response of cultured fibroblasts to TGF-beta. J. Cell. Sci. 1995; 108 (3): 1251–1261.
  22. Welch M.P., Odland G.F., Clark R.A. Temporal relationships of F-actin bundle formation, collagen and fibronectin matrix assembly, and fibronectin receptor expression to wound contraction. J. Cell. Biol. 1990; 110 (1): 133–145.
  23. Levenson S.M., Geever E.F., Crowley L.V., Oates J.F., Berard C.W., Rosen H. The healing of rat skin wounds. Ann. Surg. 1965; 161: 293–308.
  24. Tonnesen M.G., Feng X., Clark R.A. Angiogenesis in wound healing. J. Investig. Dermatol. Symp. Proc. 2000; 5 (1): 40–46.
  25. Desmoulière A., Redard M., Darby I., Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am. J. Pathol. 1995; 146 (1): 56–66.
  26. Jürgensmeier J.M., Schmitt C.P., Viesel E., Höfler P., Bauer G. Transforming growth factor beta-treated normal fibroblasts eliminate transformed fibroblasts by induction of apoptosis. Cancer Res. 1994; 54 (2): 393–398.
  27. Wound Healing Society. Guidelines for the best care of chronic wounds. Wound Repair Regen. 2006; 14: 647–710.
  28. International Consensus on the Diabetic Foot and Practical Guidelines on the Management and the Prevention of the Diabetic Foot. International Working Group on the Diabetic Foot. 2007. URL: http://www.iwgdf.org (available: 27.11.2014).
  29. Brem H., Golinko M.S., Stojadinovic O., Kodra A., Diegelmann R.F., Vukelic S. et al. Primary cultured fibroblasts derived from patients with chronic wounds: a methodology to produce human cell lines and test putative growth factor therapy such as GMCSF. J. Transl. Med. 2008; 6: 75.
  30. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005; 366 (9498): 1736–1743.
  31. Токмакова А.Ю., Доронина Л.П., Страхова Г.Ю. Хронические раны и сахарный диабет: современная концепция и перспективы консервативного лечения. Сахарный диабет. 2010; 4: 63–68.
  32. Mulder G.D. Diabetic foot ulcers: old problems — new technologies. Nephrol. Dial. Transplant. 2001; 16 (4): 695–669.
  33. Silhl N. Diabetes and wound healing. J. Wound Care. 1998; 7: 47–51.
  34. American Diabetes Association. Consensus Development Conference on Diabetic Foot Wound Care. Diabetes Care. 1999; 22 (8): 1354–1360.
  35. Expert Recommendations for Optimizing Outcomes Utilizing Apligraf for Diabetic Foot Ulcers. URL: http://www.podiatrytoday. com/files/PT_orgo.pdf (available: 27.11.2014).
  36. Hennessey P.J., Ford E.G., Black C.T., Andrassy R.J. Wound collagenase activity correlates directly with collagen glycosylation in diabetic rats. J. of Pediatric Surgery. 1990; 25 (1): 75–78.
  37. Spravchikov N., Sizyakov G., Gartsbein M., Accili D., Tennenbaum T., Wertheimer E. Glucose effects on skin keratinocytes: implications for diabetes skin complications. Diabetes. 2001; 50 (7): 1627–1635.
  38. Marhoffer W., Stein M., Maeser E., Federlin K. Impairment of polymorphonuclear leukocyte function and metabolic control of diabetes. Diabetes Care. 1992; 15 (2): 256–260.
  39. Tsourdi Е., Barthel А., Rietzsch Н., Reichel А., Bornstein S.R. Current Aspects in the Pathophysiology and Treatment of Chronic Wounds in Diabetes Mellitus. Biomed. Res. Intern. 2013; 6.
  40. Creager M.A., Lüscher T.F., Cosentino F., Beckman J.A. Review: Clinical Cardiology: New Frontiers Diabetes and Vascular Disease Pathophysiology. URL: http://circ.ahajournals.org/ content/108/12/1527.full (available: 27.11.2014).
  41. Devaraj S., Venugopal S.K., Singh U., Jialal I. Hyperglycemia Induces Monocytic Release of Interleukin-6 via Induction of Protein Kinase C-α and -β. Diabetes. 2005; 54 (1): 85–91.
  42. Gonzalez Y., Herrera M.T., Soldevila G., Garcia-Garcia L., Fabián G., Pérez Armendariz E.M., Bobadilla K., GuzmánBeltrán S., Sada E., Torres M. High glucose concentrations induce TNF-α production through the down-regulation of CD33 in primary human monocytes. BMC. 2012; 13: 19.
  43. VanDam S., Gispen W.H., Bravenboer B., Asbeck B.S., Erkelens D.W., Marx J.M. The role of oxidative stress in neuropathy and other diabetic complications. Diabetes Metabol. Rev. 1995; 11 (3): 181–192.
  44. Страхова Г.Ю., Арбузова М.И., Токмакова А.Ю. Эффективность коллагенсодержащих повязок в комплексной терапии хронических раневых дефектов у больных сахарным диабетом. Сахарный диабет. 2007; 4: 30–34.
  45. Schultz G.S. Molecular analysis of the environment of healing and chronic wounds: cytokines, proteases and growth factors. Wounds.1998; 10: 1–9.
  46. Schultz G.S. Extracellular matrix: review of its roles in acute and chronic wounds. URL: http://www.worldwidewounds.com/2005/ august/Schultz/Extrace-Matric-Acute-Chronic-Wounds.html (available: 27.11.2014).
  47. Vasquez R., Marien B.J., Gram C., Goodwin D.G., Menzoian J.O., Raffetto J.D. Proliferative capacity of venous ulcer wound fibroblasts in the presence of platelet derived growth factor. Vasc. Endovascul. Surg. 2004; 38 (4): 355–360.
  48. Brem H., Golinko M.S., Stojadinovic O., Kodra A., Diegelmann R.F., Vukelic S. Primary cultured fibroblasts derived from patients with chronic wounds: a methodology to produce human cell lines and test putative growth factor therapy such as GMCSF. J Transl. Med. 2008; 6: 75.
  49. Loots M.A., Lamme E.N., Mekkes J.R., Bos J.D., Middelkoop E. Cultured fibroblasts from chronic diabetic wounds on the lower extremity (non-insulin-dependent diabetes mellitus) show disturbed proliferation. Arch. Dermatol. Res. 1999; 291 (2–3): 93–99.
  50. Siqueira M.F., Li J., Chehab L., Desta T., Chino T., Krothpali N. et al. Impaired wound healing in mouse models of diabetes is mediated by TNF-alpha dysregulation and associated with enhanced activation of fork head box O1 (FOXO1). Diabetologia. 2010; 53 (2): 378–388.
  51. Agren M.S., Eaglstein W.H., Ferguson M.W., Harding K.G., Moore K., Saarialho-Kere U.K., Schultz G.S. Causes and effects of chronic inflammation in venous leg ulcers. Acta Derm. Venereol. (Stockh). 2000; 210: 3–17.
  52. Desmoulière A., Chaponnier C., Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Reg. 2005; 13 (1): 7–12.
  53. Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J. Pathol. 2003; 200 (4): 500–503.
  54. Gibran N.S., Jang Y.C., Isik F.F., Greenhalgh D.G., Muffley L.A., Underwood R.A., Usui M.L., Larsen J., Smith D.G., Bunnett N., Ansel J.C., Olerud J.E. Diminished neuropeptide levels contribute to the impaired cutaneous healing response associated with diabetes mellitus. J. Surg. Res. 2002; 108: 122–128.
  55. Richards A.M., Floyd D.C., Terenghi G., McGrouther D.A. Cellular changes in denervated tissue during wound healing in a rat model. Brit. J. Dermatol.1999; 140: 1093–1099.
  56. Pradhan L., Andersen N.D., LoGerfo F.W., Veves A. Molecular Targets for Promoting Wound Healing in Diabetes. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery. 2007; 1: 1–13.
  57. Kwak B.R., Pepper M.S., Gros D.B., Meda P. Inhibition of endothelial wound repair by dominant negative connexin inhibitors. Mol. Biol. Cell. 2001; 12 (4): 831–845.
  58. Oviedo–Orta E., Errington R.J., Evans W.H. Gap junction intercellular communication during lymphocyte trans endothelial migration. Cell. Biol. Int. 2002; 26 (3): 253–263.
  59. Locke D., Perusinghe N., Newman T., Jayatilake H., Evans W.H., Monaghan P. Developmental expression and assembly of connexins into homomeric and heteromeric gap junction hemichannels in the mouse mammary gland. J. Cell. Physiol. 2000; 183 (2): 228–237.
  60. Oviedo-Orta E., Hoy T., Evans W.H. Intercellular communication in the immune system: differential expression of connexin 40 and 43, and perturbation of gap junction channel functions in peripheral blood and tonsil human lymphocyte subpopulations. Immunology. 2000; 99 (4): 578–590.
  61. Bowman N.N., Donahue H.J., Ehrlich H.P. Gap junctional intercellular communication contributes to the contraction of rat osteoblast populated collagen lattices. J. Bone Miner. Res. 1998; 13 (11): 1700–1706.
  62. Ehrlich H.P., Rittenberg T. Differences in the mechanism for high- versus moderate-density fibroblast-populated collagen lattice contraction. J. Cell Physiol. 2000; 185 (3): 432–439.
  63. Coutinho P., Qiu C., Frank S., Tamber K., Becker D. Dynamic changes in connexin expression correlate with key events in the wound healing process. Cell. Biol. Int. 2003; 27 (7): 525–541.
  64. Salomon D., Masgrau E., Vischer S., Ullrich S., Dupont E., Sappino P. Topography of mammalian connexins in human skin. J. Invest. Dermatol. 1994; 103 (2): 240–224.
  65. Goliger J.A., Paul D.L. Wounding alters epidermal connexin expression and gap junction-mediated intercellular communication. Mol. Biol. Cell. 1995; 6 (11): 1491–1501.
  66. Saitoh M., Oyamada M., Oyamada Y., Kaku T., Mori M. Changes in the expression of gap junction proteins (connexins) in hamster tongue epithelium during wound healing and carcinogenesis. Carcinogenesis. 1997; 18 (7): 1319–1328.
  67. Qiu C., Coutinho P., Frank S., Franke S., Law L.Y., Martin P. et al. Targeting connexin 43 expression accelerates the rate of wound repair. Curr. Biol. 2003; 13 (19): 1697–1703.

Statistics

Views

Abstract - 461

PDF (Russian) - 1638

Cited-By


Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM

PlumX

Dimensions



Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies