Abstract
Chronic wounds pose considerable public health challenges and burden. Wound healing is known to require the participation of macrophages, but mechanisms remain unclear. The M1 phenotype macrophages have a known scavenger function, but they also play multiple roles in tissue repair and regeneration when they transition to an M2 phenotype. Macrophage precursors (mononuclear cells/monocytes) follow the influx of PMN neutrophils into a wound during the natural wound-healing process, to become the major cells in the wound. Natural wound-healing process is a four-phase progression consisting of hemostasis, inflammation, proliferation, and remodeling. A lag phase of 3–6 days precedes the remodeling phase, which is characterized by fibroblast activation and finally collagen production. This normal wound-healing process can be accelerated by the intracellular delivery of ATP to wound tissue. This novel ATP-mediated acceleration arises due to an alternative activation of the M1 to M2 transition (macrophage polarization), a central and critical feature of the wound-healing process. This response is also characterized by an early increased release of pro-inflammatory cytokines (TNF, IL-1 beta, IL-6), a chemokine (MCP-1), an activation of purinergic receptors (a family of plasma membrane receptors found in almost all mammalian cells), and an increased production of platelets and platelet microparticles. These factors trigger a massive influx of macrophages, as well as in situ proliferation of the resident macrophages and increased synthesis of VEGFs. These responses are followed, in turn, by rapid neovascularization and collagen production by the macrophages, resulting in wound covering with granulation tissue within 24 h.
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References
Berendt AR (2006) Counterpoint: hyperbaric oxygen for diabetic foot wounds is not effective. Clin Infect Dis 43:193–198
Boulton AJ (2013) The pathway to foot ulceration in diabetes. Med Clin North Am 97:775–790
Brancato SK, Albina JE (2011) Wound macrophages as key regulators of repair: origin, phenotype, and function. Am J Pathol 178:19–25
Chiang B, Essick E, Ehringer W, Murphree S, Hauck MA, Li M, Chien S (2007) Enhancing skin wound healing by direct intracellular ATP delivery. Am J Surg 193:213–218
Chien S (2006) Development of direct intracellular energy delivery techniques for treatment of tissue ischemia. Recent Res Devel Biophys 5:1–37
Chien S (2010) Intracellular ATP delivery using highly fusogenic liposomes. Methods Mol Biol 605:377–392
Cohen IK, Diegelmann RF, Yager DR, Wornum IL, Graham MF, Crossland MC (1999) Wound care and wound healing. In: Schwartz SI, Shires GT, Spencer FC, Daly JM, Fischer JE, Galloway AC (eds) Principles of surgery. McGraw-Hill, New York, NY, pp 263–295
Cooper GM (1997) The cell: a molecular approach. ASM Press, Washington, DC, pp 467–517
Davidson JM (1998) Wound repair. J Hand Ther 11:80–94
Davies LC, Jenkins SJ, Allen JE, Taylor PR (2013a) Tissue-resident macrophages. Nat Immunol 14:986–995
Davies LC, Rosas M, Jenkins SJ, Liao CT, Scurr MJ, Brombacher F, Fraser DJ, Allen JE, Jones SA, Taylor PR (2013b) Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat Commun 4:1–10
Delavary BM, van der Veer WM, van Egmond M, Niessen FB, Beelen RH (2011) Macrophages in skin injury and repair. Immunobiology 216:753–762
Ehrlich HP, Grislis G, Hunt TK (1972) Metabolic and circulatory contributions to oxygen gradients in wounds. Surgery 72:578–583
Fang RC, Galiano RD (2008) A review of becaplermin gel in the treatment of diabetic neuropathic foot ulcers. Biologics 2:1–12
Ferrante CJ, Leibovich SJ (2012) Regulation of macrophage pollarization and wound healing. Adv Wound Care 1:10–16
Fine NA, Mustoe TA (2001) Wound healing. In: Greenfield LJ (ed) Surgery: scientific principles and practice. Lippincott, Philadelphia, pp 69–86
Garash R, Bajpai A, Marcinkiewicz BM, Spiller KL (2016) Drug delivery strategies to control macrophages for tissue repair and regeneration. Exp Biol Med (Maywood) 241:1054–1063
Gordon P, Okai B, Hoare JI, Erwig LP, Wilson HM (2016) SOCS3 is a modulator of human macrophage phagocytosis. J Leukoc Biol 100:771–780
Gottrup F (2002) Oxygen, wound healing and the development of infection. Present status. Eur J Surg 168:260–263
Harding KG, Morris HL, Patel GK (2002) Science, medicine and the future: healing chronic wounds. BMJ 324:160–163
Howard JD, Sarojini H, Wan R, Chien S (2014) Rapid granulation tissue regeneration by intracellular ATP delivery-a comparison with regranex. PLoS One 9:1–14
Hunt TK, Pai MP (1972) The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg Gynecol Obstet 135:561–567
Im MJC, Hoopes JE (1970) Energy metabolism in healing skin wounds. J Surg Res 10:459–464
Kapellos TS, Iqbal AJ (2016) Epigenetic control of macrophage polarisation and soluble mediator gene expression during inflammation. Mediators Inflamm 2016:1–15
Kieran I, Knock A, Bush J, So K, Metcalfe A, Hobson R, Mason T, O’Kane S, Ferguson M (2013) Interleukin-10 reduces scar formation in both animal and human cutaneous wounds: results of two preclinical and phase II randomized control studies. Wound Repair Regen 21:428–436
Kotwal GJ, Sarojini H, Chien S (2015) Pivotal role of ATP in Macrophages fast tracking wound repair and regeneration. Wound Repair Regen 23(5):724–727
Landen NX, Li D, Stahle M (2016) Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci 73:3861–3885
Levenson SM, Demetriou AA (1992) Metabolic factors. In: Cohen IK, Diegelmann RF, Lindblad WJ (eds) Wound healing: biochemical & clinical aspects. Saunders, Philadelphia, pp 248–273
Lindblad WJ (2007) Editorial: how should one study wound healing? Wound Repair Regen 14:515
Martin P, Leibovich SJ (2005) Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol 15:599–607
Medina A, Scott PG, Ghahary A, Tredget EE (2005) Pathophysiology of chronic nonhealing wounds. J Burn Care Rehabil 26:306–319
Niinikoski J (2003) Hyperbaric oxygen therapy of diabetic foot ulcers, transcutaneous oxymetry in clinical decision making. Wound Repair Regen 11:458–461
Niinikoski J, Gottrup F, Hunt TK (1991) The role of oxygen in wound repair. In: Janssen H, Rooman R, Robertson JIS (eds) Wound healing. Wrightson Biomedical, Petersfield, pp 165–174
Novak ML, Koh TJ (2013) Macrophage phenotypes during tissue repair. J Leukoc Biol 93:875–881
Ogle ME, Segar CE, Sridhar S, Botchwey EA (2016) Monocytes and macrophages in tissue repair: implications for immunoregenerative biomaterial design. Exp Biol Med (Maywood) 241:1084–1097
Ovington LG, Schultz GS (2004) The physiology of wound healing. In: Morison MJ, Ovington LG, Wilkie K, Moffatt CJ, Franks PJ (eds) Chronic wound care. Mosby, St. Louis, pp 83–100
Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684
Puisieux F, Fattal E, Lahiani M, Auger J, Jouannet P, Couvreur P, Delattre J (1994) Liposomes, an interesting tool to deliver a bioenergetic substrate (ATP). in vitro and in vivo studies. J Drug Target 2:443–448
Schaffer M, Witte M, Becker HD (2002) Models to study ischemia in chronic wounds. Int J Low Extrem Wounds 1:104–111
Silver IA (1980) The physiology of wound healing. In: Hunt TK (ed) Wound healing and wound infection: theory and surgical practice. Appleton, New York, NY, pp 11–31
Smith DG, Mills WJ, Steen RG, Williams D (1999) Levels of high energy phosphate in the dorsal skin of the foot in normal and diabetic adults: the role of 31P magnetic resonance spectroscopy and direct quantification with high pressure liquid chromatography. Foot Ankle Int 20:258–262
Snyder RJ, Lantis J, Kirsner RS, Shah V, Molyneaux M, Carter MJ (2016) Macrophages: a review of their role in wound healing and their therapeutic use. Wound Repair Regen 24:613–629
Stadelmann WK, Digenis AG, Tobin GR (1998) Impediments to wound healing. Am J Surg 176:39S–47S
Theoret CL (2005) The pathophysiology of wound repair. Vet Clin North Am Equine Pract 21:1–13
Valls MD, Cronstein BN, Montesinos MC (2009) Adenosine receptor agonists for promotion of dermal wound healing. Biochem Pharmacol 77:1117–1124
Wang D, Huang NN, Heppel LA (1990) Extracellular ATP shows synergistic enhancement of DNA synthesis when combined with agents that are active in wound healing or as neurotransmitters. Biochem Biophys Res Commun 166:251–258
Wang J, Zhang Q, Wan R, Mo Y, Li M, Tseng M, Chien S (2009) Intracellular ATP-delivery enhanced skin wound healing in rabbits. Ann Plast Surg 62:180–186
Wang J, Wan R, Mo Y, Li M, Zhang Q, Chien S (2010) Intracellular delivery of ATP enhanced healing process in full-thickness skin wounds in diabetic animals. Am J Surg 199:823–832
Yang C, Sarojini H, Chien S (2015) Chromatin remodeling complex activation results in rapid in situ macrophage proliferation in wound healing. Wound Repair Regen 23(2):A46
Zhu Z, Ding J, Ma Z, Iwashina T, Tredget EE (2016) Systemic depletion of macrophages in the subacute phase of wound healing reduces hypertrophic scar formation. Wound Repair Regen 24:644–656
Acknowledgment
These authors were supported in part by grants DK74566, AR52984, HL114235, GM106639, DK104625, DK105692, and OD021317 from the National Institutes of Health and in part from the Kentucky Cabinet for Economic Development, Office of Entrepreneurship, under the Grant Agreement KSTC-184-512-12-138, KSTC-184-512-14-174 with the Kentucky Science and Technology Corporation. Funding for the open access charge will be provided by a National Institutes of Health grant.
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Kotwal, G.J., Chien, S. (2017). Macrophage Differentiation in Normal and Accelerated Wound Healing. In: Kloc, M. (eds) Macrophages. Results and Problems in Cell Differentiation, vol 62. Springer, Cham. https://doi.org/10.1007/978-3-319-54090-0_14
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DOI: https://doi.org/10.1007/978-3-319-54090-0_14
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