Skip to main content
SpringerLink
Log in

Neuropeptides, Inflammation, and Diabetic Wound Healing: Lessons from Experimental Models and Human Subjects

  • Chapter
  • First Online:
The Diabetic Foot

Part of the book series: Contemporary Diabetes ((CDI))

Abstract

Diabetic peripheral neuropathy and vascular disease, along with trauma, have long been recognized as major risk factors for the development of diabetic foot ulcerations (DFUs). More recently, chronic inflammation, abnormal extracellular matrix (ECM) remodeling, and reduced wound neovascularization, as a result of dysregulated cell function with imbalanced secretion of cytokines, matrix metalloproteinases, and growth factors, have been implicated in DFU failure to heal. Therefore, researchers are now focusing their efforts on further understanding the cellular and molecular mechanisms of diabetes-associated impaired wound healing, in an attempt to identify new targets and novel potential therapeutic approaches for DFUs, which remain a serious unmet clinical need. A growing body of evidence suggests an important role of neuropeptides in skin repair, particularly in diabetes, where neuropeptide levels are diminished. On the other hand, there is emerging interest in dissecting the mechanisms of dysregulated inflammation, namely the changes in immune cells, such as macrophages and mast cells (MCs), in diabetic wound healing. Studies using in vitro and in vivo models of diabetic wound healing have considerably improved our understanding of the healing process. However, the currently available models have major caveats and are not ideal to study chronic, complicated, and multifactorial wounds, such as DFUs. In this chapter we summarize the involvement of neuropeptides and mast cells in diabetic wound healing, highlighting the most recent findings. We also discuss the benefits and limitations of the current wound healing models, emphasizing the need for confirmation and/or validation in multiple models and/or tissue specimens from human subjects.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ndip A, Ebah L, Mbako A. Neuropathic diabetic foot ulcers - evidence-to-practice. Int J Gen Med. 2012;5:129–34.

    PubMed  PubMed Central  Google Scholar 

  2. Pradhan L, Nabzdyk C, Andersen ND, LoGerfo FW, Veves A. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev Mol Med. 2009;11:e2.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gibran NS, Jang YC, Isik FF, Greenhalgh DG, Muffley LA, Underwood RA, et al. Diminished neuropeptide levels contribute to the impaired cutaneous healing response associated with diabetes mellitus. J Surg Res. 2002;108(1):122–8.

    Article  CAS  PubMed  Google Scholar 

  4. Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev. 2006;86(4):1309–79.

    Article  CAS  PubMed  Google Scholar 

  5. da Silva L, Carvalho E, Cruz MT. Role of neuropeptides in skin inflammation and its involvement in diabetic wound healing. Expert Opin Biol Ther. 2010;10(10):1427–39.

    Article  PubMed  CAS  Google Scholar 

  6. Bolton TB, Clapp LH. Endothelial-dependent relaxant actions of carbachol and substance P in arterial smooth muscle. Br J Pharmacol. 1986;87(4):713–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hokfelt T, Kellerth JO, Nilsson G, Pernow B. Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neurons. Brain Res. 1975;100(2):235–52.

    Article  CAS  PubMed  Google Scholar 

  8. Ziche M, Morbidelli L, Pacini M, Geppetti P, Alessandri G, Maggi CA. Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res. 1990;40(2):264–78.

    Article  CAS  PubMed  Google Scholar 

  9. Villablanca AC, Murphy CJ, Reid TW. Growth-promoting effects of substance P on endothelial cells in vitro. Synergism with calcitonin gene-related peptide, insulin, and plasma factors. Circ Res. 1994;75(6):1113–20.

    Article  CAS  PubMed  Google Scholar 

  10. Kahler CM, Sitte BA, Reinisch N, Wiedermann CJ. Stimulation of the chemotactic migration of human fibroblasts by substance P. Eur J Pharmacol. 1993;249(3):281–6.

    Article  CAS  PubMed  Google Scholar 

  11. Nilsson J, von Euler AM, Dalsgaard CJ. Stimulation of connective tissue cell growth by substance P and substance K. Nature. 1985;315(6014):61–3.

    Article  CAS  PubMed  Google Scholar 

  12. Paus R, Heinzelmann T, Robicsek S, Czarnetzki BM, Maurer M. Substance P stimulates murine epidermal keratinocyte proliferation and dermal mast cell degranulation in situ. Arch Dermatol Res. 1995;287(5):500–2.

    Article  CAS  PubMed  Google Scholar 

  13. Ansel JC, Brown JR, Payan DG, Brown MA. Substance P selectively activates TNF-alpha gene expression in murine mast cells. J Immunol. 1993;150(10):4478–85.

    CAS  PubMed  Google Scholar 

  14. Mathers AR, Tckacheva OA, Janelsins BM, Shufesky WJ, Morelli AE, Larregina AT. In vivo signaling through the neurokinin 1 receptor favors transgene expression by Langerhans cells and promotes the generation of Th1- and Tc1-biased immune responses. J Immunol. 2007;178(11):7006–17.

    Article  CAS  PubMed  Google Scholar 

  15. Smith CH, Barker JN, Morris RW, MacDonald DM, Lee TH. Neuropeptides induce rapid expression of endothelial cell adhesion molecules and elicit granulocytic infiltration in human skin. J Immunol. 1993;151(6):3274–82.

    CAS  PubMed  Google Scholar 

  16. Wiedermann CJ, Auer B, Sitte B, Reinisch N, Schratzberger P, Kahler CM. Induction of endothelial cell differentiation into capillary-like structures by substance P. Eur J Pharmacol. 1996;298(3):335–8.

    Article  CAS  PubMed  Google Scholar 

  17. Amadesi S, Reni C, Katare R, Meloni M, Oikawa A, Beltrami AP, et al. Role for substance p-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects. Circulation. 2012;125(14):1774–86. S1-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fan TP, Hu DE, Guard S, Gresham GA, Watling KJ. Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists. Br J Pharmacol. 1993;110(1):43–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kant V, Gopal A, Kumar D, Bag S, Kurade NP, Kumar A, et al. Topically applied substance P enhanced healing of open excision wound in rats. Eur J Pharmacol. 2013;715(1–3):345–53.

    Article  CAS  PubMed  Google Scholar 

  20. Lindberger M, Schroder HD, Schultzberg M, Kristensson K, Persson A, Ostman J, et al. Nerve fibre studies in skin biopsies in peripheral neuropathies. I. Immunohistochemical analysis of neuropeptides in diabetes mellitus. J Neurol Sci. 1989;93(2–3):289–96.

    Article  CAS  PubMed  Google Scholar 

  21. Nakamura M, Kawahara M, Morishige N, Chikama T, Nakata K, Nishida T. Promotion of corneal epithelial wound healing in diabetic rats by the combination of a substance P-derived peptide (FGLM-NH2) and insulin-like growth factor-1. Diabetologia. 2003;46(6):839–42.

    Article  CAS  PubMed  Google Scholar 

  22. Yang L, Di G, Qi X, Qu M, Wang Y, Duan H, et al. Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor. Diabetes. 2014;63(12):4262–74.

    Article  CAS  PubMed  Google Scholar 

  23. Kant V, Kumar D, Kumar D, Prasad R, Gopal A, Pathak NN, et al. Topical application of substance P promotes wound healing in streptozotocin-induced diabetic rats. Cytokine. 2015;73(1):144–55.

    Article  CAS  PubMed  Google Scholar 

  24. Pradhan L, Cai X, Wu S, Andersen ND, Martin M, Malek J, et al. Gene expression of pro-inflammatory cytokines and neuropeptides in diabetic wound healing. J Surg Res. 2011;167(2):336–42.

    Article  CAS  PubMed  Google Scholar 

  25. Pradhan Nabzdyk L, Kuchibhotla S, Guthrie P, Chun M, Auster ME, Nabzdyk C, et al. Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing. J Vasc Surg. 2013;58(3):766–75. e12

    Article  PubMed  Google Scholar 

  26. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32(5):593–604.

    Article  CAS  PubMed  Google Scholar 

  27. Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Muller W, et al. Differential roles of macrophages in diverse phases of skin repair. J Immunol. 2010;184(7):3964–77.

    Article  CAS  PubMed  Google Scholar 

  28. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Leal EC, Carvalho E, Tellechea A, Kafanas A, Tecilazich F, Kearney C, et al. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am J Pathol. 2015;185(6):1638–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dinh T, Tecilazich F, Kafanas A, Doupis J, Gnardellis C, Leal E, et al. Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes. 2012;61(11):2937–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lobmann R, Ambrosch A, Schultz G, Waldmann K, Schiweck S, Lehnert H. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia. 2002;45(7):1011–6.

    Article  CAS  PubMed  Google Scholar 

  32. Liu Y, Min D, Bolton T, Nube V, Twigg SM, Yue DK, et al. Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care. 2009;32(1):117–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rayment EA, Upton Z, Shooter GK. Increased matrix metalloproteinase-9 (MMP-9) activity observed in chronic wound fluid is related to the clinical severity of the ulcer. Br J Dermatol. 2008;158(5):951–61.

    Article  CAS  PubMed  Google Scholar 

  34. Park JH, Kim S, Hong HS, Son Y. Substance P promotes diabetic wound healing by modulating inflammation and restoring cellular activity of mesenchymal stem cells. Wound Repair Regen. 2016;24(2):337–48.

    Article  PubMed  Google Scholar 

  35. Ni T, Liu Y, Peng Y, Li M, Fang Y, Yao M. Substance P induces inflammatory responses involving NF-kappaB in genetically diabetic mice skin fibroblasts co-cultured with macrophages. Am J Transl Res. 2016;8(5):2179–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Montana G, Lampiasi N. Substance P induces HO-1 expression in RAW 264.7 cells promoting switch towards M2-like macrophages. PLoS One. 2016;11(12):e0167420.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Spenny ML, Muangman P, Sullivan SR, Bunnett NW, Ansel JC, Olerud JE, et al. Neutral endopeptidase inhibition in diabetic wound repair. Wound Repair Regen. 2002;10(5):295–301.

    Article  PubMed  Google Scholar 

  38. Mangiafico S, Costello-Boerrigter LC, Andersen IA, Cataliotti A, Burnett JC Jr. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Eur Heart J. 2013;34(12):886–93c.

    Article  CAS  PubMed  Google Scholar 

  39. Tellechea A, Silva EA, Min J, Leal EC, Auster ME, Pradhan-Nabzdyk L, et al. Alginate and DNA gels are suitable delivery systems for diabetic wound healing. Int J Low Extrem Wounds. 2015;14(2):146–53.

    Article  CAS  PubMed  Google Scholar 

  40. Gehlert DR. Introduction to the reviews on neuropeptide Y. Neuropeptides. 2004;38(4):135–40.

    Article  CAS  PubMed  Google Scholar 

  41. Wolak ML, DeJoseph MR, Cator AD, Mokashi AS, Brownfield MS, Urban JH. Comparative distribution of neuropeptide Y Y1 and Y5 receptors in the rat brain by using immunohistochemistry. J Comp Neurol. 2003;464(3):285–311.

    Article  CAS  PubMed  Google Scholar 

  42. Matsuda H, Brumovsky PR, Kopp J, Pedrazzini T, Hokfelt T. Distribution of neuropeptide Y Y1 receptors in rodent peripheral tissues. J Comp Neurol. 2002;449(4):390–404.

    Article  CAS  PubMed  Google Scholar 

  43. Kalra SP, Dube MG, Sahu A, Phelps CP, Kalra PS. Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc Natl Acad Sci U S A. 1991;88(23):10931–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kos K, Baker AR, Jernas M, Harte AL, Clapham JC, O'Hare JP, et al. DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue. Diabetes Obes Metab. 2009;11(4):285–92.

    Article  CAS  PubMed  Google Scholar 

  45. Yang K, Guan H, Arany E, Hill DJ, Cao X. Neuropeptide Y is produced in visceral adipose tissue and promotes proliferation of adipocyte precursor cells via the Y1 receptor. FASEB J. 2008;22(7):2452–64.

    Article  CAS  PubMed  Google Scholar 

  46. Segal-Lieberman G, Trombly DJ, Juthani V, Wang X, Maratos-Flier E. NPY ablation in C57BL/6 mice leads to mild obesity and to an impaired refeeding response to fasting. Am J Physiol Endocrinol Metab. 2003;284(6):E1131–9.

    Article  CAS  PubMed  Google Scholar 

  47. Macia L, Yulyaningsih E, Pangon L, Nguyen AD, Lin S, Shi YC, et al. Neuropeptide Y1 receptor in immune cells regulates inflammation and insulin resistance associated with diet-induced obesity. Diabetes. 2012;61(12):3228–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Singer K, Morris DL, Oatmen KE, Wang T, DelProposto J, Mergian T, et al. Neuropeptide Y is produced by adipose tissue macrophages and regulates obesity-induced inflammation. PLoS One. 2013;8(3):e57929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kuo LE, Czarnecka M, Kitlinska JB, Tilan JU, Kvetnansky R, Zukowska Z. Chronic stress, combined with a high-fat/high-sugar diet, shifts sympathetic signaling toward neuropeptide Y and leads to obesity and the metabolic syndrome. Ann N Y Acad Sci. 2008;1148:232–7.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, et al. Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med. 2007;13(7):803–11.

    Article  CAS  PubMed  Google Scholar 

  51. Ilhan A, Rasul S, Dimitrov A, Handisurya A, Gartner W, Baumgartner-Parzer S, et al. Plasma neuropeptide Y levels differ in distinct diabetic conditions. Neuropeptides. 2010;44(6):485–9.

    Article  CAS  PubMed  Google Scholar 

  52. Skarstrand H, Vaziri-Sani F, Delli AJ, Torn C, Elding Larsson H, Ivarsson S, et al. Neuropeptide Y is a minor autoantigen in newly diagnosed type 1 diabetes patients. Pediatr Diabetes. 2015;16(8):621–8.

    Article  PubMed  CAS  Google Scholar 

  53. Hirai H, Miura J, Hu Y, Larsson H, Larsson K, Lernmark A, et al. Selective screening of secretory vesicle-associated proteins for autoantigens in type 1 diabetes: VAMP2 and NPY are new minor autoantigens. Clin Immunol. 2008;127(3):366–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wallengren J, Badendick K, Sundler F, Hakanson R, Zander E. Innervation of the skin of the forearm in diabetic patients: relation to nerve function. Acta Derm Venereol. 1995;75(1):37–42.

    CAS  PubMed  Google Scholar 

  55. Levy DM, Karanth SS, Springall DR, Polak JM. Depletion of cutaneous nerves and neuropeptides in diabetes mellitus: an immunocytochemical study. Diabetologia. 1989;32(7):427–33.

    Article  CAS  PubMed  Google Scholar 

  56. Movafagh S, Hobson JP, Spiegel S, Kleinman HK, Zukowska Z. Neuropeptide Y induces migration, proliferation, and tube formation of endothelial cells bimodally via Y1, Y2, and Y5 receptors. FASEB J. 2006;20(11):1924–6.

    Article  CAS  PubMed  Google Scholar 

  57. Lee EW, Grant DS, Movafagh S, Zukowska Z. Impaired angiogenesis in neuropeptide Y (NPY)-Y2 receptor knockout mice. Peptides. 2003;24(1):99–106.

    Article  CAS  PubMed  Google Scholar 

  58. Wheway J, Herzog H, Mackay F. NPY and receptors in immune and inflammatory diseases. Curr Top Med Chem. 2007;7(17):1743–52.

    Article  CAS  PubMed  Google Scholar 

  59. Groneberg DA, Folkerts G, Peiser C, Chung KF, Fischer A. Neuropeptide Y (NPY). Pulm Pharmacol Ther. 2004;17(4):173–80.

    Article  CAS  PubMed  Google Scholar 

  60. Bedoui S, Kawamura N, Straub RH, Pabst R, Yamamura T, von Horsten S. Relevance of neuropeptide Y for the neuroimmune crosstalk. J Neuroimmunol. 2003;134(1–2):1–11.

    Article  CAS  PubMed  Google Scholar 

  61. Bedoui S, von Horsten S, Gebhardt T. A role for neuropeptide Y (NPY) in phagocytosis: implications for innate and adaptive immunity. Peptides. 2007;28(2):373–6.

    Article  CAS  PubMed  Google Scholar 

  62. De la Fuente M, Del Rio M, Medina S. Changes with aging in the modulation by neuropeptide Y of murine peritoneal macrophage functions. J Neuroimmunol. 2001;116(2):156–67.

    Article  PubMed  Google Scholar 

  63. De la Fuente M, Medina S, Del Rio M, Ferrandez MD, Hernanz A. Effect of aging on the modulation of macrophage functions by neuropeptides. Life Sci. 2000;67(17):2125–35.

    Article  PubMed  Google Scholar 

  64. Dimitrijevic M, Stanojevic S, Mitic K, Kustrimovic N, Vujic V, Miletic T, et al. The anti-inflammatory effect of neuropeptide Y (NPY) in rats is dependent on dipeptidyl peptidase 4 (DP4) activity and age. Peptides. 2008;29(12):2179–87.

    Article  CAS  PubMed  Google Scholar 

  65. Salo P, Bray R, Seerattan R, Reno C, McDougall J, Hart DA. Neuropeptides regulate expression of matrix molecule, growth factor and inflammatory mediator mRNA in explants of normal and healing medial collateral ligament. Regul Pept. 2007;142(1–2):1–6.

    Article  CAS  PubMed  Google Scholar 

  66. Salo PT, Beye JA, Seerattan RA, Leonard CA, Ivie TJ, Bray RC. Plasticity of peptidergic innervation in healing rabbit medial collateral ligament. Can J Surg. 2008;51(3):167–72.

    PubMed  PubMed Central  Google Scholar 

  67. Ackermann PW, Ahmed M, Kreicbergs A. Early nerve regeneration after achilles tendon rupture—a prerequisite for healing? A study in the rat. J Orthop Res. 2002;20(4):849–56.

    Article  PubMed  Google Scholar 

  68. Kuo LE, Abe K, Zukowska Z. Stress, NPY and vascular remodeling: implications for stress-related diseases. Peptides. 2007;28(2):435–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Abe K, Tilan JU, Zukowska Z. NPY and NPY receptors in vascular remodeling. Curr Top Med Chem. 2007;7(17):1704–9.

    Article  CAS  PubMed  Google Scholar 

  70. Wang Y, Zhang D, Ashraf M, Zhao T, Huang W, Ashraf A, et al. Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol. 2010;298(1):H275–86.

    Article  CAS  PubMed  Google Scholar 

  71. Ekstrand AJ, Cao R, Bjorndahl M, Nystrom S, Jonsson-Rylander AC, Hassani H, et al. Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc Natl Acad Sci U S A. 2003;100(10):6033–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Uhl GR, Kuhar MJ, Snyder SH. Neurotensin: immunohistochemical localization in rat central nervous system. Proc Natl Acad Sci U S A. 1977;74(9):4059–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Helmstaedter V, Taugner C, Feurle GE, Forssmann WG. Localization of neurotensin-immunoreactive cells in the small intestine of man and various mammals. Histochemistry. 1977;53(1):35–41.

    Article  CAS  PubMed  Google Scholar 

  74. Vincent JP, Mazella J, Kitabgi P. Neurotensin and neurotensin receptors. Trends Pharmacol Sci. 1999;20(7):302–9.

    Article  CAS  PubMed  Google Scholar 

  75. Goldman R, Bar-Shavit Z, Romeo D. Neurotensin modulates human neutrophil locomotion and phagocytic capability. FEBS Lett. 1983;159(1–2):63–7.

    Article  CAS  PubMed  Google Scholar 

  76. Goldman R, Bar-Shavit Z. On the mechanism of the augmentation of the phagocytic capability of phagocytic cells by Tuftsin, substance P, neurotensin, and kentsin and the interrelationship between their receptors. Ann N Y Acad Sci. 1983;419:143–55.

    Article  CAS  PubMed  Google Scholar 

  77. De la Fuente M, Garrido JJ, Arahuetes RM, Hernanz A. Stimulation of phagocytic function in mouse macrophages by neurotensin and neuromedin N. J Neuroimmunol. 1993;42(1):97–104.

    Article  PubMed  Google Scholar 

  78. Zhao D, Zhan Y, Zeng H, Koon HW, Moyer MP, Pothoulakis C. Neurotensin stimulates interleukin-8 expression through modulation of I kappa B alpha phosphorylation and p65 transcriptional activity: involvement of protein kinase C alpha. Mol Pharmacol. 2005;67(6):2025–31.

    Article  CAS  PubMed  Google Scholar 

  79. Castagliuolo I, Wang CC, Valenick L, Pasha A, Nikulasson S, Carraway RE, et al. Neurotensin is a proinflammatory neuropeptide in colonic inflammation. J Clin Invest. 1999;103(6):843–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bakirtzi K, Law IK, Xue X, Iliopoulos D, Shah YM, Pothoulakis C. Neurotensin promotes the development of colitis and intestinal angiogenesis via Hif-1alpha-miR-210 signaling. J Immunol. 2016;196(10):4311–21.

    Article  CAS  PubMed  Google Scholar 

  81. Bakirtzi K, West G, Fiocchi C, Law IK, Iliopoulos D, Pothoulakis C. The neurotensin-HIF-1alpha-VEGFalpha axis orchestrates hypoxia, colonic inflammation, and intestinal angiogenesis. Am J Pathol. 2014;184(12):3405–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Brun P, Mastrotto C, Beggiao E, Stefani A, Barzon L, Sturniolo GC, et al. Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2005;288(4):G621–9.

    Article  CAS  PubMed  Google Scholar 

  83. Zhao D, Bakirtzi K, Zhan Y, Zeng H, Koon HW, Pothoulakis C. Insulin-like growth factor-1 receptor transactivation modulates the inflammatory and proliferative responses of neurotensin in human colonic epithelial cells. J Biol Chem. 2011;286(8):6092–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Martin S, Vincent JP, Mazella J. Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of human microglia. J Neurosci. 2003;23(4):1198–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Melander O, Maisel AS, Almgren P, Manjer J, Belting M, Hedblad B, et al. Plasma proneurotensin and incidence of diabetes, cardiovascular disease, breast cancer, and mortality. JAMA. 2012;308(14):1469–75.

    Article  CAS  PubMed  Google Scholar 

  86. Li J, Song J, Zaytseva YY, Liu Y, Rychahou P, Jiang K, et al. An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature. 2016;533(7603):411–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sheppard MC, Bailey CJ, Flatt PR, Swanston-Flatt SK, Shennan KI. Immunoreactive neurotensin in spontaneous syndromes of obesity and diabetes in mice. Acta Endocrinol. 1985;108(4):532–6.

    Article  CAS  Google Scholar 

  88. Berelowitz M, Frohman LA. The role of neurotensin in the regulation of carbohydrate metabolism and in diabetes. Ann N Y Acad Sci. 1982;400:150–9.

    Article  CAS  PubMed  Google Scholar 

  89. El-Salhy M. Neuroendocrine peptides of the gastrointestinal tract of an animal model of human type 2 diabetes mellitus. Acta Diabetol. 1998;35(4):194–8.

    Article  CAS  PubMed  Google Scholar 

  90. Service FJ, Jay JM, Rizza RA, O'Brien PC, Go VL. Neurotensin in diabetes and obesity. Regul Pept. 1986;14(1):85–92.

    Article  CAS  PubMed  Google Scholar 

  91. da Silva L, Neves BM, Moura L, Cruz MT, Carvalho E. Neurotensin downregulates the pro-inflammatory properties of skin dendritic cells and increases epidermal growth factor expression. Biochim Biophys Acta. 2011;1813(10):1863–71.

    Article  PubMed  CAS  Google Scholar 

  92. Moura LI, Silva L, Leal EC, Tellechea A, Cruz MT, Carvalho E. Neurotensin modulates the migratory and inflammatory response of macrophages under hyperglycemic conditions. Biomed Res Int. 2013;2013:941764.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Pereira da Silva L, Miguel Neves B, Moura L, Cruz MT, Carvalho E. Neurotensin decreases the proinflammatory status of human skin fibroblasts and increases epidermal growth factor expression. Int J Inflamm. 2014;2014:248240.

    Article  Google Scholar 

  94. Moura LI, Cruz MT, Carvalho E. The effect of neurotensin in human keratinocytes--implication on impaired wound healing in diabetes. Exp Biol Med. 2014;239(1):6–12.

    Article  CAS  Google Scholar 

  95. Moura LI, Dias AM, Leal EC, Carvalho L, de Sousa HC, Carvalho E. Chitosan-based dressings loaded with neurotensin--an efficient strategy to improve early diabetic wound healing. Acta Biomater. 2014;10(2):843–57.

    Article  CAS  PubMed  Google Scholar 

  96. Moura LI, Dias AM, Suesca E, Casadiegos S, Leal EC, Fontanilla MR, et al. Neurotensin-loaded collagen dressings reduce inflammation and improve wound healing in diabetic mice. Biochim Biophys Acta. 2014;1842(1):32–43.

    Article  CAS  PubMed  Google Scholar 

  97. van Rossum D, Hanisch UK, Quirion R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev. 1997;21(5):649–78.

    Article  PubMed  Google Scholar 

  98. Holzer P. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience. 1988;24(3):739–68.

    Article  CAS  PubMed  Google Scholar 

  99. Maggi CA. Tachykinins and calcitonin gene-related peptide (CGRP) as co-transmitters released from peripheral endings of sensory nerves. Prog Neurobiol. 1995;45(1):1–98.

    Article  CAS  PubMed  Google Scholar 

  100. Chottova Dvorakova M, Kuncova J, Pfeil U, McGregor GP, Sviglerova J, Slavikova J, et al. Cardiomyopathy in streptozotocin-induced diabetes involves intra-axonal accumulation of calcitonin gene-related peptide and altered expression of its receptor in rats. Neuroscience. 2005;134(1):51–8.

    Article  CAS  PubMed  Google Scholar 

  101. Yorek MA, Coppey LJ, Gellett JS, Davidson EP. Sensory nerve innervation of epineurial arterioles of the sciatic nerve containing calcitonin gene-related peptide: effect of streptozotocin-induced diabetes. Exp Diabesity Res. 2004;5(3):187–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Oltman CL, Davidson EP, Coppey LJ, Kleinschmidt TL, Lund DD, Adebara ET, et al. Vascular and neural dysfunction in Zucker diabetic fatty rats: a difficult condition to reverse. Diabetes Obes Metab. 2008;10(1):64–74.

    CAS  PubMed  Google Scholar 

  103. Oltman CL, Davidson EP, Coppey LJ, Kleinschmidt TL, Yorek MA. Treatment of Zucker diabetic fatty rats with AVE7688 improves vascular and neural dysfunction. Diabetes Obes Metab. 2009;11(3):223–33.

    Article  CAS  PubMed  Google Scholar 

  104. Sheykhzade M, Dalsgaard GT, Johansen T, Nyborg NC. The effect of long-term streptozotocin-induced diabetes on contractile and relaxation responses of coronary arteries: selective attenuation of CGRP-induced relaxations. Br J Pharmacol. 2000;129(6):1212–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Song JX, Wang LH, Yao L, Xu C, Wei ZH, Zheng LR. Impaired transient receptor potential vanilloid 1 in streptozotocin-induced diabetic hearts. Int J Cardiol. 2009;134(2):290–2.

    Article  PubMed  Google Scholar 

  106. Dux M, Rosta J, Pinter S, Santha P, Jancso G. Loss of capsaicin-induced meningeal neurogenic sensory vasodilatation in diabetic rats. Neuroscience. 2007;150(1):194–201.

    Article  CAS  PubMed  Google Scholar 

  107. Adeghate E, Rashed H, Rajbandari S, Singh J. Pattern of distribution of calcitonin gene-related peptide in the dorsal root ganglion of animal models of diabetes mellitus. Ann N Y Acad Sci. 2006;1084:296–303.

    Article  CAS  PubMed  Google Scholar 

  108. Wang LH, Zhou SX, Li RC, Zheng LR, Zhu JH, Hu SJ, et al. Serum levels of calcitonin gene-related peptide and substance P are decreased in patients with diabetes mellitus and coronary artery disease. J Int Med Res. 2012;40(1):134–40.

    Article  PubMed  Google Scholar 

  109. Zheng LR, Han J, Yao L, Sun YL, Jiang DM, Hu SJ, et al. Up-regulation of calcitonin gene-related peptide protects streptozotocin-induced diabetic hearts from ischemia/reperfusion injury. Int J Cardiol. 2012;156(2):192–8.

    Article  PubMed  Google Scholar 

  110. Zelissen PM, Koppeschaar HP, Lips CJ, Hackeng WH. Calcitonin gene-related peptide in human obesity. Peptides. 1991;12(4):861–3.

    Article  CAS  PubMed  Google Scholar 

  111. Gram DX, Hansen AJ, Wilken M, Elm T, Svendsen O, Carr RD, et al. Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats. Eur J Endocrinol. 2005;153(6):963–9.

    Article  CAS  PubMed  Google Scholar 

  112. Walker CS, Li X, Whiting L, Glyn-Jones S, Zhang S, Hickey AJ, et al. Mice lacking the neuropeptide alpha-calcitonin gene-related peptide are protected against diet-induced obesity. Endocrinology. 2010;151(9):4257–69.

    Article  CAS  PubMed  Google Scholar 

  113. Bennett GS, Garrett NE, Diemel LT, Brain SD, Tomlinson DR. Neurogenic cutaneous vasodilatation and plasma extravasation in diabetic rats: effect of insulin and nerve growth factor. Br J Pharmacol. 1998;124(7):1573–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tomlinson DR, Fernyhough P, Diemel LT. Neurotrophins and peripheral neuropathy. Philos Trans R Soc Lond B Biol Sci. 1996;351(1338):455–62.

    Article  CAS  PubMed  Google Scholar 

  115. Jiang Y, Nyengaard JR, Zhang JS, Jakobsen J. Selective loss of calcitonin gene-related peptide-expressing primary sensory neurons of the a-cell phenotype in early experimental diabetes. Diabetes. 2004;53(10):2669–75.

    Article  CAS  PubMed  Google Scholar 

  116. Kjartansson J, Dalsgaard CJ. Calcitonin gene-related peptide increases survival of a musculocutaneous critical flap in the rat. Eur J Pharmacol. 1987;142(3):355–8.

    Article  CAS  PubMed  Google Scholar 

  117. Khalil Z, Helme R. Sensory peptides as neuromodulators of wound healing in aged rats. J Gerontol A Biol Sci Med Sci. 1996;51(5):B354–61.

    Article  CAS  PubMed  Google Scholar 

  118. Brain SD, Cox HM. Neuropeptides and their receptors: innovative science providing novel therapeutic targets. Br J Pharmacol. 2006;147(Suppl 1):S202–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Brain SD. Sensory neuropeptides: their role in inflammation and wound healing. Immunopharmacology. 1997;37(2–3):133–52.

    Article  CAS  PubMed  Google Scholar 

  120. Brain SD, Grant AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev. 2004;84(3):903–34.

    Article  CAS  PubMed  Google Scholar 

  121. Toda M, Suzuki T, Hosono K, Kurihara Y, Kurihara H, Hayashi I, et al. Roles of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis. Biomed Pharmacother. 2008;62(6):352–9.

    Article  CAS  PubMed  Google Scholar 

  122. Mishima T, Ito Y, Hosono K, Tamura Y, Uchida Y, Hirata M, et al. Calcitonin gene-related peptide facilitates revascularization during hindlimb ischemia in mice. Am J Physiol Heart Circ Physiol. 2011;300(2):H431–9.

    Article  CAS  PubMed  Google Scholar 

  123. Haegerstrand A, Dalsgaard CJ, Jonzon B, Larsson O, Nilsson J. Calcitonin gene-related peptide stimulates proliferation of human endothelial cells. Proc Natl Acad Sci U S A. 1990;87(9):3299–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhou Y, Zhang M, Sun GY, Liu YP, Ran WZ, Peng L, et al. Calcitonin gene-related peptide promotes the wound healing of human bronchial epithelial cells via PKC and MAPK pathways. Regul Pept. 2013;184:22–9.

    Article  CAS  PubMed  Google Scholar 

  125. Tran MT, Ritchie MH, Lausch RN, Oakes JE. Calcitonin gene-related peptide induces IL-8 synthesis in human corneal epithelial cells. J Immunol. 2000;164(8):4307–12.

    Article  CAS  PubMed  Google Scholar 

  126. Yaraee R, Ebtekar M, Ahmadiani A, Sabahi F. Neuropeptides (SP and CGRP) augment pro-inflammatory cytokine production in HSV-infected macrophages. Int Immunopharmacol. 2003;3(13–14):1883–7.

    Article  CAS  PubMed  Google Scholar 

  127. Yamaguchi M, Kojima T, Kanekawa M, Aihara N, Nogimura A, Kasai K. Neuropeptides stimulate production of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha in human dental pulp cells. Inflamm Res. 2004;53(5):199–204.

    Article  CAS  PubMed  Google Scholar 

  128. Dallos A, Kiss M, Polyanka H, Dobozy A, Kemeny L, Husz S. Effects of the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and galanin on the production of nerve growth factor and inflammatory cytokines in cultured human keratinocytes. Neuropeptides. 2006;40(4):251–63.

    Article  CAS  PubMed  Google Scholar 

  129. Ichinose M, Sawada M. Enhancement of phagocytosis by calcitonin gene-related peptide (CGRP) in cultured mouse peritoneal macrophages. Peptides. 1996;17(8):1405–14.

    Article  CAS  PubMed  Google Scholar 

  130. Wang F, Millet I, Bottomly K, Vignery A. Calcitonin gene-related peptide inhibits interleukin 2 production by murine T lymphocytes. J Biol Chem. 1992;267(29):21052–7.

    Article  CAS  PubMed  Google Scholar 

  131. Umeda Y, Takamiya M, Yoshizaki H, Arisawa M. Inhibition of mitogen-stimulated T lymphocyte proliferation by calcitonin gene-related peptide. Biochem Biophys Res Commun. 1988;154(1):227–35.

    Article  CAS  PubMed  Google Scholar 

  132. McGillis JP, Humphreys S, Rangnekar V, Ciallella J. Modulation of B lymphocyte differentiation by calcitonin gene-related peptide (CGRP). I. Characterization of high-affinity CGRP receptors on murine 70Z/3 cells. Cell Immunol. 1993;150(2):391–404.

    Article  CAS  PubMed  Google Scholar 

  133. Asahina A, Hosoi J, Murphy GF, Granstein RD. Calcitonin gene-related peptide modulates Langerhans cell antigen-presenting function. Proc Assoc Am Physicians. 1995;107(2):242–4.

    CAS  PubMed  Google Scholar 

  134. Sun W, Wang L, Zhang Z, Chen M, Wang X. Intramuscular transfer of naked calcitonin gene-related peptide gene prevents autoimmune diabetes induced by multiple low-dose streptozotocin in C57BL mice. Eur J Immunol. 2003;33(1):233–42.

    Article  CAS  PubMed  Google Scholar 

  135. Baliu-Pique M, Jusek G, Holzmann B. Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages. Eur J Immunol. 2014;44(12):3708–16.

    Article  CAS  PubMed  Google Scholar 

  136. Bertolini A, Tacchi R, Vergoni AV. Brain effects of melanocortins. Pharmacol Res. 2009;59(1):13–47.

    Article  CAS  PubMed  Google Scholar 

  137. Robbins LS, Nadeau JH, Johnson KR, Kelly MA, Roselli-Rehfuss L, Baack E, et al. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell. 1993;72(6):827–34.

    Article  CAS  PubMed  Google Scholar 

  138. Seeley RJ, Yagaloff KA, Fisher SL, Burn P, Thiele TE, van Dijk G, et al. Melanocortin receptors in leptin effects. Nature. 1997;390(6658):349.

    Article  CAS  PubMed  Google Scholar 

  139. Clark AJ, McLoughlin L, Grossman A. Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet. 1993;341(8843):461–2.

    Article  CAS  PubMed  Google Scholar 

  140. Marks DL, Hruby V, Brookhart G, Cone RD. The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R). Peptides. 2006;27(2):259–64.

    Article  CAS  PubMed  Google Scholar 

  141. Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, et al. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015;100(4):1639–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Chen W, Kelly MA, Opitz-Araya X, Thomas RE, Low MJ, Cone RD. Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell. 1997;91(6):789–98.

    Article  CAS  PubMed  Google Scholar 

  143. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88(1):131–41.

    Article  CAS  PubMed  Google Scholar 

  144. Thody AJ, Ridley K, Penny RJ, Chalmers R, Fisher C, Shuster S. MSH peptides are present in mammalian skin. Peptides. 1983;4(6):813–6.

    Article  CAS  PubMed  Google Scholar 

  145. Slominski A, Wortsman J, Mazurkiewicz JE, Matsuoka L, Dietrich J, Lawrence K, et al. Detection of proopiomelanocortin-derived antigens in normal and pathologic human skin. J Lab Clin Med. 1993;122(6):658–66.

    CAS  PubMed  Google Scholar 

  146. Mazurkiewicz JE, Corliss D, Slominski A. Spatiotemporal expression, distribution, and processing of POMC and POMC-derived peptides in murine skin. J Histochem Cytochem. 2000;48(7):905–14.

    Article  CAS  PubMed  Google Scholar 

  147. Lee M, Kim A, Chua SC Jr, Obici S, Wardlaw SL. Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet. Am J Physiol Endocrinol Metab. 2007;293(1):E121–31.

    Article  CAS  PubMed  Google Scholar 

  148. Enriori PJ, Chen W, Garcia-Rudaz MC, Grayson BE, Evans AE, Comstock SM, et al. Alpha-melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors. Mol Metab. 2016;5(10):807–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Zhang L, Dong L, Liu X, Jiang Y, Zhang L, Zhang X, et al. Alpha-melanocyte-stimulating hormone protects retinal vascular endothelial cells from oxidative stress and apoptosis in a rat model of diabetes. PLoS One. 2014;9(4):e93433.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Havel PJ, Hahn TM, Sindelar DK, Baskin DG, Dallman MF, Weigle DS, et al. Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. Diabetes. 2000;49(2):244–52.

    Article  CAS  PubMed  Google Scholar 

  151. Kim EM, Grace MK, Welch CC, Billington CJ, Levine AS. STZ-induced diabetes decreases and insulin normalizes POMC mRNA in arcuate nucleus and pituitary in rats. Am J Physiol. 1999;276(5 Pt 2):R1320–6.

    CAS  PubMed  Google Scholar 

  152. Xu S, Lind L, Zhao L, Lindahl B, Venge P. Plasma prolylcarboxypeptidase (angiotensinase C) is increased in obesity and diabetes mellitus and related to cardiovascular dysfunction. Clin Chem. 2012;58(7):1110–5.

    Article  CAS  PubMed  Google Scholar 

  153. Schneeberger M, Gomez-Valades AG, Altirriba J, Sebastian D, Ramirez S, Garcia A, et al. Reduced alpha-MSH underlies hypothalamic ER-stress-induced hepatic gluconeogenesis. Cell Rep. 2015;12(3):361–70.

    Article  CAS  PubMed  Google Scholar 

  154. Abou-Mohamed G, Papapetropoulos A, Ulrich D, Catravas JD, Tuttle RR, Caldwell RW. HP-228, a novel synthetic peptide, inhibits the induction of nitric oxide synthase in vivo but not in vitro. J Pharmacol Exp Ther. 1995;275(2):584–91.

    CAS  PubMed  Google Scholar 

  155. Rajora N, Boccoli G, Burns D, Sharma S, Catania AP, Lipton JM. Alpha-MSH modulates local and circulating tumor necrosis factor-alpha in experimental brain inflammation. J Neurosci. 1997;17(6):2181–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Rajora N, Boccoli G, Catania A, Lipton JM. alpha-MSH modulates experimental inflammatory bowel disease. Peptides. 1997;18(3):381–5.

    Article  CAS  PubMed  Google Scholar 

  157. Catania A, Delgado R, Airaghi L, Cutuli M, Garofalo L. Carlin A, et al. alpha-MSH in systemic inflammation. Central and peripheral actions. Ann N Y Acad Sci. 1999;885:183–7.

    Article  CAS  PubMed  Google Scholar 

  158. Gatti S, Colombo G, Buffa R, Turcatti F, Garofalo L. Carboni N, et al. alpha-Melanocyte-stimulating hormone protects the allograft in experimental heart transplantation. Transplantation. 2002;74(12):1678–84.

    Article  CAS  PubMed  Google Scholar 

  159. Catania A, Gatti S, Colombo G, Lipton JM. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev. 2004;56(1):1–29.

    Article  CAS  PubMed  Google Scholar 

  160. Xu PB, Mao YF, Meng HB, Tian YP, Deng XM. STY39, a novel alpha-melanocyte-stimulating hormone analogue, attenuates bleomycin-induced pulmonary inflammation and fibrosis in mice. Shock. 2011;35(3):308–14.

    Article  CAS  PubMed  Google Scholar 

  161. Jung EJ, Kim SC, Jeong SH, Lee JY, Han DJ. Alpha-melanocyte stimulating hormone preserves islet graft survival through down-regulation of Toll-like receptors. Transplant Proc. 2012;44(4):1086–90.

    Article  CAS  PubMed  Google Scholar 

  162. Hamrah P, Haskova Z, Taylor AW, Zhang Q, Ksander BR, Dana MR. Local treatment with alpha-melanocyte stimulating hormone reduces corneal allorejection. Transplantation. 2009;88(2):180–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Shah PP, Desai PR, Boakye CH, Patlolla R, Kikwai LC, Babu RJ, et al. Percutaneous delivery of alpha-melanocyte-stimulating hormone for the treatment of imiquimod-induced psoriasis. J Drug Target. 2016;24(6):537–47.

    Article  CAS  PubMed  Google Scholar 

  164. Haylett AK, Nie Z, Brownrigg M, Taylor R, Rhodes LE. Systemic photoprotection in solar urticaria with alpha-melanocyte-stimulating hormone analogue [Nle4-D-Phe7]-alpha-MSH. Br J Dermatol. 2011;164(2):407–14.

    Article  CAS  PubMed  Google Scholar 

  165. Cooper A, Robinson SJ, Pickard C, Jackson CL, Friedmann PS, Healy E. Alpha-melanocyte-stimulating hormone suppresses antigen-induced lymphocyte proliferation in humans independently of melanocortin 1 receptor gene status. J Immunol. 2005;175(7):4806–13.

    Article  CAS  PubMed  Google Scholar 

  166. Nishida T, Taylor AW. Specific aqueous humor factors induce activation of regulatory T cells. Invest Ophthalmol Vis Sci. 1999;40(10):2268–74.

    CAS  PubMed  Google Scholar 

  167. Bhardwaj R, Becher E, Mahnke K, Hartmeyer M, Schwarz T, Scholzen T, et al. Evidence for the differential expression of the functional alpha-melanocyte-stimulating hormone receptor MC-1 on human monocytes. J Immunol. 1997;158(7):3378–84.

    CAS  PubMed  Google Scholar 

  168. Yang Y, Zhang W, Meng L, Yu H, Lu N, Fu G, et al. Alpha-melanocyte stimulating hormone inhibits monocytes adhesion to vascular endothelium. Exp Biol Med. 2015;240(11):1537–42.

    Article  CAS  Google Scholar 

  169. Taherzadeh S, Sharma S, Chhajlani V, Gantz I, Rajora N. Demitri MT, et al. alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages. Am J Physiol. 1999;276(5 Pt 2):R1289–94.

    CAS  PubMed  Google Scholar 

  170. Star RA, Rajora N, Huang J, Stock RC, Catania A, Lipton JM. Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone. Proc Natl Acad Sci U S A. 1995;92(17):8016–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Mandrika I, Muceniece R, Wikberg JE. Effects of melanocortin peptides on lipopolysaccharide/interferon-gamma-induced NF-kappaB DNA binding and nitric oxide production in macrophage-like RAW 264.7 cells: evidence for dual mechanisms of action. Biochem Pharmacol. 2001;61(5):613–21.

    Article  CAS  PubMed  Google Scholar 

  172. Adachi S, Nakano T, Vliagoftis H, Metcalfe DD. Receptor-mediated modulation of murine mast cell function by alpha-melanocyte stimulating hormone. J Immunol. 1999;163(6):3363–8.

    CAS  PubMed  Google Scholar 

  173. Bohm M, Schulte U, Kalden H, Luger TA. Alpha-melanocyte-stimulating hormone modulates activation of NF-kappa B and AP-1 and secretion of interleukin-8 in human dermal fibroblasts. Ann N Y Acad Sci. 1999;885:277–86.

    Article  CAS  PubMed  Google Scholar 

  174. Hartmeyer M, Scholzen T, Becher E, Bhardwaj RS, Schwarz T, Luger TA. Human dermal microvascular endothelial cells express the melanocortin receptor type 1 and produce increased levels of IL-8 upon stimulation with alpha-melanocyte-stimulating hormone. J Immunol. 1997;159(4):1930–7.

    CAS  PubMed  Google Scholar 

  175. Redondo P, Garcia-Foncillas J, Okroujnov I, Bandres E. Alpha-MSH regulates interleukin-10 expression by human keratinocytes. Arch Dermatol Res. 1998;290(8):425–8.

    Article  CAS  PubMed  Google Scholar 

  176. Weng WT, Huang SC, Ma YL, Chan HH, Lin SW. Wu JC, et al. alpha-Melanocyte-stimulating hormone inhibits angiogenesis through attenuation of VEGF/VEGFR2 signaling pathway. Biochim Biophys Acta. 2014;1840(6):1850–60.

    Article  CAS  PubMed  Google Scholar 

  177. Zou L, Sato N, Kone BC. Alpha-melanocyte stimulating hormone protects against H2O2-induced inhibition of wound restitution in IEC-6 cells via a Syk kinase- and NF-kappabeta-dependent mechanism. Shock. 2004;22(5):453–9.

    Article  CAS  PubMed  Google Scholar 

  178. Bonfiglio V, Camillieri G, Avitabile T, Leggio GM, Drago F. Effects of the COOH-terminal tripeptide alpha-MSH(11-13) on corneal epithelial wound healing: role of nitric oxide. Exp Eye Res. 2006;83(6):1366–72.

    Article  CAS  PubMed  Google Scholar 

  179. de Souza KS, Cantaruti TA, Azevedo GM Jr, Galdino DA, Rodrigues CM, Costa RA, et al. Improved cutaneous wound healing after intraperitoneal injection of alpha-melanocyte-stimulating hormone. Exp Dermatol. 2015;24(3):198–203.

    Article  PubMed  CAS  Google Scholar 

  180. Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol. 2007;127(3):514–25.

    Article  CAS  PubMed  Google Scholar 

  181. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–46.

    Article  CAS  PubMed  Google Scholar 

  182. Jameson JM, Sharp LL, Witherden DA, Havran WL. Regulation of skin cell homeostasis by gamma delta T cells. Front Biosci. 2004;9:2640–51.

    Article  CAS  PubMed  Google Scholar 

  183. Noli C, Miolo A. The mast cell in wound healing. Vet Dermatol. 2001;12(6):303–13.

    Article  CAS  PubMed  Google Scholar 

  184. Cumberbatch M, Dearman RJ, Griffiths CE, Kimber I. Langerhans cell migration. Clin Exp Dermatol. 2000;25(5):413–8.

    Article  CAS  PubMed  Google Scholar 

  185. Deonarine K, Panelli MC, Stashower ME, Jin P, Smith K, Slade HB, et al. Gene expression profiling of cutaneous wound healing. J Transl Med. 2007;5:11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Shaw TJ, Martin P. Wound repair at a glance. J Cell Sci. 2009;122(Pt 18):3209–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol. 2001;69(4):513–21.

    CAS  PubMed  Google Scholar 

  188. Steed DL. The role of growth factors in wound healing. Surg Clin North Am. 1997;77(3):575–86.

    Article  CAS  PubMed  Google Scholar 

  189. Poncet P, Arock M, David B. MHC class II-dependent activation of CD4+ T cell hybridomas by human mast cells through superantigen presentation. J Leukoc Biol. 1999;66(1):105–12.

    Article  CAS  PubMed  Google Scholar 

  190. Stelekati E, Bahri R, D'Orlando O, Orinska Z, Mittrucker HW, Langenhaun R, et al. Mast cell-mediated antigen presentation regulates CD8+ T cell effector functions. Immunity. 2009;31(4):665–76.

    Article  CAS  PubMed  Google Scholar 

  191. Maione AG, Smith A, Kashpur O, Yanez V, Knight E, Mooney DJ, et al. Altered ECM deposition by diabetic foot ulcer-derived fibroblasts implicates fibronectin in chronic wound repair. Wound Repair Regen. 2016;24(4):630–43.

    Article  PubMed  PubMed Central  Google Scholar 

  192. Acosta JB, del Barco DG, Vera DC, Savigne W, Lopez-Saura P, Guillen Nieto G, et al. The pro-inflammatory environment in recalcitrant diabetic foot wounds. Int Wound J. 2008;5(4):530–9.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Vaalamo M, Leivo T, Saarialho-Kere U. Differential expression of tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4) in normal and aberrant wound healing. Hum Pathol. 1999;30(7):795–802.

    Article  CAS  PubMed  Google Scholar 

  194. Pirila E, Korpi JT, Korkiamaki T, Jahkola T, Gutierrez-Fernandez A, Lopez-Otin C, et al. Collagenase-2 (MMP-8) and matrilysin-2 (MMP-26) expression in human wounds of different etiologies. Wound Repair Regen. 2007;15(1):47–57.

    Article  PubMed  Google Scholar 

  195. Wysocki AB, Staiano-Coico L, Grinnell F. Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol. 1993;101(1):64–8.

    Article  CAS  PubMed  Google Scholar 

  196. Duckworth WC, Fawcett J, Reddy S, Page JC. Insulin-degrading activity in wound fluid. J Clin Endocrinol Metab. 2004;89(2):847–51.

    Article  CAS  PubMed  Google Scholar 

  197. Khanna S, Biswas S, Shang Y, Collard E, Azad A, Kauh C, et al. Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS One. 2010;5(3):e9539.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Siqueira MF, 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 forkhead box O1 (FOXO1). Diabetologia. 2010;53(2):378–88.

    Article  CAS  PubMed  Google Scholar 

  199. Alba-Loureiro TC, Hirabara SM, Mendonca JR, Curi R, Pithon-Curi TC. Diabetes causes marked changes in function and metabolism of rat neutrophils. J Endocrinol. 2006;188(2):295–303.

    Article  CAS  PubMed  Google Scholar 

  200. Marhoffer W, Stein M, Schleinkofer L, Federlin K. Evidence of ex vivo and in vitro impaired neutrophil oxidative burst and phagocytic capacity in type 1 diabetes mellitus. Diabetes Res Clin Pract. 1993;19(3):183–8.

    Article  CAS  PubMed  Google Scholar 

  201. Fitzgerald RH, Mills JL, Joseph W, Armstrong DG. The diabetic rapid response acute foot team: 7 essential skills for targeted limb salvage. Eplasty. 2009;9:e15.

    PubMed  PubMed Central  Google Scholar 

  202. Boulton AJ, Armstrong DG, Albert SF, Frykberg RG, Hellman R, Kirkman MS, et al. Comprehensive foot examination and risk assessment. A report of the Task Force of the Foot Care Interest Group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Phys Ther. 2008;88(11):1436–43.

    Article  PubMed  Google Scholar 

  203. Bjarnsholt T, Kirketerp-Moller K, Jensen PO, Madsen KG, Phipps R, Krogfelt K, et al. Why chronic wounds will not heal: a novel hypothesis. Wound Repair Regen. 2008;16(1):2–10.

    Article  PubMed  Google Scholar 

  204. Costerton JW, Lewandowski Z, Caldwell DE, Korber DR, Lappin-Scott HM. Microbial biofilms. Annu Rev Microbiol. 1995;49:711–45.

    Article  CAS  PubMed  Google Scholar 

  205. Kirshenbaum AS, Kessler SW, Goff JP, Metcalfe DD. Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells. J Immunol. 1991;146(5):1410–5.

    CAS  PubMed  Google Scholar 

  206. Rodewald HR, Dessing M, Dvorak AM, Galli SJ. Identification of a committed precursor for the mast cell lineage. Science. 1996;271(5250):818–22.

    Article  CAS  PubMed  Google Scholar 

  207. Chen CC, Grimbaldeston MA, Tsai M, Weissman IL, Galli SJ. Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci U S A. 2005;102(32):11408–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Arinobu Y, Iwasaki H, Gurish MF, Mizuno S, Shigematsu H, Ozawa H, et al. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc Natl Acad Sci U S A. 2005;102(50):18105–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Gurish MF, Pear WS, Stevens RL, Scott ML, Sokol K, Ghildyal N, et al. Tissue-regulated differentiation and maturation of a v-abl-immortalized mast cell-committed progenitor. Immunity. 1995;3(2):175–86.

    Article  CAS  PubMed  Google Scholar 

  210. Kube P, Audige L, Kuther K, Welle M. Distribution, density and heterogeneity of canine mast cells and influence of fixation techniques. Histochem Cell Biol. 1998;110(2):129–35.

    Article  CAS  PubMed  Google Scholar 

  211. Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, et al. Mast cells and inflammation. Biochim Biophys Acta. 2012;1822(1):21–33.

    Article  CAS  PubMed  Google Scholar 

  212. Metcalfe DD. Mast cells and mastocytosis. Blood. 2008;112(4):946–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Nishida K, Yamasaki S, Ito Y, Kabu K, Hattori K, Tezuka T, et al. Fc{epsilon}RI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane. J Cell Biol. 2005;170(1):115–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Lundequist A, Pejler G. Biological implications of preformed mast cell mediators. Cell Mol Life Sci. 2011;68(6):965–75.

    Article  CAS  PubMed  Google Scholar 

  215. Zhang B, Weng Z, Sismanopoulos N, Asadi S, Therianou A, Alysandratos KD, et al. Mitochondria distinguish granule-stored from de novo synthesized tumor necrosis factor secretion in human mast cells. Int Arch Allergy Immunol. 2012;159(1):23–32.

    Article  CAS  PubMed  Google Scholar 

  216. Theoharides TC, Bielory L. Mast cells and mast cell mediators as targets of dietary supplements. Ann Allergy Asthma Immunol. 2004;93(2 Suppl 1):S24–34.

    Article  CAS  PubMed  Google Scholar 

  217. Douaiher J, Succar J, Lancerotto L, Gurish MF, Orgill DP, Hamilton MJ, et al. Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing. Adv Immunol. 2014;122:211–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Theoharides TC, Kempuraj D, Tagen M, Conti P, Kalogeromitros D. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev. 2007;217:65–78.

    Article  CAS  PubMed  Google Scholar 

  219. Galli SJ. New concepts about the mast cell. N Engl J Med. 1993;328(4):257–65.

    Article  CAS  PubMed  Google Scholar 

  220. Siraganian RP. Mast cell signal transduction from the high-affinity IgE receptor. Curr Opin Immunol. 2003;15(6):639–46.

    Article  CAS  PubMed  Google Scholar 

  221. Blank U, Rivera J. The ins and outs of IgE-dependent mast-cell exocytosis. Trends Immunol. 2004;25(5):266–73.

    Article  CAS  PubMed  Google Scholar 

  222. Kraft S, Rana S, Jouvin MH, Kinet JP. The role of the FcepsilonRI beta-chain in allergic diseases. Int Arch Allergy Immunol. 2004;135(1):62–72.

    Article  CAS  PubMed  Google Scholar 

  223. Metz M, Siebenhaar F, Maurer M. Mast cell functions in the innate skin immune system. Immunobiology. 2008;213(3-4):251–60.

    Article  CAS  PubMed  Google Scholar 

  224. Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol. 2010;10(6):440–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature. 1990;346(6281):274–6.

    Article  CAS  PubMed  Google Scholar 

  226. Galli SJ, Nakae S, Tsai M. Mast cells in the development of adaptive immune responses. Nat Immunol. 2005;6(2):135–42.

    Article  CAS  PubMed  Google Scholar 

  227. Mekori YA, Metcalfe DD. Mast cells in innate immunity. Immunol Rev. 2000;173:131–40.

    Article  CAS  PubMed  Google Scholar 

  228. Benoist C, Mathis D. Mast cells in autoimmune disease. Nature. 2002;420(6917):875–8.

    Article  CAS  PubMed  Google Scholar 

  229. Rottem M, Mekori YA. Mast cells and autoimmunity. Autoimmun Rev. 2005;4(1):21–7.

    Article  CAS  PubMed  Google Scholar 

  230. Oskeritzian CA. Mast cell plasticity and sphingosine-1-phosphate in immunity, inflammation and cancer. Mol Immunol. 2015;63(1):104–12.

    Article  CAS  PubMed  Google Scholar 

  231. Ng MF. The role of mast cells in wound healing. Int Wound J. 2010;7(1):55–61.

    Article  PubMed  PubMed Central  Google Scholar 

  232. Weber A, Knop J, Maurer M. Pattern analysis of human cutaneous mast cell populations by total body surface mapping. Br J Dermatol. 2003;148(2):224–8.

    Article  CAS  PubMed  Google Scholar 

  233. Fewtrell CM, Foreman JC, Jordan CC, Oehme P, Renner H, Stewart JM. The effects of substance P on histamine and 5-hydroxytryptamine release in the rat. J Physiol. 1982;330:393–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Carraway R, Cochrane DE, Lansman JB, Leeman SE, Paterson BM, Welch HJ. Neurotensin stimulates exocytotic histamine secretion from rat mast cells and elevates plasma histamine levels. J Physiol. 1982;323:403–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Goetzl EJ, Cheng PP, Hassner A, Adelman DC, Frick OL, Sreedharan SP. Neuropeptides, mast cells and allergy: novel mechanisms and therapeutic possibilities. Clin Exp Allergy. 1990;20(Suppl 4):3–7.

    Article  PubMed  Google Scholar 

  236. Chahdi A, Mousli M, Landry Y. Substance P-related inhibitors of mast cell exocytosis act on G-proteins or on the cell surface. Eur J Pharmacol. 1998;341(2-3):329–35.

    Article  CAS  PubMed  Google Scholar 

  237. Barrocas AM, Cochrane DE, Carraway RE, Feldberg RS. Neurotensin stimulation of mast cell secretion is receptor-mediated, pertussis-toxin sensitive and requires activation of phospholipase C. Immunopharmacology. 1999;41(2):131–7.

    Article  CAS  PubMed  Google Scholar 

  238. Mousli M, Hugli TE, Landry Y, Bronner C. Peptidergic pathway in human skin and rat peritoneal mast cell activation. Immunopharmacology. 1994;27(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  239. Palomaki VA, Laitinen JT. The basic secretagogue compound 48/80 activates G proteins indirectly via stimulation of phospholipase D-lysophosphatidic acid receptor axis and 5-HT1A receptors in rat brain sections. Br J Pharmacol. 2006;147(6):596–606.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  240. Chahdi A, Fraundorfer PF, Beaven MA. Compound 48/80 activates mast cell phospholipase D via heterotrimeric GTP-binding proteins. J Pharmacol Exp Ther. 2000;292(1):122–30.

    CAS  PubMed  Google Scholar 

  241. Cao J, Papadopoulou N, Kempuraj D, Boucher WS, Sugimoto K, Cetrulo CL, et al. Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol. 2005;174(12):7665–75.

    Article  CAS  PubMed  Google Scholar 

  242. Theoharides TC, Zhang B, Kempuraj D, Tagen M, Vasiadi M, Angelidou A, et al. IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci U S A. 2010;107(9):4448–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. el Sayed SO, Dyson M. Responses of dermal mast cells to injury. J Anat. 1993;182(Pt 3):369–76.

    PubMed  PubMed Central  Google Scholar 

  244. Wulff BC, Wilgus TA. Mast cell activity in the healing wound: more than meets the eye? Exp Dermatol. 2013;22(8):507–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Rao KN, Brown MA. Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann N Y Acad Sci. 2008;1143:83–104.

    Article  CAS  PubMed  Google Scholar 

  246. Dunnick CA, Gibran NS, Heimbach DM. Substance P has a role in neurogenic mediation of human burn wound healing. J Burn Care Rehabil. 1996;17(5):390–6.

    Article  CAS  PubMed  Google Scholar 

  247. Younan GJ, Heit YI, Dastouri P, Kekhia H, Xing W, Gurish MF, et al. Mast cells are required in the proliferation and remodeling phases of microdeformational wound therapy. Plast Reconstr Surg. 2011;128(6):649e–58e.

    Article  PubMed  CAS  Google Scholar 

  248. Nishikori Y, Kakizoe E, Kobayashi Y, Shimoura K, Okunishi H, Dekio S. Skin mast cell promotion of matrix remodeling in burn wound healing in mice: relevance of chymase. Arch Dermatol Res. 1998;290(10):553–60.

    Article  CAS  PubMed  Google Scholar 

  249. Noli C, Miolo A. The role of mast cells in the early stages of wound healing. Int Wound J. 2010;7(6):540.

    Article  PubMed  PubMed Central  Google Scholar 

  250. Wulff BC, Parent AE, Meleski MA, DiPietro LA, Schrementi ME, Wilgus TA. Mast cells contribute to scar formation during fetal wound healing. J Invest Dermatol. 2012;132(2):458–65.

    Article  CAS  PubMed  Google Scholar 

  251. Mekori YA, Zeidan Z. Mast cells in nonallergic immune responses in vivo. Isr J Med Sci. 1990;26(6):337–41.

    CAS  PubMed  Google Scholar 

  252. Prieto-Garcia A, Zheng D, Adachi R, Xing W, Lane WS, Chung K, et al. Mast cell restricted mouse and human tryptase.heparin complexes hinder thrombin-induced coagulation of plasma and the generation of fibrin by proteolytically destroying fibrinogen. J Biol Chem. 2012;287(11):7834–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Weller K, Foitzik K, Paus R, Syska W, Maurer M. Mast cells are required for normal healing of skin wounds in mice. FASEB J. 2006;20(13):2366–8.

    Article  CAS  PubMed  Google Scholar 

  254. Egozi EI, Ferreira AM, Burns AL, Gamelli RL, Dipietro LA. Mast cells modulate the inflammatory but not the proliferative response in healing wounds. Wound Repair Regen. 2003;11(1):46–54.

    Article  PubMed  Google Scholar 

  255. Younan G, Suber F, Xing W, Shi T, Kunori Y, Abrink M, et al. The inflammatory response after an epidermal burn depends on the activities of mouse mast cell proteases 4 and 5. J Immunol. 2010;185(12):7681–90.

    Article  CAS  PubMed  Google Scholar 

  256. Chen R, Fairley JA, Zhao ML, Giudice GJ, Zillikens D, Diaz LA, et al. Macrophages, but not T and B lymphocytes, are critical for subepidermal blister formation in experimental bullous pemphigoid: macrophage-mediated neutrophil infiltration depends on mast cell activation. J Immunol. 2002;169(7):3987–92.

    Article  CAS  PubMed  Google Scholar 

  257. Qu Z, Huang X, Ahmadi P, Stenberg P, Liebler JM, Le AC, et al. Synthesis of basic fibroblast growth factor by murine mast cells. Regulation by transforming growth factor beta, tumor necrosis factor alpha, and stem cell factor. Int Arch Allergy Immunol. 1998;115(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  258. Katayama I, Yokozeki H, Nishioka K. Mast-cell-derived mediators induce epidermal cell proliferation: clue for lichenified skin lesion formation in atopic dermatitis. Int Arch Allergy Immunol. 1992;98(4):410–4.

    Article  CAS  PubMed  Google Scholar 

  259. Cairns JA, Walls AF. Mast cell tryptase is a mitogen for epithelial cells. Stimulation of IL-8 production and intercellular adhesion molecule-1 expression. J Immunol. 1996;156(1):275–83.

    CAS  PubMed  Google Scholar 

  260. Shiota N, Nishikori Y, Kakizoe E, Shimoura K, Niibayashi T, Shimbori C, et al. Pathophysiological role of skin mast cells in wound healing after scald injury: study with mast cell-deficient W/W(V) mice. Int Arch Allergy Immunol. 2010;151(1):80–8.

    Article  PubMed  Google Scholar 

  261. Puxeddu I, Piliponsky AM, Bachelet I, Levi-Schaffer F. Mast cells in allergy and beyond. Int J Biochem Cell Biol. 2003;35(12):1601–7.

    Article  CAS  PubMed  Google Scholar 

  262. Azizkhan RG, Azizkhan JC, Zetter BR, Folkman J. Mast cell heparin stimulates migration of capillary endothelial cells in vitro. J Exp Med. 1980;152(4):931–44.

    Article  CAS  PubMed  Google Scholar 

  263. Norrby K, Sorbo J. Heparin enhances angiogenesis by a systemic mode of action. Int J Exp Pathol. 1992;73(2):147–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  264. Gailit J, Marchese MJ, Kew RR, Gruber BL. The differentiation and function of myofibroblasts is regulated by mast cell mediators. J Invest Dermatol. 2001;117(5):1113–9.

    Article  CAS  PubMed  Google Scholar 

  265. Kupietzky A, Levi-Schaffer F. The role of mast cell-derived histamine in the closure of an in vitro wound. Inflamm Res. 1996;45(4):176–80.

    Article  CAS  PubMed  Google Scholar 

  266. Yamamoto T, Hartmann K, Eckes B, Krieg T. Mast cells enhance contraction of three-dimensional collagen lattices by fibroblasts by cell-cell interaction: role of stem cell factor/c-kit. Immunology. 2000;99(3):435–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Moyer KE, Saggers GC, Ehrlich HP. Mast cells promote fibroblast populated collagen lattice contraction through gap junction intercellular communication. Wound Repair Regen. 2004;12(3):269–75.

    Article  PubMed  Google Scholar 

  268. Pistorio AL, Ehrlich HP. Modulatory effects of connexin-43 expression on gap junction intercellular communications with mast cells and fibroblasts. J Cell Biochem. 2011;112(5):1441–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Au SR, Au K, Saggers GC, Karne N, Ehrlich HP. Rat mast cells communicate with fibroblasts via gap junction intercellular communications. J Cell Biochem. 2007;100(5):1170–7.

    Article  CAS  PubMed  Google Scholar 

  270. Foley TT, Saggers GC, Moyer KE, Ehrlich HP. Rat mast cells enhance fibroblast proliferation and fibroblast-populated collagen lattice contraction through gap junctional intercellular communications. Plast Reconstr Surg. 2011;127(4):1478–86.

    Article  CAS  PubMed  Google Scholar 

  271. Harunari N, Zhu KQ, Armendariz RT, Deubner H, Muangman P, Carrougher GJ, et al. Histology of the thick scar on the female, red Duroc pig: final similarities to human hypertrophic scar. Burns. 2006;32(6):669–77.

    Article  PubMed  PubMed Central  Google Scholar 

  272. Kischer CW, Bunce H 3rd, Shetlah MR. Mast cell analyses in hypertrophic scars, hypertrophic scars treated with pressure and mature scars. J Invest Dermatol. 1978;70(6):355–7.

    Article  CAS  PubMed  Google Scholar 

  273. Smith CJ, Smith JC, Finn MC. The possible role of mast cells (allergy) in the production of keloid and hypertrophic scarring. J Burn Care Rehabil. 1987;8(2):126–31.

    Article  CAS  PubMed  Google Scholar 

  274. Antsiferova M, Martin C, Huber M, Feyerabend TB, Forster A, Hartmann K, et al. Mast cells are dispensable for normal and activin-promoted wound healing and skin carcinogenesis. J Immunol. 2013;191(12):6147–55.

    Article  CAS  PubMed  Google Scholar 

  275. Nauta AC, Grova M, Montoro DT, Zimmermann A, Tsai M, Gurtner GC, et al. Evidence that mast cells are not required for healing of splinted cutaneous excisional wounds in mice. PLoS One. 2013;8(3):e59167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Willenborg S, Eckes B, Brinckmann J, Krieg T, Waisman A, Hartmann K, et al. Genetic ablation of mast cells redefines the role of mast cells in skin wound healing and bleomycin-induced fibrosis. J Invest Dermatol. 2014;134(7):2005–15.

    Article  CAS  PubMed  Google Scholar 

  277. Hinz B, Mastrangelo D, Iselin CE, Chaponnier C, Gabbiani G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol. 2001;159(3):1009–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Lopez X, Castells M, Ricker A, Velazquez EF, Mun E, Goldfine AB. Human insulin analog--induced lipoatrophy. Diabetes Care. 2008;31(3):442–4.

    Article  PubMed  Google Scholar 

  279. Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN, et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med. 2009;15(8):940–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Divoux A, Moutel S, Poitou C, Lacasa D, Veyrie N, Aissat A, et al. Mast cells in human adipose tissue: link with morbid obesity, inflammatory status, and diabetes. J Clin Endocrinol Metab. 2012;97(9):E1677–85.

    Article  CAS  PubMed  Google Scholar 

  281. Wang Z, Zhang H, Shen XH, Jin KL, Ye GF, Qian L, et al. Immunoglobulin E and mast cell proteases are potential risk factors of human pre-diabetes and diabetes mellitus. PLoS One. 2011;6(12):e28962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Geoffrey R, Jia S, Kwitek AE, Woodliff J, Ghosh S, Lernmark A, et al. Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat. J Immunol. 2006;177(10):7275–86.

    Article  CAS  PubMed  Google Scholar 

  283. Martino L, Masini M, Bugliani M, Marselli L, Suleiman M, Boggi U, et al. Mast cells infiltrate pancreatic islets in human type 1 diabetes. Diabetologia. 2015;58(11):2554–62.

    Article  CAS  PubMed  Google Scholar 

  284. Carlos D, Yaochite JN, Rocha FA, Toso VD, Malmegrim KC, Ramos SG, et al. Mast cells control insulitis and increase Treg cells to confer protection against STZ-induced type 1 diabetes in mice. Eur J Immunol. 2015;45(10):2873–85.

    Article  CAS  PubMed  Google Scholar 

  285. Shi MA, Shi GP. Different roles of mast cells in obesity and diabetes: lessons from experimental animals and humans. Front Immunol. 2012;3:7.

    Article  PubMed  PubMed Central  Google Scholar 

  286. Nishikori Y, Shiota N, Okunishi H. The role of mast cells in cutaneous wound healing in streptozotocin-induced diabetic mice. Arch Dermatol Res. 2014;306(9):823–35.

    Article  CAS  PubMed  Google Scholar 

  287. Tellechea A, Leal EC, Kafanas A, Auster ME, Kuchibhotla S, Ostrovsky Y, et al. Mast cells regulate wound healing in diabetes. Diabetes. 2016;65(7):2006–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Bellas E, Seiberg M, Garlick J, Kaplan DL. In vitro 3D full-thickness skin-equivalent tissue model using silk and collagen biomaterials. Macromol Biosci. 2012;12(12):1627–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Xie Y, Rizzi SC, Dawson R, Lynam E, Richards S, Leavesley DI, et al. Development of a three-dimensional human skin equivalent wound model for investigating novel wound healing therapies. Tissue Eng Part C Methods. 2010;16(5):1111–23.

    Article  CAS  PubMed  Google Scholar 

  290. Stojadinovic O, Tomic-Canic M. Human ex vivo wound healing model. Methods Mol Biol. 2013;1037:255–64.

    Article  PubMed  CAS  Google Scholar 

  291. Mendoza-Garcia J, Sebastian A, Alonso-Rasgado T, Bayat A. Optimization of an ex vivo wound healing model in the adult human skin: functional evaluation using photodynamic therapy. Wound Repair Regen. 2015;23(5):685–702.

    Article  PubMed  Google Scholar 

  292. Sullivan SR, Underwood RA, Gibran NS, Sigle RO, Usui ML, Carter WG, et al. Validation of a model for the study of multiple wounds in the diabetic mouse (db/db). Plast Reconstr Surg. 2004;113(3):953–60.

    Article  PubMed  Google Scholar 

  293. Trousdale RK, Jacobs S, Simhaee DA, Wu JK, Lustbader JW. Wound closure and metabolic parameter variability in a db/db mouse model for diabetic ulcers. J Surg Res. 2009;151(1):100–7.

    Article  CAS  PubMed  Google Scholar 

  294. Vinik AI, Holland MT, Le Beau JM, Liuzzi FJ, Stansberry KB, Colen LB. Diabetic neuropathies. Diabetes Care. 1992;15(12):1926–75.

    Article  CAS  PubMed  Google Scholar 

  295. Walters DP, Gatling W, Mullee MA, Hill RD. The prevalence of diabetic distal sensory neuropathy in an English community. Diabet Med. 1992;9(4):349–53.

    Article  CAS  PubMed  Google Scholar 

  296. Rathur HM, Boulton AJ. Recent advances in the diagnosis and management of diabetic neuropathy. J Bone Joint Surg. 2005;87(12):1605–10.

    Article  CAS  Google Scholar 

  297. Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care. 2000;23(5):606–11.

    Article  CAS  PubMed  Google Scholar 

  298. Biessels GJ, Bril V, Calcutt NA, Cameron NE, Cotter MA, Dobrowsky R, et al. Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab). J Peripher Nerv Syst. 2014;19(2):77–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Keswani SG, Katz AB, Lim FY, Zoltick P, Radu A, Alaee D, et al. Adenoviral mediated gene transfer of PDGF-B enhances wound healing in type I and type II diabetic wounds. Wound Repair Regen. 2004;12(5):497–504.

    Article  PubMed  Google Scholar 

  300. McBride JD, Jenkins AJ, Liu X, Zhang B, Lee K, Berry WL, et al. Elevated circulation levels of an antiangiogenic SERPIN in patients with diabetic microvascular complications impair wound healing through suppression of Wnt signaling. J Invest Dermatol. 2014;134(6):1725–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Luo JD, Wang YY, Fu WL, Wu J, Chen AF. Gene therapy of endothelial nitric oxide synthase and manganese superoxide dismutase restores delayed wound healing in type 1 diabetic mice. Circulation. 2004;110(16):2484–93.

    Article  CAS  PubMed  Google Scholar 

  302. Michaels JT, Churgin SS, Blechman KM, Greives MR, Aarabi S. Galiano RD, et al. db/db mice exhibit severe wound-healing impairments compared with other murine diabetic strains in a silicone-splinted excisional wound model. Wound Repair Regen. 2007;15(5):665–70.

    Article  PubMed  Google Scholar 

  303. Fang RC, Kryger ZB, Buck DW 2nd, De la Garza M, Galiano RD, Mustoe TA. Limitations of the db/db mouse in translational wound healing research: is the NONcNZO10 polygenic mouse model superior? Wound Repair Regen. 2010;18(6):605–13.

    Article  PubMed  Google Scholar 

  304. Buck DW 2nd, Jin DP, Geringer M, Hong SJ, Galiano RD, Mustoe TA. The TallyHo polygenic mouse model of diabetes: implications in wound healing. Plast Reconstr Surg. 2011;128(5):427e–37e.

    Article  PubMed  CAS  Google Scholar 

  305. Bauer BS, Ghahary A, Scott PG, Iwashina T, Demare J, Russell JC, et al. The JCR:LA-cp rat: a novel model for impaired wound healing. Wound Repair Regen. 2004;12(1):86–92.

    Article  PubMed  Google Scholar 

  306. Kong P, Xie X, Li F, Liu Y, Lu Y. Placenta mesenchymal stem cell accelerates wound healing by enhancing angiogenesis in diabetic Goto-Kakizaki (GK) rats. Biochem Biophys Res Commun. 2013;438(2):410–9.

    Article  CAS  PubMed  Google Scholar 

  307. Wang H, Chen L, Liu Y, Luo B, Xie N, Tan T, et al. Implantation of placenta-derived mesenchymal stem cells accelerates murine dermal wound closure through immunomodulation. Am J Transl Res. 2016;8(11):4912–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  308. Shin HS, Oh HY. The effect of platelet-rich plasma on wounds of OLETF rats using expression of matrix metalloproteinase-2 and -9 mRNA. Archiv Plast Surg. 2012;39(2):106–12.

    Article  Google Scholar 

  309. Duttlinger R, Manova K, Chu TY, Gyssler C, Zelenetz AD, Bachvarova RF, et al. W-sash affects positive and negative elements controlling c-kit expression: ectopic c-kit expression at sites of kit-ligand expression affects melanogenesis. Development. 1993;118(3):705–17.

    Article  CAS  PubMed  Google Scholar 

  310. Grimbaldeston MA, Chen CC, Piliponsky AM, Tsai M, Tam SY, Galli SJ. Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol. 2005;167(3):835–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  311. Dyson M, Young S, Pendle CL, Webster DF, Lang SM. Comparison of the effects of moist and dry conditions on dermal repair. J Invest Dermatol. 1988;91(5):434–9.

    Article  CAS  PubMed  Google Scholar 

  312. Galiano RD, Michaels J, Dobryansky M, Levine JP, Gurtner GC. Quantitative and reproducible murine model of excisional wound healing. Wound Repair Regen. 2004;12(4):485–92.

    Article  PubMed  Google Scholar 

  313. Perez R, Davis SC. Relevance of animal models for wound healing. Wounds. 2008;1:3–8.

    Google Scholar 

  314. Davidson JM. Animal models for wound repair. Arch Dermatol Res. 1998;290(Suppl):S1–11.

    Article  PubMed  Google Scholar 

  315. Wong VW, Sorkin M, Glotzbach JP, Longaker MT, Gurtner GC. Surgical approaches to create murine models of human wound healing. J Biomed Biotechnol. 2011;2011:969618.

    PubMed  Google Scholar 

  316. Harada E, Kanno T. Rabbit's ear in cold acclimation studied on the change in ear temperature. J Appl Physiol. 1975;38(3):389–94.

    Article  CAS  PubMed  Google Scholar 

  317. Hill RW, Veghte JH. Jackrabbit ears: surface temperatures and vascular responses. Science. 1976;194(4263):436–8.

    Article  CAS  PubMed  Google Scholar 

  318. Slepchuk NA, Rumiantsev GV. Role of a decrease in the body's heat content on the thermoregulatory reaction of the vessels of the external ear. Fiziol Zh SSSR Im I M Sechenova. 1978;64(6):843–9.

    CAS  PubMed  Google Scholar 

  319. Smith TL, Gordon S, Holden MB, Smith BP, Russell GB, Koman LA. A rabbit ear model for cold stress testing. Microsurgery. 1994;15(8):563–7.

    Article  CAS  PubMed  Google Scholar 

  320. Sullivan TP, Eaglstein WH, Davis SC, Mertz P. The pig as a model for human wound healing. Wound Repair Regen. 2001;9(2):66–76.

    Article  CAS  PubMed  Google Scholar 

  321. Lindblad WJ. Considerations for selecting the correct animal model for dermal wound-healing studies. J Biomater Sci Polym Ed. 2008;19(8):1087–96.

    Article  CAS  PubMed  Google Scholar 

  322. Renner S, Braun-Reichhart C, Blutke A, Herbach N, Emrich D, Streckel E, et al. Permanent neonatal diabetes in INS(C94Y) transgenic pigs. Diabetes. 2013;62(5):1505–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  323. Gordillo GM, Bernatchez SF, Diegelmann R, Di Pietro LA, Eriksson E, Hinz B, et al. Preclinical models of wound healing: is man the model? proceedings of the wound healing society symposium. Adv Wound Care. 2013;2(1):1–4.

    Article  Google Scholar 

  324. Ansell DM, Holden KA, Hardman MJ. Animal models of wound repair: are they cutting it? Exp Dermatol. 2012;21(8):581–5.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Ana Tellechea PharmD, PhD

  2. Division of Translational Medicine, Department of Medicine, New York University School of Medicine, New York, NY, USA

    Ana Tellechea PharmD, PhD

  3. Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Leena Pradhan-Nabzdyk PhD, MBA & Frank W. LoGerfo MD

  4. The Rongxiang Xu, MD, Center for Regenerative Therapeutics Research Director, Joslin-Beth Israel Deaconess Foot Center, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Aristidis Veves MD, DSc

Authors
  1. Ana Tellechea PharmD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leena Pradhan-Nabzdyk PhD, MBA
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank W. LoGerfo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aristidis Veves MD, DSc
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ana Tellechea PharmD, PhD .

Editor information

Editors and Affiliations

  1. Rongxiang Xu, MD, Professor of Surgery, Harvard Medical School Director, The Rongxiang Xu, MD, Center for Regenerative Therapeutics Research Director, Joslin-Beth Israel Deaconess Foot Center Beth Israel Deaconess Medical Center, Boston, MA, USA

    Aristidis Veves

  2. Chief, Division of Podiatry, Beth Israel Deaconess Medical Center, Associate Professor of Surgery, Harvard Medical School, Co-director, Joslin-Bl Deaconess Diabetic Foot Center Consultant, Joslin Diabetes Center, Boston, MA, USA

    John M. Giurini

  3. Associate Professor of Surgery, Harvard Medical School, Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Joslin Diabetes Center, Boston, MA, USA

    Raul J. Guzman

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Tellechea, A., Pradhan-Nabzdyk, L., LoGerfo, F.W., Veves, A. (2018). Neuropeptides, Inflammation, and Diabetic Wound Healing: Lessons from Experimental Models and Human Subjects. In: Veves, A., Giurini, J., Guzman, R. (eds) The Diabetic Foot. Contemporary Diabetes. Humana, Cham. https://doi.org/10.1007/978-3-319-89869-8_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-89869-8_8

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-319-89868-1

  • Online ISBN: 978-3-319-89869-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation