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Neuropeptides and Diabetic Wound-Healing

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The Diabetic Foot

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

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Abstract

Diabetes impairs wound-healing, which in turn predisposes patients to develop nonhealing foot ulcers and amputations. Vascular dysfunction, peripheral neuropathy, and immune dysregulation are among the known contributors to nonhealing foot ulcers. In recent years, research efforts have been initiated towards deciphering the role of neuropeptides in wound-healing. In particular, Substance P, neuropeptide Y, and calcitonin gene-related peptide are known to have physiological roles in pain transmission, satiety, and maintenance of vascular tone. Cytokine secretion, immune cell trafficking, and growth factor signaling are some of the mechanisms modulated by peripheral autonomic and sensory neuropeptides through which they affect inflammation and proliferation. Thus, neuropeptides released by cutaneous nerves can directly participate in the healing process by affecting the inflammatory and proliferative phases of wound-healing. We therefore believe that, in diabetic patients with peripheral neuropathy, impaired wound-healing could be a result of neuropeptide dysregulation. The present chapter gives a broad overview of different neuropeptides that could play a fundamental role in the wound-healing process. Additionally, we have discussed different in vivo models that could further help delineate the role of neuropeptides in diabetic wound-healing.

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References

  1. 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.

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  3. Quattrini C, Jeziorska M, Malik RA. Small fiber neuropathy in diabetes: clinical consequence and assessment. Int J Low Extrem Wounds. 2004;3:16–21.

    PubMed  CAS  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;86:1309–79.

    PubMed  CAS  Google Scholar 

  5. Luger TA. Neuromediators—a crucial component of the skin immune system. J Dermatol Sci. 2002;30:87–93.

    PubMed  CAS  Google Scholar 

  6. Kohara H, Tajima S, Yamamoto M, Tabata Y. Angiogenesis induced by controlled release of neuropeptide substance P. Biomaterials. 2010;31(33):8617–25.

    PubMed  CAS  Google Scholar 

  7. Jing C, Jia-Han W, Hong-Xing Z. Double-edged effects of neuropeptide substance P on repair of cutaneous trauma. Wound Repair Regen. 2010;18:319–24.

    PubMed  Google Scholar 

  8. Lindberger M, Schroder HD, Schultzberg M, Kristensson K, Persson A, Ostman J, Link H. Nerve fibre studies in skin biopsies in peripheral neuropathies. I. Immunohistochemical analysis of neuropeptides in diabetes mellitus. J Neurol Sci. 1989;93:289–96.

    PubMed  CAS  Google Scholar 

  9. Spenny ML, Muangman P, Sullivan SR, Bunnett NW, Ansel JC, Olerud JE, Gibran NS. Neutral endopeptidase inhibition in diabetic wound repair. Wound Repair Regen. 2002;10:295–301.

    PubMed  Google Scholar 

  10. Pernow B. Substance P. Pharmacol Rev. 1983;35:85–141.

    PubMed  CAS  Google Scholar 

  11. Matis WL, Lavker RM, Murphy GF. Substance P induces the expression of an endothelial-leukocyte adhesion molecule by microvascular endothelium. J Invest Dermatol. 1990;94:492–5.

    PubMed  CAS  Google Scholar 

  12. Vishwanath R, Mukherjee R. Substance P promotes lymphocyte-endothelial cell adhesion preferentially via LFA-1/ICAM-1 interactions. J Neuroimmunol. 1996;71:163–71.

    PubMed  CAS  Google Scholar 

  13. Delgado AV, McManus AT, Chambers JP. Production of tumor necrosis factor-alpha, interleukin 1-beta, interleukin 2, and interleukin 6 by rat leukocyte subpopulations after exposure to substance P. Neuropeptides. 2003;37:355–61.

    PubMed  CAS  Google Scholar 

  14. Ho WZ, Lai JP, Zhu XH, Uvaydova M, Douglas SD. Human monocytes and macrophages express substance P and neurokinin-1 receptor. J Immunol. 1997;159:5654–60.

    PubMed  CAS  Google Scholar 

  15. Lai JP, Douglas SD, Ho WZ. Human lymphocytes express substance P and its receptor. J Neuroimmunol. 1998;86:80–6.

    PubMed  CAS  Google Scholar 

  16. Lai JP, Douglas SD, Shaheen F, Pleasure DE, Ho WZ. Quantification of substance p mRNA in human immune cells by real-time reverse transcriptase PCR assay. Clin Diagn Lab Immunol. 2002;9:138–43.

    PubMed  CAS  Google Scholar 

  17. Lambrecht BN. Immunologists getting nervous: neuropeptides, dendritic cells and T cell activation. Respir Res. 2001;2:133–8.

    PubMed  CAS  Google Scholar 

  18. Lambrecht BN, Germonpre PR, Everaert EG, Carro-Muino I, De Veerman M, de Felipe C, Hunt SP, Thielemans K, Joos GF, Pauwels RA. Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation. Eur J Immunol. 1999;29:3815–25.

    PubMed  CAS  Google Scholar 

  19. Weinstock JV, Blum A, Walder J, Walder R. Eosinophils from granulomas in murine schistosomiasis mansoni produce substance P. J Immunol. 1988;141:961–6.

    PubMed  CAS  Google Scholar 

  20. O’Connor TM, O’Connell J, O’Brien DI, Goode T, Bredin CP, Shanahan F. The role of substance P in inflammatory disease. J Cell Physiol. 2004;201:167–80.

    PubMed  Google Scholar 

  21. Schratzberger P, Reinisch N, Prodinger WM, Kahler CM, Sitte BA, Bellmann R, Fischer-Colbrie R, Winkler H, Wiedermann CJ. Differential chemotactic activities of sensory neuropeptides for human peripheral blood mononuclear cells. J Immunol. 1997;158:3895–901.

    PubMed  CAS  Google Scholar 

  22. Bulut K, Felderbauer P, Deters S, Hoeck K, Schmidt-Choudhury A, Schmidt WE, Hoffmann P. Sensory neuropeptides and epithelial cell restitution: the relevance of SP- and CGRP-stimulated mast cells. Int J Colorectal Dis. 2008;23:535–41.

    PubMed  Google Scholar 

  23. Felderbauer P, Bulut K, Hoeck K, Deters S, Schmidt WE, Hoffmann P. Substance P induces intestinal wound healing via fibroblasts–evidence for a TGF-beta-dependent effect. Int J Colorectal Dis. 2007;22:1475–80.

    PubMed  Google Scholar 

  24. Ericsson A, Schalling M, McIntyre KR, Lundberg JM, Larhammar D, Seroogy K, Hokfelt T, Persson H. Detection of neuropeptide Y and its mRNA in megakaryocytes: enhanced levels in certain autoimmune mice. Proc Natl Acad Sci U S A. 1987;84:5585–9.

    PubMed  CAS  Google Scholar 

  25. Strand FL. Neuropeptides: regulators of physiological processes. Cambridge, MA: MIT; 1999.

    Google Scholar 

  26. Ahlborg G, Lundberg JM. Exercise-induced changes in neuropeptide Y, noradrenaline and endothelin-1 levels in young people with type I diabetes. Clin Physiol. 1996;16:645–55.

    PubMed  CAS  Google Scholar 

  27. 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;75:37–42.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  32. Zukowska Z, Pons J, Lee EW, Li L. Neuropeptide Y: a new mediator linking sympathetic nerves, blood vessels and immune system? Can J Physiol Pharmacol. 2003;81:89–94.

    PubMed  CAS  Google Scholar 

  33. 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;51:167–72.

    PubMed  Google Scholar 

  34. 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;142:1–6.

    PubMed  CAS  Google Scholar 

  35. 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;20:849–56.

    PubMed  Google Scholar 

  36. Zukowska Z, Grant DS, Lee EW. Neuropeptide Y: a novel mechanism for ischemic angiogenesis. Trends Cardiovasc Med. 2003;13:86–92.

    PubMed  CAS  Google Scholar 

  37. Kitlinska J, Lee EW, Movafagh S, Pons J, Zukowska Z. Neuropeptide Y-induced angiogenesis in aging. Peptides. 2002;23:71–7.

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  41. Russwurm S, Stonans I, Stonane E, Wiederhold M, Luber A, Zipfel PF, Deigner HP, Reinhart K. Procalcitonin and CGRP-1 mRNA expression in various human tissues. Shock. 2001;16:109–12.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  43. 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;5:187–93.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  45. 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.

    PubMed  CAS  Google Scholar 

  46. 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;129:1212–8.

    PubMed  CAS  Google Scholar 

  47. 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.

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  49. 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.

    PubMed  CAS  Google Scholar 

  50. Toda M, Suzuki T, Hosono K, Kurihara Y, Kurihara H, Hayashi I, Kitasato H. Hoka S. Majima M: Roles of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis. Biomed Pharmacother; 2008.

    Google Scholar 

  51. 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;87:3299–303.

    PubMed  CAS  Google Scholar 

  52. Zhang JS, Tan YR, Xiang Y, Luo ZQ, Qin XQ. Regulatory peptides modulate adhesion of polymorphonuclear leukocytes to bronchial epithelial cells through regulation of interleukins, ICAM-1 and NF-kappaB/IkappaB. Acta Biochim Biophys Sin (Shanghai). 2006;38:119–28.

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  54. 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;40:251–63.

    PubMed  CAS  Google Scholar 

  55. 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;53:199–204.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  58. Foster CA, Mandak B, Kromer E, Rot A. Calcitonin gene-related peptide is chemotactic for human T lymphocytes. Ann N Y Acad Sci. 1992;657:397–404.

    PubMed  CAS  Google Scholar 

  59. Gantz I, Fong TM. The melanocortin system. Am J Physiol Endocrinol Metab. 2003;284:E468–74.

    PubMed  CAS  Google Scholar 

  60. Seidah NG, Benjannet S, Hamelin J, Mamarbachi AM, Basak A, Marcinkiewicz J, Mbikay M, Chretien M, Marcinkiewicz M. The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Ann N Y Acad Sci. 1999;885:57–74.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  62. Slominski A, Wortsman J, Mazurkiewicz JE, Matsuoka L, Dietrich J, Lawrence K, Gorbani A, Paus R. Detection of proopiomelanocortin-derived antigens in normal and pathologic human skin. J Lab Clin Med. 1993;122:658–66.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  64. Hochgeschwender U, Costa JL, Reed P, Bui S, Brennan MB. Altered glucose homeostasis in proopiomelanocortin-null mouse mutants lacking central and peripheral melanocortin. Endocrinology. 2003;144:5194–202.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  66. 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:R1320–6.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  68. 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;275:584–91.

    PubMed  CAS  Google Scholar 

  69. 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;17:2181–6.

    PubMed  CAS  Google Scholar 

  70. Rajora N, Boccoli G, Catania A, Lipton JM. Alpha-MSH modulates experimental inflammatory bowel disease. Peptides. 1997;18:381–5.

    PubMed  CAS  Google Scholar 

  71. Catania A, Delgado R, Airaghi L, Cutuli M, Garofalo L, Carlin A, Demitri MT, Lipton JM. Alpha-MSH in systemic inflammation. Central and peripheral actions. Ann N Y Acad Sci. 1999;885:183–7.

    PubMed  CAS  Google Scholar 

  72. Gatti S, Colombo G, Buffa R, Turcatti F, Garofalo L, Carboni N, Ferla L, Fassati LR, Lipton JM, Catania A. Alpha-melanocyte-stimulating hormone protects the allograft in experimental heart transplantation. Transplantation. 2002;74:1678–84.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  75. 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.

    PubMed  CAS  Google Scholar 

  76. Bhardwaj RS, Schwarz A, Becher E, Mahnke K, Aragane Y, Schwarz T, Luger TA. Pro-opiomelanocortin-derived peptides induce IL-10 production in human monocytes. J Immunol. 1996;156:2517–21.

    PubMed  CAS  Google Scholar 

  77. Taherzadeh S, Sharma S, Chhajlani V, Gantz I, Rajora N, Demitri MT, Kelly L, Zhao H, Ichiyama T, Catania A, Lipton JM. Alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages. Am J Physiol. 1999;276:R1289–94.

    PubMed  CAS  Google Scholar 

  78. Catania A, Cutuli M, Garofalo L, Airaghi L, Valenza F, Lipton JM, Gattinoni L. Plasma concentrations and anti-L-cytokine effects of alpha-melanocyte stimulating hormone in septic patients. Crit Care Med. 2000;28:1403–7.

    PubMed  CAS  Google Scholar 

  79. 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;92:8016–20.

    PubMed  CAS  Google Scholar 

  80. 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;61:613–21.

    PubMed  CAS  Google Scholar 

  81. Kalden DH, Scholzen T, Brzoska T, Luger TA. Mechanisms of the antiinflammatory effects of alpha-MSH. Role of transcription factor NF-kappa B and adhesion molecule expression. Ann N Y Acad Sci. 1999;885:254–61.

    PubMed  CAS  Google Scholar 

  82. 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;159:1930–7.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  84. 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;83:1366–72.

    PubMed  CAS  Google Scholar 

  85. Evers BM. Neurotensin and growth of normal and neoplastic tissues. Peptides. 2006;27:2424–33.

    PubMed  Google Scholar 

  86. Gross KJ, Pothoulakis C. Role of neuropeptides in inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:918–32.

    PubMed  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 (Copenh). 1985;108:532–6.

    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.

    PubMed  CAS  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;35:194–8.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  91. Goldman R, Bar-Shavit Z, Shezen E, Terry S, Blumberg S. Enhancement of phagocytosis by ­neurotensin, a newly found biological activity of the neuropeptide. Adv Exp Med Biol. 1982;155:133–41.

    PubMed  CAS  Google Scholar 

  92. Koff WC, Dunegan MA. Modulation of macrophage-mediated tumoricidal activity by neuropeptides and neurohormones. J Immunol. 1985;135:350–4.

    PubMed  CAS  Google Scholar 

  93. Lemaire I. Neurotensin enhances IL-1 production by activated alveolar macrophages. J Immunol. 1988;140:2983–8.

    PubMed  CAS  Google Scholar 

  94. Garrido JJ, Arahuetes RM, Hernanz A, De la Fuente M. Modulation by neurotensin and neuromedin N of adherence and chemotaxis capacity of murine lymphocytes. Regul Pept. 1992;41:27–37.

    PubMed  CAS  Google Scholar 

  95. Evers BM, Bold RJ, Ehrenfried JA, Li J, Townsend Jr CM, Klimpel GR. Characterization of functional neurotensin receptors on human lymphocytes. Surgery. 1994;116:134–9; discussion 139–40.

    PubMed  CAS  Google Scholar 

  96. Hartschuh W, Weihe E, Reinecke M. Peptidergic (neurotensin, VIP, substance P) nerve fibres in the skin. Immunohistochemical evidence of an involvement of neuropeptides in nociception, pruritus and inflammation. Br J Dermatol. 1983;109 Suppl 25:14–7.

    PubMed  CAS  Google Scholar 

  97. Donelan J, Boucher W, Papadopoulou N, Lytinas M, Papaliodis D, Dobner P, Theoharides TC. Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc Natl Acad Sci U S A. 2006;103:7759–64.

    PubMed  CAS  Google Scholar 

  98. 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;67:2025–31.

    PubMed  CAS  Google Scholar 

  99. Zhao D, Kuhnt-Moore S, Zeng H, Wu JS, Moyer MP, Pothoulakis C. Neurotensin stimulates IL-8 expression in human colonic epithelial cells through Rho GTPase-mediated NF-kappa B pathways. Am J Physiol Cell Physiol. 2003;284:C1397–404.

    PubMed  CAS  Google Scholar 

  100. Brun P, Mastrotto C, Beggiao E, Stefani A, Barzon L, Sturniolo GC, Palu G, Castagliuolo I. Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2005;288:G621–9.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  102. Linke A, Goren I, Bosl MR, Pfeilschifter J, Frank S. The suppressor of cytokine signaling (SOCS)-3 determines keratinocyte proliferative and migratory potential during skin repair. J Invest Dermatol. 2010;130:876–85.

    PubMed  CAS  Google Scholar 

  103. Gallagher KA, Liu ZJ, Xiao M, Chen H, Goldstein LJ, Buerk DG, Nedeau A, Thom SR, Velazquez OC. Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J Clin Invest. 2007;117:1249–59.

    PubMed  CAS  Google Scholar 

  104. Jacobsen JN, Steffensen B, Hakkinen L, Krogfelt KA, Larjava HS. Skin wound healing in diabetic beta6 integrin-deficient mice. APMIS. 2010;118:753–64.

    PubMed  CAS  Google Scholar 

  105. Fadini GP, Albiero M, Menegazzo L, Boscaro E, Pagnin E, Iori E, Cosma C, Lapolla A, Pengo V, Stendardo M, Agostini C, Pelicci PG, Giorgio M, Avogaro A. The redox enzyme p66Shc contributes to diabetes and ischemia-induced delay in cutaneous wound healing. Diabetes. 2010;59:2306–14.

    PubMed  CAS  Google Scholar 

  106. Carvajal-Gonzalez JM, Roman AC, Cerezo-Guisado MI, Rico-Leo EM, Martin-Partido G, Fernandez-Salguero PM. Loss of dioxin-receptor expression accelerates wound healing in vivo by a mechanism involving TGFbeta. J Cell Sci. 2009;122:1823–33.

    PubMed  CAS  Google Scholar 

  107. Loboda A, Jazwa A, Grochot-Przeczek A, Rutkowski AJ, Cisowski J, Agarwal A, Jozkowicz A, Dulak J. Heme oxygenase-1 and the vascular bed: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2008;10:1767–812.

    PubMed  CAS  Google Scholar 

  108. Wertheimer E, Spravchikov N, Trebicz M, Gartsbein M, Accili D, Avinoah I, Nofeh-Moses S, Sizyakov G, Tennenbaum T. The regulation of skin proliferation and differentiation in the IR null mouse: implications for skin complications of diabetes. Endocrinology. 2001;142:1234–41.

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  110. Follak N, Kloting L, Wolf E, Merk H. Delayed remodeling in the early period of fracture healing in spontaneously diabetic BB/OK rats depending on the diabetic metabolic state. Histol Histopathol. 2004;19:473–86.

    PubMed  CAS  Google Scholar 

  111. Nagai N, Murao T, Okamoto N, Ito Y. Kinetic analysis of the rate of corneal wound healing in Otsuka Long-Evans Tokushima fatty rats, a model of type 2 diabetes mellitus. J Oleo Sci. 2010;59:441–9.

    PubMed  CAS  Google Scholar 

  112. Perez R, Davis SC. Relevance of animal models for wound healing. Wounds. 2008;20(1):3–8.

    Google Scholar 

  113. Muangman P, Tamura RN, Muffley LA, Isik FF, Scott JR, Xie C, Kegel G, Sullivan SR, Liang Z, Gibran NS. Substance P enhances wound closure in nitric oxide synthase knockout mice. J Surg Res. 2009;153:201–9.

    PubMed  CAS  Google Scholar 

  114. Scott JR, Tamura RN, Muangman P, Isik FF, Xie C, Gibran NS. Topical substance P increases inflammatory cell density in genetically diabetic murine wounds. Wound Repair Regen. 2008;16:529–33.

    PubMed  Google Scholar 

  115. Younan G, Ogawa R, Ramirez M, Helm D, Dastouri P, Orgill DP. Analysis of nerve and neuropeptide patterns in vacuum-assisted closure-treated diabetic murine wounds. Plast Reconstr Surg. 2010;126:87–96.

    PubMed  CAS  Google Scholar 

  116. Gibran NS, Jang YC, Isik FF, Greenhalgh DG, Muffley LA, Underwood RA, Usui ML, Larsen J, Smith DG, Bunnett N, Ansel JC, Olerud JE. Diminished neuropeptide levels contribute to the impaired cutaneous healing response associated with diabetes mellitus. J Surg Res. 2002;108:122–8.

    PubMed  CAS  Google Scholar 

  117. Feldberg W. The peripheral innervation of the vessels of the external ear of the rabbit. J Physiol. 1926;61:518–29.

    PubMed  CAS  Google Scholar 

  118. Harada E, Kanno T. Rabbit’s ear in cold acclimation studied on the change in ear temperature. J Appl Physiol. 1975;38:389–94.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  120. 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;64:843–9.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  123. Hashizume N, Saika S, Okada Y, Miyamoto T, Shimizu K, Ohnishi Y. Effects of antiinflammatory drugs on migration of the rabbit corneal epithelium. J Cataract Refract Surg. 2001;27:1499–502.

    PubMed  CAS  Google Scholar 

  124. Jiang D, He Y, Mai C. A study on the course of corneal epithelial healing in diabetic rabbits. Zhonghua Yan Ke Za Zhi. 1996;32:255–7.

    PubMed  CAS  Google Scholar 

  125. Azar DT, Gipson IK. Repair of the corneal epithelial adhesion structures following keratectomy wounds in diabetic rabbits. Acta Ophthalmol Suppl. 1989;192:72–9.

    PubMed  CAS  Google Scholar 

  126. Hatchell DL, Ubels JL, Stekiel T, Hatchell MC. Corneal epithelial wound healing in normal and diabetic rabbits treated with tretinoin. Arch Ophthalmol. 1985;103:98–100.

    PubMed  CAS  Google Scholar 

  127. Hatchell DL, Magolan Jr JJ, Besson MJ, Goldman AI, Pederson HJ, Schultz KJ. Damage to the epithelial basement membrane in the corneas of diabetic rabbits. Arch Ophthalmol. 1983;101:469–71.

    PubMed  CAS  Google Scholar 

  128. Massimeo A. The repair of corneal wounds in experimental alloxan diabetes in the rabbit. Boll Ocul. 1960;39:54–66.

    PubMed  CAS  Google Scholar 

  129. Wang J, Wan R, Mo Y, Li M, Zhang Q, Chien S. Intracellular delivery of adenosine triphosphate enhanced healing process in full-thickness skin wounds in diabetic rabbits. Am J Surg. 2010;199:823–32.

    PubMed  CAS  Google Scholar 

  130. O’Breen A, Mc Redmond G, Dockery P, Brien T, Pandit A. Assessment of wound healing in the alloxan-induced diabetic rabbit ear model. J Invest Surg. 2008;21:261–9.

    Google Scholar 

  131. Hirsch T, Spielmann M, Zuhaili B, Fossum M, Metzig M, Koehler T, Steinau HU, Yao F, Onderdonk AB, Steinstraesser L, Eriksson E. Human beta-defensin-3 promotes wound healing in infected diabetic wounds. J Gene Med. 2009;11:220–8.

    PubMed  CAS  Google Scholar 

  132. Hirsch T, Spielmann M, Zuhaili B, Koehler T, Fossum M, Steinau HU, Yao F, Steinstraesser L, Onderdonk AB, Eriksson E. Enhanced susceptibility to infections in a diabetic wound healing model. BMC Surg. 2008;8:5.

    PubMed  Google Scholar 

  133. Hirsch T, Spielmann M, Velander P, Zuhaili B, Bleiziffer O, Fossum M, Steinstraesser L, Yao F, Eriksson E. Insulin-like growth factor-1 gene therapy and cell transplantation in diabetic wounds. J Gene Med. 2008;10:1247–52.

    PubMed  CAS  Google Scholar 

  134. Velander P, Theopold C, Hirsch T, Bleiziffer O, Zuhaili B, Fossum M, Hoeller D, Gheerardyn R, Chen M, Visovatti S, Svensson H, Yao F, Eriksson E. Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia. Wound Repair Regen. 2008;16:288–93.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Dana 805, Boston, MA, 02215, USA

    Leena Pradhan PhD & Frank W. LoGerfo MD

  2. Joslin-Beth Israel Deaconess Foot Center and Microcirculation Lab, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215-5321, USA

    Aristidis Veves MD, DSc

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  1. Leena Pradhan PhD
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  2. Frank W. LoGerfo MD
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  3. Aristidis Veves MD, DSc
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Correspondence to Leena Pradhan PhD .

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Editors and Affiliations

  1. Center, Department of Surgery, Beth Israel Deaconess Medical, 1 Deaconess Road, Boston, 02215, Massachusetts, USA

    Aristidis Veves

  2. , Division of Podiatry, Beth Israel Deaconess Medical Center, 1 Deaconess Road, Boston, 02215, Massachusetts, USA

    John M. Giurini

  3. Center, Department of Surgery, Beth Israel Deaconess Medical, 110 Francis Street, Boston, 02215, Massachusetts, USA

    Frank W. LoGerfo

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Pradhan, L., LoGerfo, F.W., Veves, A. (2012). Neuropeptides and Diabetic Wound-Healing. In: Veves, A., Giurini, J., LoGerfo, F. (eds) The Diabetic Foot. Contemporary Diabetes. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-791-0_8

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