Skip to main content
SpringerLink
Log in

Molecular Regulation of Skin Wound Healing

  • Chapter
  • First Online:
Lactoferrin and its Role in Wound Healing

Abstract

The skin wound healing is complex physiological event for restoration of the intact structure in injured tissues. It begins with hemostasis and is followed by inflammation, which is prerequisite for subsequent events such as reepithelialization, granulation tissue formation, and wound contraction. Reepithelialization and granulation tissue formation in turn involves proliferation and migration of keratinocytes and fibroblasts, respectively. Wound contraction contributes for the reduction of the wound size and therefore to shorten the healing period. Many growth factors, cytokines, chemokines, and proteases regulate cell functions during the wound healing process. Spatial and temporal alterations in the actions of these molecules result in the failure of wound healing, non-healing chronic wounds.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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. Martin P (1997) Wound healing–aiming for perfect skin regeneration. Science 276(5309):75–81

    PubMed  CAS  Google Scholar 

  2. Shaw TJ, Martin P (2009) Wound repair at a glance. J Cell Sci 122(Pt 18):3209–3213

    PubMed  CAS  Google Scholar 

  3. Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83(3):835–870

    PubMed  CAS  Google Scholar 

  4. Noli C, Miolo A (2001) The mast cell in wound healing. Vet Dermatol 12(6):303–313

    PubMed  CAS  Google Scholar 

  5. Jameson JM, Sharp LL, Witherden DA, Havran WL (2004) Regulation of skin cell homeostasis by gamma delta T cells. Front Biosci 9:2640–2651

    PubMed  CAS  Google Scholar 

  6. Cumberbatch M, Dearman RJ, Griffiths CE, Kimber I (2000) Langerhans cell migration. Clin Exp Dermatol 25(5):413–418

    PubMed  CAS  Google Scholar 

  7. Engelhardt E, Toksoy A, Goebeler M, Debus S et al (1998) Chemokines IL-8, GROalpha, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am J Pathol 153(6):1849–1860

    PubMed  CAS  Google Scholar 

  8. Jackman SH, Yoak MB, Keerthy S, Beaver BL (2000) Differential expression of chemokines in a mouse model of wound healing. Ann Clin Lab Sci 30(2):201–207

    PubMed  CAS  Google Scholar 

  9. Gibran NS, Ferguson M, Heimbach DM, Isik FF (1997) Monocyte chemoattractant protein-1 mRNA expression in the human burn wound. J Surg Res 70(1):1–6

    PubMed  CAS  Google Scholar 

  10. Low QE, Drugea IA, Duffner LA, Quinn DG et al (2001) Wound healing in MIP-1alpha(−/−) and MCP-1(−/−) mice. Am J Pathol 159(2):457–463

    PubMed  CAS  Google Scholar 

  11. Nagaoka T, Kaburagi Y, Hamaguchi Y, Hasegawa M et al (2000) Delayed wound healing in the absence of intercellular adhesion molecule-1 or L-selectin expression. Am J Pathol 157(1):237–247

    PubMed  CAS  Google Scholar 

  12. Jung U, Ley K (1999) Mice lacking two or all three selectins demonstrate overlapping and distinct functions for each selectin. J Immunol 162(11):6755–6762

    PubMed  CAS  Google Scholar 

  13. Hubner G, Brauchle M, Smola H, Madlener M et al (1996) Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. Cytokine 8(7):548–556

    PubMed  CAS  Google Scholar 

  14. Mori R, Shaw TJ, Martin P (2008) Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J Exp Med 205(1):43–51

    PubMed  CAS  Google Scholar 

  15. Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461

    PubMed  CAS  Google Scholar 

  16. Eming SA, Krieg T, Davidson JM (2007) Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 127(3):514–525

    PubMed  CAS  Google Scholar 

  17. DiPietro LA, Polverini PJ (1993) Role of the macrophage in the positive and negative regulation of wound neovascularization. Behring Inst Mitt 92:238–247

    PubMed  CAS  Google Scholar 

  18. Leibovich SJ, Ross R (1975) The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 78(1):71–100

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  20. Jameson J, Ugarte K, Chen N, Yachi P et al (2002) A role for skin gammadelta T cells in wound repair. Science 296(5568):747–749

    PubMed  CAS  Google Scholar 

  21. Jameson JM, Cauvi G, Sharp LL, Witherden DA et al (2005) Gammadelta T cell-induced hyaluronan production by epithelial cells regulates inflammation. J Exp Med 201(8):1269–1279

    PubMed  CAS  Google Scholar 

  22. Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341(10):738–746

    PubMed  CAS  Google Scholar 

  23. Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172(7):973–981

    PubMed  CAS  Google Scholar 

  24. Feldmeyer L, Werner S, French LE, Beer HD (2010) Interleukin-1, inflammasomes and the skin. Eur J Cell Biol 89(9):638–644

    PubMed  CAS  Google Scholar 

  25. Higashiyama M, Matsumoto K, Hashimoto K, Yoshikawa K (1991) Increased production of transforming growth factor-alpha in psoriatic epidermis. J Dermatol 18(2):117–119

    PubMed  CAS  Google Scholar 

  26. Barrandon Y, Green H (1987) Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-alpha and epidermal growth factor. Cell 50(7):1131–1137

    PubMed  CAS  Google Scholar 

  27. Werner S, Breeden M, Hubner G, Greenhalgh DG et al (1994) Induction of keratinocyte growth factor expression is reduced and delayed during wound healing in the genetically diabetic mouse. J Invest Dermatol 103(4):469–473

    PubMed  CAS  Google Scholar 

  28. McCawley LJ, O’Brien P, Hudson LG (1998) Epidermal growth factor (EGF)- and scatter factor/hepatocyte growth factor (SF/HGF)- mediated keratinocyte migration is coincident with induction of matrix metalloproteinase (MMP)-9. J Cell Physiol 176(2):255–265

    PubMed  CAS  Google Scholar 

  29. Raja SK, Garcia MS, Isseroff RR (2007) Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front Biosci 12:2849–2868

    PubMed  CAS  Google Scholar 

  30. Hebda PA (1988) Stimulatory effects of transforming growth factor-beta and epidermal growth factor on epidermal cell outgrowth from porcine skin explant cultures. J Invest Dermatol 91(5):440–445

    PubMed  CAS  Google Scholar 

  31. Li Y, Fan J, Chen M, Li W et al (2006) Transforming growth factor-alpha: a major human serum factor that promotes human keratinocyte migration. J Invest Dermatol 126(9):2096–2105

    PubMed  CAS  Google Scholar 

  32. Hashimoto K, Higashiyama S, Asada H, Hashimura E et al (1994) Heparin-binding epidermal growth factor-like growth factor is an autocrine growth factor for human keratinocytes. J Biol Chem 269(31):20060–20066

    PubMed  CAS  Google Scholar 

  33. Brown GL, Curtsinger L 3rd, Brightwell JR, Ackerman DM et al (1986) Enhancement of epidermal regeneration by biosynthetic epidermal growth factor. J Exp Med 163(5):1319–1324

    PubMed  CAS  Google Scholar 

  34. Schultz GS, White M, Mitchell R, Brown G et al (1987) Epithelial wound healing enhanced by transforming growth factor-alpha and vaccinia growth factor. Science 235(4786):350–352

    PubMed  CAS  Google Scholar 

  35. Kim I, Mogford JE, Chao JD, Mustoe TA (2001) Wound epithelialization deficits in the transforming growth factor-alpha knockout mouse. Wound Repair Regen 9(5):386–390

    PubMed  CAS  Google Scholar 

  36. Shirakata Y, Kimura R, Nanba D, Iwamoto R et al (2005) Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing. J Cell Sci 118(Pt 11):2363–2370

    PubMed  CAS  Google Scholar 

  37. Bhora FY, Dunkin BJ, Batzri S, Aly HM et al (1995) Effect of growth factors on cell proliferation and epithelialization in human skin. J Surg Res 59(2):236–244

    PubMed  CAS  Google Scholar 

  38. DeLapp NW, Dieckman DK (1990) Effect of basic fibroblast growth factor (bFGF) and insulin-like growth factors type I (IGF-I) and type II (IGF-II) on adult human keratinocyte growth and fibronectin secretion. J Invest Dermatol 94(6):777–780

    PubMed  CAS  Google Scholar 

  39. Hebda PA, Klingbeil CK, Abraham JA, Fiddes JC (1990) Basic fibroblast growth factor stimulation of epidermal wound healing in pigs. J Invest Dermatol 95(6):626–631

    PubMed  CAS  Google Scholar 

  40. Sanz Garcia S, Santos Heredero X, Izquierdo Hernandez A, Pascual Pena E et al (2000) Experimental model for local application of growth factors in skin re-epithelialisation. Scand J Plast Reconstr Surg Hand Surg 34(3):199–206

    PubMed  CAS  Google Scholar 

  41. Ortega S, Ittmann M, Tsang SH, Ehrlich M et al (1998) Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc Natl Acad Sci USA 95(10):5672–5677

    PubMed  CAS  Google Scholar 

  42. Miller DL, Ortega S, Bashayan O, Basch R et al (2000) Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol 20(6):2260–2268

    PubMed  CAS  Google Scholar 

  43. Werner S, Peters KG, Longaker MT, Fuller-Pace F et al (1992) Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci USA 89(15):6896–6900

    PubMed  CAS  Google Scholar 

  44. Brauchle M, Fassler R, Werner S (1995) Suppression of keratinocyte growth factor expression by glucocorticoids in vitro and during wound healing. J Invest Dermatol 105(4):579–584

    PubMed  CAS  Google Scholar 

  45. Guo L, Degenstein L, Fuchs E (1996) Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev 10(2):165–175

    PubMed  CAS  Google Scholar 

  46. Ashcroft GS (1999) Bidirectional regulation of macrophage function by TGF-beta. Microbes Infect 1(15):1275–1282

    PubMed  CAS  Google Scholar 

  47. Huang JS, Wang YH, Ling TY, Chuang SS et al (2002) Synthetic TGF-beta antagonist accelerates wound healing and reduces scarring. FASEB J 16(10):1269–1270

    PubMed  CAS  Google Scholar 

  48. Tredget EB, Demare J, Chandran G, Tredget EE et al (2005) Transforming growth factor-beta and its effect on reepithelialization of partial-thickness ear wounds in transgenic mice. Wound Repair Regen 13(1):61–67

    PubMed  Google Scholar 

  49. Sharma GD, He J, Bazan HE (2003) p38 and ERK1/2 coordinate cellular migration and proliferation in epithelial wound healing: evidence of cross-talk activation between MAP kinase cascades. J Biol Chem 278(24):21989–21997

    PubMed  CAS  Google Scholar 

  50. Tscharntke M, Pofahl R, Chrostek-Grashoff A, Smyth N et al (2007) Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1. J Cell Sci 120(Pt 8):1480–1490

    PubMed  CAS  Google Scholar 

  51. Tscharntke M, Pofahl R, Krieg T, Haase I (2005) Ras-induced spreading and wound closure in human epidermal keratinocytes. FASEB J 19(13):1836–1838

    PubMed  CAS  Google Scholar 

  52. Pullar CE, Baier BS, Kariya Y, Russell AJ et al (2006) beta4 integrin and epidermal growth factor coordinately regulate electric field-mediated directional migration via Rac1. Mol Biol Cell 17(11):4925–4935

    PubMed  CAS  Google Scholar 

  53. Haase I, Evans R, Pofahl R, Watt FM (2003) Regulation of keratinocyte shape, migration and wound epithelialization by IGF-1- and EGF-dependent signalling pathways. J Cell Sci 116(Pt 15):3227–3238

    PubMed  CAS  Google Scholar 

  54. Schweizer J, Bowden PE, Coulombe PA, Langbein L et al (2006) New consensus nomenclature for mammalian keratins. J Cell Biol 174(2):169–174

    PubMed  CAS  Google Scholar 

  55. Guo L, Degenstein L, Dowling J, Yu QC et al (1995) Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration. Cell 81(2):233–243

    PubMed  CAS  Google Scholar 

  56. Stoler A, Kopan R, Duvic M, Fuchs E (1988) Use of monospecific antisera and cRNA probes to localize the major changes in keratin expression during normal and abnormal epidermal differentiation. J Cell Biol 107(2):427–446

    PubMed  CAS  Google Scholar 

  57. Mansbridge JN, Knapp AM (1987) Changes in keratinocyte maturation during wound healing. J Invest Dermatol 89(3):253–263

    PubMed  CAS  Google Scholar 

  58. Jiang CK, Magnaldo T, Ohtsuki M, Freedberg IM et al (1993) Epidermal growth factor and transforming growth factor alpha specifically induce the activation- and hyperproliferation-associated keratins 6 and 16. Proc Natl Acad Sci USA 90(14):6786–6790

    PubMed  CAS  Google Scholar 

  59. Komine M, Rao LS, Kaneko T, Tomic-Canic M et al (2000) Inflammatory versus proliferative processes in epidermis. Tumor necrosis factor alpha induces K6b keratin synthesis through a transcriptional complex containing NFkappa B and C/EBPbeta. J Biol Chem 275(41):32077–32088

    PubMed  CAS  Google Scholar 

  60. Komine M, Rao LS, Freedberg IM, Simon M et al (2001) Interleukin-1 induces transcription of keratin K6 in human epidermal keratinocytes. J Invest Dermatol 116(2):330–338

    PubMed  CAS  Google Scholar 

  61. Wawersik M, Coulombe PA (2000) Forced expression of keratin 16 alters the adhesion, differentiation, and migration of mouse skin keratinocytes. Mol Biol Cell 11(10):3315–3327

    PubMed  CAS  Google Scholar 

  62. Wong P, Coulombe PA (2003) Loss of keratin 6 (K6) proteins reveals a function for intermediate filaments during wound repair. J Cell Biol 163(2):327–337

    PubMed  CAS  Google Scholar 

  63. Margadant C, Charafeddine RA, Sonnenberg A (2010) Unique and redundant functions of integrins in the epidermis. FASEB J 24(11):4133–4152

    PubMed  CAS  Google Scholar 

  64. Borradori L, Sonnenberg A (1999) Structure and function of hemidesmosomes: more than simple adhesion complexes. J Invest Dermatol 112(4):411–418

    PubMed  CAS  Google Scholar 

  65. Rabinovitz I, Tsomo L, Mercurio AM (2004) Protein kinase C-alpha phosphorylation of specific serines in the connecting segment of the beta 4 integrin regulates the dynamics of type II hemidesmosomes. Mol Cell Biol 24(10):4351–4360

    PubMed  CAS  Google Scholar 

  66. Dans M, Gagnoux-Palacios L, Blaikie P, Klein S et al (2001) Tyrosine phosphorylation of the beta 4 integrin cytoplasmic domain mediates Shc signaling to extracellular signal-regulated kinase and antagonizes formation of hemidesmosomes. J Biol Chem 276(2):1494–1502

    PubMed  CAS  Google Scholar 

  67. Wilhelmsen K, Litjens SH, Sonnenberg A (2006) Multiple functions of the integrin alpha6beta4 in epidermal homeostasis and tumorigenesis. Mol Cell Biol 26(8):2877–2886

    PubMed  CAS  Google Scholar 

  68. Wilhelmsen K, Litjens SH, Kuikman I, Margadant C et al (2007) Serine phosphorylation of the integrin beta4 subunit is necessary for epidermal growth factor receptor induced hemidesmosome disruption. Mol Biol Cell 18(9):3512–3522

    PubMed  CAS  Google Scholar 

  69. Larjava H, Salo T, Haapasalmi K, Kramer RH et al (1993) Expression of integrins and basement membrane components by wound keratinocytes. J Clin Invest 92(3):1425–1435

    PubMed  CAS  Google Scholar 

  70. Adams JC, Watt FM (1991) Expression of beta 1, beta 3, beta 4, and beta 5 integrins by human epidermal keratinocytes and non-differentiating keratinocytes. J Cell Biol 115(3):829–841

    PubMed  CAS  Google Scholar 

  71. Cavani A, Zambruno G, Marconi A, Manca V et al (1993) Distinctive integrin expression in the newly forming epidermis during wound healing in humans. J Invest Dermatol 101(4):600–604

    PubMed  CAS  Google Scholar 

  72. Breuss JM, Gallo J, DeLisser HM, Klimanskaya IV et al (1995) Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci 108(Pt 6):2241–2251

    PubMed  CAS  Google Scholar 

  73. Haapasalmi K, Zhang K, Tonnesen M, Olerud J et al (1996) Keratinocytes in human wounds express alpha v beta 6 integrin. J Invest Dermatol 106(1):42–48

    PubMed  CAS  Google Scholar 

  74. Grose R, Hutter C, Bloch W, Thorey I et al (2002) A crucial role of beta 1 integrins for keratinocyte migration in vitro and during cutaneous wound repair. Development 129(9):2303–2315

    PubMed  CAS  Google Scholar 

  75. Calvin M (1998) Cutaneous wound repair. Wounds Compend Clin Res Pract 10(1):12–32

    Google Scholar 

  76. Frank S, Madlener M, Werner S (1996) Transforming growth factors beta1, beta2, and beta3 and their receptors are differentially regulated during normal and impaired wound healing. J Biol Chem 271(17):10188–10193

    PubMed  CAS  Google Scholar 

  77. Buetow BS, Crosby JR, Kaminski WE, Ramachandran RK et al (2001) Platelet-derived growth factor B-chain of hematopoietic origin is not necessary for granulation tissue formation and its absence enhances vascularization. Am J Pathol 159(5):1869–1876

    PubMed  CAS  Google Scholar 

  78. Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79(4):1283–1316

    PubMed  CAS  Google Scholar 

  79. Roberts AB, Sporn MB, Assoian RK, Smith JM et al (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83(12):4167–4171

    PubMed  CAS  Google Scholar 

  80. Brown RL, Ormsby I, Doetschman TC, Greenhalgh DG (1995) Wound healing in the transforming growth factor-beta-deficient mouse. Wound Repair Regen 3(1):25–36

    PubMed  CAS  Google Scholar 

  81. Bonomo SR, Davidson JD, Tyrone JW, Lin X et al (2000) Enhancement of wound healing by hyperbaric oxygen and transforming growth factor beta3 in a new chronic wound model in aged rabbits. Arch Surg 135(10):1148–1153

    PubMed  CAS  Google Scholar 

  82. Bradham DM, Igarashi A, Potter RL, Grotendorst GR (1991) Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol 114(6):1285–1294

    PubMed  CAS  Google Scholar 

  83. Clark RA (1990) Fibronectin matrix deposition and fibronectin receptor expression in healing and normal skin. J Invest Dermatol 94(6 Suppl):128S–134S

    PubMed  CAS  Google Scholar 

  84. Xu J, Clark RA (1996) Extracellular matrix alters PDGF regulation of fibroblast integrins. J Cell Biol 132(1–2):239–249

    PubMed  CAS  Google Scholar 

  85. Grinnell F (1994) Fibroblasts, myofibroblasts, and wound contraction. J Cell Biol 124(4):401–404

    PubMed  CAS  Google Scholar 

  86. Coleman C, Tuan TL, Buckley S, Anderson KD et al (1998) Contractility, transforming growth factor-beta, and plasmin in fetal skin fibroblasts: role in scarless wound healing. Pediatr Res 43(3):403–409

    PubMed  CAS  Google Scholar 

  87. Nedelec B, Ghahary A, Scott PG, Tredget EE (2000) Control of wound contraction. Basic and clinical features. Hand Clin 16(2):289–302

    PubMed  CAS  Google Scholar 

  88. Grinnell F, Ho CH, Lin YC, Skuta G (1999) Differences in the regulation of fibroblast contraction of floating versus stressed collagen matrices. J Biol Chem 274(2):918–923

    PubMed  CAS  Google Scholar 

  89. Tingstrom A, Heldin CH, Rubin K (1992) Regulation of fibroblast-mediated collagen gel contraction by platelet-derived growth factor, interleukin-1 alpha and transforming growth factor-beta 1. J Cell Sci 102(Pt 2):315–322

    PubMed  Google Scholar 

  90. Moulin V, Castilloux G, Auger FA, Garrel D et al (1998) Modulated response to cytokines of human wound healing myofibroblasts compared to dermal fibroblasts. Exp Cell Res 238(1):283–293

    PubMed  CAS  Google Scholar 

  91. Lee YR, Oshita Y, Tsuboi R, Ogawa H (1996) Combination of insulin-like growth factor (IGF)-I and IGF-binding protein-1 promotes fibroblast-embedded collagen gel contraction. Endocrinology 137(12):5278–5283

    PubMed  CAS  Google Scholar 

  92. Pilcher BK, Levine NS, Tomasek JJ (1995) Thrombin promotion of isometric contraction in fibroblasts: its extracellular mechanism of action. Plast Reconstr Surg 96(5):1188–1195

    PubMed  CAS  Google Scholar 

  93. Gullberg D, Tingstrom A, Thuresson AC, Olsson L et al (1990) Beta 1 integrin-mediated collagen gel contraction is stimulated by PDGF. Exp Cell Res 186(2):264–272

    PubMed  CAS  Google Scholar 

  94. Carver W, Molano I, Reaves TA, Borg TK et al (1995) Role of the alpha 1 beta 1 integrin complex in collagen gel contraction in vitro by fibroblasts. J Cell Physiol 165(2):425–437

    PubMed  CAS  Google Scholar 

  95. Langholz O, Rockel D, Mauch C, Kozlowska E et al (1995) Collagen and collagenase gene expression in three-dimensional collagen lattices are differentially regulated by alpha 1 beta 1 and alpha 2 beta 1 integrins. J Cell Biol 131(6 Pt 2):1903–1915

    PubMed  CAS  Google Scholar 

  96. Riikonen T, Westermarck J, Koivisto L, Broberg A et al (1995) Integrin alpha 2 beta 1 is a positive regulator of collagenase (MMP-1) and collagen alpha 1(I) gene expression. J Biol Chem 270(22):13548–13552

    PubMed  CAS  Google Scholar 

  97. Iocono JA, Colleran KR, Remick DG, Gillespie BW et al (2000) Interleukin-8 levels and activity in delayed-healing human thermal wounds. Wound Repair Regen 8(3):216–225

    PubMed  CAS  Google Scholar 

  98. Zhu YK, Liu XD, Skold MC, Umino T et al (2001) Cytokine inhibition of fibroblast-induced gel contraction is mediated by PGE(2) and NO acting through separate parallel pathways. Am J Respir Cell Mol Biol 25(2):245–253

    PubMed  CAS  Google Scholar 

  99. Pellegrin S, Mellor H (2007) Actin stress fibres. J Cell Sci 120(Pt 20):3491–3499

    PubMed  CAS  Google Scholar 

  100. Paterson HF, Self AJ, Garrett MD, Just I et al (1990) Microinjection of recombinant p21rho induces rapid changes in cell morphology. J Cell Biol 111(3):1001–1007

    PubMed  CAS  Google Scholar 

  101. Katoh K, Kano Y, Amano M, Onishi H et al (2001) Rho-kinase–mediated contraction of isolated stress fibers. J Cell Biol 153(3):569–584

    PubMed  CAS  Google Scholar 

  102. Somlyo AP, Somlyo AV (2000) Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol 522(Pt 2):177–185

    PubMed  CAS  Google Scholar 

  103. Amano M, Ito M, Kimura K, Fukata Y et al (1996) Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem 271(34):20246–20249

    PubMed  CAS  Google Scholar 

  104. Kimura K, Ito M, Amano M, Chihara K et al (1996) Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273(5272):245–248

    PubMed  CAS  Google Scholar 

  105. Koyama M, Ito M, Feng J, Seko T et al (2000) Phosphorylation of CPI-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase. FEBS Lett 475(3):197–200

    PubMed  CAS  Google Scholar 

  106. Kitazawa T, Eto M, Woodsome TP, Brautigan DL (2000) Agonists trigger G protein-mediated activation of the CPI-17 inhibitor phosphoprotein of myosin light chain phosphatase to enhance vascular smooth muscle contractility. J Biol Chem 275(14):9897–9900

    PubMed  CAS  Google Scholar 

  107. Katoh K, Kano Y, Noda Y (2011) Rho-associated kinase-dependent contraction of stress fibres and the organization of focal adhesions. J R Soc Interface 8(56):305–311

    PubMed  CAS  Google Scholar 

  108. Hinz B (2007) Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 127(3):526–537

    PubMed  CAS  Google Scholar 

  109. Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G (1993) Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122(1):103–111

    PubMed  CAS  Google Scholar 

  110. Hinz B, Mastrangelo D, Iselin CE, Chaponnier C et al (2001) Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol 159(3):1009–1020

    PubMed  CAS  Google Scholar 

  111. Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8(6):464–478

    PubMed  CAS  Google Scholar 

  112. Liekens S, De Clercq E, Neyts J (2001) Angiogenesis: regulators and clinical applications. Biochem Pharmacol 61(3):253–270

    PubMed  CAS  Google Scholar 

  113. Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49(3):507–521

    PubMed  CAS  Google Scholar 

  114. Munoz-Chapuli R, Quesada AR, Angel Medina M (2004) Angiogenesis and signal transduction in endothelial cells. Cell Mol Life Sci 61(17):2224–2243

    PubMed  CAS  Google Scholar 

  115. Battegay EJ, Rupp J, Iruela-Arispe L, Sage EH et al (1994) PDGF-BB modulates endothelial proliferation and angiogenesis in vitro via PDGF beta-receptors. J Cell Biol 125(4):917–928

    PubMed  CAS  Google Scholar 

  116. Ferrara N (1999) Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int 56(3):794–814

    PubMed  CAS  Google Scholar 

  117. Cooke JP, Losordo DW (2002) Nitric oxide and angiogenesis. Circulation 105(18):2133–2135

    PubMed  Google Scholar 

  118. Morbidelli L, Chang CH, Douglas JG, Granger HJ et al (1996) Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am J Physiol 270(1 Pt 2):H411–H415

    PubMed  CAS  Google Scholar 

  119. Parenti A, Morbidelli L, Cui XL, Douglas JG et al (1998) Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinase1/2 activation in postcapillary endothelium. J Biol Chem 273(7):4220–4226

    PubMed  CAS  Google Scholar 

  120. Frank S, Hubner G, Breier G, Longaker MT et al (1995) Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem 270(21):12607–12613

    PubMed  CAS  Google Scholar 

  121. Brown LF, Yeo KT, Berse B, Yeo TK et al (1992) Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med 176(5):1375–1379

    PubMed  CAS  Google Scholar 

  122. Tsou R, Fathke C, Wilson L, Wallace K et al (2002) Retroviral delivery of dominant-negative vascular endothelial growth factor receptor type 2 to murine wounds inhibits wound angiogenesis. Wound Repair Regen 10(4):222–229

    PubMed  Google Scholar 

  123. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA et al (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219(4587):983–985

    PubMed  CAS  Google Scholar 

  124. Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108(Pt 6):2369–2379

    PubMed  CAS  Google Scholar 

  125. Pepper MS, Ferrara N, Orci L, Montesano R (1992) Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 189(2):824–831

    PubMed  CAS  Google Scholar 

  126. Klein S, Giancotti FG, Presta M, Albelda SM et al (1993) Basic fibroblast growth factor modulates integrin expression in microvascular endothelial cells. Mol Biol Cell 4(10):973–982

    PubMed  CAS  Google Scholar 

  127. Klein S, Bikfalvi A, Birkenmeier TM, Giancotti FG et al (1996) Integrin regulation by endogenous expression of 18-kDa fibroblast growth factor-2. J Biol Chem 271(37):22583–22590

    PubMed  CAS  Google Scholar 

  128. Ruegg C, Mariotti A (2003) Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis. Cell Mol Life Sci 60(6):1135–1157

    PubMed  CAS  Google Scholar 

  129. Brooks PC, Clark RA, Cheresh DA (1994) Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264(5158):569–571

    PubMed  CAS  Google Scholar 

  130. Friedlander M, Brooks PC, Shaffer RW, Kincaid CM et al (1995) Definition of two angiogenic pathways by distinct alpha v integrins. Science 270(5241):1500–1502

    PubMed  CAS  Google Scholar 

  131. Fisher C, Gilbertson-Beadling S, Powers EA, Petzold G et al (1994) Interstitial collagenase is required for angiogenesis in vitro. Dev Biol 162(2):499–510

    PubMed  CAS  Google Scholar 

  132. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867

    PubMed  CAS  Google Scholar 

  133. Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214(2):199–210

    PubMed  CAS  Google Scholar 

  134. Haslett C (1992) Resolution of acute inflammation and the role of apoptosis in the tissue fate of granulocytes. Clin Sci (Lond) 83(6):639–648

    CAS  Google Scholar 

  135. Ma J, Chen T, Mandelin J, Ceponis A et al (2003) Regulation of macrophage activation. Cell Mol Life Sci 60(11):2334–2346

    PubMed  CAS  Google Scholar 

  136. Liechty KW, Kim HB, Adzick NS and Crombleholme TM (2000) Fetal wound repair results in scar formation in interleukin-10-deficient mice in a syngeneic murine model of scarless fetal wound repair. J Pediatr Surg 35(6), 866–872; discussion 872–863

    Google Scholar 

  137. D’Amico G, Frascaroli G, Bianchi G, Transidico P et al (2000) Uncoupling of inflammatory chemokine receptors by IL-10: generation of functional decoys. Nat Immunol 1(5):387–391

    PubMed  Google Scholar 

  138. Ashcroft GS, Lei K, Jin W, Longenecker G et al (2000) Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing. Nat Med 6(10):1147–1153

    PubMed  CAS  Google Scholar 

  139. McCluskey J, Martin P (1995) Analysis of the tissue movements of embryonic wound healing–DiI studies in the limb bud stage mouse embryo. Dev Biol 170(1):102–114

    PubMed  CAS  Google Scholar 

  140. Sullivan KM, Lorenz HP, Meuli M, Lin RY et al. (1995) A model of scarless human fetal wound repair is deficient in transforming growth factor beta. J Pediatr Surg 30(2), 198–202; discussion 202–193

    Google Scholar 

  141. Hsu M, Peled ZM, Chin GS, Liu W et al. (2001) Ontogeny of expression of transforming growth factor-beta 1 (TGF-beta 1), TGF-beta 3, and TGF-beta receptors I and II in fetal rat fibroblasts and skin. Plast Reconstr Surg 107(7), 1787–1794; discussion 1795–1786

    Google Scholar 

  142. Nath RK, LaRegina M, Markham H, Ksander GA et al (1994) The expression of transforming growth factor type beta in fetal and adult rabbit skin wounds. J Pediatr Surg 29(3):416–421

    PubMed  CAS  Google Scholar 

  143. Krummel TM, Michna BA, Thomas BL, Sporn MB et al (1988) Transforming growth factor beta (TGF-beta) induces fibrosis in a fetal wound model. J Pediatr Surg 23(7):647–652

    PubMed  CAS  Google Scholar 

  144. Lin RY, Sullivan KM, Argenta PA, Meuli M et al (1995) Exogenous transforming growth factor-beta amplifies its own expression and induces scar formation in a model of human fetal skin repair. Ann Surg 222(2):146–154

    PubMed  CAS  Google Scholar 

  145. Shah M, Foreman DM, Ferguson MW (1995) Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci 108(Pt 3):985–1002

    PubMed  CAS  Google Scholar 

  146. Longaker MT, Chiu ES, Adzick NS, Stern M et al (1991) Studies in fetal wound healing. V. A prolonged presence of hyaluronic acid characterizes fetal wound fluid. Ann Surg 213(4):292–296

    PubMed  CAS  Google Scholar 

  147. Hellstrom S, Laurent C (1987) Hyaluronan and healing of tympanic membrane perforations. An experimental study. Acta Otolaryngol Suppl 442:54–61

    PubMed  CAS  Google Scholar 

  148. Gill SE, Parks WC (2008) Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol 40(6–7):1334–1347

    PubMed  CAS  Google Scholar 

  149. Toriseva M, Kahari VM (2009) Proteinases in cutaneous wound healing. Cell Mol Life Sci 66(2):203–224

    PubMed  CAS  Google Scholar 

  150. Salo T, Makela M, Kylmaniemi M, Autio-Harmainen H et al (1994) Expression of matrix metalloproteinase-2 and -9 during early human wound healing. Lab Invest 70(2):176–182

    PubMed  CAS  Google Scholar 

  151. Sudbeck BD, Pilcher BK, Welgus HG, Parks WC (1997) Induction and repression of collagenase-1 by keratinocytes is controlled by distinct components of different extracellular matrix compartments. J Biol Chem 272(35):22103–22110

    PubMed  CAS  Google Scholar 

  152. Agren MS (1999) Matrix metalloproteinases (MMPs) are required for re-epithelialization of cutaneous wounds. Arch Dermatol Res 291(11):583–590

    PubMed  CAS  Google Scholar 

  153. Mirastschijski U, Haaksma CJ, Tomasek JJ, Agren MS (2004) Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds. Exp Cell Res 299(2):465–475

    PubMed  CAS  Google Scholar 

  154. Pilcher BK, Dumin JA, Sudbeck BD, Krane SM et al (1997) The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 137(6):1445–1457

    PubMed  CAS  Google Scholar 

  155. Pilcher BK, Dumin J, Schwartz MJ, Mast BA et al (1999) Keratinocyte collagenase-1 expression requires an epidermal growth factor receptor autocrine mechanism. J Biol Chem 274(15):10372–10381

    PubMed  CAS  Google Scholar 

  156. Philipp K, Riedel F, Germann G, Hormann K et al (2005) TGF-beta antisense oligonucleotides reduce mRNA expression of matrix metalloproteinases in cultured wound-healing-related cells. Int J Mol Med 15(2):299–303

    PubMed  CAS  Google Scholar 

  157. Pilcher BK, Sudbeck BD, Dumin JA, Welgus HG et al (1998) Collagenase-1 and collagen in epidermal repair. Arch Dermatol Res 290(Suppl):S37–S46

    PubMed  CAS  Google Scholar 

  158. McGuire JK, Li Q, Parks WC (2003) Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium. Am J Pathol 162(6):1831–1843

    PubMed  CAS  Google Scholar 

  159. Tsuboi R, Sato C, Kurita Y, Ron D et al (1993) Keratinocyte growth factor (FGF-7) stimulates migration and plasminogen activator activity of normal human keratinocytes. J Invest Dermatol 101(1):49–53

    PubMed  CAS  Google Scholar 

  160. Garrod DR, Berika MY, Bardsley WF, Holmes D et al (2005) Hyper-adhesion in desmosomes: its regulation in wound healing and possible relationship to cadherin crystal structure. J Cell Sci 118(Pt 24):5743–5754

    PubMed  CAS  Google Scholar 

  161. Wallis S, Lloyd S, Wise I, Ireland G et al (2000) The alpha isoform of protein kinase C is involved in signaling the response of desmosomes to wounding in cultured epithelial cells. Mol Biol Cell 11(3):1077–1092

    PubMed  CAS  Google Scholar 

  162. Xue M, Thompson P, Kelso I, Jackson C (2004) Activated protein C stimulates proliferation, migration and wound closure, inhibits apoptosis and upregulates MMP-2 activity in cultured human keratinocytes. Exp Cell Res 299(1):119–127

    PubMed  CAS  Google Scholar 

  163. Bullard KM, Lund L, Mudgett JS, Mellin TN et al (1999) Impaired wound contraction in stromelysin-1-deficient mice. Ann Surg 230(2):260–265

    PubMed  CAS  Google Scholar 

  164. Di Colandrea T, Wang L, Wille J, D’Armiento J et al (1998) Epidermal expression of collagenase delays wound-healing in transgenic mice. J Invest Dermatol 111(6):1029–1033

    PubMed  Google Scholar 

  165. Salonurmi T, Parikka M, Kontusaari S, Pirila E et al (2004) Overexpression of TIMP-1 under the MMP-9 promoter interferes with wound healing in transgenic mice. Cell Tissue Res 315(1):27–37

    PubMed  CAS  Google Scholar 

  166. Geer DJ, Andreadis ST (2003) A novel role of fibrin in epidermal healing: plasminogen-mediated migration and selective detachment of differentiated keratinocytes. J Invest Dermatol 121(5):1210–1216

    PubMed  CAS  Google Scholar 

  167. Bechtel MJ, Reinartz J, Rox JM, Inndorf S et al (1996) Upregulation of cell-surface-associated plasminogen activation in cultured keratinocytes by interleukin-1 beta and tumor necrosis factor-alpha. Exp Cell Res 223(2):395–404

    PubMed  CAS  Google Scholar 

  168. Cale JM, Lawrence DA (2007) Structure-function relationships of plasminogen activator inhibitor-1 and its potential as a therapeutic agent. Curr Drug Targets 8(9):971–981

    PubMed  CAS  Google Scholar 

  169. Maquerlot F, Galiacy S, Malo M, Guignabert C et al (2006) Dual role for plasminogen activator inhibitor type 1 as soluble and as matricellular regulator of epithelial alveolar cell wound healing. Am J Pathol 169(5):1624–1632

    PubMed  CAS  Google Scholar 

  170. Pivarcsi A, Kemeny L, Dobozy A (2004) Innate immune functions of the keratinocytes. A review. Acta Microbiol Immunol Hung 51(3):303–310

    PubMed  CAS  Google Scholar 

  171. Tokumaru S, Sayama K, Shirakata Y, Komatsuzawa H et al (2005) Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. J Immunol 175(7):4662–4668

    PubMed  CAS  Google Scholar 

  172. Loots MA, Lamme EN, Zeegelaar J, Mekkes JR et al (1998) Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol 111(5):850–857

    PubMed  CAS  Google Scholar 

  173. Yager DR, Zhang LY, Liang HX, Diegelmann RF et al (1996) Wound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluids. J Invest Dermatol 107(5):743–748

    PubMed  CAS  Google Scholar 

  174. Ashcroft GS, Horan MA, Ferguson MW (1997) The effects of ageing on wound healing: immunolocalisation of growth factors and their receptors in a murine incisional model. J Anat 190(Pt 3):351–365

    PubMed  Google Scholar 

  175. Pierce GF, Tarpley JE, Tseng J, Bready J et al (1995) Detection of platelet-derived growth factor (PDGF)-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic nonhealing wounds. J Clin Invest 96(3):1336–1350

    PubMed  CAS  Google Scholar 

  176. Wenk J, Brenneisen P, Meewes C, Wlaschek M et al (2001) UV-induced oxidative stress and photoaging. Curr Probl Dermatol 29:83–94

    PubMed  CAS  Google Scholar 

  177. Morasso MI, Tomic-Canic M (2005) Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol Cell 97(3):173–183

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Functional Bio-molecules Research Team, National Institute of Livestock and Grassland Science, Ikenodai 2, 305-0901, Tsukuba, Ibaraki, Japan

    Yoshiharu Takayama

Authors
  1. Yoshiharu Takayama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshiharu Takayama .

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Takayama, Y. (2012). Molecular Regulation of Skin Wound Healing. In: Lactoferrin and its Role in Wound Healing. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2467-9_1

Download citation

Publish with us

Policies and ethics

Search

Navigation