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Molecular Medicine

, Volume 14, Issue 7–8, pp 528–537 | Cite as

Host Defense Peptides in Wound Healing

  • Lars Steinstraesser
  • Till Koehler
  • Frank Jacobsen
  • Adrien Daigeler
  • Ole Goertz
  • Stefan Langer
  • Marco Kesting
  • Hans Steinau
  • Elof Eriksson
  • Tobias Hirsch
Review Article

Abstract

Host defense peptides are effector molecules of the innate immune system. They show broad antimicrobial action against gram-positive and -negative bacteria, and they likely play a key role in activating and mediating the innate as well as adaptive immune response in infection and inflammation. These features make them of high interest for wound healing research. Non-healing and infected wounds are a major problem in patient care and health care spending. Increasing infection rates, growing bacterial resistance to common antibiotics, and the lack of effective therapeutic options for the treatment of problematic wounds emphasize the need for new approaches in therapy and pathophysiologic understanding. This review focuses on the current knowledge of host defense peptides affecting wound healing and infection. We discuss the current data and highlight the potential future developments in this field of research.

References

  1. 1.
    Vinh DC, Embil JM. (2005) Rapidly progressive soft tissue infections. Lancet Infect. Dis. 5:501–13.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Wilson MA. (2003) Skin and soft-tissue infections: impact of resistant gram-positive bacteria. Am. J. Surg. 186:35S–41S; discussion 42S–3S, 41S–4S.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Kalorama-Informations. (2002) Woundcare Markets, Volume I: Chronic Ulcers. Kalorama Informations, a Division of https://doi.org/Market.Research.com.
  4. 4.
    Rice LB. (2003) Do we really need new anti-infective drugs? Curr. Opin. Pharmacol. 3:459–63.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Grundmann H, Aires-de-Sousa M, Boyce J, Tiemersma E. (2006) Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet 368:874–85.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Schroder JM, Harder J. (2006) Antimicrobial skin peptides and proteins. Cell Mol. Life Sci. 63:469–86.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Fulton C, Anderson GM, Zasloff M, Bull R, Quinn AG. (1997) Expression of natural peptide antibiotics in human skin. Lancet 350:1750–1.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Beisswenger C, Bals R. (2005) Functions of antimicrobial peptides in host defense and immunity. Curr. Protein Pept. Sci. 6:255–64.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Ganz T. (2003) Defensins: antimicrobial peptides of innate immunity. Nat. Rev. Immunol. 3:710–20.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Fearon DT, Locksley RM. (1996) The instructive role of innate immunity in the acquired immune response. Science 272:50–3.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Medzhitov R, Janeway CA Jr. (1997) Innate immunity: the virtues of a nonclonal system of recognition. Cell 91:295–8.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Bals R. (2000) Antimicrobial peptides and pep ide antibiotics [in German]. Med. Klin. (Munich) 95:496–502.CrossRefGoogle Scholar
  13. 13.
    Hancock RE, Scott MG. (2000) The role of antimicrobial peptides in animal defenses. Proc. Natl. Acad. Sci. U. S. A. 97:8856–61.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Brahmachary M, et al. 2004. ANTIMIC: a database of antimicrobial sequences. Nucleic Acids Res. [Internet]. [cited 2007 Dec 20];32(database issue): D586–9. Available from: https://doi.org/nar.oxfordjournals.org/cgi/content/full/32/suppl_1/D586.
  15. 15.
    Antimicrobial Sequences Database (ASDb) [Internet]. 2004-. Trieste (Italy): Antiinfective Peptides Laboratory Tossi Group, Department of Biochemistry, Biophysics, and Macromolecular Chemistry, University of Trieste. [cited 2007 Dec 20]. Available from: https://doi.org/www.bbcm.units.it/∼tossi/amsdb.html.
  16. 16.
    Wang Z, Wang G. 2004. APD: the Antimicrobial Peptide Database. Nucleic Acids Res. [Internet]. [cited 2007 Dec 20];32(database issue):D590–2. vailable from: https://doi.org/nar.oxfordjournals.org/cgi/content/full/32/suppl_1/D590.
  17. 17.
    Zasloff M. (2002) Antimicrobial peptides of multicellular organisms. Nature 415:389–95.CrossRefGoogle Scholar
  18. 18.
    Hoffmann JA, Kafatos FC, Janeway CA, Ezekowitz RA. (1999) Phylogenetic perspectives in innate immunity. Science 284:1313–8.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Hancock RE. (2001) Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infect. Dis. 1:156–64.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Steinstraesser L, et al. (2003) Protegrin-1 increases bacterial clearance in sepsis but decreases survival. Crit. Care Med. 31:221–6.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Steinstraesser L, et al. (2002) Activity of novispirin G10 against Pseudomonas aeruginosa in vitro and in infected burns. Antimicrob. Agents Chemother. 46:1837–44.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Andreu D, Rivas L. (1998) Animal antimicrobial peptides: an overview. Biopolymers 47:415–33.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Hancock RE. (1997) Peptide antibiotics. Lancet 349:418–22.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    van’t Hof W, Veerman EC, Helmerhorst EJ, Amerongen AV. (2001) Antimicrobial peptides: properties and applicability. Biol. Chem. 382:597–619.CrossRefGoogle Scholar
  25. 25.
    Koczulla AR, Bals R. (2003) Antimicrobial peptides: current status and therapeutic potential. Drugs 63:389–406.CrossRefGoogle Scholar
  26. 26.
    Larrick JW, Hirata M, Balint RF, Lee J, Zhong J, Wright SC. (1995) Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein. Infect. Immun. 63:1291–7.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Sorensen OE, et al. (2001) Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood 97:3951–9.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Zanetti M, Gennaro R, Romeo D. (1995) Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain. FEBS Lett. 374:1–5.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Ganz T, Lehrer RI. (1997) Antimicrobial peptides of leukocytes. Curr. Opin. Hematol. 4:53–8.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Agerberth B, et al. (2000) The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood 96:3086–93.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Yang D, et al. (2000) LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J. Exp. Med. 192:1069–74.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Ong PY, et al. (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347:1151–60.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Sorensen O, Arnljots K, Cowland JB, Bainton DF, Borregaard N. (1997) The human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils. 114 90:2796–803.Google Scholar
  34. 34.
    Gallo RL, Nizet V. (2003) Endogenous production of antimicrobial peptides in innate immunity and human disease. Curr. Allergy Asthma Rep. 3:402–9.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Gallo RL, Murakami M, Ohtake T, Zaiou M. (2002) Biology and clinical relevance of naturally occurring antimicrobial peptides. J. Allergy Clin. Immunol. 110:823–31.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Dorschner RA, et al. (2001) Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus. J. Invest. Dermatol. 117:91–7.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Turner J, Cho Y, Dinh NN, Waring AJ, Lehrer RI. (1998) Activities of LL-37, a cathelin-associated antimicrobial peptide of human neutrophils. Antimicrob. Agents Chemother. 42:2206–14.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Frohm M, et al. (1996) Biochemical and antibacterial analysis of human wound and blister fluid. Eur. J. Biochem. 237:86–92.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Travis SM, et al. (2000) Bactericidal activity of mammalian cathelicidin-derived peptides. Infect. Immun. 68:2748–55.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Zanetti M, Gennaro R, Skerlavaj B, Tomasinsig L, Circo R. (2002) Cathelicidin peptides as candidates for a novel class of antimicrobials. Curr. Pharm. Des. 8:779–93.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Frohm M, et al. (1997) The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J. Biol. Chem. 272:15258–63.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    De Y, et al. (2000) LL-37, the neutrophil granule-and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J. Exp. Med. 192:1069–74.CrossRefGoogle Scholar
  43. 43.
    Niyonsaba F, Someya A, Hirata M, Ogawa H, Nagaoka I. (2001) Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and LL-37 on histamine release and prostaglandin D(2) production from mast cells. Eur. J. Immunol. 31:1066–75.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Feger F, Varadaradjalou S, Gao Z, Abraham SN, Arock M. (2002) The role of mast cells in host defense and their subversion by bacterial pathogens. Trends Immunol. 23:151–8.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Hirata M, et al. (1994) Characterization of a rabbit cationic protein (CAP18) with lipopolysaccharide-inhibitory activity. Infect. Immun. 62:1421–6.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Larrick JW, et al. (1994) A novel granulocyte-derived peptide with lipopolysaccharide-neutralizing activity. J. Immunol. 152:231–40.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE. (2002) The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J. Immunol. 169:3883–91.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Lehrer RI, Lichtenstein AK, Ganz T. (1993) Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu. Rev. Immunol. 11:105–28.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Lehrer RI, Ganz T, Selsted ME. (1991) Defensins: endogenous antibiotic peptides of animal cells. Cell 64:229–30.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    White SH, Wimley WC, Selsted ME. (1995) Structure, function, and membrane integration of defensins. Curr. Opin. Struct. Biol. 5:521–7.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Lehrer RI, Barton A, Daher KA, Harwig SS, Ganz T, Selsted ME. (1989) Interaction of human defensins with Escherichia coli: mechanism of bactericidal activity. J. Clin. Invest. 84:553–61.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Ganz T, Oren A, Lehrer RI. (1992) Defensins: microbicidal and cytotoxic peptides of mammalian host defense cells. Med. Microbiol. Immunol. (Berlin) 181:99–105.CrossRefGoogle Scholar
  53. 53.
    Lehrer RI, Ganz T. (2002) Defensins of vertebrate animals. Curr. Opin. Immunol. 14:96–102.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Selsted ME, et al. (1993) Purification, primary structures, and antibacterial activities of beta-defensins, a new family of antimicrobial peptides from bovine neutrophils. J. Biol. Chem. 268:6641–8.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Ganz T, et al. (1985) Defensins: natural peptide antibiotics of human neutrophils. J. Clin. Invest. 76:1427–35.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Mallow EB, et al. (1996) Human enteric defensins. Gene structure and developmental expression. J. Biol. Chem. 271:4038–45.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Selsted ME, Harwig SS. (1989) Determination of the disulfide array in the human defensin HNP-2: a covalently cyclized peptide. J. Biol. Chem. 264:4003–7.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Skalicky JJ, Selsted ME, Pardi A. (1994) Structure and dynamics of the neutrophil defensins NP-2, NP-5, and HNP-1: NMR studies of amide hydrogen exchange kinetics. Proteins 20:52–67.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Wilde CG, Griffith JE, Marra MN, Snable JL, Scott RW. (1989) Purification and characterization of human neutrophil peptide 4, a novel member of the defensin family. J. Biol. Chem. 264:11200–3.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Selsted ME, Harwig SS, Ganz T, Schilling JW, Lehrer RI. (1985) Primary structures of three human neutrophil defensins. J. Clin. Invest. 76:1436–9.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Chaly YV, Paleolog EM, Kolesnikova TS, Tikhonov, II, Petratchenko EV, Voitenok NN. (2000) Neutrophil alpha-defensin human neutrophil peptide modulates cytokine production in human monocytes and adhesion molecule expression in endothelial cells. Eur. Cytokine Netw. 11:257–66.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Braff MH, Bardan A, Nizet V, Gallo RL. (2005) Cutaneous defense mechanisms by antimicrobial peptides. J. Invest. Dermatol. 125:9–13.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Lehrer RI, Ganz T, Szklarek D, Selsted ME. (1988) Modulation of the in vitro candidacidal activity of human neutrophil defensins by target cell metabolism and divalent cations. J. Clin. Invest. 81:1829–35.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Schroder JM, Harder J. (1999) Human beta-defensin-2. Int. J. Biochem. Cell Biol. 31:645–51.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Daher KA, Selsted ME, Lehrer RI. (1986) Direct inactivation of viruses by human granulocyte defensins. J. Virol. 60:1068–74.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Porter EM, van Dam E, Valore EV, Ganz T. (1997) Broad-spectrum antimicrobial activity of human intestinal defensin 5. Infect. Immun. 65:2396–401.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Bensch KW, Raida M, Magert HJ, Schulz-Knappe P, Forssmann WG. (1995) hBD-1: a novel beta-defensin from human plasma. FEBS Lett. 368:331–5.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Ali RS, Falconer A, Ikram M, Bissett CE, Cerio R, Quinn AG. (2001) Expression of the peptide antibiotics human beta defensin-1 and human beta defensin-2 in normal human skin. J. Invest. Dermatol. 117:106–11.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Zhao C, Wang I, Lehrer RI. (1996) Widespread expression of beta-defensin hBD-1 in human secretory glands and epithelial cells. FEBS Lett. 396:319–22.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Mathews M, et al. (1999) Production of beta-defensin antimicrobial peptides by the oral mucosa and salivary glands. Infect. Immun. 67:2740–5.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Goldman MJ, Anderson GM, Stolzenberg ED, Kari UP, Zasloff M, Wilson JM. (1997) Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88:553–60.CrossRefGoogle Scholar
  72. 72.
    Valore EV, Park CH, Quayle AJ, Wiles KR, McCray PB Jr, Ganz T. (1998) Human beta-defensin-1: an antimicrobial peptide of urogenital tissues. J. Clin. Invest. 101:1633–42.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Duits LA, Ravensbergen B, Rademaker M, Hiemstra PS, Nibbering PH. (2002) Expression of beta-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cells. Immunology 106:517–25.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Feng Z, Jiang B, Chandra J, Ghannoum M, Nelson S, Weinberg A. (2005) Human beta-defensins: differential activity against candidal species and regulation by Candida albicans. J. Dent. Res. 84:445–50.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Joly S, Organ CC, Johnson GK, McCray PB Jr, Guthmiller JM. (2005) Correlation between beta-defensin expression and induction profiles in gingival keratinocytes. Mol. Immunol. 42:1073–84.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Sorensen OE, Thapa DR, Rosenthal A, Liu L, Roberts AA, Ganz T. (2005) Differential regulation of beta-defensin expression in human skin by microbial stimuli. J. Immunol. 174:4870–9.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Hiratsuka T, et al. (2003) Increased concentrations of human beta-defensins in plasma and bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis. Thorax 58:425–30.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Zhu BD, Feng Y, Huang N, Wu Q, Wang BY. (2003) Mycobacterium bovis bacille Calmette-Guerin (BCG) enhances human beta-defensin-1 gene transcription in human pulmonary gland epithelial cells. Acta Pharmacol. Sin. 24:907–12.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Harder J, Bartels J, Christophers E, Schroder JM. (1997) Apeptide antibiotic from human skin. Nature 387:861.CrossRefGoogle Scholar
  80. 80.
    O’Neil DA, et al. (1999) Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium. J. Immunol. 163:6718–24.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Bals R, et al. (1998) Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J. Clin. Invest. 102:874–80.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Oren A, Ganz T, Liu L, Meerloo T. (2003) In human epidermis, beta-defensin 2 is packaged in lamellar bodies. Exp. Mol. Pathol. 74:180–2.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Liu AY, et al. (2002) Human beta-defensin-2 production in keratinocytes is regulated by interleukin-1, bacteria, and the state of differentiation. J. Invest. Dermatol. 118:275–81.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Liu L, Roberts AA, Ganz T. (2003) By IL-1 signaling, monocyte-derived cells dramatically enhance the epidermal antimicrobial response to lipopolysaccharide. J. Immunol. 170:575–80.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Tsutsumi-Ishii Y, Nagaoka I. (2003) Modulation of human beta-defensin-2 transcription in pulmonary epithelial cells by lipopolysaccharide-stimulated mononuclear phagocytes via proinflammatory cytokine production. J. Immunol. 170:4226–36.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Fang XM, et al. (2003) Differential expression of alpha- and beta-defensins in human peripheral blood. Eur. J. Clin. Invest. 33:82–7.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Selsted ME, Ouellette AJ. (2005) Mammalian defensins in the antimicrobial immune response. Nat. Immunol. 6:551–7.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Birchler T, et al. (2001) Human Toll-like receptor 2 mediates induction of the antimicrobial peptide human beta-defensin 2 in response to bacterial lipoprotein. Eur. J. Immunol. 31:3131–7.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Tsutsumi-Ishii Y, Nagaoka I. (2002) NF-kappa B-mediated transcriptional regulation of human beta-defensin-2 gene following lipopolysaccharide stimulation. J. Leukoc. Biol. 71:154–62.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Hertz CJ, et al. (2003) Activation of Toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human beta defensin-2. J. Immunol. 171:6820–6.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Wang X, Zhang Z, Louboutin JP, Moser C, Weiner DJ, Wilson JM. (2003) Airway epithelia regulate expression of human beta-defensin 2 through Toll-like receptor 2. FASEB J. 17:1727–9.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Krisanaprakornkit S, Kimball JR, Dale BA. (2002) Regulation of human beta-defensin-2 in gingival epithelial cells: the involvement of mitogen-activated protein kinase pathways, but not the NF-kappaB transcription factor family. J. Immunol. 168:316–24.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Moon SK, et al. (2002) Activation of a Srcdependent Raf-MEK1/2-ERK signaling pathway is required for IL-1alpha-induced upregulation of beta-defensin 2 in human middle ear epithelial cells. Biochim. Biophys. Acta 1590:41–51.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Yang D, et al. (1999) Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286:525–8.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Schmid P, Grenet O, Medina J, Chibout SD, Osborne C, Cox DA. (2001) An intrinsic antibiotic mechanism in wounds and tissue-engineered skin. J. Invest. Dermatol. 116:471–2.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. (2004) IL-22 increases the innate immunity of tissues. Immunity 21:241–54.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Kawai K, Shimura H, Minagawa M, Ito A, Tomiyama K, Ito M. (2002) Expression of functional Toll-like receptor 2 on human epidermal keratinocytes. J. Dermatol. Sci. 30:185–94.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Diamond G, Russell JP, Bevins CL. (1996) Inducible expression of an antibiotic peptide gene in lipopolysaccharide-challenged tracheal epithelial cells. Proc. Natl. Acad. Sci. U. S. A. 93:5156–60.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Harder J, et al. (2000) Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia. Am. J. Respir. Cell Mol. Biol. 22:714–21.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Singh PK, et al. (1998) Production of beta-defensins by human airway epithelia. Proc. Natl. Acad. Sci. U. S. A. 95:14961–6.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Ong PY, et al. (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347:1151–60.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Milner SM, Ortega MR. (1999) Reduced antimicrobial peptide expression in human burn wounds. Burns 25:411–3.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Garcia JR, et al. (2001) Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity: its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction. Cell Tissue Res. 306:257–64.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Harder J, Bartels J, Christophers E, Schroder JM. (2001) Isolation and characterization of human beta-defensin-3, a novel human inducible peptide antibiotic. J. Biol. Chem. 276:5707–13.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Dunsche A, Acil Y, Dommisch H, Siebert R, Schroder JM, Jepsen S. (2002) The novel human beta-defensin-3 is widely expressed in oral tissues. Eur. J. Oral Sci. 110:121–4.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Hattenbach LO, Gumbel H, Kippenberger S. (1998) Identification of beta-defensins in human conjunctiva. Antimicrob. Agents Chemother. 42:3332.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Sawamura D, et al. (2005) Beta defensin-3 engineered epidermis shows highly protective effect for bacterial infection. Gene Ther. 12:857–61.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Miller LS, et al. (2005) TGF-alpha regulates TLR expression and function on epidermal keratinocytes. J. Immunol. 174:6137–43.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Sahly H, et al. (2003) Burkholderia is highly resistant to human Beta-defensin 3. Antimicrob. Agents Chemother. 47:1739–41.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Maisetta G, et al. (2006) In vitro bactericidal activity of human beta-defensin 3 against multidrug-resistant nosocomial strains. Antimicrob. Agents Chemother. 50:806–9.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Garcia JR, et al. (2001) Human beta-defensin 4: a novel inducible peptide with a specific saltsensitive spectrum of antimicrobial activity. FASEB J. 15:1819–21.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Harder J, Meyer-Hoffert U, Wehkamp K, Schwichtenberg L, Schroder JM. (2004) Differential gene induction of human beta-defensins (hBD-1, -2, -3, and -4) in keratinocytes is inhibited by retinoic acid. J. Invest. Dermatol. 123:522–9.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Niyonsaba F, Iwabuchi K, Matsuda H, Ogawa H, Nagaoka I. (2002) Epithelial cell-derived human beta-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway. Int. Immunol. 14:421–6.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Gallo RL, Huttner KM. (1998) Antimicrobial peptides: an emerging concept in cutaneous biology. J. Invest. Dermatol. 111:739–43.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Schittek B, et al. (2001) Dermcidin: a novel human antibiotic peptide secreted by sweat glands. Nat. Immunol. 2:1133–7.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Wiedow O, Harder J, Bartels J, Streit V, Christophers E. (1998) Antileukoprotease in human skin: an antibiotic peptide constitutively produced by keratinocytes. Biochem. Biophys. Res. Commun. 248:904–9.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Wingens M, et al. (1998) Induction of SLPI (ALP/HUSI-I) in epidermal keratinocytes. J. Invest. Dermatol. 111:996–1002.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Harder J, Schroder JM. (2002) RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin. J. Biol. Chem. 277:46779–84.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Glaser R, Harder J, Lange H, Bartels J, Christophers E, Schroder JM. (2005) Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat. Immunol. 6:57–64.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Chen VL, France DS, Martinelli GP. (1986) De novo synthesis of lysozyme by human epidermal cells. J. Invest. Dermatol. 87:585–7.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Qu XD, Lehrer RI. (1998) Secretory phospholipase A2 is the principal bactericide for staphylococci and other gram-positive bacteria in human tears. Infect. Immun. 66:2791–7.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Ganz T. (1987) Extracellular release of antimicrobial defensins by human polymorphonuclear leukocytes. Infect. Immun. 55:568–71.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Steinstraesser L, et al. (2005) Inhibition of early steps in the lentiviral replication cycle by cathelicidin host defense peptides. Retrovirology 2:2.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Brogden KA. (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat. Rev. Microbiol. 3:238–50.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Territo MC, Ganz T, Selsted ME, Lehrer R. (1989) Monocyte-chemotactic activity of defensins from human neutrophils. J. Clin. Invest. 84:2017–20.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Giacometti A, et al. (2004) Cathelicidin peptide sheep myeloid antimicrobial peptide-29 prevents endotoxin-induced mortality in rat models of septic shock. Am. J. Respir. Crit. Care Med. 169:187–94.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Gough M, Hancock RE, Kelly NM. (1996) Antiendotoxin activity of cationic peptide antimicrobial agents. Infect. Immun. 64:4922–7.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Cirioni O, et al. (2006) LL-37 protects rats against lethal sepsis caused by gram-negative bacteria. Antimicrob. Agents Chemother. 50:1672–9.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Elsbach P. (2003) What is the real role of antimicrobial polypeptides that can mediate several other inflammatory responses? J. Clin. Invest. 111:1643–5.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Ganz T. (2002) Immunology: versatile defensins. Science 298:977–9.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Niyonsaba F, Ushio H, Nagaoka I, Okumura K, Ogawa H. (2005) The human beta-defensins (-1, -2, -3, -4) and cathelicidin LL-37 induce IL-18 secretion through p38 and ERK MAPK activation in primary human keratinocytes. J. Immunol. 175:1776–84.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu L, Ganz T, Borregaard N. (2003) Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J. Immunol. 170:5583–9.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Singer AJ, Clark RA. (1999) Cutaneous wound healing. N. Engl. J. Med. 341:738–46.CrossRefGoogle Scholar
  134. 134.
    Gartner MH, Benson JD, Caldwell MD. (1992) Insulin-like growth factors I and II expression in the healing wound. J. Surg. Res. 52:389–94.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Rappolee DA, Mark D, Banda MJ, Werb Z. (1988) Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science 241:708–12.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Chan YR, Gallo RL. (1998) PR-39, a syndecaninducing antimicrobial peptide, binds and affects p130(Cas). J. Biol. Chem. 273:28978–85.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Ho G, Broze GJ Jr, Schwartz AL. (1997) Role of heparan sulfate proteoglycans in the uptake and degradation of tissue factor pathway inhibitor-coagulation factor Xa complexes. J. Biol. Chem. 272:16838–44.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Penc SF, Pomahac B, Eriksson E, Detmar M, Gallo RL. (1999) Dermatan sulfate activates nuclear factor-kappaB and induces endothelial and circulating intercellular adhesion molecule-1. J. Clin. Invest. 103:1329–35.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Proudfoot AE, et al. (2001) The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity. J. Biol. Chem. 276:10620–6.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Rix DA, Douglas MS, Talbot D, Dark JH, Kirby JA. (1996) Role of glycosaminoglycans (GAGs) in regulation of the immunogenicity of human vascular endothelial cells. Clin. Exp. Immunol. 104:60–5.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Echtermeyer F, et al. (2001) Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4. J. Clin. Invest. 107:R9–14.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Gallo RL. (2000) Proteoglycans and cutaneous vascular defense and repair. J. Invest. Dermatol. Symp. Proc. 5:55–60.CrossRefGoogle Scholar
  143. 143.
    Heilborn JD, et al. (2003) The cathelicidin antimicrobial peptide LL-37 is involved in reepithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J. Invest. Dermatol. 120:379–89.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Nizet V, et al. (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414:454–7.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Braff MH, Zaiou M, Fierer J, Nizet V, Gallo RL. (2005) Keratinocyte production of cathelicidin provides direct activity against bacterial skin pathogens. Infect. Immun. 73:6771–81.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. (2004) New insights into atopic dermatitis. J. Clin. Invest. 113:651–7.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Christophers E, Henseler T. (1987) Contrasting disease patterns in psoriasis and atopic dermatitis. Arch. Dermatol. Res. 279 Suppl:S48–51.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Jacobsen F, et al. (2005) Transient cutaneous adenoviral gene therapy with human host defense peptide hCAP-18/LL-37 is effective for the treatment of burn wound infections. Gene Ther. 12:1494–502.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Koczulla R, von Degenfeld G, Kupatt C, et al. (2003) An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J. Clin. Invest. 111:1665–72.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Steinstraesser L, Ring A, Bals R, Steinau HU, Langer S. (2006) The human host defense peptide LL37/hCAP accelerates angiogenesis in PEGT/ PBT biopolymers. Ann. Plast. Surg. 56:93–8.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Poindexter BJ. (2005) Immunofluorescence deconvolution microscopy and image reconstruction of human defensins in normal and burned skin. J. Burns Wounds 4:e7.PubMedPubMedCentralGoogle Scholar
  152. 152.
    Poindexter BJ, Bhat S, Buja LM, Bick RJ, Milner SM. (2006) Localization of antimicrobial peptides in normal and burned skin. Burns 32:402–7.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Oono T, Shirafuji Y, Huh WK, Akiyama H, Iwatsuki K. (2002) Effects of human neutrophil peptide-1 on the expression of interstitial collagenase and type I collagen in human dermal fibroblasts. Arch. Dermatol. Res. 294:185–9.PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Murphy CJ, Foster BA, Mannis MJ, Selsted ME, Reid TW. (1993) Defensins are mitogenic for epithelial cells and fibroblasts. J. Cell Physiol. 155:408–13.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Supp DM, Karpinski AC, Boyce ST. (2004) Expression of human beta-defensins HBD-1, HBD-2, and HBD-3 in cultured keratinocytes and skin substitutes. Burns 30:643–8.PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Niyonsaba F, et al. (2006) Antimicrobial peptides human beta-defensins stimulate epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines. J. Invest. Dermatol. 127:510–2.Google Scholar
  157. 157.
    Butmarc J, Yufit T, Carson P, Falanga V. (2004) Human beta-defensin-2 expression is increased in chronic wounds. Wound Repair Regen. 12:439–43.PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Menzies BE, Kenoyer A. (2006) Signal transduction and nuclear responses in Staphylococcus aureus-induced expression of human beta-defensin 3 in skin keratinocytes. 74 74:6847–54.Google Scholar
  159. 159.
    Kisich KO, Howell MD, Boguniewicz M, Heizer HR, Watson NU, Leung DY. (2007) The constitutive capacity of human keratinocytes to kill Staphylococcus aureus is dependent on beta-defensin 3. J. Invest. Dermatol. 127:2368–80.PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Jacobsen F, et al. (2005) Activity of histone H1.2 in infected burn wounds. J. Antimicrob. Chemother. 55:735–41.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Kaus A, et al. (2008) Host defence peptides in human burns. Burns. 34:32–40.PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Fukumoto K, et al. (2005) Effect of antibacterial cathelicidin peptide CAP18/LL-37 on sepsis in neonatal rats. Pediatr. Surg. Int. 21:20–4.PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Oren Z, Lerman JC, Gudmundsson GH, Agerberth B, Shai Y. (1999) Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity. Biochem. J. 341.Google Scholar
  164. 164.
    Ciornei CD, Egesten A, Bodelsson M. (2003) Effects of human cathelicidin antimicrobial peptide LL-37 on lipopolysaccharide-induced nitric oxide release from rat aorta in vitro. Acta Anaesthesiol. Scand. 47:213–20.PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Risso A, Zanetti M, Gennaro R. (1998) Cytotoxicity and apoptosis mediated by two peptides of innate immunity. Cell. Immunol. 189:107–15.PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Jacobsen F, et al. (2007) Antimicrobial activity of the recombinant designer host defence peptide P-novispirin G10 in infected full-thickness wounds of porcine skin. J. Antimicrob. Chemother. 59:493–8.PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Ciornei CD, Sigurdardottir T, Schmidtchen A, Bodelsson M. (2005) Antimicrobial and chemoattractant activity, lipopolysaccharide neutralization, cytotoxicity, and inhibition by serum of analogs of human cathelicidin LL-37. Antimicrob. Agents Chemother. 49:2845–50.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Sigurdardottir T, Andersson P, Davoudi M, Malmsten M, Schmidtchen A, Bodelsson M. (2006) In silico identification and biological evaluation of antimicrobial peptides based on human cathelicidin LL-37. Antimicrob. Agents Chemother. 50:2983–9.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Braunstein A, Papo N, Shai Y. (2004) In vitro activity and potency of an intravenously injected antimicrobial peptide and its DL amino acid analog in mice infected with bacteria. Antimicrob. Agents Chemother. 48:3127–9.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Shai Y. (2002) From innate immunity to de-novo designed antimicrobial peptides. Curr. Pharm. Des. 8:715–25.PubMedCrossRefPubMedCentralGoogle Scholar
  171. 171.
    Peschel A, Sahl H-G. (2006) The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nature 4:529–36.Google Scholar
  172. 172.
    Peschel A. (2002) How do bacteria resist human antimicrobial peptides? Trends Microbiol. 10:179–86.PubMedCrossRefPubMedCentralGoogle Scholar
  173. 173.
    Yount NY, Bayer AS, Xiong YQ, Yeaman MR. (2006) Advances in antimicrobial peptide immunobiology. Biopolymers (Peptide Sci.) 84:435–58.CrossRefGoogle Scholar
  174. 174.
    Hamilton A, Popham DL, Carl DJ, Lauth X, Nizet V, Jones AL. (2006) Penicillin-binding protein 1a promotes resistance of group B streptococcus to antimicrobial peptides. Infect. Immun. 74:6179–87.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Giacometti A, et al. (2006) Interaction of antimicrobial peptide temporin L with lipopolysaccharide in vitro and in experimental rat models of septic shock caused by gram-negative bacteria. Antimicrob. Agents Chemother. 50:2478–86.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Ghiselli R, et al. (2004) Cecropin B enhances betalactams activities in experimental rat models of gram-negative septic shock. Ann. Surg. 239:251–6.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Cirioni O, et al. (2006) Experimental study on the efficacy of combination of alpha-helical antimicrobial peptides and vancomycin against Staphylococcus aureus with intermediate resistance to glycopeptides. Peptides 27:2600–6.PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Kristian SA, et al. (2007) Impairment of innate immune killing mechanisms by bacteriostatic antibiotics. FASEB J. 21:1107–16.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Zhang L, Falla TJ. (2006) Antimicrobial peptides: therapeutic potential. Expert Opin. Pharmacother. 7:653–63.PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    Hancock RE, Sahl HG. (2006) Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotech. 24:1551–7.CrossRefGoogle Scholar
  181. 181.
    Levin M, et al. (2000) Recombinant bactericidal/ permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group. Lancet 356:961–7.PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Giroir BP, Scannon PJ, Levin M. (2001) Bactericidal/permeability-increasing protein: lessons learned from the phase III, randomized, clinical trial of rBPI21 for adjunctive treatment of children with severe meningococcemia. Crit. Care Med. 29:S130–5.PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Mookherjee N, Hancock RE. (2007) Cationic host defense peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell Mol. Life Sci. 64:922–33.PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    Hancock RE, Patrzykat A. (2002) Clinical development of cationic antimicrobial peptides: from natural to novel antibiotics. Curr. Drug Targets Infect. Disord. 2:79–83.PubMedCrossRefPubMedCentralGoogle Scholar
  185. 185.
    Steinstraesser L, et al. (2001) Protegrin-1 enhances bacterial killing in thermally injured skin. Crit. Care Med. 29:1431–7.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Lars Steinstraesser
    • 1
    • 2
  • Till Koehler
    • 3
  • Frank Jacobsen
    • 1
    • 2
  • Adrien Daigeler
    • 1
    • 2
  • Ole Goertz
    • 1
    • 2
  • Stefan Langer
    • 1
    • 2
  • Marco Kesting
    • 4
  • Hans Steinau
    • 1
    • 2
  • Elof Eriksson
    • 3
  • Tobias Hirsch
    • 1
    • 2
    • 3
  1. 1.Department for Plastic Surgery, Burn Center BG University Hospital BergmannsheilRuhr University BochumBochumGermany
  2. 2.Burn CenterRuhr University BochumBochumGermany
  3. 3.Plastic SurgeryHarvard UniversityCambridgeUSA
  4. 4.Craniofacial SurgeryTechnical University MunichMunichGermany

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