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Review

Cutaneous antimicrobial gene therapy: engineering human skin replacements to combat wound infection

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Pages 73-84 | Published online: 10 Jan 2014

References

  • Rose JK, Herndon DN. Advances in the treatment of burn patients. Burns23, S19–S26 (1997).
  • Fratianne RB, Brandt CP. Improved survival of adults with extensive burns. J. Burn Care Rehab.18, 347–351 (1997).
  • Barret JP, Herndon DN. Effects of burn wound excision on bacterial colonization and invasion. Plast. Reconstr. Surg.111, 744–750 (2003).
  • Herndon DN, Barrow RE, Rutan RL et al. A comparison of conservative versus early excision. Therapies in severely burned patients. Ann. Surg.209, 547–552 (1989).
  • Phillips TJ. Chronic cutaneous ulcers: etiology and epidemiology. J. Invest. Dermatol.102, 38S–41S (1994).
  • Falanga V. Chronic wounds: pathophysical and experimental considerations. J. Invest. Dermatol.100(5), 721–725 (1993).
  • Albert S. Cost-effective management of recalcitrant diabetic foot ulcers. Clin. Podiatr. Med. Surg.19, 483–491 (2002).
  • Brem H, Sheehan P, Rosenberg HJ, Schneider JS, Boulton AJ. Evidence-based protocol for diabetic foot ulcers. Plast. Reconstr. Surg.117(7 Suppl.), 193S–209S (2006).
  • Lipsky BA, Berendt AR, Deery HG et al. Diagnosis and treatment of diabetic foot infections. Plast. Reconstr. Surg.117(7 Suppl.), 212S–238S (2006).
  • Tentolouris N, Jude EB, Smirnof I, Knowles EA, Boulton AJ. Methicillin-resistant Staphylococcus aureus: an increasing problem in diabetic foot clinic. Diabetic Med.16, 767–771 (1999).
  • Dang CN, Prasad YD, Boulton AJ, Jude EB. Methicillin-resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem. Diabetic Med.20, 159–161 (2003).
  • Jeng JC, Fidler PE, Sokolich JC et al. Seven years’ experience with Integra as a reconstructive tool. J. Burn Care Res.28, 120–126 (2007).
  • Orgill DP, Butler CE, Regan JF et al. Vascularized collagen–glycosaminoglycan matrix provides a dermal substrate and improves take of cultured epithelial autografts. Plast. Reconstr. Surg.102, 423–429 (1998).
  • Pandya AN, Woodward B, Parkhouse DM. The use of cultured autologous keratinocytes with Integra in the resurfacing of acute burns. Plast. Reconstr. Surg.102, 825–830 (1998).
  • Medalie DA, Eming SA, Tompkins RG, Yarmush ML, Krueger GG. Evaluation of human skin reconstituted from composite grafts of cultured keratinocytes and human acellular dermis transplanted to athymic mice. J. Invest. Dermatol.107(1), 121–127 (1996).
  • Compton CC, Butler CE, Yannas IV, Warland G, Orgill DP. Organized skin structure is regenerated in vivo from collagen–GAG matrices seeded with autologous keratinocytes. J. Invest. Dermatol.110, 908–916 (1998).
  • Horch RE, Bannasch H, Stark GB. Cultured human keratinocytes as a single cell suspension in fibrin glue combined with preserved dermal grafts enhance skin reconstitution in athymic mice full-thickness wounds. Eur. J. Plast. Surg.22, 237–243 (1999).
  • Boyce ST, Kagan RJ, Meyer NA, Yakuboff KP, Warden GD. The 1999 Clinical Research Award. Cultured skin substitutes combined with Integra to replace native skin autograft and allograft for closure of full-thickness burns. J. Burn Care Rehabil.20, 453–461 (1999).
  • Chong EJ, Phan TT, Lim IJ et al. Evaluation of electrospun PCL/gelatin nanofibrous scaffold for wound healing and layered dermal reconstitution. Acta Biomater.3, 321–330 (2007).
  • Mazlyzam AL, Aminuddin BS, Fuzina NH et al. Reconstruction of living bilayer human skin equivalent utilizing human fibrin as a scaffold. Burns33, 355–363 (2007).
  • Phillips TJ, Bhawan J, Leigh IM, Baum HJ, Gilchrest BA. Cultured epidermal autografts and allografts: a study of differentiation and allograft survival. J. Am. Acad. Dermatol.23, 189–195 (1990).
  • Boyce ST, Goretsky MJ, Greenhalgh DG et al. Comparative assessment of cultured skin substitutes and native skin autograft for treatment of full-thickness burns. Ann. Surg.222(6), 743–752 (1995).
  • Cooper ML, Hansbrough JF, Spielvogel RL et al.in vivo optimization of a living dermal substitute employing cultured human fibroblasts on a biodegradable polyglycolic or polyglactin mesh. Biomaterials12, 243–248 (1991).
  • Boyce ST, Kagan RJ, Yakuboff KP et al. Cultured skin substitutes reduce donor skin harvesting for closure of excised, full-thickness burns. Ann. Surg.235, 269–279 (2002).
  • Boyce ST, Glatter R, Kitzmiller WJ. Treatment of chronic wounds with cultured cells and biopolymers: a pilot study. Wounds7(1), 24–29 (1995).
  • Boyce ST, Supp AP, Harriger MD, Greenhalgh DG, Warden GD. Topical nutrients promote engraftment and inhibit wound contraction of cultured skin substitutes in athymic mice. J. Invest. Dermatol.104(3), 345–349 (1995).
  • Boyce ST, Warden GD, Holder IA. Cytotoxicity testing of topical antimicrobial agents on human keratinocytes and fibroblasts for cultured skin grafts. J. Burn Care Rehabil.16(2), 97–103 (1995).
  • Boyce ST, Warden GD, Holder IA. Non-cytotoxic combinations of topical antimicrobial agents for use with cultured skin. Antimicrob. Agents Chemother.39(6), 1324–1328 (1995).
  • Mayhall CG. The epidemiology of burn wound infections: then and now. Clin. Infect. Dis.37, 543–550 (2003).
  • Santucci SG, Gobara S, Santos CR, Fontana C, Levin AS. Infections in a burn intensive care unit: experience of seven years. J. Hosp. Infect.53, 6–13 (2003).
  • Lantenser BA. Fusarium infections in burn patients: a case report and review of the literature. J. Burn Care Rehab.24, 285–288 (2003).
  • Schoffield CM, Murray CK, Horvath EE et al. Correlation of culture with histopathology in fungal burn wound colonization and infection. Burns33, 246– (2007).
  • Falk PS, Winnike J, Woodmansee C, Desai M, Mayhall CG. Outbreak of vancomycin-resistant enterococci in a burn unit. Infect. Control Hosp. Epidemiol.21, 575–582 (2000).
  • Maslow JN, Glaze T, Adams P, Lataillade M. Concurrent outbreak of multidrug-resistant and susceptible subclones of Acinetobacter baumannii affecting different wards of a single hospital. Infect. Control. Hosp. Epidemiol.26, 69–75 (2005).
  • Altoparlak U, Aktas F, Celebi D, Ozkurt Z, Akcay MN. Prevalence of metallo-β-lactamase among Pseudomonas aeruginosa and Acinetobacter baumannii isolated from burn wounds and in vitro activities of antibiotic combinations against these isolates. Burns31, 707–710 (2005).
  • Tredget EE, Shankowsky HA, Rennie R, Burrell RE, Logsetty S. Pseudomonas infections in the thermally injured patient. Burns30, 3–26 (2004).
  • Trottier V, Segura PG, Namias N et al. Outcomes of Acinetobacter baumannii infection in critically ill burned patients. J. Burn Care Res.28, 248–254 (2007).
  • Howell-Jones RS, Wilson MJ, Hill KE et al. A review of the microbiology, antibiotic usage and resistance in chronic skin wounds. J. Antimicrob. Chemother.55, 143–149 (2005).
  • Brook I, Frazier EH. Aerobic and anaerobic microbiology of chronic venous ulcers. Int. J. Dermatol.37, 426–428 (1998).
  • Urbancic-Rovan V, Gubina M. Infection in superficial diabetic foot ulcers. Clin. Infect. Dis.25, S184–S185 ( 1997).
  • Missoni EM, Kalenic S, Vukelic M et al. Role of yeast in diabetic foot ulcer infection. Acta Med. Croatica60, 43–50 (2006).
  • Hansson C, Faergemann J, Swanbeck G. Fungal infections occuring under bandages in leg ulcer patients. Acta Derm. Venereol.67, 341–345 (2007).
  • Chincholikar DA, Fal RB. Study of fungal and bacteria infections of the diabetic foot. Indian J. Pathol. Microbiol.54, 15–22 (2002).
  • Hartemann-Heurtier A, Robert AJS, Van GH et al. Diabetic foot ulcer and multidrug-resistant organisms: risk factors and impact. Diabetic Med.21, 710–715 (2004).
  • Centers for Disease Control and Prevention. Vancomycin-resistant Staphylococcus aureus – Pennsylvania, MMWR Morb. Mortal. Wkly Rep. 2002 51, 902 (2002).
  • Talbot GH, Bradley J, Edwards JE Jr et al. Bad bugs need drugs: an update on the development pipeline from the antimicrobial availability task force of the Infectious Diseases Society of America. Clin. Infect. Dis.42, 657–658 (2006).
  • McDonald LC. Trends in antimicrobial resistance in health care – associated pathogens and effect on treatment. Clin. Infect. Dis.42, S65–S71 (2006).
  • Cosgrove E. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin. Infect. Dis.42, S82–S89 (2006).
  • Rehm SJ, Weber JT. The far-reaching impact of antimicrobial resistance.Clin. Infect. Dis.45, S97–S98 (2007).
  • Bals R. Epithelial antimicrobial peptides in host defense against infection. Respir. Res.1, 141–150 (2000).
  • Ganz T, Lehrer RI. Antibiotic peptides from higher eukaryotes: biology and applications. Mol. Med. Today5, 292–297 (1999).
  • Schneider JJ, Unholzer A, Schaller M, Schafer-Korting M, Korting HC. Human defensins. J. Mol. Med.83, 587–595 (2005).
  • Ganz T, Lehrer RI. Antimicrobial peptides of vertebrates. Curr. Opin. Immunol.10, 41–44 (1998).
  • Lehrer RI, Lichtenstein AK, Ganz T. Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu. Rev. Immunol.11, 105–128 (1993).
  • Bals R, Want X, Wu Z et al. Human β-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J. Clin. Invest.102, 874–880 (1998).
  • Harder J, Bartels J, Christophers E, Schroder J-M. Isolation and characterization of human β-defensin-3, a novel human inducible peptide antibiotic. J. Biol. Chem.276, 5707–5713 (2001).
  • Zhao C, Wang I, Lehrer RI. Widespread expression of β-defensin hBD-1 in human secretory glands and epithelial cells. FEBS Lett.396, 319–322 (1996).
  • Garcia J-RC, Krause A, Schulz S et al. Human β-defensin 4: a novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity. FASEB J.15, 1819–1821 (2001).
  • Schutte BC, Mitros JP, Bartlett JA et al. Discovery of five conserved β-defensin gene clusters using a computational search strategy. Proc. Natl Acad. Sci. USA99, 2129–2133 (2002).
  • Scheetz T, Bartlett JA, Walters JD et al. Genomics-based approaches to gene discovery in innate immunity. Immunol. Rev.190, 137–145 (2002).
  • O’Neil DA, Porter EM, Elewaut D et al. Expression and regulation of human β-defensins hBD-1 and hBD-2 in intestinal epithelium. J. Immunol.163, 6718–6724 (1999).
  • Singh PK, Jia HP, Wiles K et al. Production of β-defensins by human airway epithelia. Proc. Natl Acad. Sci. USA95, 14961–14966 (1998).
  • Fulton C, Anderson GM, Zasloff M, Bull R, Quinn AG. Expression of natural peptide antibiotics in human skin. Lancet350, 1750–1751 (1997).
  • Ali RS, Falconer A, Ikram M et al. Expression of the peptide antibiotics human β defensin-1 and human β defensin-2 in normal human skin. J. Invest. Dermatol.117, 106–111 (2001).
  • Liu AY, Destoumieux D, Wong AV et al. Human β-defensin-2 production in keratinocytes is regulated by interleukin-1, bacteria, and the state of differentiation. J. Invest. Dermatol.118, 275–281 (2002).
  • Liu L, Wang L, Jia HP et al. Structure and mapping of the human β-defensin HBD-2 gene and its expression at sites of inflammation. Gene222, 237–244 (1998).
  • Milner SM, Ortega MR. Reduced antimicrobial peptide expression in human burn wounds. Burns25, 411–413 (1999).
  • Nomura I, Goleva E, Howell MD et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J. Immunol.171, 3262–3269 (2003).
  • Sørensen OE, Thapa DR, Rosenthal A et al. Differential regulation of β-defensin expression in human skin by microbial stimuli. J. Immunol.174, 4870–4879 (2005).
  • Harder J, Meyer-Hoffert U, Wehkamp K, Schwichtenberg L, Schroeder J-M. Differential gene induction of human β-defensins (hBD-1, -2, -3, and -4) in keratinocytes is inhibited by retinoic acid. J. Invest. Dermatol.123, 522–529 (2004).
  • Yamaguchi Y, Nagase T, Makita R et al. Identification of multiple novel epididymis-specific β-defensin isoforms in humans and mice. J. Immunol.169, 2516–2523 (2002).
  • Agerberth B, Gunne H, Odeberg J et al. FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Proc. Natl Acad. Sci. USA92, 195–199 (1995).
  • Sørensen OE, Arnljots K, Cowland JB, Bainton DF, Borregaard N. The human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils. Blood90, 2796–2803 (1997).
  • Frohm M, Agerberth B, Ahangari G et al. The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J. Biol. Chem.272, 15258–15263 (1997).
  • Heilborn JD, Nilsson MF, Kratz G et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J. Invest. Dermatol.120, 379–389 (2003).
  • Dorschner RA, Pestonjamasp VK, Tamakuwala S et al. Cutaneous injury induces the release of cathelicidin antimicrobial peptides active against Group A Streptococcus. J. Invest. Dermatol.117, 91–97 (2001).
  • Heimbach D, Nilsson MF, Kratz G et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J. Invest. Dermatol.120, 379–389 (2003).
  • Van Dyke T, Paquette D, Grossi S et al. Clinical and microbial evaluation of a histatin-containing mouthrinse in humans with experimental gingivitis: a Phase-2 multi-center study. J. Clin. Periodontol.29, 168–176 (2002).
  • Paquette DW, Simpson DM, Friden P, Braman V, Williams RC. Safety and clinical effects of topical histatin gels in humans with experimental gingivitis. J. Clin. Periodontol.29, 1051–1058 (2002).
  • Krause A, Neitz S, Magert HJ et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett.480, 147–150 (2000).
  • Hunter HN, Fulton DB, Ganz T, Vogel HJ. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J. Biol. Chem.277, 37597–37603 (2002).
  • Krause A, Sillard R, Kleemeier B et al. Isolation and biochemical characterization of LEAP-2, a novel blood peptide expressed in the liver. Protein Sci.12, 143–152 (2003).
  • Schittek B, Hipfel R, Sauer B et al. Dermcidin: a novel human antibiotic peptide secreted by sweat glands. Nat. Immunol.2, 1133–1137 (2001).
  • Rieg S, Garbe C, Sauer B, Kalbacher H, Schittek B. Dermcidin is constitutively produced by eccrine sweat glands and is not induced in epidermal cells under inflammatory skin conditions. Br. J. Dermatol.151, 534–539 (2004).
  • Simpson AJ, Maxwell AI, Govan JR, Haslett C, Sallenave JM. Elafin (elastase-specific inhibitor) has anti-microbial activity against Gram-positive and Gram-negative respiratory pathogens. FEBS Lett.452, 309–313 (1999).
  • Glaser R, Harder J, Lange H et al. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat. Immunol.6, 57–64 (2005).
  • Chen X, Niyonsaba F, Ushio H et al. Synergistic effect of antibacterial agents human β-defensins, cathelicidin LL-37 and lysozyme against Staphylococcus aureus and Escherichia coli. J. Dermatol. Sci.40, 123–132 (2005).
  • Allaker RP, Grosvenor PW, McAnerney DC et al. Mechanisms of adrenomedullin antimicrobial action. Peptides27, 661–666 (2006).
  • Mallbris L, O’Brien KP, Hulthen A et al. Neutrophil gelatinase-associated lipocalin is a marker for dysregulated keratinocyte differentiation in human skin. Exp. Dermatol.11, 584–591 (2002).
  • Harder J, Schroder J-M. Psoriatic scales: a promising source for the isolation of human skin-derived antimicrobial proteins. J. Leukoc. Biol.77, 476–486 (2005).
  • Wiedow O, Harder J, Bartels J, Streit V, Christophers E. Antileukoprotease in human skin: an antibiotic peptide constitutively produced by keratinocytes. Biochem. Biophys. Res. Commun.248, 904–909 (1998).
  • Wang H, Gupta D, Li X, Dziarski R. Peptidoglycan recognition protein 2 (N-acetylmuramoyl-l-Ala amidase) is induced in keratinocytes by bacteria through the p38 kinase pathway. Infect. Immun.73, 7216–7225 (2005).
  • Harder J, Schroeder J-M. RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin. J. Biol. Chem.277, 46779–46784 (2007).
  • Takemura H, Kaku M, Kohno S et al. Evaluation of susceptibility of Gram-positive and -negative bacteria to human defensins by using radial diffusion assay. Antimicrob. Agents Chemother.40, 2280–2284 (1996).
  • Welling MW, Hiemstra PS, van den Barselaar MT et al. Antibacterial activity of human neutrophil defensins in experimental infections in mice is accompanied by increased leukocyte accumulation. J. Clin. Invest.102, 1583–1590 (1998).
  • Smeianov V, Scott K, Reid G. Activity of cecropin P1 and FA-LL-37 against urogenital microflora. Microbes. and. Infection.2, 773–777 (2000).
  • Sahly H, Schubert S, Harder J et al. Activity of human β-defensins 2 and 3 against ESBL-producing Klebsiella strains. J. Antimicrob. Chemother.57, 562–565 (2006).
  • Burd RS, Furrer JL, Sullivan J, Smith AL. Murine β-defensin-3 is an inducible peptide with limited tissue expression and broad-spectrum antimicrobial activity. Shock18, 461–464 (2002).
  • Feng Z, Jiang B, Chandra J et al. Human β-defensins: differential activity against Candidal species and regulation by Candida albicans. J. Dent. Res.84, 445–450 (2005).
  • Komatsuzawa H, Ouhara K, Yamada S et al. Innate defenses against methicillin-resistant Staphylococcus aureus (MRSA) infection. J. Pathol.208, 249–260 (2006).
  • Maisetta G, Batoni G, Esin S et al.in vitro bactericidal activity of human β-defensin 3 against multidrug-resistant nosocomial strains. Antimicrob. Agents Chemother.50, 806–809 (2006).
  • Jenssen H, Hamill P, Hancock RE. Peptide antimicrobial agents. Clin. Microbiol. Rev.19, 491–511 (2006).
  • Lehrer RI, Barton A, Daher KA et al. Interaction of human defensins with Escherichia coli: mechanism of bactericidal activity. J. Clin. Invest.84, 553–561 (1989).
  • Sahl H-G, Pag U, Bonness S et al. Mammalian defensins: structures and mechanism of antibiotic activity. J. Leukoc. Biol.77, 466–475 (2005).
  • Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors of bacteria? Nat. Rev. Micro.3, 238–250 (2005).
  • Yang D, Chertov OBSN, Chen Q et al. β-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science286, 525–528 (1999).
  • Andrès E, Dimarcq JL. Clinical development of antimicrobial peptides. Int. J. Antimicrob. Agents25, 448–449 (2005).
  • Reddy KV, Yedery RD, Aranha C. Antimicrobial peptides: premises and promises. Int. J. Antimicrob. Agents24, 536–547 (2004).
  • Hancock RE, Sahl H-G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol.24, 1551–1557 (2006).
  • Morgan JR, Barrandon Y, Green H, Mulligan RC. Expression of an exogenous growth hormone gene in transplantable human epidermal cells. Science.237, 1476–1479 (1987).
  • Fenjves ES. Approaches to gene transfer in keratinocytes. J. Invest. Dermatol.103, 70–75S (1994).
  • Chen BF, Chang WC, Chen ST, Chen DS, Hwang LH. Long-term expression of the biologically active growth hormone in genetically modified fibroblasts after implantation into a hypophysectomized rat. Hum. Gene Ther.6, 917–926 (1995).
  • Breitbart AS, Mason JM, Urmacher C et al. Gene-enhanced tissue engineering: applications for wound healing using cultured dermal fibroblasts transduced retrovirally with the PDGF-B gene. Ann. Plast. Surg.43, 632–639 (2002).
  • Supp DM, Supp AP, Morgan JR, Boyce ST. Genetic modification of cultured skin substitutes by transduction of human keratinocytes and fibroblasts with Platelet Derived Growth Factor-A. Wound Repair Regen.8, 26–35 (2000).
  • Yao F, Eriksson E. Gene therapy in wound repair and regeneration. Wound. Rep. Regen.8, 443–451 (2000).
  • Featherstone C, Uitto J. ex vivo gene therapy cures a blistering skin disease. Trends Mol. Med.13, 219–222 (2007).
  • Seitz CS, Giudice GJ, Balding SD, Marinkovich MP, Khavari PA. BP180 gene delivery in junctional epidermolysis bullosa. Gene Ther.6, 42–47 (1999).
  • Mavillo F, Pellegrini G, Ferrari S et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat. Med.12, 1397–1402 (2007).
  • Volpers C, Kochanek S. Adenoviral vectors for gene transfer and therapy. J. Gene Med.6, S164–S171 (2004).
  • Kuroki T, Kashiwagi M, Ishino K, Huh N-H, Ohba M. Adenovirus-mediated gene transfer to keratinocytes – a review. J. Invest. Dermatol. Symp. Proc.4, 153–157 (1999).
  • Supp DM, Supp AP, Bell SM, Boyce ST. Enhanced vascularization of cultured skin substitutes genetically modified to overexpress vascular endothelial growth factor. J. Invest. Dermatol.114, 5–13 (2000).
  • Supp DM, Boyce ST. Overexpression of vascular endothelial growth factor accelerates early vascularization and improves healing of genetically modified cultured skin substitutes. J. Burn Care Rehab.23, 10–20 (2002).
  • Eming SA, Medalie DA, Tompkins RG, Yarmush ML, Morgan JR. Genetically modified human keratinocytes overexpressing PDGF-A enhance the performance of a composite skin graft. Hum. Gene Ther.9, 529–539 (1998).
  • Hamoen KE, Morgan JR. Transient hyperproliferation of a transgenic human epidermis expressing hepatocyte growth factor. Cell Transplant11, 385–395 (2002).
  • Andreadis ST. Gene-modified tissue-engineered skin: the next generation of skin substitutes. Adv. Biochem. Eng. Biotechnol.103, 241–274 (2007).
  • Bals R, Weiner DJ, Moscioni AD, Meegalla RL, Wilson JM. Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide. Infect. Immun.67, 6084–6089 (1999).
  • Bals R, Weiner DJ, Meegalla RL, Wilson JM. Transfer of a cathelicidin peptide antibiotic gene restores bacterial killing in a cystic fibrosis xenograft model. J. Clin. Invest.103, 1113–1117 (1999).
  • Shu Q, Shi Z, Zhao Z et al. Protection against Pseudomonas aeruginosa pneumonia and sepsis-induced lung injury by overexpression of β-defensin-2 in rats. Shock26, 365–371 (2006).
  • Akinbi HT, Epaud R, Bhatt H, Weaver TE. Bacterial killing is enhanced by expression of lysozyme in the lungs of transgenic mice. J. Immunol.165, 5760–5766 (2000).
  • Jacobsen F, Mittler D, Hirsch T et al. 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, 1494–1502 (2005).
  • Huang GT-J, Zhang H-BKD, Liu L, Ganz T. A model for antimicrobial gene therapy: demonstration of human β-defensin 2 antimicrobial activities in vivo. Hum. Gene Ther.13, 2017–2025 (2002).
  • Sawamura D, Goto M, Shibaki A et al. β defensin-3 engineered epidermis shows highly protective effect for bacterial infection. Gene Ther.12, 857–861 (2005).
  • Smiley AK, Gardner J, Klingenberg JM, Neely AN, Supp DM. Expression of human β defensin 4 in genetically modified keratinocytes enhances antimicrobial activity. J. Burn Care Res.28, 127–132 (2006).
  • Yeaman MR, Yount NY. Mechanisms of antimicrobial peptide action and resistance. Pharmacol. Rev.55, 27–55 (2003).
  • Nahaie RR, Goodfellow M, Minken De Hajek V. Polar lipid and isoprenoid quinone composition in the classification of Staphylococcus. J. Gen. Microbiol.130, 2427–2437 (1984).
  • Peschel A, Sahl H-G. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat. Rev. Micro.4, 529–536 (2006).
  • Shafer WM, Qu XD, Waring AJ, Lehrer RI. Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family. Proc. Natl Acad. Sci. USA95, 1829–1833 (1998).
  • Gyurko C, Lendemenn U, Troxler RF. Candida albicans mutants deficient in respiration are resistant to the small cationic salivary antimicrobial peptide histatin 5. Antimicrob. Agents Chemother.44(2), 338–354 (2000).
  • Olofsson SK, Cars O. Optimizing drug exposure to minimize selection of antibiotic resistance. Clin. Infect. Dis.45, S129–S136 (2007).
  • Barak O, Treat JR, James WD. Antimicrobial peptides: effectors of innate immunity in the skin. Adv. Dermatol. 21, 357–374 (2005).
  • Fieguth A, Feldbrugge H, Gerich T, Kleemann WJ, Troger HD. The time-dependent expression of fibronectin, MRP8, MRP14 and defensin in surgically treated human skin wounds. Forensic Sci. Int.131, 156–161 (2003).
  • Nizet V. Antimicrobial peptide resistance mechanisms of human bacterial pathogens. Curr. Issues Mol. Biol.8, 223–238 (2006).
  • Harder J, Bartels J, Christophers E, Schroder J-M. A peptide antibiotic from human skin. Nature387, 861–(1997).
  • Ong PY, Ohtake T, Brandt C et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med.347, 1151–1160 (2002).
  • Ortega MR, Ganz T, Milner SM. Human β defensin is absent in burn blister fluid. Burns26, 724–726 (2000).
  • Philpott MP. Defensins and acne. Mol. Immunol.40, 457–462 (2003).
  • Chronnell CMT, Ghali LR, Ali RS et al. Human β defensin-1 and -2 expression in human pilosebaceous units: upregulation in acne vulgaris lesions. J. Invest. Dermatol.117, 1120–1125 (2001).
  • Yan H, Hancock RE. Synergistic interactions between mammalian antimicrobial defense peptides. Antimicrob. Agents Chemother.45, 1558–1560 (2001).
  • Chen X, Niyonsaba F, Ushio H et al. Synergistic effect of antibacterial agents human β-defensins, cathelicidin LL-37 and lysozyme against Staphylococcus aureus and Escherichia coli. J. Dermatol. Sci.40, 123–132 (2005).
  • Giacometti A, Cirioni O, Barchiesi F, Fortuna M, Scalise G. In-vitro activity of cationic peptides alone and in combination with clinically used antimicrobial agents against Pseudomonas aeruginosa. J. Antimicrob. Chemother.44, 641–645 (1999).
  • Levy SB. Multidrug resistance – a sign of the times. N. Engl. J. Med.338, 1376–1378 (1998).
  • Power E. Impact of antibiotic restrictions: the pharmaceutical perspective. Clin. Microbiol. Infect.12, 25–34 (2006).
  • Luzhetskyy A, Pelzer S, Bechthold A. The future of natural products as a source of new antibiotics. Curr. Opin. Investig. Drugs8, 608–613 (2007).
  • Margolis DJ, Crombleholme TM, Herlyn M. Clinical protocol: Phase I trial to evaluate the safety of H5.020CMV.PDGF-B for the treatment of a diabetic insensate foot ulcer. Wound Rep. Reg.8, 480–493 (2000).
  • Margolis DJ, Crombleholme TM, Herlyn M et al. Clinical protocol. Phase I trial to evaluate the safety of H5.020CMV.PDGF-B and limb compression bandage for the treatment of venous leg ulcer: trial A. Hum. Gene Ther.15, 1003–1019 (2004).

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