The human cathelicidin antimicrobial peptide LL-37 as a potential treatment for polymicrobial infected wounds

Frontiers in Immunology

Volumn 4, Issue JUL, 2013, Pages

  Duplantier, Allen J ^a   van Hoek, Monique L ^a  

^a GEORGE MASON UNIVERSITY   (United States)

Author keywords

Antimicrobial peptide; Biofilm; Cathelicidin; Chronic wounds; Infected wounds

Indexed keywords

BRILACIDIN; CATHELICIDIN ANTIMICROBIAL PEPTIDE LL 37; LACTOFERRIN; LIPOPOLYSACCHARIDE; OMIGANAN; PROTEINASE; TOLL LIKE RECEPTOR 4;

ANTIBACTERIAL ACTIVITY; ANTIMICROBIAL ACTIVITY; APOPTOSIS; BACTERIAL MEMBRANE; BIOFILM; CLINICAL TRIAL (TOPIC); DIABETES MELLITUS; DRUG SENSITIVITY; FOOT ULCER; GALLERIA MELLONELLA; GRAM NEGATIVE BACTERIUM; GRAM POSITIVE BACTERIUM; HOST CELL; HUMAN; INFECTION; LEG AMPUTATION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; POLYACRYLAMIDE GEL ELECTROPHORESIS; PROTEIN EXPRESSION; PROTEIN STRUCTURE; PSEUDOMONAS AERUGINOSA; PSEUDOMONAS INFECTION; REVIEW; STAPHYLOCOCCUS AUREUS; STAPHYLOCOCCUS INFECTION; WOUND HEALING; WOUND INFECTION;

EID: 84883688534     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2013.00143     Document Type: Review

References (114)

1. Abee, T., Kovács, A. T., Kuipers, O. P., and van der Veen, S. (2011). Biofilm formation and dispersal in Gram-positive bacteria. Curr. Opin. Biotechnol. 22, 172-179. doi:10.1016/j.copbio.2010.10.016
2. Amer, L. S., Bishop, B. M., and van Hoek, M. L. (2010). Antimicrobial and antibiofilm activity of cathelicidins and short, synthetic peptides against Francisella. Biochem. Biophys. Res. Commun. 396, 246-251. doi:10.1016/j.bbrc.2010.04.073
3. Ammons, M. C. (2010). Anti-biofilm strategies and the need for innovations in wound care. Recent Pat. Antiinfect. Drug. Discov. 5, 10-17. doi:10.2174/157489110790112581
4. Ammons, M. C., Ward, L. S., Dowd, S., and James, G. A. (2011). Combined treatment of Pseudomonas aeruginosa biofilm with lactoferrin and xylitol inhibits the ability of bacteria to respond to damage resulting from lactoferrin iron chelation. Int. J. Antimicrob. Agents 37, 316-323. doi:10.1016/j.ijantimicag.2010.12.019
5. Ammons, M. C., Ward, L. S., Fisher, S. T., Wolcott, R. D., and James, G. A. (2009). In vitro susceptibility of established biofilms composed of a clinical wound isolate of Pseudomonas aeruginosa treated with lactoferrin and xylitol. Int. J. Antimicrob. Agents 33, 230-236. doi:10.1016/j.ijantimicag.2008.08.013
6. Bals, R. (2000). Epithelial antimicrobial peptides in host defense against infection. Respir. Res. 1, 141-150. doi:10.1186/rr25
7. Baranska-Rybak, W., Sonesson, A., Nowicki, R., and Schmidtchen, A. (2006). Glycosaminoglycans inhibit the antibacterial activity of LL-37 in biological fluids. J. Antimicrob. Chemother. 57, 260-265. doi:10.1093/jac/dki460
8. Bowdish, D. M., Davidson, D. J., Speert, D. P., and Hancock, R. E. (2004). The human cationic peptide LL-37 induces activation of the extracellular signal-regulated kinase and p38 kinase pathways in primary human monocytes. J. Immunol. 172, 3758-3765.
9. Braff, M. H., Zaiou, M., Fierer, J., Nizet, V., and Gallo, R. L. (2005). Keratinocyte production of cathelicidin provides direct activity against bacterial skin pathogens. Infect. Immun. 73, 6771-6781. doi:10.1128/IAI.73.10.6771-6781.2005
10. Brandenburg, L.-O., Merres, J., Albrecht, L.-J., Varoga, D., and Pufe, T. (2012). Antimicrobial peptides: multifunctional drugs for different applications. Polymers 4, 539-560. doi:10.3390/polym4010539
11. Brogden, K. A. (2005). Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat. Rev. Microbiol. 3, 238-250. doi:10.1038/nrmicro1098
12. Brown, K. V., Murray, C. K., and Clasper, J. C. (2010). Infectious complications of combat-related mangled extremity injuries in the British military. J. Trauma 69 (Suppl. 1), S109-S115. doi:10.1097/TA.0b013e3181e4b33d
13. Burton, M. F., and Steel, P. G. (2009). The chemistry and biology of LL-37. Nat. Prod. Rep. 26, 1572-1584. doi:10.1039/b912533g
14. Carretero, M., Escámez, M. J., García, M., Duarte, B., Holguín, A., Retamosa, L., et al. (2008). In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37. J. Invest. Dermatol. 128, 223-236. doi:10.1038/sj.jid.5701043
15. Chalekson, C. P., Neumeister, M. W., and Jaynes, J. (2002). Improvement in burn wound infection and survival with antimicrobial peptide D2A21 (Demegel). Plast. Reconstr. Surg. 109, 1338-1343. doi:10.1097/00006534-200204010-00020
16. Chamorro, C. I., Weber, G., Grönberg, A., Pivarcsi, A., and StÅhle, M. (2009). The human antimicrobial peptide LL-37 suppresses apoptosis in keratinocytes. J. Invest. Dermatol. 129, 937-944. doi:10.1038/jid.2008.321
17. Chang, T. W., Lin, Y. M., Wang, C. F., and Liao, Y. D. (2012). Outer membrane lipoprotein Lpp is Gram-negative bacterial cell surface receptor for cationic antimicrobial peptides. J. Biol. Chem. 287, 418-428. doi:10.1074/jbc. M111.290361
18. Ciornei, C. D., Sigurdardóttir, T., Schmidtchen, A., and 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, 2845-2850. doi:10.1128/AAC.49.7.2845-2850.2005
19. Coenye, T. (2010). Response of sessile cells to stress: from changes in gene expression to phenotypic adaptation. FEMS Immunol. Med. Microbiol. 59, 239-252. doi:10.1111/j.1574-695X.2010.00682.x
20. Costerton, J. W., Lewandowski, Z., Caldwell, D. E., Korber, D. R., and Lappin-Scott, H. M. (1995). Microbial biofilms. Annu. Rev. Microbiol. 49, 711-745. doi:10.1146/annurev.mi.49.100195.003431
21. Davies, D. G., and Marques, C. N. (2009). A fatty acid messenger is responsible for inducing dispersion in microbial biofilms. J. Bacteriol. 191, 1393-1403. doi:10.1128/JB.01214-08
22. de Latour, F. A., Amer, L. S., Papanstasiou, E. A., Bishop, B. M., and van Hoek, M. L. (2010). Antimicrobial activity of the Naja atra cathelicidin and related small peptides. Biochem. Biophys. Res. Commun. 396, 825-830. doi:10.1016/j.bbrc.2010.04.158
23. Dean, S. N., Bishop, B. M., and van Hoek, M. L. (2011a). Susceptibility of Pseudomonas aeruginosa biofilm to alpha-helical peptides: D-enantiomer of LL-37. Front. Microbiol. 2:128. doi:10.3389/fmicb.2011.00128
24. Dean, S. N., Bishop, B. M., and van Hoek, M. L. (2011b). Natural and synthetic cathelicidin peptides with anti-microbial and anti-biofilm activity against Staphylococcus aureus. BMC Microbiol. 11:114. doi:10.1186/1471-2180-11-114
25. Development Program LL-37. (2012). Available at: http://www.pergamum.com/ll-37/development/
26. Dowd, S. E., Sun, Y., Secor, P. R., Rhoads, D. D., Wolcott, B. M., James, G. A., et al. (2008). Survey of bacterial diversity in chronic wounds using pyrosequencing, DGGE, and full ribosome shotgun sequencing. BMC Microbiol. 8:43. doi:10.1186/1471-2180-8-43
27. Dowd, S. E., Sun, Y., Smith, E., Kennedy, J. P., Jones, C. E., and Wolcott, R. (2009). Effects of biofilm treatments on the multi-species Lubbock chronic wound biofilm model. J. Wound Care 18, 508.
28. Durr, U. H., Sudheendra, U. S., and Ramamoorthy, A. (2006). LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim. Biophys. Acta 1758, 1408-1425. doi:10.1016/j.bbamem.2006.03.030
29. Edwards, R., and Harding, K. G. (2004). Bacteria and wound healing. Curr. Opin. Infect. Dis. 17, 91-96. doi:10.1097/00001432-200404000-00004
30. Eissa, A., Amodeo, V., Smith, C. R., and Diamandis, E. P. (2011). Kallikrein-related peptidase-8 (KLK8) is an active serine protease in human epidermis and sweat and is involved in a skin barrier proteolytic cascade. J. Biol. Chem. 286, 687-706. doi:10.1074/jbc. M110.125310
31. Elssner, A., Duncan, M., Gavrilin, M., and Wewers, M. D. (2004). A novel P2×7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release. J. Immunol. 172, 4987-4994.
32. Fisher, T. K., Wolcott, R., Wolk, D. M., Bharara, M., Kimbriel, H. R., and Armstrong, D. G. (2010). Diabetic foot infections: a need for innovative assessments. Int. J. Low. Extrem. Wounds 9, 31-36. doi:10.1177/1534734610363459
33. Flemming, K., Klingenberg, C., Cavanagh, J. P., Sletteng, M., Stensen, W., Svendsen, J. S., et al. (2009). High in vitro antimicrobial activity of synthetic antimicrobial peptidomimetics against staphylococcal biofilms. J. Antimicrob. Chemother. 63, 136-145. doi:10.1093/jac/dkn464
34. Girnita, A., Zheng, H., Grönberg, A., Girnita, L., and Ståhle, M. (2012). Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor. Oncogene 31, 352-365. doi:10.1038/onc.2011.239
35. Gronberg, A., Zettergren, L., and Agren, M. S. (2011). Stability of the cathelicidin peptide LL-37 in a non-healing wound environment. Acta Derm. Venereol. 91, 511-515. doi:10.2340/00015555-1102
36. Heilborn, J. D., Nilsson, M. F., Kratz, G., Weber, G., Sørensen, O., Borregaard, N., et al. (2003). The cathelicidin anti-microbial peptide LL-37 is involved in reepithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J. Invest. Dermatol. 120, 379-389. doi:10.1046/j.1523-1747.2003.12069.x
37. Hirsch, T., Spielmann, M., Zuhaili, B., Fossum, M., Metzig, M., Koehler, T., et al. (2009). Human beta-defensin-3 promotes wound healing in infected diabetic wounds. J. Gene Med. 11, 220-228. doi:10.1002/jgm.1287
38. Hoyer, J., Schatzschneider, U., Schulz-Siegmund, M., and Neundorf, I. (2012). Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery. Beilstein J. Org. Chem. 8, 1788-1797. doi:10.3762/bjoc.8.204
39. Hurdle, J. G., O'Neill, A. J., Chopra, I., and Lee, R. E. (2011). Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat. Rev. Microbiol. 9, 62-75. doi:10.1038/nrmicro2474
40. Isaksson, J., Brandsdal, B. O., Engqvist, M., Flaten, G. E., Svendsen, J. S., and Stensen, W. (2011). A synthetic antimicrobial peptidomimetic (LTX 109): stereochemical impact on membrane disruption. J. Med. Chem. 54, 5786-5795. doi:10.1021/jm200450h
41. Jacobsen, A. S., and Jenssen, H. (2012). Human cathelicidin LL-37 prevents bacterial biofilm formation. Future Med. Chem. 4, 1587-1599. doi:10.4155/fmc.12.97
42. James, G. A., Swogger, E., Wolcott, R., Pulcini, E. D., Secor, P., Sestrich, J., et al. (2008). Biofilms in chronic wounds. Wound Repair Regen. 16, 37-44. doi:10.1111/j.1524-475X.2007.00321.x
43. Jiang, Z., Higgins, M. P., Whitehurst, J., Kisich, K. O., Voskuil, M. I., and Hodges, R. S. (2011). Anti-tuberculosis activity of alpha-helical antimicrobial peptides: de novo designed L- and D-enantiomers versus L- and D-LL-37. Protein Pept. Lett. 18, 241-252. doi:10.2174/092986611794578288
44. Johansson, J., Gudmundsson, G. H., Rottenberg, M. E., Berndt, K. D., and Agerberth, B. (1998). Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37. J. Biol. Chem. 273, 3718-3724. doi:10.1074/jbc.273.6.3718
45. Johnson, E. N., Burns, T. C., Hayda, R. A., Hospenthal, D. R., and Murray, C. K. (2007). Infectious complications of open type III tibial fractures among combat casualties. Clin. Infect. Dis. 45, 409-415. doi:10.1086/520029
46. Kai-Larsen, Y., and Agerberth, B. (2008). The role of the multifunctional peptide LL-37 in host defense. Front. Biosci. 13, 3760-3767. doi:10.2741/2964
47. Kamiya, H., Ehara, T., and Matsumoto, T. (2012). Inhibitory effects of lactoferrin on biofilm formation in clinical isolates of Pseudomonas aeruginosa. J. Infect. Chemother. 18, 47-52. doi:10.1007/s10156-011-0287-1
48. Kanada, K. N., Nakatsuji, T., and Gallo, R. L. (2012). Doxycycline indirectly inhibits proteolytic activation of tryptic kallikrein-related peptidases and activation of cathelicidin. J. Invest. Dermatol. 132, 1435-1442. doi:10.1038/jid.2012.14
49. Kanthawong, S., Bolscher, J. G., Veerman, E. C., van Marle, J., de Soet, H. J., Nazmi, K., et al. (2012). Antimicrobial and antibiofilm activity of LL-37 and its truncated variants against Burkholderia pseudomallei. Int. J. Antimicrob. Agents 39, 39-44. doi:10.1016/j.ijantimicag.2011.09.010
50. Kiran, M. D., Adikesavan, N. V., Cirioni, O., Giacometti, A., Silvestri, C., Scalise, G., et al. (2008). Discovery of a quorum-sensing inhibitor of drug-resistant staphylococcal infections by structure-based virtual screening. Mol. Pharmacol. 73, 1578-1586. doi:10.1124/mol.107.044164
51. Lan, Y., Ye, Y., Kozlowska, J., Lam, J. K., Drake, A. F., and Mason, A. J. (2010). Structural contributions to the intracellular targeting strategies of antimicrobial peptides. Biochim. Biophys. Acta 1798, 1934-1943. doi:10.1016/j.bbamem.2010.07.003
52. Lippross, S., Klueter, T., Steubesand, N., Oestern, S., Mentlein, R., Hildebrandt, F., et al. (2012). Multiple trauma induces serum production of host defence peptides. Injury 43, 137-142. doi:10.1016/j.injury.2011.03.044
53. Lopez-Leban, F., Kiran, M. D., Wolcott, R., and Balaban, N. (2010). Molecular mechanisms of RIP, an effective inhibitor of chronic infections. Int. J. Artif. Organs 33, 582-589.
54. Madani, F., Lindberg, S., Langel, U., Futaki, S., and Gräslund, A. (2011). Mechanisms of cellular uptake of cell-penetrating peptides. J. Biophys. 2011, 414729. doi:10.1155/2011/414729
55. Marsh, E. N., Buer, B. C., and Ramamoorthy, A. (2009). Fluorine - a new element in the design of membrane-active peptides. Mol. Biosyst. 5, 1143-1147. doi:10.1039/b909864j
56. Mendez-Samperio, P. (2010). The human cathelicidin hCAP18/LL-37: a multifunctional peptide involved in mycobacterial infections. Peptides 31, 1791-1798. doi:10.1016/j.peptides.2010.06.016
57. Mikkelsen, H., Sivaneson, M., and Filloux, A. (2011). Key two-component regulatory systems that control biofilm formation in Pseudomonas aeruginosa. Environ. Microbiol. 13, 1666-1681. doi:10.1111/j.1462-2920.2011.02495.x
58. Monds, R. D., and O'Toole, G. A. (2009). The developmental model of microbial biofilms: ten years of a paradigm up for review. Trends Microbiol. 17, 73-87. doi:10.1016/j.tim.2008.11.001
59. Mookherjee, N., Brown, K. L., Bowdish, D. M., Doria, S., Falsafi, R., Hokamp, K., et al. (2006). Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J. Immunol. 176, 2455-2464.
60. Morrisey, I., Dallow, J., Siegwart, E., Smith, A., Scott, R., and Korczak, B. (2012). "The activity of PMX-30063 against staphylococci and streptococci," in 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), London, P1458.
61. Murray, C. K. (2008a). Infectious disease complications of combat-related injuries. Crit. Care Med. 36(Suppl. 7), S358-S364. doi:10.1097/CCM.0b013e31817e2ffc
62. Murray, C. K. (2008b). Epidemiology of infections associated with combat-related injuries in Iraq and Afghanistan. J. Trauma 64(Suppl. 3), S232-S238. doi:10.1097/TA.0b013e318163c3f5
63. Nagaoka, I., Hirota, S., Niyonsaba, F., Hirata, M., Adachi, Y., Tamura, H., et al. (2001). Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-alpha by blocking the binding of LPS to CD14(+) cells. J. Immunol. 167, 3329-3338.
64. Nagaoka, I., Tamura, H., and Hirata, M. (2006). An antimicrobial cathelicidin peptide, human CAP18/LL-37, suppresses neutrophil apoptosis via the activation of formyl-peptide receptor-like 1 and P2×7. J. Immunol. 176, 3044-3052.
65. Nell, M. J., Tjabringa, G. S., Wafelman, A. R., Verrijk, R., Hiemstra, P. S., Drijfhout, J. W., et al. (2006). Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application. Peptides 27, 649-660. doi:10.1016/j.peptides.2005.09.016
66. Nijnik, A., and Hancock, R. E. (2009). The roles of cathelicidin LL-37 in immune defences and novel clinical applications. Curr. Opin. Hematol. 16, 41-47. doi:10.1097/MOH.0b013e32831ac517
67. Nijnik, A., Pistolic, J., Filewod, N. C., and Hancock, R. E. (2012). Signaling pathways mediating chemokine induction in keratinocytes by cathelicidin LL-37 and flagellin. J. Innate Immun. 4, 377-386. doi:10.1159/000335901
68. Oudhoff, M. J., Blaauboer, M. E., Nazmi, K., Scheres, N., Bolscher, J. G., and Veerman, E. C. (2010). The role of salivary histatin and the human cathelicidin LL-37 in wound healing and innate immunity. Biol. Chem. 391, 541-548. doi:10.1515/BC.2010.057
69. Overhage, J., Campisano, A., Bains, M., Torfs, E. C., Rehm, B. H., and Hancock, R. E. (2008). Human host defense peptide LL-37 prevents bacterial biofilm formation. Infect. Immun. 76, 4176-4182. doi:10.1128/IAI.00318-08
70. Park, H. J., Cho, D. H., Kim, H. J., Lee, J. Y., Cho, B. K., Bang, S. I., et al. (2009). Collagen synthesis is suppressed in dermal fibroblasts by the human antimicrobial peptide LL-37. J. Invest. Dermatol. 129, 843-850. doi:10.1038/jid.2008.320
71. Petrova, O. E., and Sauer, K. (2012). Sticky situations: key components that control bacterial surface attachment. J. Bacteriol. 194, 2413-2425. doi:10.1128/JB.00003-12
72. Porcelli, F., Verardi, R., Shi, L., Henzler-Wildman, K. A., Ramamoorthy, A., and Veglia, G. (2008). NMR structure of the cathelicidin-derived human antimicrobial peptide LL-37 in dodecylphosphocholine micelles. Biochemistry 47, 5565-5572. doi:10.1021/bi702036s
73. Reinholz, M., Ruzicka, T., and Schauber, J. (2012). Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease. Ann. Dermatol. 24, 126-135. doi:10.5021/ad.2012.24.2.126
74. Ressner, R. A., Murray, C. K., Griffith, M. E., Rasnake, M. S., Hospenthal, D. R., Wolf, S. E., et al. (2008). Outcomes of bacteremia in burn patients involved in combat operations overseas. J. Am. Coll. Surg. 206, 439-444. doi:10.1016/j.jamcollsurg.2007.09.017
75. Rivas-Santiago, B., Trujillo, V., Montoya, A., Gonzalez-Curiel, I., Castañeda-Delgado, J., Cardenas, A., et al. (2012). Expression of antimicrobial peptides in diabetic foot ulcer. J. Dermatol. Sci. 65, 19-26. doi:10.1016/j.jdermsci.2011.09.013
76. Ross, J. E., Jones, R. N., Rhomberg, P. R., and Fritsche, T. R. (2007). "In vitro activity of omiganan pentahydrochloride against>1,600 clinical trial isolates," in 45th Infectious Diseases Society of America Annual Meeting, San Diego, CA, Abstr. 433.
77. Saiman, L., Tabibi, S., Starner, T. D., San Gabriel, P., Winokur, P. L., Jia, H. P., et al. (2001). Cathelicidin peptides inhibit multiply antibiotic-resistant pathogens from patients with cystic fibrosis. Antimicrob. Agents Chemother. 45, 2838-2844. doi:10.1128/AAC.45.10.2838-2844.2001
78. Schauber, J., Oda, Y., Büchau, A. S., Yun, Q. C., Steinmeyer, A., Zügel, U., et al. (2008). Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D3. J. Invest. Dermatol. 128, 816-824. doi:10.1038/sj.jid.5701102
79. Schiemann, F., Brandt, E., Gross, R., Lindner, B., Mittelstädt, J., Sommerhoff, C. P., et al. (2009). The cathelicidin LL-37 activates human mast cells and is degraded by mast cell tryptase: counter-regulation by CXCL4. J. Immunol. 183, 2223-2231. doi:10.4049/jimmunol.0803587
80. Schierle, C. F., De la Garza, M., Mustoe, T. A., and Galiano, R. D. (2009). Staphylococcal biofilms impair wound healing by delaying reepithelialization in a murine cutaneous wound model. Wound Repair Regen. 17, 354-359. doi:10.1111/j.1524-475X.2009.00489.x
81. Schittek, B., Paulmann, M., Senyürek, I., and Steffen, H. (2008). The role of antimicrobial peptides in human skin and in skin infectious diseases. Infect. Disord. Drug Targets 8, 135-143. doi:10.2174/1871526510808030135
82. Schmidtchen, A., Frick, I. M., Andersson, E., Tapper, H., and Björck, L. (2002). Proteinases of common pathogenic bacteria degrade and inactivate the antibacterial peptide LL-37. Mol. Microbiol. 46, 157-168. doi:10.1046/j.1365-2958.2002.03146.x
83. Scott, M. G., Vreugdenhil, A. C., Buurman, W. A., Hancock, R. E., and Gold, M. R. (2000). Cutting edge: cationic antimicrobial peptides block the binding of lipopolysaccharide (LPS) to LPS binding protein. J. Immunol. 164, 549-553.
84. Shaykhiev, R., Beisswenger, C., Kändler, K., Senske, J., Püchner, A., Damm, T., et al. (2005). Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure. Am. J. Physiol. Lung Cell Mol. Physiol. 289, L842-L848. doi:10.1152/ajplung.00286.2004
85. Shu, W., Liu, J., Ji, H., and Lu, M. (2000). Core structure of the outer membrane lipoprotein from Escherichia coli at 1.9 A resolution. J. Mol. Biol. 299, 1101-1112. doi:10.1006/jmbi.2000.3776
86. Sochacki, K. A., Barns, K. J., Bucki, R., and Weisshaar, J. C. (2011). Real-time attack on single Escherichia coli cells by the human antimicrobial peptide LL-37. Proc. Natl. Acad. Sci. U.S.A. 108, E77-E81. doi:10.1073/pnas.1101130108
87. Sørensen, O., Cowland, J. B., Askaa, J., and Borregaard, N. (1997). An ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma. J. Immunol. Methods 206, 53-59. doi:10.1016/S0022-1759(97)00084-7
88. Sørensen, O. E., Cowland, J. B., Theilgaard-Mönch, K., Liu, L., Ganz, T., and Borregaard, N. (2003). Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J. Immunol. 170, 5583-5589.
89. Sørensen, O. E., Follin, P., Johnsen, A. H., Calafat, J., Tjabringa, G. S., Hiemstra, P. S., et al. (2001). Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood 97, 3951-3959. doi:10.1182/blood. V97.12.3951
90. Subramanian, H., Gupta, K., Guo, Q., Price, R., and Ali, H. (2011). Mas-related gene X2 (MrgX2) is a novel G protein-coupled receptor for the antimicrobial peptide LL-37 in human mast cells: resistance to receptor phosphorylation, desensitization, and internalization. J. Biol. Chem. 286, 44739-44749. doi:10.1074/jbc. M111.277152
91. Sun, Y., Dowd, S. E., Smith, E., Rhoads, D. D., and Wolcott, R. D. (2008). In vitro multispecies Lubbock chronic wound biofilm model. Wound Repair Regen. 16, 805-813. doi:10.1111/j.1524-475X.2008.00434.x
92. Takeshima, K., Chikushi, A., Lee, K. K., Yonehara, S., and Matsuzaki, K. (2003). Translocation of analogues of the antimicrobial peptides magainin and buforin across human cell membranes. J. Biol. Chem. 278, 1310-1315. doi:10.1074/jbc. M208762200
93. Thoma-Uszynski, S., Stenger, S., Takeuchi, O., Ochoa, M. T., Engele, M., Sieling, P. A., et al. (2001). Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291, 1544-1547. doi:10.1126/science.291.5508.1544
94. Tokumaru, S., Sayama, K., Shirakata, Y., Komatsuzawa, H., Ouhara, K., Hanakawa, Y., et al. (2005). Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. J. Immunol. 175, 4662-4668.
95. Tomasinsig, L., Pizzirani, C., Skerlavaj, B., Pellegatti, P., Gulinelli, S., Tossi, A., et al. (2008). The human cathelicidin LL-37 modulates the activities of the P2×7 receptor in a structure-dependent manner. J. Biol. Chem. 283, 30471-30481. doi:10.1074/jbc. M802185200
96. Vandamme, D., Landuyt, B., Luyten, W., and Schoofs, L. (2012). A comprehensive summary of LL-37, the factotum human cathelicidin peptide. Cell. Immunol. 280, 22-35. doi:10.1016/j.cellimm.2012.11.009
97. Wang, G. (2008). Structures of human host defense cathelicidin LL-37 and its smallest antimicrobial peptide KR-12 in lipid micelles. J. Biol. Chem. 283, 32637-32643. doi:10.1074/jbc. M805533200
98. Wang, G., Li, X., and Wang, Z. (2009). APD2: the updated antimicrobial peptide database and its application in peptide design. Nucleic Acids Res. 37, D933-D937. doi:10.1093/nar/gkn823
99. Wewers, M. D., and Sarkar, A. (2009). P2X(7) receptor and macrophage function. Purinergic Signal. 5, 189-195. doi:10.1007/s11302-009-9131-9
100. Wolcott, R. D., Cox, S. B., and Dowd, S. E. (2010a). Healing and healing rates of chronic wounds in the age of molecular pathogen diagnostics. J. Wound Care 19, 272-278.
101. Wolcott, R. D., Rhoads, D. D., Bennett, M. E., Wolcott, B. M., Gogokhia, L., Costerton, J. W., et al. (2010b). Chronic wounds and the medical biofilm paradigm. J. Wound Care 19, 45-46.
102. Wolcott, R. D., Rumbaugh, K. P., James, G., Schultz, G., Phillips, P., Yang, Q., et al. (2010c). Biofilm maturity studies indicate sharp debridement opens a timedependent therapeutic window. J. Wound Care 19, 320-328.
103. Wolcott, R. D., Kennedy, J. P., and Dowd, S. E. (2009). Regular debridement is the main tool for maintaining a healthy wound bed in most chronic wounds. J. Wound Care 18, 54-56.
104. Wolcott, R. D., Lopez-Leban, F., and Kiran, M. D. (2011). "Wound Healing by an Anti-Staphylococcal Biofilm Approach," Biofilm Highlights, Chap. 7, eds H.-C. Flemming, J. Wingender, and U. Szewzyk (Berlin: Springer-Verlag), 141-161.
105. Wolcott, R. D., and Rhoads, D. D. (2008). A study of biofilm-based wound management in subjects with critical limb ischaemia. J. Wound Care 17, 145-148.
106. Wolcott, R. D., Rhoads, D. D., and Dowd, S. E. (2008). Biofilms and chronic wound inflammation. J. Wound Care 17, 333-341.
107. Yamasaki, K., Schauber, J., Coda, A., Lin, H., Dorschner, R. A., Schechter, N. M., et al. (2006). Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J. 20, 2068-2080. doi:10.1096/fj.06-6075com
108. Yang, D., Chen, Q., Schmidt, A. P., Anderson, G. M., Wang, J. M., Wooters, J., 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, 1069-1074. doi:10.1084/jem.192.7.1069
109. Yeaman, M. R., and Yount, N. Y. (2003). Mechanisms of antimicrobial peptide action and resistance. Pharmacol. Rev. 55, 27-55. doi:10.1124/pr.55.1.2
110. Yoshioka, M., Fukuishi, N., Kubo, Y., Yamanobe, H., Ohsaki, K., Kawasoe, Y., et al. (2008). Human cathelicidin CAP18/LL-37 changes mast cell function toward innate immunity. Biol. Pharm. Bull. 31, 212-216. doi:10.1248/bpb.31.212
111. Zaiou, M., Nizet, V., and Gallo, R. L. (2003). Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. J. Invest. Dermatol. 120, 810-816. doi:10.1046/j.1523-1747.2003.12132.x
112. Zasloff, M. (2002). Antimicrobial peptides of multicellular organisms. Nature 415, 389-395. doi:10.1038/415389a
113. Zhang, X., Oglecka, K., Sandgren, S., Belting, M., and Esbjörner, E. K. (2010). Dual functions of the human antimicrobial peptide LL-37-target membrane perturbation and host cell cargo delivery. Biochim. Biophys. Acta 1798, 2201-2208. doi:10.1016/j.bbamem.2009.12.011
114. Zhang, Z., Cherryholmes, G., Chang, F., Rose, D. M., Schraufstatter, I., and Shively, J. E. (2009). Evidence that cathelicidin peptide LL-37 may act as a functional ligand for CXCR2 on human neutrophils. Eur. J. Immunol. 39, 3181-3194. doi:10.1002/eji.200939496