title: Stability of the cathelicidin peptide LL-37 in a non-healing wound environment.
abstract: The endogenous cathelicidin peptide LL-37 is strongly expressed at the wound edge early in the process of acute wound healing, but only weakly expressed in chronic wounds. Excessive proteolysis may limit the therapeutic usefulness of exogenous LL-37, especially in ulcers colonized with Pseudomonas aeruginosa that produce elastase, which degrades LL-37. This study investigated the stability of synthetic LL-37 against two types of proteinases in the presence or absence of wound fluid samples (diluted to 10-20%) from nine non-healing venous leg ulcers. Incubation of LL-37 (10 µg/ml) at 37°C for 6 h resulted in complete degradation by the serine proteinase trypsin (≥ 10 ng/ml), while no degradation was observed with matrix metalloproteinase-9. LL-37 susceptibility to trypsin was diminished considerably in the presence of wound fluid, and there was no apparent cleavage of exogenous LL-37 incubated in wound fluid for up to 24 h at 37°C even when using fluids from ulcers with resident P. aeruginosa (n = 2). In conclusion, LL-37 was degraded by trypsin, but not by matrix metalloproteinase-9, and was fairly resistant to proteolytic cleavage ex vivo by incubation with wound fluid from non-healing venous leg ulcers. Thus, the proteolytic environment of chronic wounds does not seem to prevent the therapeutic use of topical LL-37.
authors.affiliation: Lipopeptide AB, Stockholm, Sweden. alvar.gronberg@ki.se
authors.forename: Alvar
authors.initials: A
authors.lastname: Grönberg
authors.forename: Louise
authors.initials: L
authors.lastname: Zettergren
authors.forename: Magnus S
authors.initials: MS
authors.lastname: Agren
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism* / Q000627:therapeutic use; D004355:Drug Stability; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism; D014647:Varicose Ulcer / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D014945:Wound Healing; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D019272:Leukocyte Elastase; D014357:Trypsin; D020780:Matrix Metalloproteinase 9; D054804:Cathelicidins