LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline.

Hdl Handle:
http://hdl.handle.net/10147/127461
Title:
LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline.
Authors:
Bergsson, Gudmundur; Reeves, Emer P; McNally, Paul; Chotirmall, Sanjay H; Greene, Catherine M; Greally, Peter; Murphy, Philip; O'Neill, Shane J; McElvaney, Noel G
Affiliation:
Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland. bergsson@here.is
Citation:
LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline. 2009, 183 (1):543-51 J. Immunol.
Journal:
Journal of immunology (Baltimore, Md. : 1950)
Issue Date:
1-Jul-2009
URI:
http://hdl.handle.net/10147/127461
DOI:
10.4049/jimmunol.0803959
PubMed ID:
19542465
Additional Links:
http://www.jimmunol.org/content/183/1/543.full.pdf+html
Abstract:
There is an abundance of antimicrobial peptides in cystic fibrosis (CF) lungs. Despite this, individuals with CF are susceptible to microbial colonization and infection. In this study, we investigated the antimicrobial response within the CF lung, focusing on the human cathelicidin LL-37. We demonstrate the presence of the LL-37 precursor, human cathelicidin precursor protein designated 18-kDa cationic antimicrobial protein, in the CF lung along with evidence that it is processed to active LL-37 by proteinase-3. We demonstrate that despite supranormal levels of LL-37, the lung fluid from CF patients exhibits no demonstrable antimicrobial activity. Furthermore Pseudomonas killing by physiological concentrations of exogenous LL-37 is inhibited by CF bronchoalveolar lavage (BAL) fluid due to proteolytic degradation of LL-37 by neutrophil elastase and cathepsin D. The endogenous LL-37 in CF BAL fluid is protected from this proteolysis by interactions with glycosaminoglycans, but while this protects LL-37 from proteolysis it results in inactivation of LL-37 antimicrobial activity. By digesting glycosaminoglycans in CF BAL fluid, endogenous LL-37 is liberated and the antimicrobial properties of CF BAL fluid restored. High sodium concentrations also liberate LL-37 in CF BAL fluid in vitro. This is also seen in vivo in CF sputum where LL-37 is complexed to glycosaminoglycans but is liberated following nebulized hypertonic saline resulting in increased antimicrobial effect. These data suggest glycosaminoglycan-LL-37 complexes to be potential therapeutic targets. Factors that disrupt glycosaminoglycan-LL-37 aggregates promote the antimicrobial effects of LL-37 with the caveat that concomitant administration of antiproteases may be needed to protect the now liberated LL-37 from proteolytic cleavage.
Item Type:
Article
Language:
en
MeSH:
Adjuvants, Immunologic; Adolescent; Antibody Specificity; Antimicrobial Cationic Peptides; Cathepsin D; Child; Cystic Fibrosis; Glycosaminoglycans; Humans; Hydrolysis; Leukocyte Elastase; Lung; Macromolecular Substances; Molecular Weight; Myeloblastin; Nebulizers and Vaporizers; Protein Precursors; Protein Processing, Post-Translational; Saline Solution, Hypertonic; Solubility; Sputum
ISSN:
1550-6606

Full metadata record

DC FieldValue Language
dc.contributor.authorBergsson, Gudmunduren
dc.contributor.authorReeves, Emer Pen
dc.contributor.authorMcNally, Paulen
dc.contributor.authorChotirmall, Sanjay Hen
dc.contributor.authorGreene, Catherine Men
dc.contributor.authorGreally, Peteren
dc.contributor.authorMurphy, Philipen
dc.contributor.authorO'Neill, Shane Jen
dc.contributor.authorMcElvaney, Noel Gen
dc.date.accessioned2011-04-06T14:49:11Z-
dc.date.available2011-04-06T14:49:11Z-
dc.date.issued2009-07-01-
dc.identifier.citationLL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline. 2009, 183 (1):543-51 J. Immunol.en
dc.identifier.issn1550-6606-
dc.identifier.pmid19542465-
dc.identifier.doi10.4049/jimmunol.0803959-
dc.identifier.urihttp://hdl.handle.net/10147/127461-
dc.description.abstractThere is an abundance of antimicrobial peptides in cystic fibrosis (CF) lungs. Despite this, individuals with CF are susceptible to microbial colonization and infection. In this study, we investigated the antimicrobial response within the CF lung, focusing on the human cathelicidin LL-37. We demonstrate the presence of the LL-37 precursor, human cathelicidin precursor protein designated 18-kDa cationic antimicrobial protein, in the CF lung along with evidence that it is processed to active LL-37 by proteinase-3. We demonstrate that despite supranormal levels of LL-37, the lung fluid from CF patients exhibits no demonstrable antimicrobial activity. Furthermore Pseudomonas killing by physiological concentrations of exogenous LL-37 is inhibited by CF bronchoalveolar lavage (BAL) fluid due to proteolytic degradation of LL-37 by neutrophil elastase and cathepsin D. The endogenous LL-37 in CF BAL fluid is protected from this proteolysis by interactions with glycosaminoglycans, but while this protects LL-37 from proteolysis it results in inactivation of LL-37 antimicrobial activity. By digesting glycosaminoglycans in CF BAL fluid, endogenous LL-37 is liberated and the antimicrobial properties of CF BAL fluid restored. High sodium concentrations also liberate LL-37 in CF BAL fluid in vitro. This is also seen in vivo in CF sputum where LL-37 is complexed to glycosaminoglycans but is liberated following nebulized hypertonic saline resulting in increased antimicrobial effect. These data suggest glycosaminoglycan-LL-37 complexes to be potential therapeutic targets. Factors that disrupt glycosaminoglycan-LL-37 aggregates promote the antimicrobial effects of LL-37 with the caveat that concomitant administration of antiproteases may be needed to protect the now liberated LL-37 from proteolytic cleavage.-
dc.language.isoenen
dc.relation.urlhttp://www.jimmunol.org/content/183/1/543.full.pdf+htmlen
dc.subject.meshAdjuvants, Immunologic-
dc.subject.meshAdolescent-
dc.subject.meshAntibody Specificity-
dc.subject.meshAntimicrobial Cationic Peptides-
dc.subject.meshCathepsin D-
dc.subject.meshChild-
dc.subject.meshCystic Fibrosis-
dc.subject.meshGlycosaminoglycans-
dc.subject.meshHumans-
dc.subject.meshHydrolysis-
dc.subject.meshLeukocyte Elastase-
dc.subject.meshLung-
dc.subject.meshMacromolecular Substances-
dc.subject.meshMolecular Weight-
dc.subject.meshMyeloblastin-
dc.subject.meshNebulizers and Vaporizers-
dc.subject.meshProtein Precursors-
dc.subject.meshProtein Processing, Post-Translational-
dc.subject.meshSaline Solution, Hypertonic-
dc.subject.meshSolubility-
dc.subject.meshSputum-
dc.titleLL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland. bergsson@here.isen
dc.identifier.journalJournal of immunology (Baltimore, Md. : 1950)en
dc.description.provinceLeinster-

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