Type

Journal Article

Authors

Noel G McElvaney
Shane J O'Neill
Philip Murphy
Peter Greally
Catherine M Greene
Sanjay H Chotirmall
Paul McNally
Emer P Reeves
Gudmundur Bergsson

Subjects

Microbiology

Topics
hydrolysis leukocyte elastase antimicrobial cationic peptides sputum pharmacology antagonists inhibitors adjuvants immunologic physiology saline solution hypertonic child solubility protein processing post translational cap18 lipopolysaccharide binding protein microbiology cathepsin d lung glycosaminoglycans antibody specificity humans molecular weight nebulizers and vaporizers cystic fibrosis adolescent immunology protein precursors administration dosage metabolism macromolecular substances enzymology myeloblastin

LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline. (2009)

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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Noel G McElvaney, Shane J O'Neill, Philip Murphy, Peter Greally, Catherine M Greene, Sanjay H Chotirmall, Paul McNally, Emer P Reeves, Gudmundur Bergsson

Experts in our system

1
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 194
 
2
Shane J O'Neill
Royal College of Surgeons in Ireland
Total Publications: 84
 
3
Philip Murphy
TU Dublin (Tallaght Campus)
Total Publications: 30
 
4
Peter Greally
TU Dublin (Tallaght Campus)
Total Publications: 30
 
5
Catherine M Greene
Royal College of Surgeons in Ireland
Total Publications: 150
 
6
Sanjay H Chotirmall
Royal College of Surgeons in Ireland
Total Publications: 22
 
7
Paul McNally
Royal College of Surgeons in Ireland
Total Publications: 26
 
8
Emer P Reeves
Royal College of Surgeons in Ireland
Total Publications: 63