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* Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland; and
Department of Respiratory Medicine and
Department of Clinical Microbiology, Adelaide and Meath Hospital, Incorporating the National Children Hospital, Tallaght, Dublin, Ireland
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Irish Research Council for Science, Engineering and Technology (Embark Initiative), the National Childrens Hospital CF Research Fund, the Cystic Fibrosis Research Trust, the Cystic Fibrosis Hope Source, the Cystic Fibrosis Association of Ireland, the Health Research Board of Ireland and the Program for Research in Third Level Institutes administered by higher education authorities.
2 Address correspondence and reprint requests to Dr. Gudmundur Bergsson, Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, P.O. Box 9063, Dublin, Ireland. E-mail address: bergsson{at}here.is
3 Abbreviations used in this paper: SLPI, secretory leucoprotease inhibitor; hCAP18, human cathelicidin precursor protein designated 18-kDa cationic antimicrobial protein; CF, cystic fibrosis; GAG, glycosaminoglycan; BAL, bronchoalveolar lavage; CMK, N-(methoxysuccinyl)-Ala-Ala-Pro-Val-chloromethyl ketone; ACT, antichymotrypsin; A1AT, 
-1-antitrypsin; DPBS, Dulbecco’s PBS; CFU, colony forming unit.
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