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Eur Respir J 2007, doi:10.1183/09031936.00080806
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ORIGINAL ARTICLE |
Release of the antimicrobial LL37 peptide from DNA/F-actin bundles in CF sputum
1 Dept of Physiology and the Institute for Medicine and Engineering, University of Pennsylvania, 1010 Vagelos Research Laboratories, 3340 Smith Walk, Philadelphia, PA, 19104 U.S.A
* To whom correspondence should be addressed. E-mail: buckirob{at}mail.med.upenn.edu.
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Abstract |
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Cationic antibacterial peptides (ABPs) are secreted in airways and function in the first line of defense against infectious agents. They attack multiple molecular targets to cooperatively penetrate and disrupt microbial surfaces and membrane barriers. Antibacterial properties of ABPs including cathelicidin LL37 are reduced in cystic fibrosis (CF) airways as a result of direct interaction with DNA and F-actin. Microscopic evaluation of a mixed solution of DNA and F-actin after addition of rhodamine B-labeled LL37 peptide reveals the presence of a bundle structure similar to that present in CF sputum. Analysis of CF sputum after centrifugation shows that LL37 is mostly bound to components of the pellet fraction containing DNA, F-actin and cell remnants. Factors that dissolve actin/DNA bundles and fluidize CF sputum such as Dornase alfa (rhDNase I), gelsolin, poly-aspartate or their combinations increase the amount of LL37 peptide detected in the supernatant of CF sputum. The presence of bacterial endotoxin (LPS) in CF sputum and the ability of LPS to inhibit the antibacterial activity of LL37 suggest that inactivation of LL37 function in CF sputum partially results from its interaction with LPS. LL37-LPS interaction was prevented by a lipopolysaccharide-binding protein (LBP)-derived peptide known for its ability to neutralize LPS, whereas LBPW91A a mutant peptide that lacks ability to bind LPS had no effect. A combination of factors that dissolve DNA/F-actin aggregates together with LPS-binding agents may represent a potential for the treatment of chronic infections that occur in CF airways.
Keywords: Cystic fibrosis, gelsolin, LL37 peptide, LPS, poly-Aspartate, rhDNase I
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