Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 49, Issue 6, Pages 935-942Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2013-0106OC
Keywords
cystic fibrosis; midkine; Pseudomonas aeruginosa; host defense
Funding
- Swedish Research Council [2010-4224]
- Swedish Heart and Lung Foundation [20100164]
- Medical Faculty of Lund University
- Swedish Government
- Bergh Foundation
- Greta and Johan Kock Foundation
- Alfred Osterlund Foundation
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Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in impaired host defense during cystic fibrosis (CF), where Pseudomonas aeruginosa becomes a key pathogen. We investigated the expression pattern of the antibacterial growth factor midkine (MK) in CF and the possible interference with its activity by the altered airway microenvironment. High MK expression was found in CF lung tissue compared with control samples, involving epithelia of the large and small airways, alveoli, and cells of the submucosa (i.e., neutrophils and mast cells). In CF sputum, MK was present at 100-fold higher levels, but was also subject to increased degradation, compared with MK in sputum from healthy control subjects. MK exerted a bactericidal effect on P. aeruginosa, but increasing salt concentrations and low pH impaired this activity. Molecular modeling suggested that the effects of salt and pH were attributable to electrostatic screening and a charge-neutralization of the membrane, respectively. Both the neutrophil elastase and elastase of P. aeruginosa cleaved MK to smaller fragments, resulting in impaired bactericidal activity. Thus, MK is highly expressed in CF, but its bactericidal properties may be impaired by the altered microenvironment, as reflected by the in vitro conditions used in this study.
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