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dc.contributor.authorHalldorsson, Skarphedinn
dc.contributor.authorGudjonsson, Thorarinn
dc.contributor.authorGottfredsson, Magnus
dc.contributor.authorSingh, Pradeep K
dc.contributor.authorGudmundsson, Gudmundur Hrafn
dc.contributor.authorBaldursson, Olafur
dc.date.accessioned2010-01-26T10:55:13Z
dc.date.available2010-01-26T10:55:13Z
dc.date.issued2010-01-01
dc.date.submitted2010-01-26
dc.identifier.citationAm. J. Respir. Cell Mol. Biol. 2010, 42(1):62-8en
dc.identifier.issn1535-4989
dc.identifier.pmid19372247
dc.identifier.doi10.1165/rcmb.2008-0357OC
dc.identifier.urihttp://hdl.handle.net/2336/90614
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractTight junctions (TJs) play a key role in maintaining bronchial epithelial integrity, including apical-basolateral polarity and paracellular trafficking. Patients with chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) often suffer from chronic infections by the opportunistic Gram-negative bacterium Pseudomonas aeruginosa, which produces multiple virulence factors, including rhamnolipids. The macrolide antibiotic azithromycin (azm) has been shown to improve lung function in patients with CF without reducing the bacterial count within the lung. However, the mechanism of this effect is still debated. It has previously been shown that azm increased transepithelial electrical resistance (TER) in a bronchial epithelial cell line. In this study we used an air-liquid interface model of human airway epithelia and measured TER, changes in TJ expression and architecture after exposure to live P. aeruginosa PAO1, and PAO1-Deltarhl which is a PAO1 mutant lacking rhlA and rhlB, which encode key enzymes for rhamnolipid production. In addition, the cells were challenged with bacterial culture medium conditioned by these strains, purified rhamnolipids, or synthetic 3O-C(12)-HSL. Virulence factors secreted by P. aeruginosa reduced TER and caused TJ rearrangement in the bronchial epithelium, exposing the epithelium to further bacterial infiltration. Pretreatment of the bronchial epithelium with azm attenuated this effect and facilitated epithelial recovery. These data suggest that azm protects the bronchial epithelium during P. aeruginosa infection independent of antimicrobial activity, and could explain in part the beneficial results seen in clinical trials of patients with CF.
dc.language.isoenen
dc.publisherAmerican Thoracic Societyen
dc.relation.urlhttp://dx.doi.org/10.1165/rcmb.2008-0357OCen
dc.subject.meshActinsen
dc.subject.meshAnti-Bacterial Agentsen
dc.subject.meshAzithromycinen
dc.subject.meshBronchien
dc.subject.meshCell Lineen
dc.subject.meshCystic Fibrosisen
dc.subject.meshCytoskeletonen
dc.subject.meshEpithelial Cellsen
dc.subject.meshHumansen
dc.subject.meshLipidsen
dc.subject.meshMicroscopy, Confocalen
dc.subject.meshMutationen
dc.subject.meshPseudomonas Infectionsen
dc.subject.meshPseudomonas aeruginosaen
dc.subject.meshTight Junctionsen
dc.subject.meshVirulence Factorsen
dc.titleAzithromycin maintains airway epithelial integrity during Pseudomonas aeruginosa infectionen
dc.typeArticleen
dc.contributor.departmentInstitute of Biology, Biomedical Center, University of Iceland, Landspitali, Eiriksgata 5, Reykjavik, Iceland.en
dc.identifier.journalAmerican journal of respiratory cell and molecular biologyen
html.description.abstractTight junctions (TJs) play a key role in maintaining bronchial epithelial integrity, including apical-basolateral polarity and paracellular trafficking. Patients with chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) often suffer from chronic infections by the opportunistic Gram-negative bacterium Pseudomonas aeruginosa, which produces multiple virulence factors, including rhamnolipids. The macrolide antibiotic azithromycin (azm) has been shown to improve lung function in patients with CF without reducing the bacterial count within the lung. However, the mechanism of this effect is still debated. It has previously been shown that azm increased transepithelial electrical resistance (TER) in a bronchial epithelial cell line. In this study we used an air-liquid interface model of human airway epithelia and measured TER, changes in TJ expression and architecture after exposure to live P. aeruginosa PAO1, and PAO1-Deltarhl which is a PAO1 mutant lacking rhlA and rhlB, which encode key enzymes for rhamnolipid production. In addition, the cells were challenged with bacterial culture medium conditioned by these strains, purified rhamnolipids, or synthetic 3O-C(12)-HSL. Virulence factors secreted by P. aeruginosa reduced TER and caused TJ rearrangement in the bronchial epithelium, exposing the epithelium to further bacterial infiltration. Pretreatment of the bronchial epithelium with azm attenuated this effect and facilitated epithelial recovery. These data suggest that azm protects the bronchial epithelium during P. aeruginosa infection independent of antimicrobial activity, and could explain in part the beneficial results seen in clinical trials of patients with CF.


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