A novel host defense system of airways is defective in cystic fibrosis

The respiratory tract is constantly exposed to airborne microorganisms. Nevertheless, normal airways remain sterile without recruiting phagocytes. This innate immune activity has been attributed to mucociliary clearance and antimicrobial polypeptides of airway surface liquid. Defective airway immuni...

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Veröffentlicht in:	American journal of respiratory and critical care medicine Jg. 175; H. 2; S. 174 - 183
Hauptverfasser:	Moskwa, Patryk, Lorentzen, Daniel, Excoffon, Katherine J D A, Zabner, Joseph, McCray, Jr, Paul B, Nauseef, William M, Dupuy, Corinne, Bánfi, Botond
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Thoracic Society 15.01.2007
Schlagworte:	Acids Animals Bacteria Cattle Cells, Cultured Cystic fibrosis Cystic Fibrosis - enzymology Cystic Fibrosis - immunology Cystic Fibrosis - microbiology D. Cystic Fibrosis Dual Oxidases Enzymes Flavoproteins - analysis Flavoproteins - genetics Flavoproteins - metabolism Humans Hydrogen Peroxide - metabolism Immunity, Innate - genetics Immunity, Mucosal Lactoperoxidase - analysis Lactoperoxidase - genetics Lactoperoxidase - metabolism Lung Diseases - enzymology Lung Diseases - immunology Lung Diseases - microbiology Mutation Polypeptides Pseudomonas aeruginosa - immunology Rats Reactive Oxygen Species - metabolism Respiratory Mucosa - enzymology Respiratory Mucosa - immunology Respiratory Mucosa - microbiology RNA, Small Interfering - pharmacology Staphylococcus aureus - immunology Thiocyanates - metabolism Trachea - cytology Trachea - immunology Trachea - microbiology
ISSN:	1073-449X, 1535-4970
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Zusammenfassung:	The respiratory tract is constantly exposed to airborne microorganisms. Nevertheless, normal airways remain sterile without recruiting phagocytes. This innate immune activity has been attributed to mucociliary clearance and antimicrobial polypeptides of airway surface liquid. Defective airway immunity characterizes cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator, a chloride channel. The pathophysiology of defective immunity in CF remains to be elucidated. We investigated the ability of non-CF and CF airway epithelia to kill bacteria through the generation of reactive oxygen species (ROS). ROS production and ROS-mediated bactericidal activity were determined on the apical surfaces of human and rat airway epithelia and on cow tracheal explants. Dual oxidase enzyme of airway epithelial cells generated sufficient H(2)O(2) to support production of bactericidal hypothiocyanite (OSCN(-)) in the presence of airway surface liquid components lactoperoxidase and thiocyanate (SCN(-)). This OSCN(-) formation eliminated Staphylococcus aureus and Pseudomonas aeruginosa on airway mucosal surfaces, whereas it was nontoxic to the host. In contrast to normal epithelia, CF epithelia failed to secrete SCN(-), thereby rendering the oxidative antimicrobial system inactive. These data indicate a novel innate defense mechanism of airways that kills bacteria via ROS and suggest a new cellular and molecular basis for defective airway immunity in CF.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Originally Published in Press as DOI: 10.1164/rccm.200607-1029OC on November 2, 2006 This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Correspondence and requests for reprints should be addressed to Botond Bánfi, M.D., Ph.D., Inflammation Program, University of Iowa, 2501 Crosspark Road, Coralville, IA 52241. E-mail: botond-banfi@uiowa.edu Supported by grants from the Carver College of Medicine (B.B.) and from the Cystic Fibrosis Foundation (R458-CR02) (B.B.). Human airway epithelial cells were provided by the In Vitro Models and Cell Culture Core of the University of Iowa funded by the Center for Gene Therapy for Cystic Fibrosis (NIH P30 DK-54759, John Englehardt) and the Cystic Fibrosis Foundation.
ISSN:	1073-449X 1535-4970
DOI:	10.1164/rccm.200607-1029OC