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Published ahead of print on November 2, 2006, doi:10.1164/rccm.200607-1029OC

Am. J. Respir. Crit. Care Med., Volume 175, Number 2, January 2007, 174-183

A more recent version of this article appeared on January 15, 2007
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Submitted on July 26, 2006
Accepted on November 2, 2006

A Novel Host Defense System of Airways is Defective in Cystic Fibrosis

Patryk Moskwa1, Daniel Lorentzen1, Katherine J. D. A. Excoffon2, Joseph Zabner2, Paul B McCray Jr.3, William M Nauseef4, Corinne Dupuy5, and Botond Banfi6*

1 Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Inflammation Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA, 2 Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA, 3 Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA, 4 Inflammation Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Department of Veteran Affairs, Iowa City VA Medical Center, Iowa City, Iowa, USA, 5 Unite 486 INSERM, Faculte de Pharmacie, Universite Paris, Paris, France, 6 Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Inflammation Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA

* To whom correspondence should be addressed. E-mail: botond-banfi{at}uiowa.edu.

Rationale: 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 CFTR, a chloride channel. However, the pathophysiology of defective immunity in CF remains to be elucidated. Objective: We investigated the ability of non-CF and CF airway epithelia to kill bacteria through the generation of reactive oxygen species (ROS). Methods: ROS production and ROS-mediated bactericidal activity were determined on the apical surfaces of human and rat airway epithelia as well as on cow tracheal explants. Measurements and Main Results: Dual oxidase enzyme of airway epithelial cells generated sufficient H2O2 to support production of bactericidal OSCN- in the presence of airway surface liquid components lactoperoxidase and SCN-. This OSCN- formation eliminated Staphylococcus aureus and Pseudomonas aeruginosa on airway mucosal surfaces, whereas it was non-toxic to the host. In contrast to normal epithelia, CF epithelia failed to secrete SCN-, thereby rendering the oxidative antimicrobial system inactive. Conclusions: 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.
Key words: innate immunity, airway infection, Duox, reactive oxygen species




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