title: Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways.
abstract: The mechanisms for the development of bronchiectasis and airway hyperreactivity have not been fully elucidated. Although genetic, acquired diseases and environmental influences may play a role, it is also possible that motile cilia can influence this disease process. We hypothesized that deletion of a key intraflagellar transport molecule, IFT88, in mature mice causes loss of cilia, resulting in airway remodeling. Airway cilia were deleted by knockout of IFT88, and airway remodeling and pulmonary function were evaluated. In IFT88(-) mice there was a substantial loss of airway cilia on respiratory epithelium. Three months after the deletion of cilia, there was clear evidence for bronchial remodeling that was not associated with inflammation or apparent defects in mucus clearance. There was evidence for airway epithelial cell hypertrophy and hyperplasia. IFT88(-) mice exhibited increased airway reactivity to a methacholine challenge and decreased ciliary beat frequency in the few remaining cells that possessed cilia. With deletion of respiratory cilia there was a marked increase in the number of club cells as seen by scanning electron microscopy. We suggest that airway remodeling may be exacerbated by the presence of club cells, since these cells are involved in airway repair. Club cells may be prevented from differentiating into respiratory epithelial cells because of a lack of IFT88 protein that is necessary to form a single nonmotile cilium. This monocilium is a prerequisite for these progenitor cells to transition into respiratory epithelial cells. In conclusion, motile cilia may play an important role in controlling airway structure and function.
authors.affiliation: 70 President St, DDB520, MUSC, Charleston, SC 29425. Bellpd@musc.edu.
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Gilley
authors.forename: Antine E
authors.initials: AE
authors.lastname: Stenbit
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Pasek
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Sas
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Steele
authors.forename: May
authors.initials: M
authors.lastname: Amria
authors.forename: Marlene A
authors.initials: MA
authors.lastname: Bunni
authors.forename: Kimberly P
authors.initials: KP
authors.lastname: Estell
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Schwiebert
authors.forename: Patrick
authors.initials: P
authors.lastname: Flume
authors.forename: Monika
authors.initials: M
authors.lastname: Gooz
authors.forename: Courtney J
authors.initials: CJ
authors.lastname: Haycraft
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Yoder
authors.forename: Caroline
authors.initials: C
authors.lastname: Miller
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Pavlik
authors.forename: Grant A
authors.initials: GA
authors.lastname: Turner
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Sisson
authors.forename: P Darwin
authors.initials: PD
authors.lastname: Bell
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000473:pathology* / Q000503:physiopathology; D001987:Bronchiectasis / Q000473:pathology* / Q000503:physiopathology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002923:Cilia / Q000473:pathology* / Q000502:physiology*; D002925:Ciliary Motility Disorders / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009079:Mucociliary Clearance / Q000502:physiology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D016085:Bronchoconstrictor Agents; C490898:Tg737Rpw protein, mouse; D025521:Tumor Suppressor Proteins; D016210:Methacholine Chloride
keywords: bronchiectasis; hyperreactivity; lung; respiratory