DELETION OF AIRWAY CILIA RESULTS IN NON-INFLAMMATORY

35 The mechanisms for the development of bronchiectasis and airway hyperreactivity have not been 36 fully elucidated. Although genetic, acquired diseases, and environmental influences may play a 37 role, it is also possible that motile cilia can influence this disease process. We hypothesized that 38 deletion of a key intraflagellar transport molecule, IFT88, in mature mice causes loss of cilia 39 resulting in airway remodeling. Airway cilia were deleted by knockout of IFT88 and airway 40 remodeling and pulmonary function were evaluated. In IFT88(-) mice there was a substantial 41 loss of airway cilia on respiratory epithelium. Three months after the deletion of cilia, there was 42 clear evidence for bronchial remodeling that was not associated with inflammation or apparent 43 defects in mucus clearance. There was evidence for airway epithelial cell hypertrophy and 44 hyperplasia. IFT88(-) mice exhibited increased airway reactivity to a methacholine challenge, 45 and decreased ciliary beat frequency in the few remaining cells that possessed cilia. With 46 deletion of respiratory cilia there was a marked increase in the number of Clara cells as seen by 47 scanning electron microscopy. We suggest that airway remodeling may be exacerbated by the 48 presence of Clara cells, since these cells are involved in airway repair. Clara cells may be 49 prevented from differentiating into respiratory epithelial cells due to a lack of IFT88 protein that 50 is necessary to form a single non-motile cilium. This monocilium is a prerequisite for these 51 progenitor cells to transition into respiratory epithelial cells. In conclusion, motile cilia may play 52 an important role in controlling airway structure and function. 53