Lack of CFTR in a cystic fibrosis pig model disrupts airway smooth muscle development

Abstract

To better understand the pathogenesis of cystic fibrosis (CF) lung disease, we recently generated CFTR‐targeted pigs. CF pigs develop lung disease typical of human CF. An unexpected finding at birth, prior to the onset of infection and inflammation, was that CF tracheas have a reduced lumen area, irregularly developed airway cartilage, and airway smooth muscle (ASM) with prominent appearing bundles. We hypothesized that these abnormal‐appearing ASM bundles were due to differences in ASM proliferation. To test this hypothesis, tracheas were harvested at birth for histological examination. Despite a reduction in tracheal ASM area in CF, we found that ASM cell density was increased in CF (CF: 0.52±0.06 vs. non‐CF: 0.39±0.02 cells/100 μm2). To investigate if cell proliferation was increased in CF, we stained for the proliferation marker Ki‐67 and found reduced Ki‐67 positive cells in CF (CF: 0.04%±0.01 vs. non‐CF: 0.1%±0.01). This decrease was associated with a reduction in CF ASM cell area (197±19 vs. 259±14 μm2). Finally, electron microscopic studies revealed that at birth CF ASM has a contracted appearance, likely accounting for the reduced cell area. These data suggest that CFTR is important in ASM development and might explain, in part, the increased incidence of airway hyper‐responsiveness in human CF.This work was supported, in part, by the American Asthma Foundation (Sandler).