Dissecting the fetal development of cystic fibrosis tracheal abnormalities

Abstract

Cystic fibrosis (CF) is a genetic condition that leads to chronic lung disease, the principal cause of mortality. It had been presumed that CF neonatal lungs are normal at birth, but we recently showed that tracheas from human infants and pigs with CF have structural defects including reduced caliber and circularity. To identify primary and secondary features related to development of these changes we studied fetal tracheas (d82‐83 gestational age, ~70% of gestation) from non‐CF and CF pigs. CF trachea lumen circumference and area were reduced (P<0.001 each), while trachea circularity was similar to non‐CF fetal pigs. Trachealis smooth muscle area (normalized to trachea size) was similar between groups, but fetal CF pigs had higher incidence of altered smooth muscle bundles (P<0.001). We examined the submucosal glands, which were composed of uncommon ducts invading from the surface epithelium into the subjacent tissue with a lack of acinus differentiation. Unlike hypoplastic submucosal glands seen in newborn CF pigs, fetal CF pig submucosal gland area (normalized to trachea size) was similar to non‐CF fetal pigs. Our results suggest that fetal CF pig trachea has structural defects including altered smooth muscle morphology, but submucosal glands are not likely a primary contributor to these CF tracheal defects. Earlier fetal studies are needed to better address the pathogenesis of tracheal abnormalities in CF.