Loss of Cystic Fibrosis Transmembrane Conductance Regulator Function Produces Abnormalities in Tracheal Development in Neonatal Pigs and Young Children

Rationale Although airway abnormalities are common in patients with cystic fibrosis (CF) it is unknown whether they are all secondary to postnatal infection and inflammation, which characterize the disease Objectives To learn whet her loss of the cystic fibrosis transmembrane conductance regulator (CFTR) might affect major airways early in life, before the onset of inflammation and infection Methods We studied newborn CFTR-/- pig trachea, using computed tomography (CT) scans, pathology, and morphometry We retro spectively analyzed trachea CT scans in young children with CF and also previously published data of infants with CF Measurements and Main Results We discovered three abnormalities in the porcine CF trachea First, the trachea and mainstem bronchi had a uniformly small caliber and cross sections of trachea were less circular than in control Second, trachealis smooth muscle had an altered bundle orientation and increased transcripts in a smooth muscle gene set Third, submucosal gland units occurred with similar frequency in the mucosa of CF and control airways, but CF sub mucosal glands were hypoplastic and had global reductions in tissue specific transcripts To learn whether any of these changes occurred in young patients with CF, we examined CT scans from children 2 years of age and younger and found that CF tracheas were less circular in cross section, but laeked differences in lumen area However, analysis of previously published morphometric data showed reduced tracheal lumen area in neonates with CF Conclusions Our findings in newborn CF pigs and young patients with CF suggest that airway changes begin during fetal life and may contribute to CF pathogenesis and clinical disease during postnatal life