Amanda R. Smith

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 whether 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 retrospectively 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 controls. 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 submucosal 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 lacked 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.

Lung structure phenotype variation in inbred mouse strains revealed through in vivo micro-CT imaging

Within pulmonary research, the development of mouse models has provided insight into disease development, progression, and treatment. Structural phenotypes of the lung in healthy inbred mouse strains are necessary for comparison to disease models. To date, progress in the assessment of lung function in these small animals using whole lung function tests has been made. However, assessment of in vivo lung structure of inbred mouse strains has yet to be well defined. Therefore, the link between the structure and function phenotypes is still unclear. With advancements in small animal imaging it is now possible to investigate lung structures such as the central and peripheral airways, whole lung, and lobar volumes of mice in vivo, through the use of micro-CT imaging. In this study, we performed in vivo micro-CT imaging of the C57BL/6, A/J, and BALB/c mouse strains using the intermittent iso-pressure breath hold (IIBH) technique. The resulting high-resolution images were used to extract lung structure phenotypes. The three-dimensional lobar structures and airways were defined and a meaningful mouse airway nomenclature was developed. In addition, using these techniques we have uncovered significant differences in the airway structures between inbred mouse strains in vivo.