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- Title
Novel Molecular and Phenotypic Insights into Congenital Lung Malformations.
- Authors
Swarr, Daniel T.; Peranteau, William H.; Pogoriler, Jennifer; Frank, David B.; Adzick, N. Scott; Hedrick, Holly L.; Morley, Mike; Su Zhou; Morrisey, Edward E.; Zhou, Su
- Abstract
<bold>Rationale: </bold>Disruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects, as they are often surgically resected.<bold>Objectives: </bold>To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions.<bold>Methods: </bold>Clinical data, and lung tissue for DNA, RNA, and histology, were obtained from 58 infants undergoing surgical resection of a congenital lung lesion. Transcriptome-wide gene expression analysis was performed on paired affected and unaffected samples from a subset of infants (n = 14). A three-dimensional organoid culture model was used to assess isolated congenital lung malformation epithelium (n = 3).<bold>Measurements and Main Results: </bold>Congenital lung lesions express higher levels of airway epithelial related genes, and dysregulated expression of genes related to the Ras and PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) signaling pathways. Immunofluorescence confirmed differentiated airway epithelial cell types throughout all major subtypes of congenital lung lesions, and three-dimensional cell culture demonstrated a cell-autonomous defect in the epithelium of these lesions.<bold>Conclusions: </bold>This study provides the first comprehensive analysis of the congenital lung malformation transcriptome and suggests that disruptions in Ras or PI3K-AKT-mTOR signaling may contribute to the pathology through an epithelial cell-autonomous defect.
- Subjects
PENNSYLVANIA; RESEARCH; LUNGS; RESEARCH methodology; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; RESPIRATORY organ abnormalities; DISEASE susceptibility; RESEARCH funding; LUNG abnormalities; PHENOTYPES
- Publication
American Journal of Respiratory & Critical Care Medicine, 2018, Vol 197, Issue 10, p1328
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201706-1243OC