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National Institute of Environmental Health Sciences

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Publication Detail

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; Zhou, Su; Morrisey, Edward E

Published In Am J Respir Crit Care Med, (2018 May 15)

Abstract: RATIONALE: 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. OBJECTIVES: To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions. METHODS: 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). MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

PubMed ID: 29328793 Exiting the NIEHS site

MeSH Terms: Cystic Adenomatoid Malformation of Lung, Congenital/genetics*; Cystic Adenomatoid Malformation of Lung, Congenital/surgery*; Female; Genetic Predisposition to Disease*; Humans; Infant; Infant, Newborn; Lung/physiopathology*; Male; Pennsylvania; Phenotype; Respiratory System Abnormalities/genetics*; Respiratory System Abnormalities/surgery*

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