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Novel Molecular and Phenotypic Insights into Congenital Lung Malformations
- Source :
- American journal of respiratory and critical care medicine. 197(10)
- Publication Year :
- 2018
-
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.
- Subjects :
- Lung Diseases
0301 basic medicine
Pulmonary and Respiratory Medicine
Male
Pathology
medicine.medical_specialty
Critical Care and Intensive Care Medicine
03 medical and health sciences
0302 clinical medicine
Branching morphogenesis
Cystic Adenomatoid Malformation of Lung, Congenital
Medicine
Humans
Genetic Predisposition to Disease
Lung
business.industry
Molecular pathogenesis
Infant, Newborn
Congenital pulmonary airway malformation
Infant
Original Articles
Pennsylvania
medicine.disease
Phenotype
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Female
Respiratory System Abnormalities
business
Subjects
Details
- ISSN :
- 15354970
- Volume :
- 197
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- American journal of respiratory and critical care medicine
- Accession number :
- edsair.doi.dedup.....809bed60f89977a9c88738f5800e8e98