Abstract
Congenital diaphragmatic hernia (CDH) causes severe pulmonary hypoplasia from herniation of abdominal contents into the thorax. Tracheal occlusion (TO) for human CDH improves survival, but morbidity and mortality remain high, and we do not fully understand the cellular pathways and processes most severely impacted by CDH and TO. We created a left diaphragmatic hernia (DH) in rabbit fetuses with subsequent TO and collected left lung sections for NextGen mRNA sequencing. DH, TO, and DHTO fetuses had comparable body and organ growth to control except for lower lung weights in DH (p<0.05). Of 13,687 expressed genes, DHTO had 687 differentially expressed genes compared to DH, but no other group-group comparison had more than 10. Considering genes in combination, many of the genes reduced in DH were more highly expressed in DHTO than in control. Benchmarking fetal rabbit lung gene expression to published lung development data, both DH and DHTO lungs were more highly correlated with the gene expression of immature lung. DNA synthesis was upregulated in DHTO compared to DH and ribosome and protein synthesis pathways were downregulated. DH reduced total and epithelial cell proliferation by half and two-thirds respectively, and DHTO increased proliferation by 2.5 and 3.4-fold respectively. Signaling pathways downregulated by DH and upregulated in DHTO were epidermal growth factor receptor signaling, ephrin signaling, and cell migration; however, levels of ephrin and EGFR signaling in DHTO exceeded that of control. Identification and inhibition of the ligands responsible for this dysregulated signaling could improve lung development in CDH.
Highlights
Congenital diaphragmatic hernia (CDH) occurs in approximately 1 in 3,000 births with half of these defects being severe and the majority involving the left diaphragm [1]
Fetal Rabbit CDH Model Fetal rabbit and fetal human lung development are comparable [28], and surgical creation of a diaphragmatic hernia during the pseudoglandular stage of lung development (E25) induces changes comparable to those seen in human
Reverses increased protein biosynthetic and reduced cell proliferation activity in CDH lung. The reversal of these genes and pathways exceeds gene expression and pathway activity levels of control lung. Many of these findings can be explained by increased epidermal growth factor receptor (EGFR) and ephrin signaling in DHTO lung
Summary
Congenital diaphragmatic hernia (CDH) occurs in approximately 1 in 3,000 births with half of these defects being severe and the majority involving the left diaphragm [1]. The first reports of TO for human CDH suggested improved survival and outcomes [4]. While TO for CDH may gain more widespread acceptance in the coming years, there remains an urgent need to understand the cellular responses to CDH and TO so that targeted therapies may be developed to improve fetal lung development and to limit any undesirable effects of TO. There have been reports of how CDH and TO impact lung matrix synthesis [6,7,8,9], lung epithelial function and surfactant [10,11,12,13] and microvascular development [14,15,16], and that tracheal occlusion reverses some of RESEARCH ARTICLE the gene expression changes induced by diaphragmatic hernia [17].
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