Highlights
- •What is currently known about this topic?
Congenital diaphragmatic hernia (CDH) is a life-threatening condition with a mortality
rate of 20%. The primary cause of death is respiratory failure due to severe pulmonary
hypoplasia and pulmonary hypertension. However, the pathophysiology of CDH remains
poorly understood.
- 2.What new information is contained in this article?
Within a rabbit model, we were able to highlight certain cellular mechanisms, including
different lipids and other metabolites, that may be critical metabolic drivers in
disease pathology and recovery of CDH.
Summary
Purpose
Fetal tracheal occlusion (TO) reverses the pulmonary hypoplasia associated with congenital
diaphragmatic hernia (CDH), but its mechanism of action remains poorly understood.
‘Omic’ readouts capture metabolic and lipid processing function, which aid in understanding
CDH and TO metabolic mechanisms.
Methods
CDH was created in fetal rabbits at 23 days, TO at 28 days and lung collection at
31 days (Term∼32 days). Lung-body weight ratio (LBWR) and mean terminal bronchiole
density (MTBD) were determined. In a cohort, left and right lungs were collected,
weighed, and samples homogenized, and extracts collected for non-targeted metabolomic
and lipidomic profiling via LC-MS and LC-MS/MS, respectively.
Results
LBWR was significantly lower in CDH while CDH+TO was similar to controls (p=0.003).
MTBD was significantly higher in CDH fetuses and restored to control and sham levels
in CDH+TO (p<0.001). CDH and CDH+TO resulted in significant differences in metabolome
and lipidome profiles compared to sham controls. A significant number of altered metabolites
and lipids between the controls and CDH groups and the CDH and CDH+TO fetuses were
identified. Significant changes in the ubiquinone and other terpenoid-quinone biosynthesis
pathway and the tyrosine metabolism pathway were observed in CDH+TO.
Conclusion
CDH+TO reverses pulmonary hypoplasia in the CDH rabbit, in association with a specific
metabolic and lipid signature. A synergistic untargeted ‘omics’ approach provides
a global signature for CDH and CDH+TO, highlighting cellular mechanisms among lipids
and other metabolites, enabling comprehensive network analysis to identify critical
metabolic drivers in disease pathology and recovery.
Keywords
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Article info
Publication history
Accepted:
January 10,
2023
Received:
January 10,
2023
Publication stage
In Press Accepted ManuscriptIdentification
Copyright
© 2023 Published by Elsevier Inc.
