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The Metabolic and Lipidomic Profiling of the Effects of Tracheal Occlusion in a Rabbit Model of Congenital Diaphragmatic Hernia

      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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