先天性膈疝兔模型中气管阻塞影响的代谢组学和脂质组学分析

The metabolic and lipidomic profiling of the effects of tracheal occlusion in a rabbit model of congenital diaphragmatic hernia.

作者信息

Easton Zachary E, Regnault Timothy R H, Mudri Martina, Zhao Shuang, Smith Shane A, Zardini Buzatto Adrianna, Li Janet, Duruisseau-Kuntz Ryan, Davidson Jacob, Li Liang, Bütter Andreana

机构信息

Department of Obstetrics and Gynaecology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada; Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.

Department of Obstetrics and Gynaecology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada; Lawson Health Research Institute and Children's Health Research Institute, London, ON, Canada; Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.

出版信息

J Pediatr Surg. 2023 May;58(5):971-980. doi: 10.1016/j.jpedsurg.2023.01.040. Epub 2023 Jan 23.

DOI:10.1016/j.jpedsurg.2023.01.040

PMID:36801071

Abstract

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.

TYPE OF STUDY

Basic Science, Prospective.

LEVEL OF EVIDENCE

II.

摘要

目的

胎儿气管闭塞（TO）可逆转与先天性膈疝（CDH）相关的肺发育不全，但其作用机制仍知之甚少。“组学”读数可捕捉代谢和脂质加工功能，有助于理解CDH和TO的代谢机制。

方法

在23日龄的胎兔中制造CDH，28日龄时进行TO，31日龄时收集肺组织（足月约32日龄）。测定肺体重比（LBWR）和平均终末细支气管密度（MTBD）。在一组实验中，收集左肺和右肺，称重，将样本匀浆，并分别通过液相色谱-质谱联用（LC-MS）和液相色谱-串联质谱联用（LC-MS/MS）收集提取物，用于非靶向代谢组学和脂质组学分析。

结果

CDH组的LBWR显著降低，而CDH + TO组与对照组相似（p = 0.003）。CDH胎儿的MTBD显著升高，而CDH + TO组恢复到对照组和假手术组水平（p < 0.001）。与假手术对照组相比，CDH组和CDH + TO组的代谢组和脂质组谱存在显著差异。在对照组与CDH组以及CDH组与CDH + TO组胎儿之间，鉴定出大量改变的代谢物和脂质。在CDH + TO组中，观察到泛醌和其他萜类醌生物合成途径以及酪氨酸代谢途径有显著变化。