Romero-Lopez Maria Del Mar, Oria Marc, Watanabe-Chailland Miki, Varela Maria Florencia, Romick-Rosendale Lindsey, Peiro Jose L
Center for Fetal and Placental Research, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH 45229, USA.
Perinatal Institute, Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Metabolites. 2021 Mar 18;11(3):177. doi: 10.3390/metabo11030177.
Congenital diaphragmatic hernia (CDH) is characterized by the herniation of abdominal contents into the thoracic cavity during the fetal period. This competition for fetal thoracic space results in lung hypoplasia and vascular maldevelopment that can generate severe pulmonary hypertension (PH). The detailed mechanisms of CDH pathogenesis are yet to be understood. Acknowledgment of the lung metabolism during the in-utero CDH development can help to discern the CDH pathophysiology changes. Timed-pregnant dams received nitrofen or vehicle (olive oil) on E9.5 day of gestation. All fetal lungs exposed to nitrofen or vehicle control were harvested at day E21.5 by C-section and processed for metabolomics analysis using nuclear magnetic resonance (NMR) spectroscopy. The three groups analyzed were nitrofen-CDH (NCDH), nitrofen-control (NC), and vehicle control (VC). A total of 64 metabolites were quantified and subjected to statistical analysis. The multivariate analysis identified forty-four metabolites that were statistically different between the three groups. The highest Variable importance in projection (VIP) score (>2) metabolites were lactate, glutamate, and adenosine 5'-triphosphate (ATP). Fetal CDH lungs have changes related to oxidative stress, nucleotide synthesis, amino acid metabolism, glycerophospholipid metabolism, and glucose metabolism. This work provides new insights into the molecular mechanisms behind the CDH pathophysiology and can explore potential novel treatment targets for CDH patients.
先天性膈疝（CDH）的特征是在胎儿期腹腔内容物疝入胸腔。这种对胎儿胸腔空间的竞争导致肺发育不全和血管发育异常，进而引发严重的肺动脉高压（PH）。CDH发病机制的详细情况尚不清楚。了解子宫内CDH发育过程中的肺代谢有助于识别CDH病理生理学变化。在妊娠第9.5天，给定时怀孕的母鼠给予硝呋烯腙或赋形剂（橄榄油）。在妊娠第21.5天通过剖宫产收集所有暴露于硝呋烯腙或赋形剂对照的胎儿肺，并使用核磁共振（NMR）光谱进行代谢组学分析。分析的三组分别是硝呋烯腙诱导的CDH组（NCDH）、硝呋烯腙对照组（NC）和赋形剂对照组（VC）。总共对64种代谢物进行了定量并进行统计分析。多变量分析确定了44种在三组之间存在统计学差异的代谢物。投影变量重要性（VIP）得分最高（>2）的代谢物是乳酸、谷氨酸和三磷酸腺苷（ATP）。胎儿CDH肺存在与氧化应激、核苷酸合成、氨基酸代谢、甘油磷脂代谢和葡萄糖代谢相关的变化。这项工作为CDH病理生理学背后的分子机制提供了新的见解，并可为CDH患者探索潜在的新治疗靶点。
