Division of Histology and Embryology, International Joint Laboratory for Embryonic Development & Prenatal Medicine, Medical College, Jinan University, Guangzhou, China.
Department of Pathology, The First People's Hospital of Foshan, Foshan, China.
Am J Respir Cell Mol Biol. 2023 Aug;69(2):197-209. doi: 10.1165/rcmb.2022-0345OC.
Accumulating evidence has shown that hyperglycemia during pregnancy negatively affects lung development. However, the pathological mechanism of lung dysplasia caused by hyperglycemia remains unclear. In this study, we demonstrated the phenotypes of the impaired lung epithelial cell differentiation of mouse lungs in pregestational diabetes mellitus (PGDM) and gestational diabetes mellitus (GDM), and increased levels of oxidative stress and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways occurred. Nrf2 deficiency during pregnancy led to the aforementioned similar and aggravated phenotypes of the poor saccular process as in diabetes, implying the Nrf2 signaling pathway played a very important role in both physiological and pathological conditions. Based on RNA sequencing and luciferase reporter gene analysis, we revealed that Nrf2 could regulate Wnt signaling by targeting Ctnnd2. In summary, we revealed the pathological mechanism of how diabetes affected late lung development during embryogenesis, especially elucidating the bilateral roles of Nrf2-mediated oxidative stress responses and Wnt signaling. This finding also indicated that Nrf2 could potentially be used in preventing or treating pulmonary anomalies induced by hyperglycemia during pregnancy.
越来越多的证据表明，妊娠期间的高血糖会对肺发育产生负面影响。然而，高血糖引起肺发育不良的病理机制仍不清楚。在这项研究中，我们展示了孕前糖尿病（PGDM）和妊娠期糖尿病（GDM）小鼠肺部受损的肺上皮细胞分化表型，以及氧化应激水平的增加和核因子红细胞 2 相关因子 2（Nrf2）信号通路的激活。妊娠期间 Nrf2 缺乏导致了糖尿病中类似的和加重的小泡过程不良表型，表明 Nrf2 信号通路在生理和病理条件下都起着非常重要的作用。基于 RNA 测序和荧光素酶报告基因分析，我们揭示了 Nrf2 可以通过靶向 Ctnnd2 来调节 Wnt 信号通路。总之，我们揭示了糖尿病如何在胚胎发生过程中影响晚期肺发育的病理机制，特别是阐明了 Nrf2 介导的氧化应激反应和 Wnt 信号通路的双重作用。这一发现也表明，Nrf2 可能可用于预防或治疗妊娠期间高血糖引起的肺异常。
