Montalva Louise, Zani Augusto
Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada.
Division of General and Thoracic Surgery, Department of Surgery, The Hospital for Sick Children, 1524C-555 University Ave, Toronto, ON, M5G 1X8, Canada.
Pediatr Surg Int. 2019 Jan;35(1):41-61. doi: 10.1007/s00383-018-4375-5. Epub 2018 Nov 1.
To study pulmonary hypoplasia (PH) associated with congenital diaphragmatic hernia (CDH), investigators have been employing a fetal rat model based on nitrofen administration to dams. Herein, we aimed to: (1) investigate the validity of the model, and (2) synthesize the main biological pathways implicated in the development of PH associated with CDH.
Using a defined strategy, we conducted a systematic review of the literature searching for studies reporting the incidence of CDH or factors involved in PH development. We also searched for PH factor interactions, relevance to lung development and to human PH.
Of 335 full-text articles, 116 reported the incidence of CDH after nitrofen exposure or dysregulated factors in the lungs of nitrofen-exposed rat fetuses. CDH incidence: 54% (27-85%) fetuses developed a diaphragmatic defect, whereas the whole litter had PH in varying degrees. Downregulated signaling pathways included FGF/FGFR, BMP/BMPR, Sonic Hedgehog and retinoid acid signaling pathway, resulting in a delay in early epithelial differentiation, immature distal epithelium and dysfunctional mesenchyme.
The nitrofen model effectively reproduces PH as it disrupts pathways that are critical for lung branching morphogenesis and alveolar differentiation. The low CDH rate confirms that PH is an associated phenomenon rather than the result of mechanical compression alone.
为研究与先天性膈疝（CDH）相关的肺发育不全（PH），研究人员一直采用基于给孕鼠施用硝呋烯腚的胎鼠模型。在此，我们旨在：（1）研究该模型的有效性，以及（2）综合分析与CDH相关的PH发生发展过程中涉及的主要生物学途径。
我们采用既定策略对文献进行系统综述，查找报告CDH发病率或参与PH发生发展的因素的研究。我们还搜索了PH因子相互作用、与肺发育及人类PH的相关性。
在335篇全文文章中，116篇报告了硝呋烯腚暴露后CDH的发病率或硝呋烯腚暴露的胎鼠肺中失调的因子。CDH发病率：54%（27 - 85%）的胎儿出现膈缺陷，而整窝胎儿均有不同程度的PH。下调的信号通路包括FGF/FGFR、BMP/BMPR、 Sonic Hedgehog和视黄酸信号通路，导致早期上皮分化延迟、远端上皮不成熟和间充质功能障碍。
硝呋烯腚模型有效地再现了PH，因为它破坏了对肺分支形态发生和肺泡分化至关重要的途径。低CDH发生率证实PH是一种相关现象，而非单纯机械压迫的结果。
