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Pediatric Surgery International

, Volume 35, Issue 1, pp 41–61 | Cite as

Assessment of the nitrofen model of congenital diaphragmatic hernia and of the dysregulated factors involved in pulmonary hypoplasia

  • Louise Montalva
  • Augusto Zani
Original Article

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Retinoic acid Fibroblast Branching morphogenesis Alveolar differentiation Lung development 

Notes

Funding

This work was supported by Sickkids start-up funds and by the Canadian Institute of Health Research (CIHR)—SickKids Foundation New Investigator Research Grant (NI18-1270R).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Not applicable.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Developmental and Stem Cell Biology ProgramPeter Gilgan Centre for Research and Learning, The Hospital for Sick ChildrenTorontoCanada
  2. 2.Division of General and Thoracic Surgery, Department of SurgeryThe Hospital for Sick ChildrenTorontoCanada

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