Available online 16 November 2022, 151229

Author links open overlay panelAbstract

Prenatal and postnatal treatment modalities for congenital diaphragmatic hernia (CDH) continue to improve, however patients still face high rates of morbidity and mortality caused by severe underlying persistent pulmonary hypertension and pulmonary hypoplasia. Though the majority of CDH cases are idiopathic, it is believed that CDH is a polygenic developmental defect caused by interactions between candidate genes, as well as environmental and epigenetic factors. However, the origin and pathogenesis of these developmental insults are poorly understood. Further, connections between disrupted lung development and the failure of diaphragmatic closure during embryogenesis have not been fully elucidated. Though several animal models have been useful in identifying candidate genes and disrupted signalling pathways, more studies are required to understand the pathogenesis and to develop effective preventative care. In this article, we summarize the most recent litterature on disrupted embryological lung and diaphragmatic development associated with CDH.

Section snippetsAnatomy and embryology of CDH

The respiratory system in mammals is essential for gas exchange, namely oxygen and carbon dioxide, to enable cellular functioning (metabolism, growth, waste elimination, etc.). The diaphragm and the lungs are the two main organs in the respiratory system. The diaphragm provides physical separation of the thoracic cavity and the abdominal cavity and primary mechanical regulation of thoracic volume through the induction of changes in transmural pressure upon contraction and relaxation. The

Normal Lung Development

As outlined by Schittny's summary in 2017, a functional lung requires a network of conducting airways for gas transportation into and out of the lungs, a highly integrated vascular system for the transport and exchange of gas, a large surface area with an air-blood barrier for gas exchange, and a surfactant system to prevent alveolar collapse and provide innate immunological defence of the lungs.6, 7, 8, 9, 10, 11, 12 The development of these structures begins at the embryonic period

Main Embryonic progenitors

Diaphragm development begins as early as 5 weeks of gestation in humans and originates from multiple sources, namely the pleuroperitoneal folds (PPFs), the septum transversum, and the somites. PPFs are a pair of pyramidal structures that are symmetrical relative to the developing esophagus, derived from the lateral plate mesoderm found between the pleural and peritoneal cavity.55,56 Migratory diaphragmatic muscle progenitors likely originate from the C3-C5 cervical somites.57, 58, 59

Animal Models for Studying CDH

The cause of CDH is currently unknown. However, it is likely of polygenic origin and/or the result of a multifactorial response to an insult early in fetal development. The study of CDH in humans proves to be difficult as continuous in-utero tracking of early embryonic lung development from conception to birth is not feasible. Further, lung or diaphragm biopsies obtained from CDH patients are relatively scarce, making them extremely valuable. These discrepancies brought about the use of animal

Abnormal lung and diaphragm development in CDH

Incomplete fusion of the diaphragmatic tissue progenitors allows for protrusion of the abdominal contents into the thoracic cavity. However, respiratory failure in the newborn can be attributed to pulmonary hypoplasia, pulmonary hypertension, and a lack of surfactant production. Pulmonary hypoplasia in CDH is characterized by parenchymal abnormalities including reduced alveolar surface area and airway branching, while pulmonary hypertension is characterized by vascular abnormalities including

Abnormal Vascular Development in CDH

Vascular remodelling is a contributor to pulmonary hypertension in CDH marked by blunted responses to vasodilators and a significant increase in the medial, adventitial, and total wall thickness of the pulmonary arteries marked by hypermuscularization.86, 87, 88, 89 CDH human lungs have a marked increased expression of both endothelin A and B (ETA and ETB) receptors and the rate-limiting endothelin-converting enzyme 1(ECE1) which are also established in the nitrofen rat model.86

Endothelial cell

Embryonic contributors to abnormal lung development in CDH

Though complex CDH cases (i.e. associated with another congenital anomaly) are not uncommon, up to 60% of CDH cases are reported to be isolated (i.e. not associated with other major congenital anomalies),2 with several recent reviews compiling numerous chromosomal and genetic anomalies associated with CDH.63,66,69 Briefly, aneuploidies such as Turner syndrome and several trisomies (notably 18, 13, and 21) have been reported to be associated with CDH, however, their rate of concurrent incidence

Embryonic contributors to abnormal diaphragm development in CDH

Extensive studies on the retinoic signalling pathway have identified multiple candidate genes that may contribute to abnormal diaphragm development. With the majority of CDH cases being isolated with low familial recurrence, some studies suggest de novo genetic mutations in certain chromosomal “hot spots” are key contributors to the defective mesenchymal substratum.148,149 As previously mentioned, one such area is 8p23. Zinc finger protein multitype 2 (ZFPM2, previously called FOG2) is found in

Conclusion

Despite much progress in the past several years, insults during embryonic development that contribute to CDH are still poorly understood. As CDH is likely of a multi-factorial nature, genes and/or chromosomal loci declared as “high risk” cannot be described explicitly as causative factors due to the complexity of molecular and genetic interaction during organogenesis. More research into abnormal diaphragm development, the contribution of the developing phrenic nerve and nerve endings, and the

Funding

RK is supported by project grants (148797, 178347 and 178387) from the Canadian Institutes of Health Research and is the inaugural Thorlakson Chair of Surgical Research for the University of Manitoba.

Declaration of Competing Interest

The authors declare no conflict of interest.

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