Congenital Diaphragmatic Hernia: State of the Art in Translating Experimental Research to the Bedside

Abstract

Congenital diaphragmatic hernia (CDH) is a devastating disease that still carries a high mortality and morbidity rate. Poor outcomes for fetuses and infants with CDH are mainly related to pulmonary hypoplasia (PH) and pulmonary vascular remodeling that leads to pulmonary hypertension (PHTN). Over the last five decades, research efforts have focused on modeling CDH not only to study the pathophysiology of the diaphragmatic defect, pulmonary hypoplasia, and pulmonary hypertension, but also to identify therapies that would promote lung growth and maturation, and correct vascular remodeling. As CDH is a multifactorial condition whose etiology remains unknown, there is not a single model of CDH, rather several ones that replicate different aspects of this disease. While small animals like the mouse and the rat have mainly been used to uncover biological pathways underlying the diaphragmatic defect and poor lung growth, larger animals like the lamb and the rabbit models have been instrumental for pursuing medical and surgical interventions. Overall, the use of animal models has indeed advanced our knowledge on CDH and helped us test innovative therapeutic options. For example, the lamb model of CDH has been the paradigm for testing fetal surgical procedures, including tracheal occlusion, which has been translated to clinical use. In this review, we outline the induction protocols of CDH in animals with the use of chemicals, dietary changes, genetic alterations, and surgical maneuvers, and we describe the studies that have translated experimental results to the bedside.

Amniotic fluid stem cell extracellular vesicles promote fetal lung branching and cell differentiation in experimental congenital diaphragmatic hernia

“…We acknowledge that our study has some limitations. Our findings were obtained using the nitrofen model of CDH, which is based on the administration of an herbicide that targets retinoic acid synthesis [26,62]. Nonetheless, although human pulmonary hypoplasia is not caused by maternal exposure to herbicides, nitrofen administration causes a degree of lung underdevelopment analogous to that of human fetuses with pulmonary hypoplasia [26,62].…”

“…Our findings were obtained using the nitrofen model of CDH, which is based on the administration of an herbicide that targets retinoic acid synthesis [26,62]. Nonetheless, although human pulmonary hypoplasia is not caused by maternal exposure to herbicides, nitrofen administration causes a degree of lung underdevelopment analogous to that of human fetuses with pulmonary hypoplasia [26,62]. Moreover, retinoic acid is known to play a role in fetal lung development and CDH babies have low intracellular retinoic acid levels in the lungs and low retinol and retinol-binding protein levels in the cord blood [63,64].…”

In vitro models of fetal lung development to enhance research into congenital lung diseases

“…Traditionally, research into lung development in the field of pediatric surgery has been based on in vivo studies in animal models [20][21][22]. However, the utility of animal models is generally limited by the heterogeneity of models and lower cost-effectiveness, making it difficult to validate the observations by repeating the experiments in a consistent manner.…”

Impaired Fetal Lung Development can be Rescued by Administration of Extracellular Vesicles Derived from Amniotic Fluid Stem Cells

“…The most robust experimental model of pulmonary hypoplasia relies on nitrofen administration to pregnant rats at embryonic day (E) 9.5 (30,31), which mainly targets retinoic acid synthesis (32). In this model, the whole litter has an impairment in lung development that is analogous to that of human fetuses (2,(30)(31)(32)(33). In utero nitrofen exposure causes a reduction in bronchiolar divisions and in the number of airspaces compared to lungs from unexposed fetuses (Fig.…”