Congenital Diaphragmatic Hernia: Comparison of Animal Models and Relevance to the Human Situation

Abstract

Congenital diaphragmatic hernia (CDH) occurs in 1 in 3,000 newborns. Mortality and morbidity are due to the amount of pulmonary hypoplasia (PH), the response on artificial ventilation and the presence of therapy-resistant pulmonary hypertension. The pathogenesis and etiology of CDH and its associated anomalies are still largely unknown despite all research efforts over the past years. Several animal models have been proposed to study CDH. In this review we compare surgical, pharmacological and transgenic models, and discuss their strengths and limitations to study PH.

The transcriptome of nitrofen-induced pulmonary hypoplasia in the rat model of congenital diaphragmatic hernia

“…CDH constitutes about 8% of major congenital anomalies and has the highest mortality rate (4). In rodents, nitrofen induces CDH and lung hypoplasia similar to the phenotype observed in humans (5). Whether the nitrofen-rat model shares the same pathogenesis with human CDH remains to be determined.…”

Congenital Diaphragmatic Hernia with Emphasis on Embryology, Subtypes, and Molecular Genetics

“…Although repairing a diaphragmatic defect in a newborn is relatively simple via a primary closure or a patch, the major issue is that the development of the lungs is disrupted, causing pulmonary hypoplasia and constant pulmonary hypertension (van Loenhout, Tibboel et al 2009;Keijzer and Puri 2010). Pulmonary hypoplasia, reduced airway branching, and surfactant deficiency in newborns with CDH result in respiratory failure at birth (Keijzer and Puri 2010).…”

“…Children with a CDH suffer from significant levels of morbidity and mortality due to abnormal pulmonary development. Improved treatment of newborns with CDH in the neonatal intensive care unit has substantially reduced mortality rates to less than 10% to 20% in tertiary referral centers (van Loenhout, Tibboel et al 2009;Keijzer and Puri 2010). The high morbidity rate is attributed to modern treatment methods, such as high-frequency oscillation and extracorporeal membrane oxygenation (ECMO) (van Loenhout, Tibboel et al 2009;Keijzer and Puri 2010).…”

“…In the dual-hit hypothesis, however, the lungs suffer from two insults, the first one inherent in pulmonary development before the development of the CDH and the second insult occurring with the CDH. The lungs are inherently disturbed prior to the early formation of the diaphragm before any mechanical pressure can be applied by the CDH (van Loenhout, Tibboel et al 2009;Keijzer and Puri 2010). A second insult to the ipsilateral lung subsequently occurs as a result of disturbance of fetal breathing movements due to the abdominal organs invading the thoracic cavity (van Loenhout, Tibboel et al 2009;Keijzer Congenital Diaphragmatic Hernia with Emphasis on Embryology, Subtypes, and Molecular Genetics 11 and Puri 2010).…”

“…The lungs are inherently disturbed prior to the early formation of the diaphragm before any mechanical pressure can be applied by the CDH (van Loenhout, Tibboel et al 2009;Keijzer and Puri 2010). A second insult to the ipsilateral lung subsequently occurs as a result of disturbance of fetal breathing movements due to the abdominal organs invading the thoracic cavity (van Loenhout, Tibboel et al 2009;Keijzer Congenital Diaphragmatic Hernia with Emphasis on Embryology, Subtypes, and Molecular Genetics 11 and Puri 2010). Although some authors have postulated that the hypoplastic lung causes the diaphragmatic hernia, animal models of mutant mice with inactivated Fgf10, thereby preventing lung development, still had normal diaphragms, disproving that abnormal pulmonary growth creates the diaphragmatic defect (Keijzer and Puri 2010).…”