The Pathogenesis of Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A continuing quest

Congenital diaphragmatic hernia or CDH is a developmental defect of the diaphragm that allows abdominal organs, such as intestines and liver, to herniate into the thoracic cavity during lung development. CDH has a prevalence of 1 in 2000 – 3000 newborns and accounts for approximately 8% of the known major congenital anomalies 1. In humans, three different types of hernia can be distinguished: a posterolateral Bochdalek-type (~70% of the cases), an anterior Morgagni-type (~27% of the cases) and a central hernia, septum transversum-type (~2 – 3% of the cases). Eighty-fi ve percent of the hernias occur on the left side, 13% on the right and only 2% bilateral (reviewed in 2-4). Children with a CDH suffer from a substantial amount of morbidity and mortality due to the associated abnormal pulmonary development resulting in two clinical problems, pulmonary hypoplasia and persistent pulmonary hypertension of the neonate (PPHN). Characteristics of pulmonary hypoplasia in CDH are thickened alveolar walls, an increase in interstitial tissue, reduced alveolar air spaces and reduced gas-exchange surface area. Apart from the gas exchange layer, well-documented changes are present in the vascular components consisting of media hyperplasia, peripheral muscularization of pre-acinar vessels and adventitial thickening. Both conditions are present in patients with CDH to a variable extent and despite the fact that recent progress in the care of these children has resulted in survival rates of up to 90% in some tertiary care centers, these measures have not led to a lower morbidity 5-7. In contrast, due to the absence of suffi cient lung-protective strategies, most of the newer treatment modalities have replaced mortality for a higher morbidity in these babies. The problem with these new treatment modalities, such as high frequency oscillation (HFO) and/or inhaled nitric oxide (NO) and extracorporeal membrane oxygenation (ECMO), is that they are designed for treating the sequelae of CDH, pulmonary hypoplasia and PPHN and do not contribute to the prevention of these conditions. Prenatal modulation by minimal invasive techniques such as tracheal occlusion may potentially lead to diminished need of supportive care postnatally by inducing lung growth 8. However, a sound understanding of the etiology and pathogenesis of CDH is necessary in order to prevent the severe morbidity or the anomalies altogether. Essential elements required for a better understanding, such as how the different clinical problems relate to each other, are still lacking. A basic understanding of CDH together with pulmonary hypoplasia and PPHN is fundamental in our quest for new answers to protect these children from the sequelae of this anomaly. Consequently, the aim of this dissertation was to improve our understanding of the pathogenesis of pulmonary hypoplasia in CDH, to eventually aid in fi nding ways to modulate the natural course in a prenatally diagnosed child.

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