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

textabstractCongenital diaphragmatic hernia or CDH is a developmental defect of the diaphragmthat allows abdominal organs, such as intestines and liver, to herniate intothe thoracic cavity during lung development. CDH has a prevalence of 1 in 2000– 3000 newborns and accounts for approximately 8% of the known major congenitalanomalies 1. In humans, three different types of hernia can be distinguished: a posterolateralBochdalek-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 ofmorbidity and mortality due to the associated abnormal pulmonary developmentresulting in two clinical problems, pulmonary hypoplasia and persistent pulmonaryhypertension of the neonate (PPHN). Characteristics of pulmonary hypoplasia inCDH are thickened alveolar walls, an increase in interstitial tissue, reduced alveolarair spaces and reduced gas-exchange surface area. Apart from the gas exchangelayer, well-documented changes are present in the vascular components consistingof media hyperplasia, peripheral muscularization of pre-acinar vessels and adventitialthickening. Both conditions are present in patients with CDH to a variable extentand despite the fact that recent progress in the care of these children has resulted insurvival rates of up to 90% in some tertiary care centers, these measures have not ledto a lower morbidity 5-7. In contrast, due to the absence of suffi cient lung-protectivestrategies, most of the newer treatment modalities have replaced mortality for ahigher morbidity in these babies. The problem with these new treatment modalities,such as high frequency oscillation (HFO) and/or inhaled nitric oxide (NO) and extracorporealmembrane oxygenation (ECMO), is that they are designed for treatingthe sequelae of CDH, pulmonary hypoplasia and PPHN and do not contribute to theprevention of these conditions. Prenatal modulation by minimal invasive techniquessuch as tracheal occlusion may potentially lead to diminished need of supportivecare postnatally by inducing lung growth 8. However, a sound understanding ofthe etiology and pathogenesis of CDH is necessary in order to prevent the severemorbidity or the anomalies altogether. Essential elements required for a betterunderstanding, such as how the different clinical problems relate to each other, arestill lacking. A basic understanding of CDH together with pulmonary hypoplasia andPPHN is fundamental in our quest for new answers to protect these children from thesequelae of this anomaly.Consequently, the aim of this dissertation was to improve our understanding of thepathogenesis of pulmonary hypoplasia in CDH, to eventually aid in fi nding ways tomodulate the natural course in a prenatally diagnosed child. Cover © The Pathogenesis of Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A continuing quest = De pathogenese van pulmonale hypoplasie in congenitale hernia diafragmatica: Een voortdurende strijd TABLE OF CONTENTS 1 - General Introduction & Outline Of The Dissertation 2 - Congenital diaphragmatic hernia: comparison of animal models and relevance to the human situation 3 - The pulmonary mesenchymal tissue layer is defective in an in vitro recombinant model of nitrofen-induced lung hypoplasia 4 - Apoptosis of Fibroblasts is Regulated by Epithelial Cells during Fetal Rat Lung Development in a Cell Recombinant Model 5 - Epithelial-Mesenchymal Transition in Nitrofen-Induced Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A Pilot Study 6 - Postmortem Lung Biopsy for Obtaining Lung Tissue in Congenital Diaphragmatic Hernia 7 - The Von Hippel-Lindau Pathway in Diaphragmatic Defects 8 - General Discussion & Future Perspectives 9 - Summary & Samenvatting | Abbreviations | Acknowledgements & Dankwoord | Authors & Technical Assistance | PhD Portfolio | Curriculum Vitae Auctoris ENGLISH SUMMARY NEDERLANDSE SAMENVATTING ABBREVIATIONS ACKNOWLEDGEMENTS & DANKWOORD CONTRIBUTING AUTHORS TECHNICAL ASSISTANCE & SUPPORT PHD PORTFOLIO CURRICULUM VITAE AUCTORIS