Prenatal modulation of the developing lung in congenital diaphragmatic hernia: functional, morphological, and biological consequences for the neonatal lung

• Main Author: Vuckovic, Aline
• Other Authors: Jani, Jacques
• Format: Doctoral Thesis
• Language: en
• Published: Universite Libre de Bruxelles 2016
• Subjects: Médecine pathologie humaine; Croissance et développement [animal]; Croissance et développement [humain]; congenital diaphragmatic hernia; lung hypoplasia; rabbit model; tracheal occlusion; stretch-induced lung growth; persistent pulmonary hypertension of the newborn; activator of soluble guanylate cyclase; BAY 41-2272; perfluorooctylbromide; perfluorocarbons
• Online Access: http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/228906

INTRODUCTION. Congenital diaphragmatic hernia (CDH) combines a congenital malformation of the diaphragm with lung hypoplasia, leading to severe respiratory distress and intractable pulmonary hypertension of the newborn. Despite advances in prenatal diagnosis and neonatal intensive care, CDH is associated with high mortality and devastating morbidities. In the absence of curative treatment, numerous prenatal therapies have been used experimentally with varying success. So far, only fetal tracheal occlusion has been tested in clinical trials, but the consequences for the human lung are poorly known. AIMS. To further characterize the rabbit model of CDH, which was subsequently used to assess the effects of prenatal therapies on airway and pulmonary vascular development, including tracheal occlusion, and two novel approaches, perfluorooctylbromide and an activator of soluble guanylate cyclase (BAY 41–2272), which were given through tracheal instillation.METHODS. After a diaphragmatic incision during the pseudoglandular stage, fetal rabbits were randomized against placebo/sham operation during the saccular stage for tracheal occlusion, perfluorocarbon or BAY 41–2272. At term operated fetuses and controls were subject to evaluation of lung mechanics and/or hemodynamics as well as postmortem lung analyses. Human fetal and neonatal lung tissue, including controls and CDH with tracheal occlusion or expectant management, was analyzed histologically and biochemically.RESULTS. The rabbit model of CDH was characterized by reduced lung volumes and impaired compliance, disorders of elastin deposition within alveolar walls, and downregulation of elastogenesis-related genes. Moreover, this model reproduced features of pulmonary hypertension, including high right ventricular pressure and level of N-terminal-pro-B type natriuretic peptide, remodeling of pulmonary arterioles, decreased alveolar capillary density, and downregulation of vasodilation-related genes. In the rabbit model, lung distension caused by tracheal occlusion improved alveolar formation and elastogenesis, yet without correction of lung mechanical parameters. Tracheal occlusion increased also the expression of other extracellular matrix components, which reflected myofibroblast activity, and reduced the transcription of surfactant-associated proteins. Human neonatal lungs exposed to fetal tracheal occlusion displayed alveolar deposits of collagen and myofibroblasts. In human CDH as well as in the rabbit model of CDH, tracheal occlusion enhanced the pulmonary expression of transforming growth factor-β (TGFβ) and Rho kinase−associated proteins to the detriment of activation of SMAD2/3, which is normally detected in human lungs with advancing gestation. As an alternative to tracheal occlusion, pulmonary distension by perfluorocarbon in the fetal rabbit model of CDH improved lung mechanics and alveolar elastogenesis without transcriptional changes in extracellular matrix, surfactant protein genes or TGFβ. Finally, intratracheal instillation of BAY 41–2272 in the rabbit fetuses with CDH improved hemodynamics, reduced medial hypertrophy of pulmonary arterioles, and increased capillary bed formation by stimulating endothelial cell proliferation.CONCLUSIONS. In the fetal rabbit model of CDH, poor lung function after tracheal occlusion is compatible with activation of TGFβ and imbalance in extracellular matrix and epithelial homeostasis. In human CDH newborns treated by fetal tracheal occlusion, changes in the pulmonary interstitium and impaired TGFβ signaling raise the question of disturbances of postnatal lung development induced by tracheal occlusion. As potential alternatives to tracheal occlusion, prenatal perfluorocarbon improves lung hypoplasia, whereas prenatal BAY 41–2272 attenuates pulmonary hypertension. === Doctorat en Sciences médicales (Médecine) === info:eu-repo/semantics/nonPublished