Karen Coste

Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study.

To describe the true incidence, prenatal detection rate and fetal outcome of congenital diaphragmatic hernia (CDH) in a systematically registered population over an 18‐year period and to determine any change in trends over time.

A Role for Mesenchyme Dynamics in Mouse Lung Branching Morphogenesis

Mammalian airways are highly ramified tree-like structures that develop by the repetitive branching of the lung epithelium into the surrounding mesenchyme through reciprocal interactions. Based on a morphometric analysis of the epithelial tree, it has been recently proposed that the complete branching scheme is specified early in each lineage by a programme using elementary patterning routines at specific sites and times in the developing lung. However, the coupled dynamics of both the epithelium and mesenchyme have been overlooked in this process. Using a qualitative and quantitative in vivo morphometric analysis of the E11.25 to E13.5 mouse whole right cranial lobe structure, we show that beyond the first generations, the branching stereotypy relaxes and both spatial and temporal variations are common. The branching pattern and branching rate are sensitive to the dynamic changes of the mesoderm shape that is in turn mainly dependent upon the volume and shape of the surrounding intrathoracic organs. Spatial and temporal variations of the tree architecture are related to local and subtle modifications of the mesoderm growth. Remarkably, buds never meet after suffering branching variations and continue to homogenously fill the opening spaces in the mesenchyme. Moreover despite inter-specimen variations, the growth of the epithelial tree and the mesenchyme remains highly correlated over time at the whole lobe level, implying a long-range regulation of the lung lobe morphogenesis. Together, these findings indicate that the lung epithelial tree is likely to adapt in real time to fill the available space in the mesenchyme, rather than being rigidly specified and predefined by a global programme. Our results strongly support the idea that a comprehensive understanding of lung branching mechanisms cannot be inferred from the branching pattern or behavior alone. Rather it needs to be elaborated upon with the reconsideration of mesenchyme-epithelium coupled growth and lung tissues mechanics.

Effects of maternal retinoic acid administration in a congenital diaphragmatic hernia rabbit model

Maternal retinoid administration has beneficial effects on lung development in the nitrofen rodent toxic model of congenital diaphragmatic hernia (DH). We wanted to investigate the effects in a surgical model, where the retinoid signaling pathway is not primarily disrupted by the toxic agent. We created DH in fetal rabbits at day 23 of gestation, administrated to the does all trans‐retinoic acid (ATRA) or vehicle (VHC) intramuscularly for 8 consecutive days and harvested normal and operated (DH) fetuses at 31 d (n = 7 in each group). Normal lungs exposed to ATRA had increased surfactant protein mRNA levels without change in type II pneumocyte density. There was no measurable effect on lung‐to‐body weight ratio and airway morphometry by ATRA. In DH lungs (DH/VHC) surfactant protein mRNA levels were increased, as well as the density of type II pneumocytes. When supplemented with ATRA (DH/ATRA) these parameters returned to normal (VHC). Cell proliferation or apoptosis were not influenced by ATRA supplementation. In conclusion, maternal ATRA supplementation does not affect gross anatomic, morphologic or proliferation indices in hypoplastic lungs related to surgically induced DH in rabbit. However, ATRA lowers surfactant protein expression and normalizes type I/II pneumocyte ratio to what is observed in normal lungs. Pediatr Pulmonol. 2008; 43:594–603.

Hyperechoic congenital lung lesions in a non-selected population: from prenatal detection till perinatal management.

To present longitudinal observations of hyperechoic lung lesions (HLL) in a non‐selected population from the time of prenatal diagnosis by ultrasound (US) until postnatal surgery.

Fetal midgut volvulus as a sign for cystic fibrosis.

M. Durand1, K. Coste2,3, A. Martin1, T. Scheye2, I. Creveaux4,3, P. Vanlieferinghen2, H. Laurichesse-Delmas1,3, P. J. Dechelotte5,3, A. Labbe2,3, B. Jacquetin1, D. Lemery1,3 and D. Gallot1,3* 1Maternal Fetal Medicine Unit, CHU Clermont-Ferrand, France 2Department of Pediatrics, CHU Clermont-Ferrand, France 3GReD CNRS UMR6247, Clermont Université, France 4Laboratory of Molecular Biology, CHU Clermont-Ferrand, France 5Laboratory of Pathology, CHU Clermont-Ferrand, France

Prenatal diagnosis of lobar bronchial atresia

We report three cases of fetal lobar bronchial atresia referred to our Fetal Medicine Center during the mid‐trimester of pregnancy over the last 15 years. Lobar bronchial atresia can mimic a main stem bronchial atresia on mid‐trimester ultrasound examination as it induces extensive lobar enlargement, major mediastinal shift and eversion of the diaphragm. It was associated with severe pulmonary hypoplasia in all three cases, even though polyhydramnios and ascites were absent in two. Termination of pregnancy was performed at parental request after extensive counseling in each of the cases and necropsy confirmed one or two enlarged lung lobes leading to major compression of the remaining lobe(s) of the ipsilateral lung, the contralateral lung and the heart. No other anomalies were observed and the karyotype was normal in all cases. Copyright

Effects of tracheal occlusion with retinoic acid administration on normal lung development

Tracheal occlusion (TO) is an investigational therapy for severe congenital diaphragmatic hernia that decreases pulmonary hypoplasia, but sustained TO also induces deficient surfactant synthesis. Intramuscular maternal administration of retinoic acid (RA) in a surgical rabbit model of congenital diaphragmatic hernia showed a beneficial effect on lung maturation. We evaluated the potential of RA delivery into the trachea and studied the combined effects of TO and RA on normal lung development.

Fetal skin fibroblasts: A cell model for studying the retinoid pathway in congenital diaphragmatic hernia

BACKGROUND Although there is strong evidence that genetic factors play a pathogenic role in congenital diaphragmatic hernia (CDH), few causal genes have been identified in humans. A number of studies, essentially in animal models, have suggested that disruption of the retinoid signaling pathway plays a major role in the pathogenesis of CDH. Our hypothesis is that human fetal skin fibroblasts express some metabolic and molecular actors of the retinoid pathway and that they offer convenient cellular material for investigating the molecular retinoid pathway defects associated with CDH. METHODS We first established the expression of receptors, enzymes and binding proteins involved in the retinoic acid (RA) pathway in non-CDH fetal skin fibroblasts using RT-PCR and immunocytochemistry approaches. We then studied the expression of these genes in skin fibroblasts from seven fetuses with isolated and nonisolated CDH. RESULTS Fetal skin fibroblasts expressed enzymes involved in RA metabolism as well as nuclear receptors for signal transduction. Basal levels of retinoic acid receptor, retinaldehyde dehydrogenase 2, and CYP26 (cytochrome P450 RAI) expression were altered in two of seven fetuses. Interestingly, these genes were previously described as abnormally expressed in CDH physiopathology. CONCLUSION Our results suggest that human fetal skin fibroblasts could be useful for studying retinoid signaling pathway disruption in the context of CDH. Our proposal is strengthened by the fact that we identified CDH fetuses for which molecular and metabolic actors of the retinoid pathway were not detected.