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PS-210 Alveolar Capillary Dysplasia: A Genetically Determined Disruption Of The Alveolar/mesenchymal Cross-talk Causing Neonatal Hypoxic Failure
  1. C Lizama1,
  2. D Peca2,
  3. PE Cogo3,
  4. I Stucin-Gantar4,
  5. P Ursell5,
  6. A Zovein6,
  7. A VanHeijst7,
  8. O Danhaive8
  1. 1Cardiovascular Research Institute, University of California San Francisco, San Francisco, USA
  2. 2Neonatology, Bambino Gesu Children’s Hospital and Research Institute, Rome, Italy
  3. 3Cardiology, Bambino Gesu Children’s Hospital and Research Institute, Rome, Italy
  4. 4Neonatology, University Medical Center, Ljubjana, Slovenia
  5. 5Pathology, University of California San Francisco, San Francisco, USA
  6. 6Neonatology, University of California San Francisco, San Francico, USA
  7. 7Pediatrics, Radboud University Medical Center, Nijmegen, Netherlands
  8. 8Pediatrics, University of California San Francisco, San Francisco, USA

Abstract

Background/aims Alveolar capillary dysplasia (ACD) is characterised by pulmonary veins misalignment, capillary paucity and alveolar misdevelopment, and caused by FOXF1 mutations only in 40% of cases. Objectives were 1. to identify known and new gene defects and 2. to correlate them with molecular/cellular mechanisms.

Methods We recruited a cohort of 23 pathology-confirmed cases. When DNA was available, genome-wide copy number variation was analysed through Array Comparative Genomic Hybridization (aCGH). Mutations were tested by direct sequencing of FOXF1 and candidate genes identified by aCGH; Molecular pathways were analysed by multi-channel immunofluorescence microscopy of ACD cases compared to human fetal/neonatal lung tissue at various development stages.

Results

  1. Genomic deletions or mutations were identified in 57% of tested cases. Besides FOXF1, two of the genes involved stand out as potential candidates: MEOX2 and TBX4.

  2. ACD cases showed a markedly decreased expression of c-kit, a marker expressed in pulmonary small arteries and capillaries in fetal lung controls. In normal fetal lungs FOXF1 and TBX4 were prevalently expressed at the mesenchymal-epithelial border, and MEOX2 in pulmonary vascular smooth muscle cells (PVSMC). Their expression pattern and intensity were altered in all ACD cases, indicating that decreased FOXF-1 and/or its downstream transcription factor TBX4 disrupt lung micro vessel formation and homing to alveolar epithelium, and that a similar phenotype may derive from dysregulated PVSMC proliferation and angiogenesis related to MEOX2 insufficiency.

Conclusion Genetic defects affecting the FOXF1 pathway affect the mesenchymal, endothelial and epithelial cross-talk leading to lung developmental disruption, pulmonary hypertension and hypoxic respiratory failure.

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