Novel insight into alveolar capillary dysplasia from multi-omics and 3D imaging

A minimal diffusion barrier is key to the pulmonary gas exchange. In alveolar capillary dysplasia (ACD), a rare genetically driven disease of early infancy, this crucial interface is compromised. The pathophysiology of this mostly fatal disease is limited though. We hypothesized whether there are factors beyond FOXF1 involved in the pathogenesis of ACD. We performed ultrastructural imaging and a comprehensive molecular and genetic work-up. in lung tissues from 12 ACD subjects and 20 healthy controls. Morphometrical assessment of the pulmonary vasculature was performed using transmission and serial block face electron microscopy. Genes potentially involved in the pathobiology of the disease were identified using transcriptome profiling and single gene sequencing. Immunostaining was used to confirm translation into proteins. ACD subjects were genetically analyzed using exome sequencing and CGH arrays. Independent from FOXF1 status, ACD pulmonary capillaries showed a unique pattern of altered, hypertrophied, multi-layered basement membranes. FN1, COL4A1, CDH5, and VIT were identified as genes potentially contributing to these alterations. In addition, ACD tissues showed a loss of normal lung capillaries and a replacement by COL15A1+ vessels as recently described in fibrotic lung diseases. This study provides new insights into the 3D ultrastructure and pathophysiology of ACD. Future studies are needed to explore the effect of FN1 knockouts and the therapeutic downregulation of FN1 overexpression in ACD.