Multilamellated basement membranes in the capillary network of alveolar capillary dysplasia

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 fibrovascular interface is compromised while the underlying pathophysiology is insufficiently understood. Recent in-depth analyses of vascular alterations in adult lung disease encouraged to extend these studies to ACD and compare the changes of the microvasculature. Lung tissue samples of children with ACD (n=12), adults with non-specific interstitial pneumonia (n=12), and controls (n=20) were studied using single gene sequencing, immunostaining, exome sequencing, and broad transcriptome profiling in addition to analysis of the vasculature by transmission electron microscopy. In ACD, pulmonary capillary basement membranes were hypertrophied, thickened, and multilamellated. Transcriptome profiling revealed increased CDH5, COL4A1, COL15A1, PTK2B, and FN1 and decreased VIT expression, confirmed by immunohistochemistry. In contrast, NSIP samples showed a regular basement membrane architecture with preserved VIT expression but also increased COL15A1+ vessels. This study provides insight into the ultrastructure and pathophysiology of ACD. The lack of normally developed lung capillaries seems to cause a replacement by COL15A1+ vessels, a mechanism recently described in interstitial lung disease. The VIT loss and FN1 overexpression might contribute to the unique appearance of basement membranes in ACD. Future studies are needed to explore the therapeutic potential of downregulating the expression of FN1 and balancing of VIT deficiency.

• Kamp, J. C.
• Neubert, L.
• Schupp, J. C.
• Braubach, P.
• Wrede, C.
• Laenger, F.
• Salditt, T.
• Reichmann, J.
• Welte, T.
• Ruhparwar, A.
• Ius, F.
• Schwerk, N.
• Bergmann, A. K.
• von Hardenberg, S.
• Griese, M.
• Rapp, C.
• Olsson, K. M.
• Fuge, J.
• Park, D. H.
• Hoeper, M. M.
• Jonigk, D. D.
• Knudsen, L.
• Kuehnel, M. P.