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Cystic Adenomatoid Malformations Are Induced by Localized FGF10 Overexpression in Fetal Rat Lung

¹ The Children's Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; ² Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; and ³ Department of Physiology, Oporto Medical School, University of Porto, Porto, Portugal

Correspondence and requests for reprints should be addressed to Alan W. Flake, M.D., Department of Surgery, The Children's Hospital of Philadelphia, Abramson Research Center, Rm 1116B, 3615 Civic Center Blvd., Philadelphia, PA 19104-4318. E-mail: flake{at}email.chop.edu

Fibroblast growth factor-10 (FGF10) is a mesenchymal growth factor, involved in epithelial and mesenchymal interactions during lung branching morphogenesis. In the present work, FGF10 overexpression was transiently induced in a temporally and spatially restricted manner, during the pseudoglandular or canalicular stages of rat lung development, by trans-uterine ultrasound-guided intraparenchymal microinjections of adenoviral vector encoding the rfgf10 transgene. The morphologic and histologic classification of the resulting malformations were dependent upon developmental stage and location. Overexpression of FGF10 restricted to the proximal tracheobronchial tree during the pseudoglandular phase resulted in large cysts lined by tall columnar epithelium composed primarily of Clara cells with a paucity of Type II pneumocytes, resembling bronchiolar type epithelium. In contrast, FGF10 overexpression in the distal lung parenchyma during the canalicular phase resulted in small cysts lined by cuboidal epithelial cells composed of primarily Type II pneumocytes resembling acinar epithelial differentiation. The cystic malformations induced by FGF10 overexpression appear to closely recapitulate the morphology and histology of the spectrum of human congenital cystic adenomatoid malformation (CCAM). These findings support a role for FGF10 in the induction of human CCAM and provide further mechanistic insight into the role of FGF10 in normal and abnormal lung development.

Key Words: fibroblast growth factor-10 • congenital cystic adenomatoid malformation • adenoviral vector • lung development • gene transfer

CLINICAL RELEVANCE Our results demonstrate that overexpression of a single gene induces cystic lung lesions resembling the entire spectrum of congenital cystic adenomatoid malformation (CCAM). These results provide unique insight into developmental mechanisms that may contribute to CCAM formation.