Congenital Deletion of in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice.

Recent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of in the lung epithelial cells of neonatal doxycycline-induced triple transgenic mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP-C trafficking. We found that the congenital deletion of caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of in lung epithelial cells caused increased expression of and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of may support studies of the pathogenesis and preclinical development of therapies for chILD.