Development of pulmonary fibrosis in conditional Nedd4-2 deficient mice

Idiopathic pulmonary fibrosis (IPF) is a severe lung disease, which is characterized by chronic irreversible progressive fibrosis and a variable clinical course with acute respiratory worsening constituting a primary cause of death in patients. Nedd4-2 is an ubiquitin ligase that is crucial in the regulation of the epithelial sodium channel ENaC and TGFs signaling which are both known to play important roles in pulmonary inflammatory diseases and fibrosis. Here, we studied mice with conditional deletion of Nedd4-2 in lung epithelial cells of adult mice. Our results show that conditional Nedd4-2-/- mice develop spontaneous chronic progressive fibrotic lung disease with a continuous decline in lung compliance and increasing levels of IL-13, IL-1s and TGFs and collagen content in the lung. Histology revealed patchy fibrotic lesions in the periphery of the lung with massive deposition of collagen, destruction of the lung parenchyma and signs of histological honeycombing. Micro-CT images of Nedd4-2-/- mice showed reticular opacities, ground glass opacities, traction bronchiectasis and honeycombing up to 4 months after deletion of Nedd4-2. As reported for patients with IPF, we observed an acute deterioration associated with severe weight loss and hypoxia resulting in an overall mortality of 70% at 4 months after deletion of Nedd4-2 was induced. Our data suggest that this model may be useful to identify pathogenesis-modulating factors underlying e.g. acute exacerbations, to identify new biological pathways in early pathogenesis, and to develop novel therapeutic strategies for patients with IPF.