Development of pulmonary fibrosis in conditional Nedd4-2 deficient mice

In this study, we characterized a mouse model with conditional deletion of Nedd4-2 in lung epithelial cells of adult mice. Nedd4-2 is a ubiquitin ligase which is critical for regulation of the epithelial sodium channel ENaC and TGFβ signaling which are known to play an important role in pulmonary inflammatory diseases and fibrosis. To obtain conditional Nedd4-2 deficient mice (Nedd4-2-/-), we crossed mice with Nedd4-2 flanked by lox-P sites (Nedd4-2fl/fl) with mice carrying the reverse tetracycline-dependent transactivator under control of the CCSP-Promoter (CCSP-rtTA2-M2) and mice expressing a PTet responsive Cre recombinase (LC-1). Cre activity was induced with doxycycline (dox) starting at the age of 4 weeks. We studied pulmonary morphology by μCT imaging and histology as well as collagen content, and lung mechanics after different periods of induction. Further, we tested response to TGFβ stimulation in alveolar type 2 (AT2) cells isolated from Nedd4-2-/-mice.Our results show that conditional Nedd4-2-/- mice develop spontaneous chronic progressive fibrotic lung disease with continuous decline in lung compliance and increased collagen deposition in the lung. Histology as well as μCT Images revealed patchy fibrotic lesions in the periphery of the lung and signs of honeycombing. Finally, AT2 cells from Nedd4-2-/- mice showed a increased response to TGFβ stimulation.We conclude that this model may be powerful instrument to identify new biological pathways ...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Idiopathic interstitial pneumonias Source Type: research