Regarding the relative role and relationship of these extra- and intracellular pathogenic processes caused by Nedd4-2 deficiency, our data show that increased ENaC-mediated airway sodium hyperabsorption in freshly excised airway tissues, airway surface liquid depletion and reduced mucociliary clearance were already present after 2 weeks of doxycycline induction (Fig. 4), i.e., several months before elevated levels of active TGFβ and signs of pulmonary fibrosis were detectable in conditional Nedd4-2−/− mice (Figs. 2 and 6). Here, TGFB1 is linked to pulmonary fibrosis.