Genetic Deletion of Muc5b Reduces Interstitial Lung Disease in Neonatal Nedd4-2 Deficient Mice

MUC5B has been implicated as a major risk factor for the development of pulmonary fibrosis. However, insights into its role in the in vivo pathogenesis of interstitial lung disease (ILD) remain incomplete. We previously developed a mouse model ( Nedd4-2 -/- ) exhibiting severe spontaneous ILD driven by congenital Nedd4-2 deletion. To functionally assess the contribution of MUC5B to ILD pathogenesis, we generated mice with a lung-specific Muc5b knockout on the Nedd4-2 -/- background ( Nedd4-2 -/- /Muc5b -/- ). We conducted a comparative analysis of neonatal Nedd4-2 -/- /Muc5b -/- mice against Nedd4-2 -/- , Muc5b -/- , and control littermates during the first month of life. Assessments included survival, oxygen saturation, lung mechanics, bronchoalveolar lavage (BAL) fluid analysis, and lung histology. Muc5b protein levels were quantified by Western blot, and cellular phenotypes were spatially analyzed using Imaging Mass Cytometry (IMC). Genetic deletion of Muc5b significantly rescued the ILD phenotype of Nedd4-2 -/- mice, resulting in reduced mortality (p< 0.05) and improved pulmonary function. This improvement was mechanistically linked to the prevention of airway mucus obstruction, which was prominent in Nedd4-2 -/- mice, and confirmed by reduced Muc5b protein in BAL (p= 0.04). Consequently, Nedd4-2 -/- /Muc5b -/- mice exhibited reduced concentrations of the key inflammatory markers KC, IL-1β, IL-13, TNF-α and MIP-2 in BAL. IMC analysis further confirmed that Muc5b deletion attenuated inflammatory cell accumulation and reduced the expression of mesenchymal markers within the lung parenchyma. Taken together, genetic deletion of Muc5b ameliorates the severity of spontaneous ILD in neonatal Nedd4-2 -/- mice by preventing mucus obstruction and subsequent pulmonary inflammation. These data highlight a central role for Muc5b in this ILD model and support its potential as a therapeutic target. Funding: German Research Foundation (DFG) – 431232613; German Federal Ministry of Education and Research (BMBF) – 01GL2401D; 82DZL009C1 Publication History Article published online: 26 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany