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 idiopathic pulmonary fibrosis. However, insights into its role in the <italic>in vivo</italic> pathogenesis of interstitial lung disease (ILD) remain limited. We previously developed a mouse model for early onset ILD-like disease caused by congenital deletion of the ubiquitin ligase <italic>Nedd4-2</italic> (<italic>Nedd4-2^−/−</italic>). In this study, we introduced a lung-specific knockout of <italic>Muc5b</italic> (<italic>Muc5b^−/−</italic>) in these mice (<italic>Nedd4-2^−/−/Muc5b^−/−</italic>) to investigate the <italic>in vivo</italic> role of <italic>Muc5b</italic> in the pathogenesis of ILD. Here we compared the pulmonary phenotype of <italic>Nedd4‑2^−/−</italic> mice to <italic>Muc5b^−/−</italic>, <italic>Nedd4-2^−/−/Muc5b^−/−</italic> and control mice during the first month of life. We assessed survival, oxygen saturation and pulmonary function. Furthermore, we evaluated inflammation in bronchoalveolar lavage (BAL) and lung morphology by histology. We found that spontaneous mortality was reduced in <italic>Nedd4-2^−/−/Muc5b^−/−</italic> (<italic>p</italic> < 0.001) compared to <italic>Nedd4-2^−/−</italic> mice accompanied by improved pulmonary function and reduced distal airway mucus obstruction. Mucin western blots revealed reduced Muc5b (p = 0.0012) and Muc5ac (p = 0.0059) intensities in BAL of <italic>Nedd4-2^−/−/Muc5b^−/−</italic> versus <italic>Nedd4-2^−/−</italic> mice. Decreased mucus plugging led to reduced concentrations of the inflammatory markers KC, IL-1β, IL-13, TNF-α and MIP-2 in the BAL of <italic>Nedd4-2^−/−/Muc5b^−/−</italic> mice. Lastly, reduced alveolitis was associated with less fibrotic remodeling in <italic>Nedd4-2^−/−/Muc5b^−/−</italic> mice. Taken together genetic deletion of <italic>Muc5b</italic> reduces ILD by decreased mucus obstruction in distal airways of neonatal <italic>Nedd4-2^−/−</italic> mice. These data highlight the central role of <italic>Muc5b</italic> in the pathogenesis of ILD and its potential role as therapeutic target for patients.