Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice

The gain-of-function MUC5B promoter variant rs35705950 is the dominant risk factor for developing idiopathic pulmonary fibrosis (IPF). Here we show in humans that MUC5B , a mucin thought to be restricted to conducting airways, is co-expressed with surfactant protein C ( SFTPC ) in type 2 alveolar epithelia and in epithelial cells lining honeycomb cysts, indicating that cell types involved in lung fibrosis in distal airspace express MUC5B . In mice, we demonstrate that Muc5b concentration in bronchoalveolar epithelia is related to impaired mucociliary clearance (MCC) and to the extent and persistence of bleomycin-induced lung fibrosis. We also establish the ability of the mucolytic agent P-2119 to restore MCC and to suppress bleomycin-induced lung fibrosis in the setting of Muc5b overexpression. Our findings suggest that mucociliary dysfunction might play a causative role in bleomycin-induced pulmonary fibrosis in mice overexpressing Muc5b, and that MUC5B in distal airspaces is a potential therapeutic target in humans with IPF. The promoter variant rs35705950 confers a gain of function to the MUC5B gene and is the dominant risk factor for idiopathic pulmonary fibrosis. Here the authors show that mice overexpressing Muc5b in distal airspaces show impaired mucociliary clearance and increased susceptibility to bleomycin-induced lung fibrosis, and that both characteristics are reduced by treatment with a mucolytic agent.