Abstract
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.
Highlights
The gain-of-function MUC5B promoter variant rs35705950 is the dominant risk factor for developing idiopathic pulmonary fibrosis (IPF)
We show that Muc5b overproduction in the distal lungs of mice are associated with mucociliary clearance (MCC) dysfunction and exaggerates the development of fibrosis, and that this can be prevented by treatment with a mucolytic agent
In human IPF lung tissue, we found that MUC5B is co-expressed with surfactant protein C in columnar epithelial cells lining honeycomb cysts (Fig. 1a) and in type 2 alveolar epithelia (Fig. 1b), indicating that cell types involved in lung fibrosis in the distal airspace express MUC5B
Summary
The gain-of-function MUC5B promoter variant rs35705950 is the dominant risk factor for developing idiopathic pulmonary fibrosis (IPF). In patients with IPF, excess MUC5B protein is especially observed in epithelial cells in the respiratory bronchiole and honeycomb cyst[7,8], regions of lung involved in lung fibrosis. It remains unclear how MUC5B leads to the development of IPF. We show that Muc5b overproduction in the distal lungs of mice are associated with MCC dysfunction and exaggerates the development of fibrosis, and that this can be prevented by treatment with a mucolytic agent. Our findings show a causative, dose-dependent role for Muc5b in murine lung fibrosis, and support development of mucolytic intervention strategies for human disease
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