Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice.

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.

• Authors: Laura A Hancock, Corinne E Hennessy, George M Solomon, Evgenia Dobrinskikh, Alani Estrella, Naoko Hara, David B Hill, William J Kissner, Matthew R Markovetz, Diane E Grove Villalon, Matthew E Voss, Guillermo J Tearney, Kate S Carroll, Yunlong Shi, Marvin I Schwarz, William R Thelin, Steven M Rowe, Ivana V Yang, Christopher M Evans, David A Schwartz
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 5363 (12 18 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30560893 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Video-Audio Media)

Chemical References

• Expectorants
• MUC5B protein, human
• Muc5b protein, mouse
• Mucin-5B
• Pulmonary Surfactant-Associated Protein C
• SFTPC protein, human
• Bleomycin

Topics

• Animals
• Bleomycin (toxicity)
• Disease Models, Animal
• Epithelial Cells (metabolism, pathology)
• Expectorants (pharmacology, therapeutic use)
• Female
• Gain of Function Mutation
• Genetic Predisposition to Disease
• Humans
• Idiopathic Pulmonary Fibrosis (chemically induced, drug therapy, genetics, pathology)
• Lung (cytology, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mucin-5B (genetics, metabolism)
• Mucociliary Clearance (drug effects, genetics)
• Promoter Regions, Genetic (genetics)
• Pulmonary Surfactant-Associated Protein C (metabolism)
• Respiratory Mucosa (cytology, metabolism, pathology)