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Nat Commun. 2018 Dec 18;9(1):5363. doi: 10.1038/s41467-018-07768-9.

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

Author information

1
Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA.
2
Department of Medicine, University of Alabama at Birmingham, School of Medicine, Birmingham, AL, 35294, USA.
3
Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, 27599, USA.
4
Physics and Astronomy, University of North Carolina, Chapel Hill, NC, 27599, USA.
5
Parion Sciences, Inc, Durham, NC, 27713, USA.
6
Wellman Center for Photomedicine and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.
7
Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA.
8
Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA.
9
Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA. david.schwartz@ucdenver.edu.
10
Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA. david.schwartz@ucdenver.edu.

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.

PMID:
30560893
PMCID:
PMC6299094
DOI:
10.1038/s41467-018-07768-9
[Indexed for MEDLINE]
Free PMC Article

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