Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice

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 and David A. Schwartz ()
Additional contact information
Laura A. Hancock: University of Colorado Denver, School of Medicine
Corinne E. Hennessy: University of Colorado Denver, School of Medicine
George M. Solomon: University of Alabama at Birmingham, School of Medicine
Evgenia Dobrinskikh: University of Colorado Denver, School of Medicine
Alani Estrella: University of Colorado Denver, School of Medicine
Naoko Hara: University of Colorado Denver, School of Medicine
David B. Hill: University of North Carolina
William J. Kissner: University of North Carolina
Matthew R. Markovetz: University of North Carolina
Diane E. Grove Villalon: Parion Sciences, Inc
Matthew E. Voss: Parion Sciences, Inc
Guillermo J. Tearney: Massachusetts General Hospital, Boston, Massachusetts; Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston
Kate S. Carroll: The Scripps Research Institute
Yunlong Shi: The Scripps Research Institute
Marvin I. Schwarz: University of Colorado Denver, School of Medicine
William R. Thelin: Parion Sciences, Inc
Steven M. Rowe: University of Alabama at Birmingham, School of Medicine
Ivana V. Yang: University of Colorado Denver, School of Medicine
Christopher M. Evans: University of Colorado Denver, School of Medicine
David A. Schwartz: University of Colorado Denver, School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07768-9

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