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

Autor: Hancock LA; Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA., Hennessy CE; Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA., Solomon GM; Department of Medicine, University of Alabama at Birmingham, School of Medicine, Birmingham, AL, 35294, USA., Dobrinskikh E; Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA., Estrella A; Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA., Hara N; Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA., Hill DB; Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, 27599, USA.; Physics and Astronomy, University of North Carolina, Chapel Hill, NC, 27599, USA., Kissner WJ; Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, 27599, USA., Markovetz MR; Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, 27599, USA., Grove Villalon DE; Parion Sciences, Inc, Durham, NC, 27713, USA., Voss ME; Parion Sciences, Inc, Durham, NC, 27713, USA., Tearney GJ; 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., Carroll KS; Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA., Shi Y; Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA., Schwarz MI; Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA., Thelin WR; Parion Sciences, Inc, Durham, NC, 27713, USA., Rowe SM; Department of Medicine, University of Alabama at Birmingham, School of Medicine, Birmingham, AL, 35294, USA., Yang IV; Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA., Evans CM; Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA.; Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA., Schwartz DA; Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA. david.schwartz@ucdenver.edu.; Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA. david.schwartz@ucdenver.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2018 Dec 18; Vol. 9 (1), pp. 5363. Date of Electronic Publication: 2018 Dec 18.
DOI: 10.1038/s41467-018-07768-9
Abstrakt: 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.
Databáze: MEDLINE