title: Defective postsecretory maturation of MUC5B mucin in cystic fibrosis airways.
abstract: In cystic fibrosis (CF), airway mucus becomes thick and viscous, and its clearance from the airways is impaired. The gel-forming mucins undergo an ordered "unpacking/maturation" process after granular release that requires an optimum postsecretory environment, including hydration and pH. We hypothesized that this unpacking process is compromised in the CF lung due to abnormal transepithelial fluid transport that reduces airway surface hydration and alters ionic composition. Using human tracheobronchial epithelial cells derived from non-CF and CF donors and mucus samples from human subjects and domestic pigs, we investigated the process of postsecretory mucin unfolding/maturation, how these processes are defective in CF airways, and the probable mechanism underlying defective unfolding. First, we found that mucins released into a normal lung environment transform from a compact granular form to a linear form. Second, we demonstrated that this maturation process is defective in the CF airway environment. Finally, we demonstrated that independent of HCO3-and pH levels, airway surface dehydration was the major determinant of this abnormal unfolding process. This defective unfolding/maturation process after granular release suggests that the CF extracellular environment is ion/water depleted and likely contributes to abnormal mucus properties in CF airways prior to infection and inflammation.
authors.affiliation: Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Lubna H
authors.initials: LH
authors.lastname: Abdullah
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Evans
authors.affiliation: Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: T Tiffany
authors.initials: TT
authors.lastname: Wang
authors.affiliation: Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Amina A
authors.initials: AA
authors.lastname: Ford
authors.affiliation: Lineberger Cancer Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Makhov
authors.affiliation: Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Coakley
authors.affiliation: Lineberger Cancer Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Griffith
authors.affiliation: Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: C William
authors.initials: CW
authors.lastname: Davis
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Ballard
authors.affiliation: Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kesimer
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002034:Bumetanide / Q000494:pharmacology; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D055257:Mucin-5B / Q000378:metabolism*; D013552:Swine; D014132:Trachea / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: C524578:MUC5B protein, human; D055257:Mucin-5B; D002034:Bumetanide; C039465:5-dimethylamiloride; D000584:Amiloride