title: Excess Secretion of Gel-Forming Mucins and Associated Innate Defense Proteins with Defective Mucin Un-Packaging Underpin Gallbladder Mucocele Formation in Dogs.
abstract: Mucosal protection of the gallbladder is vital yet we know very little about the mechanisms involved. In domestic dogs, an emergent syndrome referred to as gallbladder mucocele formation is characterized by excessive secretion of abnormal mucus that results in obstruction and rupture of the gallbladder. The cause of gallbladder mucocele formation is unknown. In these first mechanistic studies of this disease, we investigated normal and mucocele-forming dog gallbladders to determine the source, identity, biophysical properties, and protein associates of the culprit mucins with aim to identify causes for abnormal mucus behavior. We established that mucocele formation involves an adoptive excess secretion of gel forming mucins with abnormal properties by the gallbladder epithelium. The mucus is characterized by a disproportionally significant increase in Muc5ac relative to Muc5b, defective mucin un-packaging, and mucin-interacting innate defense proteins that are capable of dramatically altering the physical and functional properties of mucus. These findings provide an explanation for abnormal mucus behavior and based on similarity to mucus observed in the airways of people with cystic fibrosis, suggest that abnormal mechanisms for maintenance of gallbladder epithelial hydration may be an instigating factor for mucocele formation in dogs.
authors.affiliation: Department of Pathology and Laboratory Medicine and Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kesimer
authors.affiliation: Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Cullen
authors.affiliation: Department of Pathology and Laboratory Medicine and Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Cao
authors.affiliation: Department of Pathology and Laboratory Medicine and Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Radicioni
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Mathews
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Seiler
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Jody L
authors.initials: JL
authors.lastname: Gookin
mesh_terms: D000818:Animals; D004285:Dogs; D004847:Epithelial Cells / Q000473:pathology / Q000648:ultrastructure; D004848:Epithelium / Q000473:pathology; D005089:Exocytosis; D005704:Gallbladder / Q000000981:diagnostic imaging / Q000473:pathology* / Q000601:surgery / Q000648:ultrastructure; D005782:Gels / Q000378:metabolism*; D006031:Glycosylation; D007113:Immunity, Innate; D015151:Immunoblotting; D008297:Male; D013058:Mass Spectrometry; D055271:Mucin 5AC / Q000378:metabolism*; D055257:Mucin-5B / Q000378:metabolism*; D009078:Mucocele / Q000000981:diagnostic imaging / Q000473:pathology* / Q000601:surgery; D009092:Mucous Membrane / Q000473:pathology; D009093:Mucus / Q000378:metabolism; D010641:Phenotype; D012421:Rupture; D014463:Ultrasonography
chemical_list: D005782:Gels; D055271:Mucin 5AC; D055257:Mucin-5B