Excess Secretion of Gel-Forming Mucins and Associated Innate Defense Proteins with Defective Mucin Un-Packaging Underpin Gallbladder Mucocele Formation in Dogs.

Mehmet Kesimer,Jody L Gookin,Kyle G Mathews,Giorgia Radicioni,John Cullen,Gabriela Seiler,Rui Cao,Wei-Chun Chin

doi:10.1371/journal.pone.0138988

Mehmet Kesimer, Jody L Gookin + Show 6 more

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https://doi.org/10.1371/journal.pone.0138988

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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.

Highlights

The gallbladder is lined by a layer of epithelial cells that serve at the frontline of defense against bile; one of the most noxious productions by the human body
The breeds of dog affected and endocrinopathies commonly associated with gallbladder mucocele formation have existed long before emergence of the disease as a clinical entity and are not found in all dogs diagnosed with the disease
A theory that poor gallbladder motility[16] causes gallbladder mucocele formation is difficult to prove once the gallbladder is filled with mucus and gallbladder paresis does not result in mucocele formation in people

Summary

Introduction

The gallbladder is lined by a layer of epithelial cells that serve at the frontline of defense against bile; one of the most noxious productions by the human body. There are 4 major gel-forming mucins found at human mucosal surfaces, MUC2, MUC5AC, MUC5B, and MUC6 Their localization in the body depends on the functional requirements of the epithelial barrier. As a basis for understanding the pathogenesis of mucocele formation in dogs, these studies are the first to investigate normal and affected gallbladders for ostensibly mechanistic causes for abnormal mucus formation. In view of this objective, here we sought to determine the source of mucin secretion, identity and properties of the mucins involved, and composition of the mucin-associated proteome participating in formation of the adhesive, rubber-like mucus that accumulates during gallbladder mucocele formation

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