Ductal Mucus Obstruction and Reduced Fluid Secretion Are Early Defects in Chronic Pancreatitis.

Anita Balázs,Zhe Zhou-Suckow,Matthias Sendler,László Tiszlavicz,Julia Duerr,Zoltán Rakonczay,Balázs Kui,József Maléth,Peter Hegyi,Julia Mayerle,Marcus A Mall,Jolanthe Schatterny,Zsolt Balla,Jens-P Kühn

doi:10.3389/fphys.2018.00632

Abstract

Objective: Defective mucus production in the pancreas may be an important factor in the initiation and progression of chronic pancreatitis (CP), therefore we aimed to (i) investigate the qualitative and quantitative changes of mucus both in human CP and in an experimental pancreatitis model and (ii) to correlate the mucus phenotype with epithelial ion transport function.Design: Utilizing human tissue samples and a murine model of cerulein induced CP we measured pancreatic ductal mucus content by morphometric analysis and the relative expression of different mucins in health and disease. Pancreatic fluid secretion in CP model was measured in vivo by magnetic resonance cholangiopancreatography (MRCP) and in vitro on cultured pancreatic ducts. Time-changes of ductal secretory function were correlated to those of the mucin production.Results: We demonstrate increased mucus content in the small pancreatic ducts in CP. Secretory mucins MUC6 and MUC5B were upregulated in human, Muc6 in mouse CP. In vivo and in vitro fluid secretion was decreased in cerulein-induced CP. Analysis of time-course changes showed that impaired ductal ion transport is paralleled by increased Muc6 expression.Conclusion: Mucus accumulation in the small ducts is a combined effect of mucus hypersecretion and epithelial fluid secretion defect, which may lead to ductal obstruction. These results suggest that imbalance of mucus homeostasis may have an important role in the early-phase development of CP, which may have novel diagnostic and therapeutic implications.

Highlights

Chronic pancreatitis (CP) is a self-sustaining, progressive inflammatory disease, associated with an increased risk for developing pancreatic cancer, impaired quality of life, and markedly decreased life expectancy (Kleeff et al, 2017)
Mucus Content Is Increased in Small Ducts in Chronic Pancreatitis
Morphometric analysis revealed a significant increase of epithelial mucus content in small ducts, while no difference was observed in large interlobular ducts (Figure 1E)

Summary

Introduction

Chronic pancreatitis (CP) is a self-sustaining, progressive inflammatory disease, associated with an increased risk for developing pancreatic cancer, impaired quality of life, and markedly decreased life expectancy (Kleeff et al, 2017). There are various reports on the natural prevalence of mucinous cell hypertrophy (Walters, 1965; Cubilla and Fitzgerald, 1976; Allen-Mersh, 1988; Sipos et al, 2009), a comparative study found higher frequency in CP patients, than in controls without pancreatic disease (60% and 16%, respectively) (Andea et al, 2003), suggestive of increased mucus secretion Supporting this notion, there are reports of increased mucopolysaccharide concentration (Wakabayashi and Takeda, 1976) and abundant mucus content of precipitated plugs in the pancreatic juice of CP patients (Harada et al, 1981). Several studies led to the general belief that protein precipitates originate solely from acinar cell secretion (Guy et al, 1983; Freedman et al, 1993; Ko et al, 2012), which could be due to a number of challenges of mucus biochemistry, as isolating, detecting, and visualizing large molecular weight and highly glycosylated mucins require specific methodology (Mucins, 2018)

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Discussion

Conclusion