title: The role of pancreatic ductal secretion in protection against acute pancreatitis in mice*.
abstract: OBJECTIVE
  A common potentially fatal disease of the pancreas is acute pancreatitis, for which there is no treatment. Most studies of this disorder focus on the damage to acinar cells since they are assumed to be the primary target of multiple stressors affecting the pancreas. However, increasing evidence suggests that the ducts may also have a crucial role in induction of the disease. To test this hypothesis, we sought to determine the specific role of the duct in the induction of acute pancreatitis using well-established disease models and mice with deletion of the Na/H exchanger regulatory factor-1 that have selectively impaired ductal function.
  
  
  METHODS
  Randomized animal study.
  
  
  METHODS
  Animal research laboratory.
  
  
  METHODS
  Wild-type and Na/H exchanger regulatory factor-1 knockout mice.
  
  
  METHODS
  Acute necrotizing pancreatitis was induced by i.p. administration of cerulein or by intraductal administration of sodium taurocholate. The pancreatic expression of Na/H exchanger regulatory factor-1 and cystic fibrosis transmembrane conductance regulator (a key player in the control of ductal secretion) was analyzed by immunohistochemistry. In vivo pancreatic ductal secretion was studied in anesthetized mice. Functions of pancreatic acinar and ductal cells as well as inflammatory cells were analyzed in vitro.
  
  
  RESULTS
  Deletion of Na/H exchanger regulatory factor-1 resulted in gross mislocalization of cystic fibrosis transmembrane conductance regulator, causing marked reduction in pancreatic ductal fluid and bicarbonate secretion. Importantly, deletion of Na/H exchanger regulatory factor-1 had no deleterious effect on functions of acinar and inflammatory cells. Deletion of Na/H exchanger regulatory factor-1, which specifically impaired ductal function, increased the severity of acute pancreatitis in the two mouse models tested.
  
  
  CONCLUSIONS
  Our findings provide the first direct evidence for the crucial role of ductal secretion in protecting the pancreas from acute pancreatitis and strongly suggest that improved ductal function should be an important modality in prevention and treatment of the disease.
authors.affiliation: 1First Department of Medicine, University of Szeged, Szeged, Hungary. 2Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 3Department of Pathology, University of Szeged, Szeged, Hungary. 4Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary. 5Department of Microbiology, University of Szeged, Szeged, Hungary. 6Institute of Surgical Research, University of Szeged, Szeged, Hungary. 7Department of Surgery, Tufts Medical Center, Boston, MA. 8Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary. 9Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
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authors.forename: Tamás
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authors.forename: Péter
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mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016009:Chi-Square Distribution; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism / Q000502:physiology; D010183:Pancreatic Ducts / Q000378:metabolism*; D019283:Pancreatitis, Acute Necrotizing / Q000378:metabolism* / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D012016:Reference Values; D012038:Regeneration / Q000502:physiology; D012680:Sensitivity and Specificity; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism
chemical_list: D026905:Amino Acid Transport Systems; D015415:Biomarkers; D010750:Phosphoproteins; D012333:RNA, Messenger; C483904:Slc36a1 protein, mouse; D017923:Sodium-Hydrogen Exchangers; D027981:Symporters; C093376:sodium-hydrogen exchanger regulatory factor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator