title: Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis.
abstract: OBJECTIVE
  Excessive consumption of ethanol is one of the most common causes of acute and chronic pancreatitis. Alterations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) also cause pancreatitis. However, little is known about the role of CFTR in the pathogenesis of alcohol-induced pancreatitis.
  
  
  METHODS
  We measured CFTR activity based on chloride concentrations in sweat from patients with cystic fibrosis, patients admitted to the emergency department because of excessive alcohol consumption, and healthy volunteers. We measured CFTR levels and localization in pancreatic tissues and in patients with acute or chronic pancreatitis induced by alcohol. We studied the effects of ethanol, fatty acids, and fatty acid ethyl esters on secretion of pancreatic fluid and HCO3(-), levels and function of CFTR, and exchange of Cl(-) for HCO3(-) in pancreatic cell lines as well as in tissues from guinea pigs and CFTR knockout mice after administration of alcohol.
  
  
  RESULTS
  Chloride concentrations increased in sweat samples from patients who acutely abused alcohol but not in samples from healthy volunteers, indicating that alcohol affects CFTR function. Pancreatic tissues from patients with acute or chronic pancreatitis had lower levels of CFTR than tissues from healthy volunteers. Alcohol and fatty acids inhibited secretion of fluid and HCO3(-), as well as CFTR activity, in pancreatic ductal epithelial cells. These effects were mediated by sustained increases in concentrations of intracellular calcium and adenosine 3',5'-cyclic monophosphate, depletion of adenosine triphosphate, and depolarization of mitochondrial membranes. In pancreatic cell lines and pancreatic tissues of mice and guinea pigs, administration of ethanol reduced expression of CFTR messenger RNA, reduced the stability of CFTR at the cell surface, and disrupted folding of CFTR at the endoplasmic reticulum. CFTR knockout mice given ethanol or fatty acids developed more severe pancreatitis than mice not given ethanol or fatty acids.
  
  
  CONCLUSIONS
  Based on studies of human, mouse, and guinea pig pancreata, alcohol disrupts expression and localization of the CFTR. This appears to contribute to development of pancreatitis. Strategies to increase CFTR levels or function might be used to treat alcohol-associated pancreatitis.
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Maléth
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Anita
authors.initials: A
authors.lastname: Balázs
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Petra
authors.initials: P
authors.lastname: Pallagi
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Balla
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Kui
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Máté
authors.initials: M
authors.lastname: Katona
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary; Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Linda
authors.initials: L
authors.lastname: Judák
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Németh
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Lajos V
authors.initials: LV
authors.lastname: Kemény
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Rakonczay
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Viktória
authors.initials: V
authors.lastname: Venglovecz
authors.affiliation: Department of Laboratory Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Imre
authors.initials: I
authors.lastname: Földesi
authors.affiliation: Department of Emergency Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Pető
authors.affiliation: Second Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Áron
authors.initials: Á
authors.lastname: Somorácz
authors.affiliation: Second Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Borka
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Doranda
authors.initials: D
authors.lastname: Perdomo
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Gergely L
authors.initials: GL
authors.lastname: Lukacs
authors.affiliation: Institute for Cell & Molecular Biosciences, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Gray
authors.affiliation: Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, England.
authors.forename: Stefania
authors.initials: S
authors.lastname: Monterisi
authors.affiliation: Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, England.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zaccolo
authors.affiliation: Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.affiliation: Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.affiliation: Institute of Radiology, University Medicine, Ernst Moritz University, Greifswald, Germany.
authors.forename: Jens-Peter
authors.initials: JP
authors.lastname: Kühn
authors.affiliation: Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.affiliation: Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, Boston, Massachusetts.
authors.forename: Miklós
authors.initials: M
authors.lastname: Sahin-Tóth
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary; MTA-SZTE Lendület Translational Gastroenterology Research Group, Szeged, Hungary. Electronic address: hegyi.peter@med.u-szeged.hu.
authors.forename: Péter
authors.initials: P
authors.lastname: Hegyi
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D000431:Ethanol / Q000633:toxicity*; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D009154:Mutation; D010195:Pancreatitis / Q000139:chemically induced*; D017510:Protein Folding / Q000187:drug effects
chemical_list: D001639:Bicarbonates; D018118:Chloride Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000431:Ethanol; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: Alcoholism; Cl(−) Channel; Duct; Exocrine Pancreas