title: A novel, protective role of ursodeoxycholate in bile-induced pancreatic ductal injury.
abstract: We have previously shown that chenodeoxycholic acid (CDCA) strongly inhibits pancreatic ductal HCO3 (-) secretion through the destruction of mitochondrial function, which may have significance in the pathomechanism of acute pancreatitis (AP). Ursodeoxycholic acid (UDCA) is known to protect the mitochondria against hydrophobic bile acids and has an ameliorating effect on cell death. Therefore, our aim was to investigate the effect of UDCA pretreatment on CDCA-induced pancreatic ductal injury. Guinea pig intrainterlobular pancreatic ducts were isolated by collagenase digestion. Ducts were treated with UDCA for 5 and 24 h, and the effect of CDCA on intracellular Ca(2+) concentration ([Ca(2+)]i), intracellular pH (pHi), morphological and functional changes of mitochondria, and the rate of apoptosis were investigated. AP was induced in rat by retrograde intraductal injection of CDCA (0.5%), and the disease severity of pancreatitis was assessed by measuring standard laboratory and histological parameters. Twenty-four-hour pretreatment of pancreatic ducts with 0.5 mM UDCA significantly reduced the rate of ATP depletion, mitochondrial injury, and cell death induced by 1 mM CDCA and completely prevented the inhibitory effect of CDCA on acid-base transporters. UDCA pretreatment had no effect on CDCA-induced Ca(2+) signaling. Oral administration of UDCA (250 mg/kg) markedly reduced the severity of CDCA-induced AP. Our results clearly demonstrate that UDCA 1) suppresses the CDCA-induced pancreatic ductal injury by reducing apoptosis and mitochondrial damage and 2) reduces the severity of CDCA-induced AP. The protective effect of UDCA against hydrophobic bile acids may represent a novel therapeutic target in the treatment of biliary AP.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary;
authors.forename: Máté
authors.initials: M
authors.lastname: Katona
authors.affiliation: Institute for Translational Medicine and First Department of Medicine, University of Pécs, Pécs, Hungary; First Department of Medicine, University of Szeged, Szeged, Hungary; MTA-SZTE Translational Gastroenterology Research Group, University of Szeged, Szeged, Hungary;
authors.forename: Péter
authors.initials: P
authors.lastname: Hegyi
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary;
authors.forename: Balázs
authors.initials: B
authors.lastname: Kui
authors.affiliation: Department of Pathophysiology, University of Szeged, Szeged, Hungary; and Department of Pathophysiology, University of Szeged, Szeged, Hungary; and.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Balla
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary; Department of Pathophysiology, University of Szeged, Szeged, Hungary; and.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Rakonczay
authors.affiliation: Department of Pathology, University of Szeged, Szeged, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Rázga
authors.affiliation: Department of Pathology, University of Szeged, Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Tiszlavicz
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary;
authors.forename: József
authors.initials: J
authors.lastname: Maléth
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; venglovecz.viktoria@med.u-szeged.hu.
authors.forename: Viktória
authors.initials: V
authors.lastname: Venglovecz
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001647:Bile Acids and Salts; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002635:Chenodeoxycholic Acid; D004847:Epithelial Cells / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D010183:Pancreatic Ducts / Q000293:injuries*; D010195:Pancreatitis / Q000139:chemically induced* / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
chemical_list: D001647:Bile Acids and Salts; D005765:Gastrointestinal Agents; D002635:Chenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D000255:Adenosine Triphosphate
keywords: acute pancreatitis; chenodeoxycholic acid; epithelial cells; mitochondria; ursodeoxycholic acid