title: A weakly acidic solution containing deoxycholic acid induces esophageal epithelial apoptosis and impairs integrity in an in vivo perfusion rabbit model.
abstract: Impaired esophageal mucosal integrity may be an important contributor in the pathophysiology of gastroesophageal reflux disease (GERD). Nevertheless, the effect of potentially harmful agents on epithelial integrity is mainly evaluated in vitro for a short period of time and the possible induction of epithelial apoptosis has been neglected. Our objective was to assess the effect of an acidic and weakly acidic solution containing deoxycholic acid (DCA) on the esophageal epithelium in an in vivo rabbit model of esophageal perfusion and to evaluate the role of the epithelial apoptosis. The esophagus of 55 anesthetized rabbits was perfused for 30 min with different solutions at pH 7.2, pH 5.0, pH 1.0, and pH 5.0 containing 200 and 500 μM DCA. Thereafter, animals were euthanized immediately or at 24 or 48 h after the perfusion. Transepithelial electrical resistance, epithelial dilated intercellular spaces, and apoptosis were assessed in Ussing chambers, by transmission electron microscopy, and by TUNEL staining, respectively. No macroscopic or major microscopic alterations were observed after the esophageal perfusions. The acidic and weakly acidic solution containing DCA induced similar long-lasting functional impairment of the epithelial integrity but different ultrastructural morphological changes. Only the solution containing DCA induced epithelial apoptosis in vivo and in vitro in rabbit and human tissue. In contrast to acid, a weakly acidic solution containing DCA induces epithelial apoptosis and a long-lasting impaired mucosal integrity. The presence of apoptotic cells in the esophageal epithelium may be used as a marker of impaired integrity and/or bile reflux exposure.
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit (KU) Leuven, Leuven, Belgium;
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Pardon
authors.affiliation: Digestive Diseases Research Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain;
authors.forename: Maria
authors.initials: M
authors.lastname: Vicario
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit (KU) Leuven, Leuven, Belgium;
authors.forename: Hanne
authors.initials: H
authors.lastname: Vanheel
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit (KU) Leuven, Leuven, Belgium;
authors.forename: Tim
authors.initials: T
authors.lastname: Vanuytsel
authors.affiliation: Abdominal Transplant Surgery, University Hospitals Leuven, Belgium and Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium;
authors.forename: Laurens J
authors.initials: LJ
authors.lastname: Ceulemans
authors.affiliation: Department of Pathology, Institute of Pathology, Bayreuth Hospital, Bayreuth, Germany; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain;
authors.forename: Marcel
authors.initials: M
authors.lastname: Jimenez
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit (KU) Leuven, Leuven, Belgium;
authors.forename: Jan
authors.initials: J
authors.lastname: Tack
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit (KU) Leuven, Leuven, Belgium; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; ricard.farre@med.kuleuven.be.
authors.forename: Ricard
authors.initials: R
authors.lastname: Farré
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003840:Deoxycholic Acid / Q000633:toxicity*; D017097:Electric Impedance; D000071041:Esophageal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005110:Extracellular Space / Q000187:drug effects; D005764:Gastroesophageal Reflux / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D010477:Perfusion; D011817:Rabbits; D013997:Time Factors
chemical_list: D003840:Deoxycholic Acid
keywords: GERD; apoptosis; bile acid; permeability; weakly acidic reflux