title: Gastro protective properties of the novel prostone SPI-8811 against acid-injured porcine mucosa.
abstract: OBJECTIVE
  To evaluate the protective properties of novel prostone ClC-2 agonist SPI-8811 in porcine model of gastric acid injury.
  
  
  METHODS
  Porcine gastric mucosa was mounted in Ussing chambers and injured by bathing mucosal tissues in an HCl Ringer's solution (pH = 1.5) with or without SP1-8811 (1 μmol/L), cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor (inhibitor 172, 10 μmol/L, apical) and ClC-2 inhibitor ZnCl₂, 300 μmol/L, apical), on the apical surface of tissues. Transepithelial resistance and mucosal-to-serosal ³H-mannitol fluxes were measured over a 90-min period. Tissues were analyzed by morph metric techniques, Immunofluorescence and by western blots.
  
  
  RESULTS
  Compared with control tissues, acid exposure decreased transepithelial electrical resistance (TER) and increased ³H-mannitol flux. Pretreatment of gastric mucosa with SPI-8811 was protective against acid-induced decreases in TER (TER, 50 Ω.cm² vs 100 Ω.cm²) and abolished increases in flux (³H-mannitol flux, 0.10 μmol/L.cm² vs 0.04 μmol/L.cm²). Evidence of histological damage in the presence of acid was markedly attenuated by SPI-0811. Immunofluorescence and western analysis for occludin revealed enhanced localization to the region of the tight junction (TJ) after treatment with SPI-8811. Pretreatment with the ClC-2 inhibitor ZnCl₂, but not the selective CFTR inhibitor 172, attenuated SPI-8811-mediated mucosal protection, suggesting a role for ClC-2. Prostone may serve both protective and reparative roles in injured tissues.
  
  
  CONCLUSIONS
  ClC-2 agonist SPI-8811 stimulated enhancement of mucosal barrier function by protecting TJ protein occludin in porcine gastric mucosa and thus protected the gastric acid injury in porcine stomach.
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA.
authors.forename: Meghali
authors.initials: M
authors.lastname: Nighot
authors.forename: Adam
authors.initials: A
authors.lastname: Moeser
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ueno
authors.forename: Anthony
authors.initials: A
authors.lastname: Blikslager
mesh_terms: D000818:Animals; D000090007:CLC-2 Chloride Channels; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000032:analysis; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000032:analysis; D017097:Electric Impedance; D005753:Gastric Mucosa / Q000187:drug effects*; D008353:Mannitol / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010539:Permeability; D011453:Prostaglandins / Q000494:pharmacology*; D013552:Swine
chemical_list: D000090007:CLC-2 Chloride Channels; D065101:Chloride Channel Agonists; D018118:Chloride Channels; D011453:Prostaglandins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D008353:Mannitol; C581134:cobiprostone