Original Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Sep 14, 2012; 18(34): 4684-4692
Published online Sep 14, 2012. doi: 10.3748/wjg.v18.i34.4684
Gastro protective properties of the novel prostone SPI-8811 against acid-injured porcine mucosa
Meghali Nighot, Adam Moeser, Ryuji Ueno, Anthony Blikslager
Meghali Nighot, Anthony Blikslager, Departments of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, United States
Adam Moeser, Departments of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, United States
Ryuji Ueno, Departments of Sucampo Pharmaceuticals, Inc., Bethesda, MD 20810, United States
Author contributions: All the authors contributed equally to this manuscript.
Supported by Sucampo Pharmaceuticals Inc., Bethesda, MD
Correspondence to: Dr. Anthony Blikslager, Departments of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, United States. anthony_blikslager@ncsu.edu
Telephone: +1-919-5137725 Fax: +1-919-5136336
Received: October 29, 2011
Revised: July 23, 2012
Accepted: August 14, 2012
Published online: September 14, 2012
Abstract

AIM: 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.cm2vs 100 Ω.cm2) and abolished increases in flux (3H-mannitol flux, 0.10 μmol/L.cm2vs 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.

CONCLUSION: 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.

Keywords: Stomach, Mucosal permeability, ClC-2 chloride channel, Tight junction