Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone

Adam J. Moeser, Prashant K. Nighot, Kory J. Engelke, Ryuji Ueno, Anthony T. Blikslager

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77 Scopus citations

Abstract

Previous studies utilizing an ex vivo porcine model of intestinal ischemic injury demonstrated that prostaglandin (PG)E2 stimulates repair of mucosal barrier function via a mechanism involving Cl- secretion and reductions in paracellular permeability. Further experiments revealed that the signaling mechanism for PGE2-induced mucosal recovery was mediated via type-2 Cl- channels (ClC-2). Therefore, the objective of the present study was to directly investigate the role of ClC-2 in mucosal repair by evaluating mucosal recovery in ischemia-injured intestinal mucosa treated with the selective ClC-2 agonist lubiprostone. Ischemia-injured porcine ileal mucosa was mounted in Ussing chambers, and short-circuit current (Isc) and transepithelial electrical resistance (TER) were measured in response to lubiprostone. Application of 0.01-1 μM lubiprostone to ischemia-injured mucosa induced concentration-dependent increases in TER, with 1 μM lubiprostone stimulating a twofold increase in TER (ΔTER = 26 Ω · cm2; P < 0.01). However, lubiprostone (1 μM) stimulated higher elevations in TER despite lower Isc responses compared with the nonselective secretory agonist PGE2 (1 μM). Furthermore, lubiprostone significantly (P < 0.05) reduced mucosal-to-serosal fluxes of 3H-labeled mannitol to levels comparable to those of normal control tissues and restored occludin localization to tight junctions. Activation of ClC-2 with the selective agonist lubiprostone stimulated elevations in TER and reductions in mannitol flux in ischemia-injured intestine associated with structural changes in tight junctions. Prostones such as lubiprostone may provide a selective and novel pharmacological mechanism of accelerating recovery of acutely injured intestine compared with the nonselective action of prostaglandins such as PGE2.

Original languageEnglish (US)
Pages (from-to)G647-G656
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume292
Issue number2
DOIs
StatePublished - Feb 2007

All Science Journal Classification (ASJC) codes

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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