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MUCOSAL BIOLOGY

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

¹Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina; and ²Sucampo Pharmaceuticals, Incorporated, Bethesda, Maryland

Submitted 1 May 2006 ; accepted in final form 11 October 2006

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 (I_sc) 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 (TER = 26 ·cm²; P < 0.01). However, lubiprostone (1 µM) stimulated higher elevations in TER despite lower I_sc 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.

ischemia; type 2 chloride channels; repair

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