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

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 PGE(2)-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 mu M lubiprostone to ischemia-injured mucosa induced concentration-dependent increases in TER, with 1 mu M lubiprostone stimulating a twofold increase in TER ( Delta TER = 26 Omega center dot cm(2); P < 0.01). However, lubiprostone ( 1 mu M) stimulated higher elevations in TER despite lower Isc responses compared with the nonselective secretory agonist PGE(2) ( 1 mu M). Furthermore, lubiprostone significantly ( P < 0.05) reduced mucosal- to-serosal fluxes of H-3-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 PGE(2).