TY - JOUR
T1 - Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone
AU - Moeser, Adam J.
AU - Nighot, Prashant K.
AU - Engelke, Kory J.
AU - Ueno, Ryuji
AU - Blikslager, Anthony T.
PY - 2007/2
Y1 - 2007/2
N2 - 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.
AB - 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.
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U2 - 10.1152/ajpgi.00183.2006
DO - 10.1152/ajpgi.00183.2006
M3 - Article
C2 - 17053162
AN - SCOPUS:33847009038
SN - 0193-1857
VL - 292
SP - G647-G656
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 2
ER -