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)E(2) 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 microM lubiprostone to ischemia-injured mucosa induced concentration-dependent increases in TER, with 1 microM lubiprostone stimulating a twofold increase in TER (DeltaTER = 26 Omega.cm(2); P < 0.01). However, lubiprostone (1 microM) stimulated higher elevations in TER despite lower I(sc) responses compared with the nonselective secretory agonist PGE(2) (1 microM). Furthermore, lubiprostone significantly (P < 0.05) reduced mucosal-to-serosal fluxes of (3)H-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).
Moeser
Adam J
AJ
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA.
Nighot
Prashant K
PK
Engelke
Kory J
KJ
Ueno
Ryuji
R
Blikslager
Anthony T
AT
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002034:Bumetanide / Q000494:pharmacology; D000090007:CLC-2 Chloride Channels; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D002712:Chlorides / Q000494:pharmacology; D003106:Colon / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors; D015232:Dinoprostone / Q000494:pharmacology; D017097:Electric Impedance; D004594:Electrophysiology; D005227:Fatty Acids / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D007082:Ileum / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology; D000068238:Lubiprostone; D008297:Male; D008353:Mannitol / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D062793:Occludin; D010539:Permeability; D020127:Recovery of Function / Q000187:drug effects; D034421:Sus scrofa; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D017967:Zinc Compounds / Q000494:pharmacology
D000090007:CLC-2 Chloride Channels; D065101:Chloride Channel Agonists; D018118:Chloride Channels; D002712:Chlorides; D005227:Fatty Acids; D008565:Membrane Proteins; C416188:N-(4-methylphenylsulfonyl)-N'-(4-trifluoromethylphenyl)urea; D062793:Occludin; D017967:Zinc Compounds; D002034:Bumetanide; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D008353:Mannitol; D000068238:Lubiprostone; C016837:zinc chloride; D014508:Urea; D000527:Alprostadil; D015232:Dinoprostone; D007213:Indomethacin