ClC-2 chloride secretion mediates prostaglandin-induced recovery of barrier function in ischemia-injured porcine ileum.


Journal Article

BACKGROUND & AIMS:Ischemia results in the breakdown of the intestinal barrier, predisposing patients to sepsis and multiple organ failure. Prostaglandins play a critical role in mediating recovery of barrier function in ischemia-injured intestine through a mechanism involving stimulation of Cl - secretion. In the present study, we investigated the contributory role of individual Cl - channels in the recovery of barrier function in ischemia-injured porcine ileum. METHODS:Ischemia-injured porcine ileal mucosa was mounted in Ussing chambers. Short-circuit current (Isc) and transepithelial resistance (TER) were measured in response to prostaglandin E 2 (PGE 2 ) and pharmacologic inhibitors of epithelial Cl - channels. Immunoassays were used to assess the expression and localization of ion channels. RESULTS:Application of PGE 2 to ischemia-injured ileal mucosa stimulated increases in Isc, an indicator of Cl - secretion, that was followed by marked increases in TER, an indicator of barrier function recovery. In vitro studies revealed that although PGE 2 induced Cl - secretion via at least 3 distinct secretory pathways, recovery of barrier function was initiated by Cl - secretion via ClC-2 Cl - channels co-expressed with occludin and localized to tight junctions within restituting epithelium. Intravenous administration of furosemide to pigs subjected to 1 hour of ileal ischemia impaired recovery of barrier function, as evidenced by decreased TER and increased mucosal-to-serosal 3 H-mannitol flux after a 2-hour reperfusion/recovery period, confirming an important role for Cl - secretory pathways in vivo. CONCLUSIONS:ClC-2-mediated intestinal Cl - secretion restores TER in ischemia-injured intestine. These data may provide the basis for targeted pharmacologic therapy for diseases associated with impaired barrier function.

Full Text

Cited Authors

  • Moeser, AJ; Haskell, MM; Shifflett, DE; Little, D; Schultz, BD; Blikslager, AT

Published Date

  • September 2004

Published In

Volume / Issue

  • 127 / 3

Start / End Page

  • 802 - 815

PubMed ID

  • 15362036

Pubmed Central ID

  • 15362036

Electronic International Standard Serial Number (EISSN)

  • 1528-0012

International Standard Serial Number (ISSN)

  • 0016-5085

Digital Object Identifier (DOI)

  • 10.1053/j.gastro.2004.06.004


  • eng