Hypoxia inhibits colonic ion transport via activation of AMP kinase.

Hdl Handle:
http://hdl.handle.net/10147/207012
Title:
Hypoxia inhibits colonic ion transport via activation of AMP kinase.
Authors:
Collins, Danielle; Kopic, Sascha; Bachlechner, Julia; Ritter, Markus; Winter, Desmond C; Geibel, John P
Affiliation:
University College Dublin and St Vincent's University Hospital, Elm Park, Dublin,, Ireland.
Citation:
Ann Surg. 2011 Dec;254(6):957-63.
Journal:
Annals of surgery
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207012
DOI:
10.1097/SLA.0b013e31821d477f
PubMed ID:
21562404
Abstract:
BACKGROUND AND AIMS: Mucosal hypoxia is a common endpoint for many pathological processes including ischemic colitis, colonic obstruction and anastomotic failure. Previous studies suggest that hypoxia modulates colonic mucosal function through inhibition of chloride secretion. However, the molecular mechanisms underlying this observation are poorly understood. AMP-activated protein kinase (AMPK) is a metabolic energy regulator found in a wide variety of cells and has been linked to cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride secretion in several different tissues. We hypothesized that AMPK mediates many of the acute effects of hypoxia on human and rat colonic electrolyte transport. METHODS: The fluorescent chloride indicator dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide was used to measure changes in intracellular chloride concentrations in isolated single rat colonic crypts. Ussing chamber experiments in human colonic mucosa were conducted to evaluate net epithelial ion transport. RESULTS: This study demonstrates that acute hypoxia inhibits electrogenic chloride secretion via AMPK mediated inhibition of CFTR. Pre-treatment of tissues with the AMPK inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo [1,5-a] pyrimidine (compound C) in part reversed the effects of acute hypoxia on chloride secretion. CONCLUSION: We therefore suggest that AMPK is a key component of the adaptive cellular response to mucosal hypoxia in the colon. Furthermore, AMPK may represent a potential therapeutic target in diseased states or in prevention of ischemic intestinal injury.
Language:
eng
MeSH:
AMP-Activated Protein Kinases/*physiology; Animals; Cell Hypoxia/*physiology; Chloride Channels/*physiology; Chlorides/*metabolism; Colon/*blood supply; Cystic Fibrosis Transmembrane Conductance Regulator/*antagonists & inhibitors; Humans; Intestinal Mucosa/*blood supply; Ischemia/*physiopathology; Male; Membrane Potentials/physiology; Microscopy, Fluorescence; Rats; Rats, Sprague-Dawley
ISSN:
1528-1140 (Electronic); 0003-4932 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorCollins, Danielleen_GB
dc.contributor.authorKopic, Saschaen_GB
dc.contributor.authorBachlechner, Juliaen_GB
dc.contributor.authorRitter, Markusen_GB
dc.contributor.authorWinter, Desmond Cen_GB
dc.contributor.authorGeibel, John Pen_GB
dc.date.accessioned2012-02-01T10:28:08Z-
dc.date.available2012-02-01T10:28:08Z-
dc.date.issued2012-02-01T10:28:08Z-
dc.identifier.citationAnn Surg. 2011 Dec;254(6):957-63.en_GB
dc.identifier.issn1528-1140 (Electronic)en_GB
dc.identifier.issn0003-4932 (Linking)en_GB
dc.identifier.pmid21562404en_GB
dc.identifier.doi10.1097/SLA.0b013e31821d477fen_GB
dc.identifier.urihttp://hdl.handle.net/10147/207012-
dc.description.abstractBACKGROUND AND AIMS: Mucosal hypoxia is a common endpoint for many pathological processes including ischemic colitis, colonic obstruction and anastomotic failure. Previous studies suggest that hypoxia modulates colonic mucosal function through inhibition of chloride secretion. However, the molecular mechanisms underlying this observation are poorly understood. AMP-activated protein kinase (AMPK) is a metabolic energy regulator found in a wide variety of cells and has been linked to cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride secretion in several different tissues. We hypothesized that AMPK mediates many of the acute effects of hypoxia on human and rat colonic electrolyte transport. METHODS: The fluorescent chloride indicator dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide was used to measure changes in intracellular chloride concentrations in isolated single rat colonic crypts. Ussing chamber experiments in human colonic mucosa were conducted to evaluate net epithelial ion transport. RESULTS: This study demonstrates that acute hypoxia inhibits electrogenic chloride secretion via AMPK mediated inhibition of CFTR. Pre-treatment of tissues with the AMPK inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo [1,5-a] pyrimidine (compound C) in part reversed the effects of acute hypoxia on chloride secretion. CONCLUSION: We therefore suggest that AMPK is a key component of the adaptive cellular response to mucosal hypoxia in the colon. Furthermore, AMPK may represent a potential therapeutic target in diseased states or in prevention of ischemic intestinal injury.en_GB
dc.language.isoengen_GB
dc.subject.meshAMP-Activated Protein Kinases/*physiologyen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshCell Hypoxia/*physiologyen_GB
dc.subject.meshChloride Channels/*physiologyen_GB
dc.subject.meshChlorides/*metabolismen_GB
dc.subject.meshColon/*blood supplyen_GB
dc.subject.meshCystic Fibrosis Transmembrane Conductance Regulator/*antagonists & inhibitorsen_GB
dc.subject.meshHumansen_GB
dc.subject.meshIntestinal Mucosa/*blood supplyen_GB
dc.subject.meshIschemia/*physiopathologyen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMembrane Potentials/physiologyen_GB
dc.subject.meshMicroscopy, Fluorescenceen_GB
dc.subject.meshRatsen_GB
dc.subject.meshRats, Sprague-Dawleyen_GB
dc.titleHypoxia inhibits colonic ion transport via activation of AMP kinase.en_GB
dc.contributor.departmentUniversity College Dublin and St Vincent's University Hospital, Elm Park, Dublin,, Ireland.en_GB
dc.identifier.journalAnnals of surgeryen_GB
dc.description.provinceLeinster-

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