Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea.

Hdl Handle:
http://hdl.handle.net/10147/207228
Title:
Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea.
Authors:
Ward, Joseph B J; Lawler, Karen; Amu, Sylvie; Taylor, Cormac T; Fallon, Padraic G; Keely, Stephen J
Affiliation:
Molecular Medicine Laboratories, Royal College of Surgeons in Ireland, Beaumont, Hospital, Dublin, Ireland.
Citation:
FASEB J. 2011 Feb;25(2):535-43. Epub 2010 Oct 13.
Journal:
The FASEB journal : official publication of the Federation of American Societies , for Experimental Biology
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207228
DOI:
10.1096/fj.10-166983
PubMed ID:
20944011
Abstract:
Hydroxylases are oxygen-sensing enzymes that regulate cellular responses to hypoxia. Transepithelial Cl(-) secretion, the driving force for fluid secretion, is dependent on O(2) availability for generation of cellular energy. Here, we investigated the role of hydroxylases in regulating epithelial secretion and the potential for targeting these enzymes in treatment of diarrheal disorders. Ion transport was measured as short-circuit current changes across voltage-clamped monolayers of T(84) cells and mouse colon. The antidiarrheal efficacy of dimethyloxallyl glycine (DMOG) was tested in a mouse model of allergic disease. Hydroxylase inhibition with DMOG attenuated Ca(2+)- and cAMP-dependent secretory responses in voltage-clamped T(84) cells to 20.2 +/- 2.6 and 38.8 +/- 6.7% (n=16; P</=0.001) of those in control cells, respectively. Antisecretory actions of DMOG were time and concentration dependent, being maximal after 18 h of DMOG (1 mM) treatment. DMOG specifically inhibited Na(+)/K(+)-ATPase pump activity without altering its expression or membrane localization. In mice, DMOG inhibited agonist-induced secretory responses ex vivo and prevented allergic diarrhea in vivo. In conclusion, hydroxylases are important regulators of epithelial Cl(-) and fluid secretion and present a promising target for development of new drugs to treat transport disorders.
Language:
eng
MeSH:
Amino Acids, Dicarboxylic/*pharmacology; Animals; Calcium/metabolism; Calcium Signaling; Chlorides/metabolism; Colon/*cytology/drug effects/secretion; Cyclic AMP/metabolism; Diarrhea/*drug therapy/metabolism; Epithelial Cells/*metabolism; Gene Expression Regulation, Enzymologic/drug effects; Male; Mice; Mice, Inbred C57BL; Mixed Function Oxygenases/*antagonists & inhibitors; Patch-Clamp Techniques; Protein Subunits; Sodium-Potassium-Exchanging ATPase/metabolism
ISSN:
1530-6860 (Electronic); 0892-6638 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorWard, Joseph B Jen_GB
dc.contributor.authorLawler, Karenen_GB
dc.contributor.authorAmu, Sylvieen_GB
dc.contributor.authorTaylor, Cormac Ten_GB
dc.contributor.authorFallon, Padraic Gen_GB
dc.contributor.authorKeely, Stephen Jen_GB
dc.date.accessioned2012-02-01T10:02:29Z-
dc.date.available2012-02-01T10:02:29Z-
dc.date.issued2012-02-01T10:02:29Z-
dc.identifier.citationFASEB J. 2011 Feb;25(2):535-43. Epub 2010 Oct 13.en_GB
dc.identifier.issn1530-6860 (Electronic)en_GB
dc.identifier.issn0892-6638 (Linking)en_GB
dc.identifier.pmid20944011en_GB
dc.identifier.doi10.1096/fj.10-166983en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207228-
dc.description.abstractHydroxylases are oxygen-sensing enzymes that regulate cellular responses to hypoxia. Transepithelial Cl(-) secretion, the driving force for fluid secretion, is dependent on O(2) availability for generation of cellular energy. Here, we investigated the role of hydroxylases in regulating epithelial secretion and the potential for targeting these enzymes in treatment of diarrheal disorders. Ion transport was measured as short-circuit current changes across voltage-clamped monolayers of T(84) cells and mouse colon. The antidiarrheal efficacy of dimethyloxallyl glycine (DMOG) was tested in a mouse model of allergic disease. Hydroxylase inhibition with DMOG attenuated Ca(2+)- and cAMP-dependent secretory responses in voltage-clamped T(84) cells to 20.2 +/- 2.6 and 38.8 +/- 6.7% (n=16; P</=0.001) of those in control cells, respectively. Antisecretory actions of DMOG were time and concentration dependent, being maximal after 18 h of DMOG (1 mM) treatment. DMOG specifically inhibited Na(+)/K(+)-ATPase pump activity without altering its expression or membrane localization. In mice, DMOG inhibited agonist-induced secretory responses ex vivo and prevented allergic diarrhea in vivo. In conclusion, hydroxylases are important regulators of epithelial Cl(-) and fluid secretion and present a promising target for development of new drugs to treat transport disorders.en_GB
dc.language.isoengen_GB
dc.subject.meshAmino Acids, Dicarboxylic/*pharmacologyen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshCalcium/metabolismen_GB
dc.subject.meshCalcium Signalingen_GB
dc.subject.meshChlorides/metabolismen_GB
dc.subject.meshColon/*cytology/drug effects/secretionen_GB
dc.subject.meshCyclic AMP/metabolismen_GB
dc.subject.meshDiarrhea/*drug therapy/metabolismen_GB
dc.subject.meshEpithelial Cells/*metabolismen_GB
dc.subject.meshGene Expression Regulation, Enzymologic/drug effectsen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMice, Inbred C57BLen_GB
dc.subject.meshMixed Function Oxygenases/*antagonists & inhibitorsen_GB
dc.subject.meshPatch-Clamp Techniquesen_GB
dc.subject.meshProtein Subunitsen_GB
dc.subject.meshSodium-Potassium-Exchanging ATPase/metabolismen_GB
dc.titleHydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea.en_GB
dc.contributor.departmentMolecular Medicine Laboratories, Royal College of Surgeons in Ireland, Beaumont, Hospital, Dublin, Ireland.en_GB
dc.identifier.journalThe FASEB journal : official publication of the Federation of American Societies , for Experimental Biologyen_GB
dc.description.provinceLeinster-

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