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

Hdl Handle:
http://hdl.handle.net/10147/126120
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:
Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea. 2011, 25 (2):535-43 FASEB J.
Journal:
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Issue Date:
Feb-2011
URI:
http://hdl.handle.net/10147/126120
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.
Item Type:
Article
Language:
en
ISSN:
1530-6860

Full metadata record

DC FieldValue Language
dc.contributor.authorWard, Joseph B Jen
dc.contributor.authorLawler, Karenen
dc.contributor.authorAmu, Sylvieen
dc.contributor.authorTaylor, Cormac Ten
dc.contributor.authorFallon, Padraic Gen
dc.contributor.authorKeely, Stephen Jen
dc.date.accessioned2011-03-29T15:02:15Z-
dc.date.available2011-03-29T15:02:15Z-
dc.date.issued2011-02-
dc.identifier.citationHydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea. 2011, 25 (2):535-43 FASEB J.en
dc.identifier.issn1530-6860-
dc.identifier.pmid20944011-
dc.identifier.doi10.1096/fj.10-166983-
dc.identifier.urihttp://hdl.handle.net/10147/126120-
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.-
dc.language.isoenen
dc.titleHydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea.en
dc.typeArticleen
dc.contributor.departmentMolecular Medicine Laboratories, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.en
dc.identifier.journalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biologyen
dc.description.provinceLeinster-

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