Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea.
Ward, Joseph B J Lawler, Karen Amu, Sylvie Taylor, Cormac T Fallon, Padraic G Keely, Stephen J
Ward, Joseph B J
Lawler, Karen
Amu, Sylvie
Taylor, Cormac T
Fallon, Padraic G
Keely, Stephen J
Advisors
Editors
Other Contributors
Date
2012-02-01T10:02:29Z
Date Submitted
Keywords
Other Subjects
Subject 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
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
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
Publisher
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
Language
eng
ISSN
1530-6860 (Electronic)
0892-6638 (Linking)
0892-6638 (Linking)
eISSN
ISBN
DOI
10.1096/fj.10-166983
PMID
20944011