Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea
| Autor: | Cormac T. Taylor, Stephen J. Keely, Joseph B. J. Ward, Sylvie Amu, Karen Lawler, Padraic G. Fallon |
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| Rok vydání: | 2010 |
| Předmět: |
Diarrhea
Male medicine.medical_specialty Patch-Clamp Techniques Colon Pharmacology Biology Biochemistry Gene Expression Regulation Enzymologic Mixed Function Oxygenases Mice Chlorides In vivo Internal medicine Cyclic AMP Genetics medicine Animals Secretion Calcium Signaling Patch clamp Na+/K+-ATPase Molecular Biology Ion transporter Calcium signaling Calcium metabolism Epithelial Cells Amino Acids Dicarboxylic Mice Inbred C57BL Protein Subunits Endocrinology Calcium Sodium-Potassium-Exchanging ATPase Ex vivo Biotechnology |
| Zdroj: | The FASEB Journal. 25:535-543 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.10-166983 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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