Source:http://linkedlifedata.com/resource/pubmed/id/10198341
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
4 Pt 1
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pubmed:dateCreated |
1999-5-18
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pubmed:abstractText |
Previous studies have shown that high concentrations of ethanol (>/=40%) cause functional damage of the gastrointestinal epithelial barrier by direct cytotoxic effect on the epithelial cells. The effects of lower noncytotoxic doses of ethanol on epithelial barrier function are unknown. A major function of gastrointestinal epithelial cells is to provide a barrier against the hostile substances in the gastrointestinal lumen. The apicolaterally located tight junctions (TJs) form a paracellular seal between the lateral membranes of adjacent cells and act as a paracellular barrier. In this study, we investigated the effects of lower doses of ethanol on intestinal epithelial TJ barrier function using filter-grown Caco-2 intestinal epithelial monolayers. The Caco-2 TJ barrier function was assessed by measuring epithelial resistance or paracellular permeability of the filter-grown monolayers. Ethanol (0, 1, 2.5, 5, 7.5, and 10%) produced a dose-related drop in Caco-2 epithelial resistance and increase in paracellular permeability. Ethanol also produced a progressive disruption of TJ protein (ZO-1) with separation of ZO-1 proteins from the cellular junctions and formation of large gaps between the adjacent cells. Ethanol, at the doses used (</=10%), did not cause cytotoxicity (lactate dehydrogenase release) to the Caco-2 cells. Ethanol produced a disassembly and displacement of perijunctional actin and myosin filaments from the perijunctional areas. On ethanol removal, actin and myosin filaments rapidly reassembled at the cellular borders. Ethanol stimulated the Caco-2 myosin light chain kinase (MLCK) activity but did not affect the MLCK protein levels. Specific MLCK inhibitor ML-7 inhibited both ethanol increases in MLCK activity and TJ permeability without affecting the MLCK protein levels. Consistent with these findings, metabolic inhibitors sodium azide and 2,4-dinitrophenol significantly prevented ethanol-induced increase in Caco-2 TJ permeability, whereas cycloheximide or actinomycin D had no effect. The results of this study indicate that ethanol at low noncytotoxic doses causes a functional and structural opening of the Caco-2 intestinal epithelial TJ barrier by activating MLCK.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Azepines,
http://linkedlifedata.com/resource/pubmed/chemical/Cycloheximide,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Ethanol,
http://linkedlifedata.com/resource/pubmed/chemical/ML 7,
http://linkedlifedata.com/resource/pubmed/chemical/Myosin-Light-Chain Kinase,
http://linkedlifedata.com/resource/pubmed/chemical/Naphthalenes
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0002-9513
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
276
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
G965-74
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:10198341-Azepines,
pubmed-meshheading:10198341-Cell Membrane Permeability,
pubmed-meshheading:10198341-Cell Survival,
pubmed-meshheading:10198341-Cycloheximide,
pubmed-meshheading:10198341-Dose-Response Relationship, Drug,
pubmed-meshheading:10198341-Enzyme Inhibitors,
pubmed-meshheading:10198341-Ethanol,
pubmed-meshheading:10198341-Humans,
pubmed-meshheading:10198341-Intestinal Mucosa,
pubmed-meshheading:10198341-Membrane Potentials,
pubmed-meshheading:10198341-Myosin-Light-Chain Kinase,
pubmed-meshheading:10198341-Naphthalenes,
pubmed-meshheading:10198341-Tight Junctions,
pubmed-meshheading:10198341-Tumor Cells, Cultured
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pubmed:year |
1999
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pubmed:articleTitle |
Ethanol modulation of intestinal epithelial tight junction barrier.
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pubmed:affiliation |
Division of Gastroenterology, Department of Medicine, Department of Veterans Affairs Medical Center, Long Beach 90822, USA. ma.thomas_y@long-beach.va.gov
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.
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