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Ethanol modulation of intestinal epithelial tight junction barrier
1Division of Gastroenterology, Department of Medicine, Department of Veterans Affairs Medical Center, Long Beach 90822, USA. ma.thomas_y@long-beach.va.gov
The American Journal of Physiology
|April 13, 1999
Summary
Low-dose ethanol disrupts the intestinal epithelial barrier by affecting tight junctions, even without causing cell damage. This opening is mediated by myosin light chain kinase (MLCK) activation.
Area of Science:
- Gastroenterology
- Cell Biology
- Epithelial Biology
Background:
- High ethanol concentrations (>40%) damage the gastrointestinal barrier via cytotoxicity.
- The impact of lower, non-cytotoxic ethanol doses on epithelial barrier function remains unclear.
- Intestinal epithelial cells form a critical barrier regulated by apicolateral tight junctions (TJs).
Purpose of the Study:
- To investigate the effects of low, non-cytotoxic ethanol concentrations on intestinal epithelial tight junction (TJ) barrier function.
- To elucidate the molecular mechanisms underlying ethanol's impact on TJ integrity.
Main Methods:
- Utilized filter-grown Caco-2 intestinal epithelial monolayers.
- Assessed TJ barrier function by measuring epithelial resistance and paracellular permeability.
- Examined TJ protein (ZO-1) localization, cytoskeletal dynamics (actin, myosin), and myosin light chain kinase (MLCK) activity.
Main Results:
- Ethanol (1-10%) caused a dose-related decrease in epithelial resistance and increased paracellular permeability.
- Ethanol disrupted ZO-1 localization, leading to gaps between cells, without inducing cytotoxicity.
- Ethanol activated MLCK, causing perijunctional actin and myosin displacement, which was reversible upon ethanol removal.
Conclusions:
- Low, non-cytotoxic ethanol doses functionally and structurally compromise the intestinal epithelial TJ barrier.
- Ethanol-induced barrier disruption is mediated by MLCK activation, independent of cytotoxicity.
- Targeting MLCK may offer a strategy to mitigate ethanol's effects on intestinal barrier function.