Inhibition of long myosin light-chain kinase activation alleviates intestinal damage after binge ethanol exposure and burn injury.
Laboratory evidence suggests that intestinal permeability is elevated following either binge ethanol exposure or burn injury alone, and this barrier dysfunction is further perturbed when these insults are combined. We and others have previously reported a rise in both systemic and local proinflammatory cytokine production in mice after the combined insult. Knowing that long myosin light-chain kinase (MLCK) is important for epithelial barrier maintenance and can be activated by proinflammatory cytokines, we examined whether inhibition of MLCK alleviated detrimental intestinal responses seen after ethanol exposure and burn injury. To accomplish this, mice were given vehicle or a single binge ethanol exposure followed by a sham or dorsal scald burn injury. Following injury, one group of mice received membrane permeant inhibitor of MLCK (PIK). At 6 and 24 h postinjury, bacterial translocation and intestinal levels of proinflammatory cytokines were measured, and changes in tight junction protein localization and total intestinal morphology were analyzed. Elevated morphological damage, ileal IL-1β and IL-6 levels, and bacterial translocation were seen in mice exposed to ethanol and burn injury relative to either insult alone. This increase was not seen in mice receiving PIK after injury. Ethanol-exposed and burn-injured mice had reduced zonula occludens protein-1 and occludin localization to the tight junction relative to sham-injured mice. However, the observed changes in junctional complexes were not seen in our PIK-treated mice following the combined insult. These data suggest that MLCK activity may promote morphological and inflammatory responses in the ileum following ethanol exposure and burn injury.
Molecular and Cellular Biochemistry Program, Loyola University, Medical Center, Maywood, Illinois, USA.
Anita
A
Zahs
Melanie D
MD
Bird
Luis
L
Ramirez
Jerrold R
JR
Turner
Mashkoor A
MA
Choudhry
Elizabeth J
EJ
Kovacs
D000818:Animals; D002056:Burns / Q000473:pathology*; D000431:Ethanol / Q000008:administration & dosage* / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation / Q000517:prevention & control; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use*; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
D015850:Interleukin-6; D010455:Peptides; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; C065738:MLCK peptide; D000431:Ethanol; D009219:Myosin-Light-Chain Kinase