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2014 ; 38
(9
): 2414-26
Nephropedia Template TP
Alcohol Clin Exp Res
2014[Sep]; 38
(9
): 2414-26
PMID25257290
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BACKGROUND: Alcohol intoxication can increase inflammation and worsen injury, yet
the mechanisms involved are not clear. We investigated whether acute alcohol
intoxication increases microvascular permeability and investigated potential
signaling mechanisms in endothelial cells that may be involved. METHODS:
Conscious rats received a 2.5 g/kg alcohol bolus via gastric catheters to produce
acute intoxication. Microvascular leakage of intravenously administered
fluorescein isothiocyanate (FITC)-conjugated albumin (FITC-albumin) from the
mesenteric microcirculation was assessed by intravital microscopy.
Endothelial-specific mechanisms were studied using cultured endothelial cell
monolayers. Transendothelial electrical resistance (TER) served as an index of
barrier function, before and after treatment with alcohol or its metabolite
acetaldehyde. Pharmacologic agents were used to test the roles of alcohol
metabolism, oxidative stress, p38 mitogen-activated protein kinase (MAPK), myosin
light-chain kinase (MLCK), rho kinase (ROCK), and exchange protein activated by
cAMP (Epac). VE-cadherin localization was investigated to assess junctional
integrity. Rac1 and RhoA activation was assessed by ELISA assays. RESULTS:
Alcohol significantly increased FITC-albumin extravasation from the mesenteric
microcirculation. Alcohol also significantly decreased TER and disrupted
VE-cadherin organization at junctions. Acetaldehyde significantly decreased TER,
but inhibition of alcohol dehydrogenase or application of a superoxide dismutase
mimetic failed to prevent alcohol-induced decreases in TER. Inhibition of p38
MAPK, but not MLCK or ROCK, significantly attenuated the alcohol-induced barrier
dysfunction. Alcohol rapidly decreased GTP-bound Rac1 but not RhoA during the
drop in TER. Activation of Epac increased TER, but did not prevent alcohol from
decreasing TER. However, activation of Epac after initiation of alcohol-induced
barrier dysfunction quickly resolved TER to baseline levels. CONCLUSIONS: Our
results suggest that alcohol intoxication increases microvascular permeability to
plasma proteins. The data also suggest the endothelial-specific mechanism
involves the p38 MAPK, Rac1, and reorganization of VE-cadherin at junctions.
Last, activation of Epac can quickly resolve alcohol-induced endothelial barrier
dysfunction.
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