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Vol. 291, Issue 3, 1075-1085, December 1999
Division of Digestive Disease, Rush University Medical Center,
Department of Internal Medicine, Chicago, Illinois
Exposure of intestinal mucosa to ethanol (EtOH) disrupts barrier
function and growth factors [epidermal growth factor (EGF) and
transforming growth factor-
(TGF-)] are protective, but the
mechanisms remain obscure. Accordingly, we sought to determine whether
the molecular mechanism of EtOH-induced intestinal barrier dysfunction
involves oxidative stress and disassembly of microtubules and whether
the mechanism of protection by EGF or TGF- involves prevention of
these alterations. To this end, human colonic (Caco-2) monolayers were
exposed to 0 to 15% EtOH with or without pretreatment with EGF or
TGF- (10 ng/ml) or with oxidative or cytoskeletal modulators.
Effects on cell viability, barrier function, tubulin (microtubules),
and oxidative stress were then determined. Cells were also processed
for immunoblots of polymerized tubulin (S2; index of stability) and the
monomeric tubulin (S1; index of disruption). EtOH dose-dependently
decreased the stable S2 polymerized tubulin and concomitantly increased
measures of oxidative stress, including oxidation and nitration of
tubulin, fluorescence of dichlorofluorescein, and inducible nitric
oxide synthase activity. EtOH also dose-dependently disrupted barrier
function and extensively damaged microtubules, and these effects were
prevented by pretreatment with antioxidant scavengers:
L-cysteine, superoxide dismutase, and
L-N6-1-iminoethyl-lysine
(an inducible nitric oxide synthase inhibitor). In monolayers exposed
to EtOH, pretreatment with EGF or TGF- prevented the oxidation and
nitration of tubulin, increases in the levels of the unstable S1
tubulin, disruption of microtubules, and barrier dysfunction. A
microtubule stabilizer (paclitaxel,Taxol) mimicked, in part, the
effects of EGF and TGF-, whereas a microtubule disruptive drug
(colchicine) prevented the protective effects of these growth factors.
We concluded that mucosal barrier dysfunction induced by EtOH involves
oxidative stress, which causes the disassembly of the microtubule
cytoskeleton. Protection by EGF and TGF- involves the prevention of
these EtOH-induced alterations in microtubules.
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