Department of Medicine, Section of Gastroenterology/Hepatology,
Tulane University School of Medicine, New Orleans 70112; and New
Orleans Veterans Affairs Hospital, New Orleans, Louisiana 70146
Epidemiological studies indicate a relationship
between alcohol consumption and esophageal epithelial disease. We
therefore sought the contribution of the direct effects of ethanol on
esophageal epithelial structure and (transport and barrier) function.
Epithelium from the rabbit was mounted in Ussing chambers and exposed
luminally for 1 h to 1-40% ethanol. At concentrations of
1-5% potential difference (PD) increased, and at 10-40% PD
decreased. The increase in PD with 1-5% ethanol was accompanied
by an increase in short-circuit current
(Isc), and this
increase in Isc
could be blocked by ouabain pretreatment. The decrease in PD with
10-40% ethanol was associated with a decrease in electrical
resistance (R), and this decrease in
R was paralleled by an increase in
transepithelial
[14C]mannitol flux.
Reversibility of these changes was limited at ethanol concentrations
10%, and these were associated morphologically by patchy or diffuse
tissue edema. Moreover, as with ethanol exposure in vitro, exposure in
vivo produced dose-dependent changes in PD,
Isc,
R, and morphology. These observations
indicate that exposure to ethanol in concentrations and under
conditions reflecting alcohol consumption in humans can alter and
impair esophageal epithelial transport and barrier functions. Such
impairments are likely to contribute to the observed increase in risk
of esophageal disease with regular consumption of alcoholic
beverages.
resistance; transport; potential difference; short-circuit current; Ussing chambers
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INTRODUCTION |
THE HUMAN ESOPHAGUS is frequently exposed to
alcohol-containing beverages such as beer and wine and more distilled
spirits such as whiskey. Given that these contain ethanol in
concentrations ranging from 5% for beer to 10% for wine and 40% for
whiskey (19a), it is likely and we hypothesize that one or more such
exposures may result directly in esophageal epithelial structural
and/or functional damage. Indeed, there is a known relationship
between excess consumption of alcoholic beverages and diseases of the esophageal epithelium, most notably reflux esophagitis and esophageal carcinoma (3, 5, 8, 10-12, 19, 20, 22). Although the mechanisms
for such a relationship are likely to be multifactorial, the
contribution to epithelial disease of the direct effects of ethanol
appear to be underappreciated. For this reason, we sought the direct
effects of ethanol on esophageal morphology and esophageal epithelial
transport and barrier functions both in vitro and in vivo and utilized
rabbit esophageal epithelium as a model, since it is known to be
structurally and functionally similar to the epithelium lining the
human esophagus (13). Moreover, to mimic human consumption of alcoholic
beverages, in vivo experiments incorporated intermittent bolus
administration of ethanol into the upper esophagus and adequate
drainage from the distal esophagus to ensure effective (one-pass)
luminal clearance.
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MATERIALS AND METHODS |
In vitro studies. New Zealand White
male rabbits weighing between 8 and 9 lb were killed by administering
an intravenous overdose of pentobarbital sodium (60 mg/ml). The
esophagus was excised, opened lengthwise, and pinned mucosal surface
down in a paraffin tray containing ice-cold oxygenated normal Ringer
solution. The submucosa was grasped with hemostats, lifted up, and
dissected free of the underlying mucosa with a scalpel. This process
yielded a sheet of tissue consisting of stratified squamous epithelium and a small amount of underlying connective tissue. From this tissue,
four sections were cut and mounted as flat sheets between Lucite
half-chambers with an aperture of 1.13 cm2 that permitted contact with
different bathing solutions for the luminal and serosal side of the
tissue. Tissues were initially bathed with normal Ringer solution
composed of the following (in mmol/l): 140 Na+, 119.8 Cl
, 5.2 K+, 25 HCO
3, 1.2 Ca+, 1.2 Mg2+, 2.4 HPO2
4, 0.4 H2PO
4 with osmolality 268 mosmol/kgH2O and pH 7.5 when
gassed with 95% O2-5% CO2 at 37°C.
Tissues were exposed to varying concentrations of luminal ethanol
(1-40% vol/vol) by replacing different volumes of Ringer with
variable amounts of 100% ethanol in a solution in which the ion
composition resulted in final luminal ion concentrations equivalent to
those of the normal Ringer serosal bath. This same method was used to
expose tissues to varying concentrations of serosal ethanol; however,
only the replacement of normal Ringer was from the serosal
bath. The chemicals used were obtained from Sigma (St.
Louis, MO).
Luminal and serosal solutions were connected to calomel and Ag-AgCl
electrodes with Ringer-agar bridges for measurements of potential
difference (PD) and short-circuit current
(Isc) by means of a voltage clamp (World Precision Instruments, Sarasota, FL). Tissues
were continuously short-circuited except for 5- to 10-s periods when
the open-circuit PD was read. Electrical resistance (R) was calculated using Ohm's Law
(R = PD/Isc) from
the open-circuit PD and the
Isc or from the
current deflection to imposed voltage. Forty-five minutes after
mounting, to allow stabilization of electrical parameters
(equilibration period), tissues paired by
R (R
within 25% of each other and having R > 1,000
· cm2)
were exposed either luminally or serosally to ethanol (as described above). After ethanol exposure, both luminal and serosal solutions were
drained and replaced with normal Ringer solutions (washout). PD,
Isc, and
R were monitored before and after
ethanol exposure. After the experiments, tissues were fixed with 3%
glutaraldehyde in 0.1 mol/l phosphate buffer, pH 7.4, stained with
hematoxylin and eosin, and processed for light microscopy. Junction
potentials were determined for all solutions by a modification of the
method of Read and Fordtran (14) and Tobey and Orlando
(18). Junction potentials were <1 mV for all
experimental conditions except for 40% ethanol, which was
2 mV.
Therefore, corrections for junction potentials were only made under
conditions in which 40% ethanol was present.
Mannitol fluxes. Mannitol fluxes were
performed in the Ussing chamber by luminal addition of 10 mmol/l of
cold mannitol and 10 mCi of radiolabeled
[14C]mannitol (ICN,
Irvine, CA). An initial sample from the "hot" side was obtained
for calculation of specific activity, and samples from the serosal
solution were obtained at 45-min intervals for calculation of fluxes
using the counts obtained from a liquid scintillation counter. The
reported flux value was the average for two 45-min fluxes for each
tissue.
In vivo studies. Rabbits were
anesthetized intramuscularly with a mixture of ketamine (35 mg/kg) and
xylazine (5 mg/kg) and positioned so that they were inclined with their
heads up at a 45° angle (9). A tracheotomy was performed and, after
laparotomy, a cannula for drainage was inserted 2 cm into the distal
esophagus and tied in place. A small catheter was passed orally into
the upper esophagus for administration via syringe of boluses of
ethanol or Ringer solution. Alongside the oral catheter and extending 1 cm distal to its tip was a Ringer-agar bridge that was used for
measuring the transepithelial PD. A reference Ringer-agar bridge was
also placed through the laparotomy site into the peritoneum so that it
made contact with peritoneal fluid. The Ringer-agar bridges were each
inserted into a beaker containing both a saturated KCl solution and a
calomel electrode, the latter for connecting the system to a voltage
clamp (World Precision Instruments) for PD recording. The solutions
that were separated into boluses were heated to 37°C before
administration and before experimentation, and all esophagi were
flushed with Ringer solution. After the Ringer wash, a baseline PD was
recorded in each animal, and animals were then pulsed via syringe with
1 ml of either ethanol (10-40%) or normal Ringer
solution. Boluses were administered over 5 s every 5 min
for 30 min during the experimental period, and each liquid bolus was
followed by air boluses until no further solution emerged from the
drainage cannula. After the experimental period, three boluses of
normal Ringer solution were administered in all animals before
obtaining a final transepithelial PD, free from interference by
junction, diffusion, and streaming potentials. Rabbits were killed at
the end of the experiments with an intravenous overdose of
pentobarbital sodium. Esophageal catheter, cannula, and Ringer-agar
bridge positions were verified, and tissue sections were obtained from
areas of epithelium exposed to the boluses for histology and for
mounting in Ussing chambers. The tissue mounted in the Ussing chamber
was permitted to equilibrate in Ringer solution for 20 min before a
final PD, Isc,
and R were recorded for each specimen.
All in vitro and in vivo studies were approved by the institutional
Animal Welfare Committee.
Statistical significance was determined using Student's
t-test. Data are reported as means ± SE.
 |
RESULTS |
In vitro studies. The effects of
exposing esophageal epithelium to varying concentrations of luminal
ethanol (1-40%) for 1 h are shown in Fig.
1,
A-C.
At the lowest concentrations of ethanol, 1 and 5%, esophageal PD
increased and remained elevated throughout the 1-h time period. For the
highest concentration of ethanol, 40%, esophageal PD decreased and
remained below control values throughout the 1-h time period. At 10%
ethanol, there was a delayed response in that the PD remained stable
for the first 10 min and then, as with 40% ethanol, declined
progressively (Fig. 1A).

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Fig. 1.
Effects of different concentrations of luminal ethanol on rabbit
esophageal epithelial potential difference (PD;
A), short-circuit current
(Isc;
B), and resistance
(R;
C). Data are expressed as % of
initial values before ethanol exposure. Values are means + SE;
n = 5/group.
* P < 0.05 compared with
normal Ringer controls. Data were corrected for a 2-mV junction
potential during exposure to 40% ethanol. Preexposure means for
absolute values were 14 ± 1 mV for PD, 8 ± 0.6 µA/cm2 for
Isc, and 2,201 ± 45 · cm2 for
R.
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The increase in PD observed with exposure to 1 and 5% ethanol was
associated with increases in
Isc (Fig.
1B) and either no change (1%
ethanol) or a decline in electrical R
(5% ethanol; Fig. 1C). The changes
in PD observed with exposure to 10% ethanol were associated initially
with a transient rise in
Isc that peaked at 10 min and then progressively declined over time. With 10% ethanol,
R, as with 5% ethanol, declined
progressively over time. The marked fall in PD at 40% ethanol was
associated initially with significant declines in both
Isc and
R, and, while
R continued to decline over time, at
10 min the Isc
began a progressive rise to levels that exceeded baseline values at 40 min (Fig. 1, B and C). After exposure to 1 and 5%
ethanol for 1 h, the changes in PD,
Isc, and
R were unaccompanied by morphological
damage on light microscopy; however, after 10 and 40% ethanol, there
was patchy edema and generalized edema, respectively (Fig.
2, A-D).
Because exposure to all tested concentrations of ethanol altered
esophageal epithelial function, the reversibility of the changes was
assessed by removal of the ethanol-containing luminal baths and
replacement with normal Ringer solution. As shown in Fig.
3B, by
1 h after washout, the reduction in
R by 5% ethanol returned to baseline
after exposures of 5-30 min but not after exposures lasting 60 min. Notably, the reduction in R upon
exposure to 10% ethanol failed to recover to baseline, even with
exposures lasting as little as 10 min, and recovery was impaired to a
greater extent with exposures that were longer than 10 min. Similarly, exposure to 40% ethanol lowered R to
an extent that it failed to recover even after exposure times of only 5 min (Fig. 3B). As shown in Fig.
3A, exposure to 5% ethanol increased
Isc, and this
increase could recover to baseline (>100%) within 1 h of washout
irrespective of the length of time of exposure, i.e., 5-60 min.
However, the increase in
Isc associated
with exposure to 10% ethanol did not return to baseline, even with
exposure times of only 5-10 min. Notably, the delayed increase in
Isc associated with exposure to 40% ethanol (Fig.
1B) was followed after washout not
only by the abolition of this increase but with the unmasking of an
Isc that was
almost abolished by 40% ethanol exposure (Fig. 3A).

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Fig. 3.
Reversibility of
Isc
(A) and
R
(B) of the changes in rabbit
esophageal epithelium exposed luminally to 5, 10, or 40% ethanol
(EtOH) for various time periods. Pretreatment baseline is indicated by
the horizontal line, and values presented represent those achieved by 1 h after ethanol washout (ethanol replaced by normal Ringer). Values are
means + SE; nos. of rabbits are shown in bars;
* P < 0.05 compared with
initial baseline values.
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In another set of experiments, we sought to determine if the
increase in Isc
associated with low concentrations of luminal ethanol was dependent on
active (transcellular) Na+ transport. This was done by
pretreating tissues serosally for 1 h with ouabain
(10
4 M). After treatment
with ouabain, Isc
declined ~75%, in keeping with effective inhibition of
Na+-K+-ATPase activity. Subsequently, the
increase in Isc
associated with exposure to 1% ethanol was shown to be effectively
abolished (Fig. 4). In another set of
experiments, we sought to determine if the observed decrease in
R with ethanol exposure, an exposure associated with at worst tissue edema but not tissue necrosis, was the
result of an increase in permeability via the paracellular (as opposed
to transcellular) pathway. This was done by performing lumen-to-serosal
[14C]mannitol fluxes
in tissues paired by R and exposed to
either 10% ethanol or normal Ringer solution. As shown in Table
1, the reduction in
R by 10% ethanol was accompanied by a
significant increase in mannitol flux compared with the Ringer control.

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Fig. 4.
Effect of ouabain on
Isc of rabbit
esophageal epithelium mounted in Ussing chambers and its ability to
inhibit the rise in
Isc associated
with exposure to 1% ethanol. Values are means + SE;
n = 4. * P < 0.05 compared with
preethanol Isc.
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Table 1.
Effect of luminal ethanol on electrical resistance and transepithelial
mannitol flux in rabbit esophageal epithelium in Ussing chamber
preparation
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The addition of ethanol to the luminal bath creates an environment that
is hyperosmolar with respect to the serosal bath. Therefore, a set of
experiments was performed to determine if this change in luminal
osmolality contributes to the effects observed for ethanol. This was
accomplished by exposing tissues to luminal solutions of similar
osmolality (1,200 mosmol/kgH2O),
i.e., 6% ethanol or 1 M mannitol. Compared with luminal ethanol, which increased Isc and
decreased R, hyperosmolar mannitol
increased R and had little effect on
Isc (Fig.
5, A and
B).

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Fig. 5.
Comparison of effects of an equihyperosmolar (1,200 mosmol/kgH2O) luminal solution of
mannitol (1 M) to 6% ethanol on
Isc
(A) and
R
(B) of rabbit esophageal epithelium
mounted in Ussing chambers. Ethanol is noted to increase
Isc and lower
R, whereas mannitol has no effect on
Isc and increases
R. Values are means + SE;
n = 4 for each group.
* P < 0.05 compared with
ethanol.
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Because ethanol is a rapidly diffusible substance, the possibility was
also considered that part or all of its luminal effects were mediated
(after absorption) from the serosal side (1). This was tested by
exposing esophageal epithelium for 1 h serosally to ethanol at
concentrations ranging from 0.06 to 5%. The concentration of 5%
ethanol was used because luminally it clearly increased Isc and decreased
R, and the lower concentrations were
used to reflect the achievable levels of blood ethanol in the
alcohol-consuming live subject. As shown in Fig.
6, A and
B, 5% serosal ethanol had the
opposite effect of 5% luminal ethanol, i.e., it decreased Isc by 60% and
increased R by 50%, and, although the
data are not shown, this same pattern was seen for the lower
concentrations of ethanol in a dose-dependent manner.

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Fig. 6.
Effect of 5% serosal ethanol on
Isc
(A) and
R
(B) of rabbit esophageal epithelium.
Serosal ethanol decreases
Isc and increases
R compared with concurrently studied
Ringer controls. Data are expressed as % of initial values before
ethanol exposure. Values are means + SE;
n = 5. * P < 0.05 compared with
normal Ringer controls.
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In vivo studies. The prior chamber
experiments were done in vitro and using continuous exposures to
ethanol. Because this clearly is not reflective of what takes place in
vivo, in vivo experiments were designed to determine the extent to
which the in vitro findings were representative of what occurs under
conditions more representative of human alcohol consumption. The in
vivo experiments were performed in anesthetized rabbits that were
placed on a 45° incline in the head-up position. A cannula was
inserted orally into the upper esophagus for the intermittent
administration of ethanol boluses, and the distal esophagus was
cannulated to permit efficient, one-pass drainage of the administered
boluses. One-milliliter boluses of ethanol, 10-40%, were
subsequently administered every 5 min for 30 min, and in control
animals 1-ml boluses of normal Ringer solution were administered. After
each liquid bolus, an air bolus was administered to ensure adequate
drainage, and after ethanol boluses were complete, three boluses of
normal Ringer were administered to enable the transepithelial PD to be
recorded in the absence of any interference by junction, diffusion, or streaming potentials.
Baseline esophageal PD was similar for all groups of animals. As shown
in Fig. 7, boluses of normal Ringer
solution had no effect on PD. However, boluses of 10% ethanol
increased PD for the first 5-10 min, and then PD began to decline,
falling to baseline by 30-35 min. Notably, this pattern of PD
change is similar to that observed in vitro with continuous exposure to
5% ethanol (Fig. 1A). Moreover,
similar to continuous exposure to 10% ethanol in vitro, boluses of
20% ethanol in vivo initially produced no change in PD, but after 10 min PD progressively declined. In addition and in keeping with its
noxious potency, in vivo boluses of 40% ethanol, as with in vitro
exposure to 40% ethanol, resulted in a rapid and progressive decline
in PD with time, the PD in vivo being effectively abolished by 10 min
(Fig. 7). After these experiments, tissue sections were mounted in
Ussing chambers for determination of their electrical parameters. As is
evident in Table 2, ethanol exposure in
vivo was paralleled by a dose-dependent lowering of R in vitro, with
R reaching significance for tissues
exposed intermittently in vivo to 20 and 40% ethanol. Furthermore,
tissues exposed to 10 and 20% ethanol in vivo exhibited an increase in
Isc, with the
increase in Isc
at 20% ethanol being significantly above controls and reminiscent of
continuous exposure to 10% ethanol in vitro (Fig.
1B). Also, tissues exposed to 40%
ethanol in vivo exhibited a significant decrease in
Isc as is
representative of what occurs (after washout) from exposure to 40%
ethanol in vitro. As observed with in vitro exposures to ethanol, the
only morphological change in tissues exposed to ethanol in vivo was
diffuse edema, and this was apparent at exposures of 20 and 40%
ethanol (Fig. 8). There was no
damage apparent on tissues exposed in vivo to 10% ethanol (data not
shown).

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Fig. 7.
Effect of 1-ml boluses (arrows) of 10-40% ethanol or normal
Ringer solution on the in vivo esophageal PD in rabbits. After baseline
PD readings, 7 boluses of ethanol or Ringer were administered, and this
was followed by Ringer boluses for washout (arrowheads) in all groups.
Data are expressed as % of initial values. Values are means ± SE;
n = 4-8.
P < 0.05 compared with initial
values (#) and with Ringer controls (*). Preexposure absolute values
were similar: 30.7 ± 0.5 mV, 30.1 ± 0.7 mV,
30 ± 0.3 mV, and 30.2 ± 0.3 mV for Ringer and 10, 20, and 40% ethanol groups, respectively.
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Table 2.
Electrical parameters of Ussing chamber-mounted esophageal epithelium
obtained from rabbits after in vivo boluses of ethanol or normal Ringer
for 30 min
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Fig. 8.
Representative light micrograph of rabbit esophageal epithelium exposed
in vivo for 30 min to 40% ethanol. Hematoxylin and eosin,
magnification ×400. Note the presence of generalized tissue
edema.
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DISCUSSION |
In this investigation, we assessed the direct effects of ethanol on
esophageal epithelial structure and function, and we did so both in
vitro and in vivo using concentrations of ethanol commonly observed in
alcoholic beverages. Notably, in vitro experiments showed that
continuous exposure of the esophageal epithelium to ethanol resulted,
even at low concentrations, in alterations in ion transport
and/or barrier function, whereas at higher concentrations such
alterations were also associated with morphological changes. The effect
of ethanol on ion transport was documented by increases in
Isc both during
and, for 1 and 5% ethanol, after ethanol exposure. Moreover, as shown
for 1% ethanol, the increase in
Isc associated with ethanol was abolished by pretreatment with ouabain. This suggests
that, at low concentrations, ethanol has a stimulatory effect on active
ion (presumably Na+ in this predominately
Na+-transporting epithelium) transport in this tissue. Such
an effect, however, is not observed in all moist squamous epithelium,
since it has been reported that mucosal ethanol (2-6%) inhibited
rather than stimulated
Isc, a reflection
of net Na+ transport, in frog skin (2). Similar to the
lower concentrations of ethanol, 10% ethanol initially increased
Isc, but this was transient, and after 10 min
Isc began to
decline. Moreover, at 40% ethanol, the initial effect on
Isc was
inhibitory. However, this gave way after 10 min to a dramatic rise in
Isc to levels that rose above pretreatment baseline, a rise that was completely abolished after ethanol removal, unmasking a marked inhibition of
Isc by 40%
ethanol. These observations are compatible with the fact that at low
concentrations ethanol stimulates active transport and that at high
concentrations (10-40%) ethanol inhibits active transport. The
rise in Isc
during, but not after, exposure to 40% ethanol is compatible with the
generation of diffusion and/or streaming potentials induced by
damage to the tissue at this high concentration. In keeping with this
latter interpretation was the presence of generalized tissue edema in
the specimens exposed to 40% ethanol. Yorio and Bentley (21) have also
observed the toxic effects of 40% ethanol in toad bladder, finding
that, at 40% but not at lower concentrations, there was marked
inhibition of oxygen consumption (21).
The experiments in vitro also showed a detrimental effect of continuous
exposure to ethanol on esophageal epithelial barrier function. This was
apparent in that concentrations of ethanol >1% were accompanied by a
dose-dependent decline in electrical R. Moreover, because the decline in
R could occur even at concentrations having minor effects on esophageal morphology (5-10% ethanol), it
was likely that this damaging effect on the barrier resulted from an
alteration of the intercellular junctions. Consistent with this was the
finding that the decline in R
associated with exposure to 10% ethanol resulted in an increase in
transepithelial mannitol flux, this increase reflecting an increase in
paracellular permeability. Although these data indicate that at lower
concentrations the barrier-breaking effects of ethanol are the result
of altered intercellular junctions, at the highest concentration
studied (40%) there was enough morphological damage to suggest that
the increase in epithelial permeability may include both transcellular and paracellular routes. In keeping with these conclusions, Yorio and
Bentley (21) observed an increase in paracellular permeability in toad
bladders exposed to 9% ethanol. Boyett and Brugges (2) also noted an
increase in permeability to chloride when frog skin was mucosally
exposed to 2.4% ethanol; however, the route for this increase was not
established in their study (2).
The mechanisms by which ethanol alters esophageal epithelial
barrier and transport physiology are complex and largely unstudied. However, the present results showing alterations in esophageal epithelial Isc
and R are consistent with a direct
effect of ethanol on both the cells themselves and their intercellular
junctional complexes. Moreover, the inability of ethanol exposure
serosally or 1 M mannitol luminally to mimic the changes produced by
luminal ethanol indicates that such effects are independent of both
ethanol absorption and the capacity of ethanol to increase luminal
osmolality.
Because it is clear that the effects of continuous ethanol
exposure in vitro may not be representative of what occurs in humans consuming alcoholic beverages in vivo, an additional set of in vivo
experiments was performed. These experiments mimicked human consumption
by intermittently giving ethanol as boluses and by ensuring one-pass
esophageal exposure through effective bolus clearance. The
results showed that intermittent exposure to ethanol in vivo mimicked
the effects of continuous exposure to ethanol in vitro but required
somewhat higher concentrations. Thus, for example, the effects of 10%
ethanol in vivo mimicked the effects on PD,
Isc, and
R of continuous ethanol exposure to
5% ethanol in vitro, and the effects of 20% ethanol in vivo mimicked
the effects of 10% ethanol in vitro. Furthermore, 40% ethanol in
vivo, presumably because of the great magnitude of its toxicity,
resulted in the same effects as that observed in vitro. Specifically,
ethanol exposure in vivo initially produced a biphasic dose-dependent effect on PD, with the lowest concentration, 10% ethanol, increasing PD, 20% ethanol producing no change, and the highest concentration (40%) decreasing PD. Together these observations indicate that in vivo
higher concentrations of ethanol are required to achieve the same
effects as described above for lower concentrations of ethanol in
vitro, yet it is important to recognize that, even though requiring
higher concentrations, the concentrations remain well within the range
of those to which the human esophagus is exposed. The likely reason
that higher concentrations in vivo are required to give the same
effects as lower concentrations in vitro is that efficient luminal
clearance left less ethanol to diffuse into the tissue, and the ethanol
that does diffuse is effectively reduced in potency by dilution within
the luminal and epithelial aqueous environments.
After the tissues were exposed to ethanol in vivo, they were mounted in
Ussing chambers or sent for morphology. Tissues mounted in the chamber
demonstrated that the changes in PD induced in vivo were the result of
altered ion transport and/or barrier properties of the
esophageal epithelium. Specifically, impairment of barrier function was
evident in that a dose-dependent decline in
R was associated with ethanol
exposure, and altered ion transport was evident in that the lower
concentrations of ethanol (10 and 20%) were observed to increase
Isc and the
higher concentration (40%) to inhibit
Isc. Further
tissue edema was apparent in those esophagi intermittently exposed to
20 or 40% ethanol in vivo. Consequently, all of the effects observed
for continuous ethanol exposure in vitro were observed in vivo.
Consistent with our findings were those of Rubinstein and colleagues
(15) who observed a significant reduction in esophageal PD in humans in
vivo after consumption of wine and whiskey, and prior studies in rabbit
or canine esophagus (4, 16, 17) showed that luminal concentrations as
low as 5% ethanol can alter esophageal PD and increase epithelial
permeability.
In summary, the results of this investigation document that esophageal
exposure to ethanol in amounts and under conditions relevant to the
consumption of alcohol in humans can significantly alter both
esophageal morphology and esophageal epithelial transport and barrier
function. Furthermore, because the impaired functions are important for
epithelial defense (13), these initial changes likely predispose the
tissue to subsequent injury upon exposure to other potentially noxious
luminal substances, e.g., refluxed gastric acid. With respect to the
latter, it is well established that the combination of acid and ethanol
is far more injurious to the esophagus than either substance alone (4,
16, 17).
Address for reprint requests: S. Bor, Dept. of Medicine, Section of
Gastroenterology/Hepatology, Tulane Univ. School of Medicine, 1430 Tulane Ave., New Orleans, Louisiana 70112.