Division of Digestive Diseases, Departments of Medicine and Physiology, Ohio State University School of Medicine, Columbus, Ohio 43210
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ABSTRACT |
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In the
normal ileum, coupled NaCl absorption occurs via the dual operation of
Na+/H+ and
Cl/HCO
3 exchange on
the brush-border membrane (BBM) of villus cells. In a rabbit model of
chronic small intestinal inflammation we determined the cellular
mechanism of inhibition of NaCl absorption and the effect of steroids
on this inhibition. Cl
/HCO
3 but not
Na+/H+ exchange was reduced in the BBM of
villus cells during chronic ileitis.
Cl
/HCO
3 exchange
was inhibited secondary to a decrease in the affinity for
Cl
rather than an alteration in the maximal rate of
uptake of Cl
(Vmax). Methylprednisolone
(MP) stimulated
Cl
/HCO
3 exchange in
the normal ileum by increasing the Vmax of
Cl
uptake rather than altering affinity for
Cl
. MP reversed the inhibition of
Cl
/HCO
3 exchange in
rabbits with chronic ileitis. However, MP alleviated the
Cl
/HCO
3 exchange
inhibition by restoring the affinity for Cl
rather
than altering the Vmax of Cl
uptake.
These data suggest that glucocorticoids mediate the alleviation of
Cl
/HCO
3 exchange
inhibition in chronically inflamed ileum by reversing the same
mechanism that was responsible for inhibition of this transporter
rather than exerting a direct effect on the transporter itself, as was
the case in normal ileum.
glucocorticoids; inflammatory bowel disease; chloride/bicarbonate exchange; sodium/hydrogen exchange; coupled sodium chloride absorption; immune regulation of electrolyte transport
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INTRODUCTION |
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COUPLED NaCl absorption occurs via the
dual operation of Na+/H+ and
Cl/HCO
3 exchange on
the brush border membrane (BBM) of villus cells in the rabbit ileum
(4). Many agents have been demonstrated to regulate coupled NaCl
absorption by directly affecting these two exchangers in the normal
intestine (3, 7, 9). For example, serotonin, an intestinal secretagogue that is thought to mediate its effects via intracellular
Ca2+, has been demonstrated to inhibit coupled NaCl
absorption by inhibiting
Cl
/HCO
3 but not
Na+/H+ exchange on the BBM of villus cells in
the rabbit ileum (16). In contrast, forskolin, which mediates its
effect via intracellular cAMP, has been demonstrated to inhibit coupled
NaCl absorption by inhibiting Na+/H+ but not
Cl
/HCO
3 exchange
also on the BBM of villus cells (17).
Unlike these two secretagogues, an absorptagogue such as clonidine has
been demonstrated to stimulate coupled NaCl absorption by stimulating
Na+/H+ but not
Cl/HCO
3 exchange on
the BBM of villus cells in the rabbit ileum (13). Also, in intact
tissue studies other intestinal absorptagogues such as
methylprednisolone have been demonstrated to stimulate Na+
and Cl
absorption in the rabbit ileum (11, 12) and
Na+ absorption in rat ileum (22). Furthermore,
glucocorticoids have been demonstrated to increase the message for the
putative absorptive isoform of Na+/H+ exchange,
specifically NHE-3 (23). These studies illustrate that
Na+/H+ and
Cl
/HCO
3 exchange
are uniquely affected by absorptagogues and secretagogues to alter
absorption and secretion in the normal ileum.
In diarrheal diseases characterized by chronic inflammation of the
intestine, malabsorption of NaCl has been well described (1-3, 7).
However, the exact mechanism of alteration of coupled NaCl absorption
in inflammatory bowel disease (IBD) is unknown. In a rabbit model of
chronic ileal inflammation, it was previously demonstrated that
inhibition of coupled NaCl absorption by the villus cells occurs as a
result of diminished
Cl/HCO
3 but not
Na+/H+ exchange activity (18). The specific
mechanisms of alteration of
Cl
/HCO
3 exchange
was not further delineated in that study. The effect of chronic
intestinal inflammation directly on the BBM
Na+/H+ exchange was also not addressed in that study.
Malabsorption of electrolytes and fluid that is known to occur in IBD may, at least partially, be caused by the effects of a wide variety of immune-inflammatory mediators known to be produced in the chronically inflamed intestine (3, 7). Furthermore, broad-spectrum immune modulation with glucocorticoids is known to, at least partially, alleviate electrolyte and fluid malabsorption in IBD (2, 8). However, the mechanism of glucocorticoid-mediated reversal of inhibition of coupled NaCl absorption during chronic intestinal inflammation is unknown.
Given this background, one of the aims of this study was to determine
the mechanism of inhibition of
Cl/HCO
3 exchange
that resulted in diminished coupled NaCl absorption in the chronically
inflamed ileum. Another aim was to test the hypothesis that
glucocorticoids would alleviate the inhibition of
Cl
/HCO
3 exchange,
thereby alleviating the inhibition of coupled NaCl absorption during
chronic ileitis. The final aim was to determine the
mechanism of glucocorticoid-mediated reversal of inhibition of
Cl
/HCO
3 exchange in
the chronically inflamed ileum.
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METHODS |
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Induction of chronic inflammation and drug treatment. Chronic ileal inflammation was produced in rabbits as previously reported (18). Pathogen-free 1.8- to 2.0-kg New Zealand White male rabbits (Prince's Rabbitry, Oakmill, KY) were intragastrically inoculated with Eimeria magna oocytes or sham inoculated with 0.9% NaCl (control animals). None of the sham inoculations and >80% of inoculations with coccidia resulted in chronic ileal inflammation during days 13-15. Only enterocytes from those animals that had histologically confirmed chronic ileal inflammation were used for experiments. Control or inoculated rabbits were treated intramuscularly with saline or 40 mg of water-soluble methylprednisolone sodium succinate (MP) per day on days 12 and 13 after inoculation and killed on day 14 after inoculation.
Cell isolation. Villus and crypt cells were isolated from the ileum by a calcium chelation technique as previously described (15, 18). Previously established criteria were used to validate good separation of villus and crypt cells (15, 18). Some of these criteria included 1) marker enzymes (e.g., thymidine kinase, alkaline phosphatase), 2) transporter specificity (e.g., Na+/H+ on the BBM of villus but not crypt cells), 3) differences in intracellular pH (e.g., intracellular pH is higher in crypt cells compared with villus), 4) morphological differences (e.g., villus cells are larger and with better-developed BBM compared with crypt cells), and 5) differing rates of protein synthesis (e.g., higher synthesis rate in crypt cells compared with villus).
Previously established criteria were also used to study cells with good viability and to exclude cells that showed evidence of poor viability (15, 18). Some of these criteria included 1) trypan blue exclusion, 2) the demonstration of Na+/H+ and ClBBM vesicle preparation. BBM vesicles (BBMV) from rabbit ileal villus cells were prepared by CaCl2 precipitation and differential centrifugation as previously reported (20). BBMV were resuspended in a medium appropriate to each experiment. BBMV purity was assured with marker enzyme enrichment (e.g., alkaline phosphatase).
Uptake studies in BBMV.
BBMV uptake studies were performed by a rapid filtration technique as
previously described (20). For
Cl/HCO
3 exchange
experiments, BBMV were resuspended and incubated for 2 h in 105 mM K
gluconate, 50 mM HEPES-Tris, and either 50 mM KHCO3 gassed
with 5% CO2-95% N2 or 50 mM K gluconate gassed with 100% N2 with a final pH of 7.7. The reaction
was started by adding 5 µl of vesicles to 95 µl of reaction mix
containing 5 mM N-methyl-D-glucamine
(NMG)36Cl, 149.7 mM K gluconate, 10 mM valinomycin, 50 mM MES-Tris, and 0.3 mM KHCO3, pH 5.5 gassed with 5%
CO2-95% N2, or 5 mM NMG36Cl, 10 mM
valinomycin, 50 mM MES-Tris, and 150 mM K gluconate, pH 5.5 gassed with
100% N2. One millimolar DIDS was added to the reaction mix
when relevant. For Na+/H+ exchange experiments
BBMV were resuspended in 150 mM mannitol, 100 mM tetramethylammonium
(TMA) gluconate, and 50 mM MES-Tris (pH 5.5) or 50 mM HEPES-Tris (pH
7.5). The reaction was started by adding 5 µl of vesicles to 95 µl
of reaction mix containing 150 mM mannitol, 99 mM TMA gluconate, 50 mM
HEPES-Tris (pH 7.5), and 1 mM 22Na gluconate. One
millimolar amiloride was added to the reaction mix when relevant. At
desired times, uptake was arrested by mixing with ice-cold stop
solution. The mixture was filtered on 0.45-µm Millipore (HAWP)
filters and washed twice with 5 ml of ice-cold stop solution. Filters
with BBMV were dissolved in Liquiscint, and radioactivity was determined.
Data presentation. When data are averaged, means ± SE are shown in figures except when error bars are inclusive within the symbol. All uptake studies were done in triplicate. The n number for any set of experiments refers to vesicle or isolated cell preparations from different animals. Preparations in which cell viability was <85% were excluded from analysis. Student's t-test was used for statistical analysis.
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RESULTS |
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Cl/HCO
3
exchange.
Initially, the villus-crypt distribution of
Cl
/HCO
3 exchange in
the normal rabbit ileum was determined. Cl
/HCO
3 exchange
was defined as HCO3-dependent and DIDS-sensitive
36Cl uptake.
HCO
3-dependent 36Cl uptake
was present in BBMV prepared from villus cells (Fig. 1A). Furthermore, this
HCO
3-dependent 36Cl uptake
was DIDS sensitive (Fig. 1A). Similarly,
HCO
3-dependent 36Cl uptake
was present in BBMV prepared from crypt cells (Fig. 1B). This
uptake was also DIDS sensitive (Fig. 1B). Thus
Cl
/HCO
3 exchange is
present in both villus and crypt cell BBM from the normal rabbit ileum.
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Na+/H+
exchange.
Because coupled NaCl absorption is known to occur via the dual
operation of
Cl/HCO
3 and
Na+/H+ exchange in the intestine, we next
studied Na+/H+ exchange. First the villus-crypt
distribution of Na+/H+ exchange in
the normal ileum was determined. Na+/H+
exchange was defined as H+ gradient-stimulated and
amiloride-sensitive 22Na uptake. H+
gradient-dependent 22Na uptake was present in BBMV prepared
from villus cells (Fig. 3A).
Furthermore, this H+ gradient-stimulated 22Na
uptake was amiloride sensitive (Fig. 3A). However,
H+ gradient-stimulated 22Na uptake was not
present in BBMV prepared from crypt cells (Fig. 3B). This
nonspecific 22Na uptake was also not affected by amiloride
(Fig. 3B). Thus Na+/H+ exchange
activity is present in villus but not in crypt cell BBM from the normal
rabbit ileum.
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Kinetic studies.
To decipher the mechanism of inhibition of
Cl/HCO
3 exchange in
the chronically inflamed ileum, kinetic studies were performed. Uptake
studies for various concentrations were carried out at 3 s
because initial uptake studies showed that HCO
3-dependent and DIDS-sensitive
36Cl uptake in BBMV was linear for at least 8 s (data not
shown). Figure 5A
demonstrates the kinetics of Cl
uptake in villus
cell BBMV from normal and chronically inflamed ileum. This figure shows
the HCO
3-dependent and DIDS-sensitive
36Cl uptake in BBMV as a function of varying concentrations
of extravesicular Cl
. As the concentration of
extravesicular Cl
was increased,
HCO
3-dependent and DIDS-sensitive 36Cl uptake was stimulated and subsequently became
saturated in all conditions (Fig. 5A, left). With the
use of Enzfitter, kinetic parameters derived from this data (Table
1) demonstrated that the maximal rate of
uptake (Vmax) of Cl
was not altered in
the chronically inflamed ileum (Fig. 5A, right; Vmax for Cl
uptake in villus cell BBMV
was 45.8 ± 1.6 and 48.4 ± 1.7 nmol · mg
protein
1 · min
1
in normal and inflamed, respectively; n = 6, P = not
significant). However, the affinity [1/Michaelis constant
(Km)] for Cl
was
significantly reduced in the chronically inflamed ileum
(Km for Cl
uptake in villus cell
BBMV was 21.0 ± 1.2 and 50.1 ± 1.7 mM in normal and inflamed,
respectively; n = 6, P < 0.001). These
data indicated that
Cl
/HCO
3 exchange
was inhibited in the chronically inflamed ileum secondary to a decrease
in the affinity for Cl
rather than a change in the
number of transporters.
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Effect of glucocorticoids on
Cl/HCO
3
exchange.
First we characterized the effect of MP on
Cl
/HCO
3 exchange in
villus cell BBMV from the normal rabbit ileum. HCO
3-dependent and DIDS-sensitive
36Cl uptake is shown in Fig.
6A. In villus cell BBMV from
MP-treated normal rabbits
HCO
3-dependent and DIDS-sensitive 36Cl uptake was significantly enhanced (Fig. 6A).
Thus MP treatment stimulates
Cl
/HCO
3 exchange in
villus cells from the normal rabbit ileum.
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DISCUSSION |
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This study demonstrates that coupled NaCl absorption is inhibited in
the chronically inflamed ileum secondary to an inhibition of villus
cell BBM Cl/HCO
3
exchange. At the level of the transporter, the mechanism of inhibition
of Cl
/HCO
3 exchange
during chronic ileitis is a decrease in affinity for
Cl
. Treatment with glucocorticoids stimulates
Cl
/HCO
3 exchange in
the normal ileum. At the level of the transporter, the MP-mediated
stimulation of
Cl
/HCO
3 exchange in
the normal ileum is secondary to an increase in transporter numbers
without an alteration in affinity for Cl
. In the
chronically inflamed ileum, treatment with MP reverses the inhibition
of Cl
/HCO
3
exchange. However, the MP-mediated reversal of inhibition of
Cl
/HCO
3 exchange in
the chronically inflamed ileum is secondary to a restoration of the
affinity for Cl
without an alteration in transporter numbers.
Although malabsorption of electrolytes and fluid has been well
documented in human IBD (1-3, 7, 8), the mechanism of alteration
of coupled NaCl absorption during chronic ileal inflammation had not
been investigated. Undoubtedly, this is a result of a lack of good
animal models of chronic ileal inflammation. Two other models of
chronic enterocolitis in rats (10) and guinea pigs (6) have not yet
been used for electrolyte transport studies. This rabbit model of
chronic ileal inflammation possesses many of the same features as human
IBD (18). Thus it has been used previously to describe alterations in
electrolyte and nutrient transport properties and now to determine the
mechanisms of inhibition of
Cl/HCO
3 exchange
and the effect of glucocorticoids on this inhibition during chronic ileitis.
Although the intention is not to suggest that this model of chronic intestinal inflammation is the same as human IBD, this rabbit model of chronic enteritis shares many similarities with IBD in 1) trigger (an offending agent in a susceptible host triggers the immune system, which remains upregulated even after the loss of the agent), 2) clinical sequelae (malabsorption and diarrhea), 3) gross morphology (the intestine is thickened and erythematous with a cobblestone appearance), and 4) histology (microscopically no parasites are seen, the villi are blunted, the crypts are hypertrophied, and there is an increase in intraepithelial and lamina propria lymphocytes, plasma cells, and mast cells). Despite these similarities it is not suggested that this model is representative of IBD, merely that in the absence of other models of chronic small intestinal inflammation from which viable villus and crypt cells can be isolated, this is an important model for understanding the effects of inflammation. Furthermore, most transport pathways have been well characterized in the normal rabbit ileum; thus comparison in pathophysiological states is possible.
In previous intact cell studies (18) this laboratory demonstrated that
during chronic ileal inflammation
Cl/HCO
3 but not
Na+/H+ exchange activity was reduced in villus
cells. The inhibition of
Cl
/HCO
3 exchange
can be expected to inhibit coupled NaCl absorption by the ileum because
this occurs by the dual operation of
Cl
/HCO
3 and
Na+/H+ exchange on the BBM of villus cells (4).
A potential concern with these observations was that when intact cells
were used an alteration in the intracellular buffering capacity in the
chronically inflamed ileum may have been responsible for the perceived
changes in transporter activity. Because buffering capacity was not
altered in cells from the normal and inflamed ileum, an alteration in buffering capacity was not felt to explain the alteration in exchanger activity. Another concern is that the perceived unaltered
Na+/H+ exchange activity may be a combination
of stimulation of the basolateral membrane
Na+/H+ exchanger and inhibition of the BBM
Na+/H+ exchanger. The use of BBMV
will alleviate these concerns. Indeed, studies using BBMV demonstrated
that Na+/H+ exchange is unaffected whereas
Cl
/HCO
3 exchange is
inhibited in villus cells from the chronically inflamed ileum.
The previous studies also did not describe the mechanism of inhibition
of villus cell
Cl/HCO
3 exchange
during chronic ileitis. This study demonstrates that
Cl
/HCO
3 exchange
was inhibited in the chronically inflamed ileum secondary to diminished
affinity for Cl
rather than altered transporter
numbers. This suggests that
Cl
/HCO
3 exchange
may be altered at the level of glycosylation and/or phosphorylation
during chronic enteritis.
Glucocorticoids were chosen for study because they are a mainstay of
therapy of IBD. Furthermore, although the mechanism of the
glucocorticoid action on electrolyte transport in IBD is not known,
this class of drugs has been demonstrated to, at least partially,
alleviate the impairment of electrolyte malabsorption in IBD (2, 9).
This study demonstrates that glucocorticoids alleviate the inhibition
of Cl/HCO
3
exchange, which can result in the alleviation of NaCl absorption during
chronic ileitis. Furthermore, glucocorticoids reverse the same
mechanism that caused the inhibition of
Cl
/HCO
3 exchange
during chronic ileitis, specifically, altered affinity for
Cl
.
It is of note that glucocorticoids had different effects on
Cl/HCO
3 exchange in
the normal and the chronically inflamed ileum. Although glucocorticoids
increased the relative activity of
Cl
/HCO
3 exchange in
both instances, in the normal ileum the stimulation was secondary to an
increase in transporter numbers. However, in the chronically inflamed
ileum, the diminished affinity for Cl
was restored
to increase Cl
/HCO
3
exchange activity. The unique effect of glucocorticoids on
Cl
/HCO
3 exchange in
the normal and chronically inflamed ileum led us to hypothesize that
glucocorticoids differentially regulate the
Cl
/HCO
3 exchanger
in the normal and chronically inflamed ileum. In the normal ileum the
data are consistent with a positive effect of MP at the level of the
Cl
/HCO
3
exchanger. In the chronically inflamed ileum this pressor
effect of MP is lost. However, MP reverses the
Cl
/HCO
3 exchanger
inhibition during chronic enteritis by the same mechanism by which it
was inhibited in the chronically inflamed ileum. Thus we speculate that
glucocorticoids may have inhibited the release of an
immune-inflammatory mediator that was responsible for the inhibition of
Cl
/HCO
3 exchange
during chronic enteritis.
It is known that a variety of immune-inflammatory mediators are
released in the chronically inflamed intestine (3, 7). Furthermore,
many of these agents are known to alter electrolyte and nutrient
transport processes (3, 7). On the basis of the unique alterations in
electrolyte transport processes, it was hypothesized that different
immune-inflammatory mediators may regulate different transport pathways
in the chronically inflamed ileum (14, 18-21). For example, as
demonstrated in this study, coupled NaCl absorption is inhibited during
chronic ileitis by an inhibition of
Cl/HCO
3 but not
Na+/H+ exchange on the BBM of villus cells.
However, Cl
/HCO
3
exchange in the BBM of crypt cells is unaffected during chronic
ileitis. Furthermore, this laboratory previously demonstrated (5) that
a different anion exchange process, specifically short-chain fatty acid
(SCFA)/HCO
3 exchange, which is only
found in the BBM of villus cells, was also inhibited during chronic
ileitis. However, unlike villus cell BBM
Cl
/HCO
3 exchange
inhibition, which is secondary to a decrease in the affinity for
Cl
, SCFA/HCO
3
exchange was inhibited secondary to a decrease in transporter numbers
and not altered affinity for the SCFA (5). Thus these three anion
exchange processes in villus and crypt cells are uniquely affected in
the chronically inflamed intestine. The unique responses of these three
anion exchanges may be secondary to their intrinsic differences and/or unique effects of different immune-inflammatory mediators released in
the chronically inflamed ileum.
The anion exchanger family of transporters is not the only one to be uniquely affected during chronic ileitis. In fact, the Na+-solute cotransporter family of transporters is also uniquely affected during chronic ileitis. At the cellular level, Na+-glucose, Na+-amino acid, and Na+-bile acid cotransport were inhibited secondary to an effect at the level of the cotransporter as well as a reduction in Na+-K+-ATPase in the chronically inflamed ileum. However, at the cotransporter level each pathway was uniquely altered during chronic ileitis: Na+-glucose cotransport was inhibited by a decrease in the number of cotransporters without a change in affinity for glucose (20). In contrast, Na+-amino acid cotransport was inhibited by a reduction in affinity for the amino acid without a change in the number of cotransporters (19). Unlike these two Na+-solute cotransport processes, Na+-bile acid cotransport was inhibited by a decrease both in affinity for the bile acid and in cotransporter numbers (21). Therefore, these three types of Na+-dependent solute cotransport processes are inhibited by different mechanisms during chronic ileitis. As previously stated, because a variety of immune-inflammatory mediators are known to be released in the chronically inflamed ileum, it is hypothesized that different immune-inflammatory mediators may regulate different transport pathways in the chronically inflamed ileum.
This hypothesis might be further supported if a broad-spectrum immune
modulator such as glucocorticoids were to reverse the malabsorption
during chronic ileitis by reversing the same unique mechanism that
resulted in the inhibition of each of the transport pathways. Indeed,
we previously demonstrated (14) that Na+-glucose
cotransport that was inhibited by a decrease in cotransporter numbers
but not altered affinity for glucose during chronic ileitis was
reversed by MP by restoring the transporter numbers without affecting
the affinity for glucose (14). Furthermore, as this study demonstrates,
glucocorticoids reverse the inhibition of Cl/HCO
3 exchange by
reversing the same mechanism that resulted in the inhibition of this
transporter during chronic ileitis. Thus we postulate that MP may act
as a broad-spectrum immune modulator by inhibiting the release of
different immune-inflammatory mediators that cause specific alterations
in various transport processes in the chronically inflamed ileum.
MP as an immune modulator may exert its effect at many levels. One possibility is that it normalizes the morphological alterations seen in the chronically inflamed ileum (e.g., villus blunting, crypt hyperplasia). However, we previously demonstrated (14) that this brief duration of treatment with MP is not sufficient to restore the morphological alterations seen during chronic ileitis. Another possibility is that MP inhibits the formation of immune-inflammatory mediators that are responsible for the specific transport alterations during chronic ileitis. This allows for the restoration of transporter activity. This hypothesis of glucocorticoids having an effect on circulating immune-inflammatory mediators that can inhibit electrolyte transport in the intestine is supported by studies in which glucocorticoids reversed the inhibition in electrolyte and fluid absorption in patients with IBD (2, 8). Specifically which immune-inflammatory mediators are responsible for the inhibition of various transport processes in the chronically inflamed rabbit ileum will need to be delineated in future studies using specific pathway inhibitors, agonists, and antagonists.
In conclusion, this study demonstrates that in the normal ileum
glucocorticoids stimulate
Cl/HCO
3 exchange by
increasing cotransporter numbers without altering affinity for
Cl
. It also demonstrates that the mechanism of
inhibition of
Cl
/HCO
3 exchange in
the chronically inflamed ileum is secondary to a decrease in affinity
for Cl
. Furthermore, it demonstrates that the
inhibition of
Cl
/HCO
3 exchange in
the chronically inflamed ileum can be reversed by treatment with
glucocorticoids. The mechanism of reversal at the cotransporter level
is secondary to restoration of affinity for Cl
rather than altered transporter numbers. Thus the effects of MP on
Cl
/HCO
3 exchange
are profoundly different in the normal and chronically inflamed intestine.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-45062 to U. Sundaram.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: U. Sundaram, Division of Digestive Diseases, Ohio State Univ. School of Medicine, N-214 Doan Hall, 410 W. Tenth Ave., Columbus OH 43210 (E-mail: sundaram-1{at}medctr.osu.edu).
Received 29 January 1999; accepted in final form 5 November 1999.
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