Division of Physiology, Department of Medical Cell Biology, University of Uppsala, 751 23 Uppsala, Sweden
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ABSTRACT |
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Mucus thickness is suggested to be related to mucosal protection. We therefore investigated the importance of the removable mucous layer and epithelial bicarbonate transport in preservation of the gastric juxtamucosal pH (pHjm) during luminal acid. Anesthetized rats were prepared for intravital microscopy of the gastric mucosa, and pHjm was measured with pH-sensitive microelectrodes. The mucus was either left intact (IM) or removed (MR) down to the firmly attached mucous layer, and HCl (pH 1) was applied luminally. Removal of the loosely adherent mucous layer did not influence the pHjm during luminal acid (pentagastrin: IM/MR 7.03 ± 0.09/6.82 ± 0.19; pentagastrin + indomethacin: IM/MR 6.89 ± 0.20/6.95 ± 0.27; ranitidine: IM/MR 2.38 ± 0.64/2.97 ± 0.62), unless prostaglandin synthesis and acid secretion were inhibited (ranitidine + indomethacin: IM/MR 2.03 ± 0.37/1.66 ± 0.18). Neutral pHjm is maintained during endogenous acid secretion and luminal pH 1, unless DIDS was applied luminally, which resulted in a substantially decreased pHjm (1.37 ± 0.21). Neutral pHjm is maintained by a DIDS-sensitive bicarbonate transport over the surface epithelium. The loosely adherent mucous layer only contributes to maintaining pHjm during luminal pH 1 if acid secretion and prostaglandin synthesis are inhibited.
pH-sensitive microelectrodes; 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid; rat
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INTRODUCTION |
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THE GASTRIC MUCOSA PRODUCES degrading factors such as gastric acid and proteolytic enzymes. To maintain mucosal integrity, an effective defense system is required. The first line of defense against acid, the mucus-bicarbonate barrier, is one of the least-understood components and is at present being focused on by several research groups.
We have previously shown that a pH gradient with a neutral pH at the surface epithelial cells is maintained in the mucus covering the corpus mucosa down to a luminal pH of 2 in acid-secreting and nonsecreting mucosae (25). One explanation of this gradient is that bicarbonate, secreted from the surface epithelial cells into the mucous gel, neutralizes back-diffused acid and that endogenous acid traverses the mucus only in distinct "channels" leading from the gland openings toward the lumen (9, 16). Bicarbonate production in the surface epithelial cells is stimulated by endogenous prostaglandins (10, 11, 27). Furthermore, Teorell (28) demonstrated that for each proton secreted from the parietal cell, one bicarbonate ion is released from the basolateral membrane of the parietal cell to the capillaries leading to the surface epithelium. This blood-borne transport of bicarbonate during acid secretion is probably important for the maintenance of a neutral surface pH (19, 26) when the luminal pH is low (pH 1).
In the Necturus antrum, a luminal mucous layer has been shown to be necessary for keeping the juxtamucosal and intracellular pH neutral in the presence of luminal acid (20). Infection by Helicobacter pylori and the use of ulcerogenic drugs (nonsteroidal anti-inflammatory drugs) inhibit mucin synthesis and secretion and decrease the thickness of the mucous layer (4, 12, 15, 17). On the basis of these and other studies (7), the hypothesis that mucus thickness is correlated to mucosal protection has been proposed.
We have recently found it possible to separate the mucous layer covering the corpus mucosa into two different layers, in addition to loose mucus in the gastric lumen (3). The most luminal of the two layers, the loosely adherent mucus, can be removed by suction or by rubbing with a cotton tip, whereas the inner layer, the firmly adherent mucus, cannot be removed by applying this physical strain. The physical properties and physiological importance of the different layers are unknown, as is their composition and possible differences between them in permeability to acid.
In this study, we investigated the importance of the loosely adherent
mucous layer for the pH at the epithelial surface [juxtamucosal pH
(pHjm)] during inhibition or stimulation of acid secretion (the later resulting in production and transport of bicarbonate from
the parietal cells to the microcirculation supplying the surface
epithelial cells) in the presence of a luminal pH of 1. The influence
of prostaglandin-stimulated bicarbonate production on the
pHjm was also investigated. To determine the route by which bicarbonate traverses the epithelial cells, an inhibitor of the apical
Cl/HCO
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MATERIALS AND METHODS |
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Animal preparation.
Male Sprague-Dawley rats (Charles River, Uppsala, Sweden) weighing
160-290 g were used for the experiments. They were kept under
standardized conditions (21-22°C, 12:12-h light/dark) in cages
with mesh bottoms and had free access to tap water and pelleted food
(Ewos, Södertälje, Sweden). The animals were deprived of food, but not water, for 17-20 h before they were anesthetized with thiobutabarbital sodium (Inactin, 120 mg/kg ip). Spontaneous breathing was facilitated by a short PE-200 cannula placed in the
trachea, and the body temperature was maintained at 37.5 ± 0.5°C by means of a heating pad controlled by a rectal thermistor. A
PE-50 cannula containing heparin (12.5 IU/ml) dissolved in isotonic saline was placed in the right femoral artery to monitor blood pressure. The right femoral vein was catheterized for administration of
Ringer solution (in mM: 120 NaCl, 2.5 KCl, 0.75 CaCl2, and 25 NaHCO3) either alone or with pentagastrin (40 µg · ml1 · h
1) dissolved
in the solution. All experiments were approved by the Uppsala
University Ethical Committee for Animal Experiments.
Chemicals. The following chemicals and drugs were used: thiobutabarbital sodium (Inactin; Research Biochemicals International, Natick, MA), heparin (KabiVitrum, Stockholm, Sweden), silicone grease (Kebo Lab, Stockholm, Sweden), proton cocktail (hydrogen ion Ionophore II-Cocktail; Fluka, Buchs, Switzerland), 1 M HCl (Titrisol; Merck, Darmstadt, Germany), tributylchlorosilane (Fluka), HEPES (Sigma, St. Louis, MO), pentagastrin (Peptavlon; ICI Pharmaceuticals, Macclesfield, England), Indomethacin (Confortid; Dumex, Copenhagen, Denmark), ranitidine (Zantac; Glaxo Wellcome, Mölndal, Sweden), and DIDS (Sigma).
Statistics. The results are expressed as means ± SE. Differences in pHjm within the same group and between groups of animals were evaluated statistically by ANOVA in medians (Mann-Whitney test). Differences in acid secretion were evaluated by ANOVA (single-factor factorial, nonrepeated measures followed by Fisher protected least significant differences test). Differences were regarded as significant when P < 0.05. All statistical calculations were performed on a Macintosh computer with the software Statview II SE Graphics (Abacus Concepts, Berkeley, CA).
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RESULTS |
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Figure 1 shows the mean values for
pHjm and for pentagastrin-stimulated acid secretion in
groups I and II. pHjm was neutral during the control period
in both groups (see Table 1).
When HCl at pH 1 was applied luminally in group I (n = 7, IM), pHjm immediately decreased to 6.1 ± 0.1, but
4 min later it had returned to >7. The pHjm remained at a
slightly but significantly lower level as long as the acid was in the
lumen. In group II (n = 8, MR), acid (pH 1) was applied
after the outer adherent mucous layer had been removed. An immediate
transient reduction of the pHjm to 5.6 ± 0.7 was
noted, followed by a steady-state pHjm at a level slightly
but significantly lower than the control level; this was maintained
throughout the acidic period. The pHjm values did not
differ significantly between groups I and II at any time during the
experiment. When the acid was washed away in both groups, the
pHjm returned to values not different from the control
levels.
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Basal acid secretion was significantly higher in group II (0.29 ± 0.13 µeq · min1 · cm
2)
than in group I (0.08 ± 0.01 µeq · min
1 · cm
2). Even
during stimulation of acid secretion with pentagastrin, there was a
tendency toward higher acid secretion (significant at 0-15 min) in
group II compared with group I. Differences in acid output might be due
to seasonal differences since the experiments were conducted groupwise
at different times.
Figure 2 shows the mean values for
pHjm and for acid secretion in the pentagastrin- and
indomethacin-treated groups III (IM) and IV (MR). The pHjm
was neutral during the control period in both groups (see Table 1).
When acid at pH 1 was applied topically in group III (n = 6, IM), the pHjm immediately stabilized at a slightly but
significantly lower level (pH 6.9 ± 0.2), which was maintained
throughout the acidic period.
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In group IV (n = 5, MR), an immediate transient initial
dip of the pHjm to 5.9 ± 1 was observed in response
to the presence of acid in the lumen, followed by return to a level
slightly but significantly lower than during the control period. The
pHjm values in groups III and IV did not differ
significantly at any time between each other or between the groups
without indomethacin pretreatment (I and II). Basal acid secretion
before pentagastrin stimulation was 0.12 ± 0.05 µeq · min1 · cm
2 in group
III and 0.14 ± 0.04 µeq · min
1 · cm
2 in group IV.
Figure 3 shows the mean values for
pHjm and for the acid secretion in the groups given
ranitidine (V, n = 5, IM; VI, n = 5, MR). The pHjm was neutral in both groups during the control
period (see Table 1). In the presence of luminal acid at pH 1, the
epithelial surface was acidified to pH 2.2 ± 0.5 in group V (6 min after acid application, IM) and to 1.8 ± 0.2 in group VI (20 min after acid application, MR). These pHjm levels were
significantly lower than in the pentagastrin-stimulated groups
I-IV. When the acid was washed away, the pHjm returned
to neutral or near-neutral values within 10 min, significantly
different from the control level before acid and the
pentagastrin-treated groups (I-IV) only at two time points in
group V. Groups V and VI did not differ significantly from each other
at any time.
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In the groups in which acid secretion and prostaglandin synthesis were
inhibited (VII, n = 6, IM; and VIII, n = 5, MR) the initial pHjm (Fig.
4) was slightly lower (significant at one
point) than in the pentagastrin-stimulated groups (I-IV; see Table
1). When acid at pH 1 was applied luminally in group VII (IM), the pHjm decreased to 2.0 ± 0.3 (10 min after acid
application). This was significantly lower than in the
pentagastrin-stimulated groups (I-IV) but not compared with the
ranitidine-treated groups V and VI. The pHjm remained at a
significantly lower level compared with groups I-IV throughout the
experiment.
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In group VIII (MR), the pHjm dropped to a lowest level of 1.4 ± 0.1 (15 min after acid application) in the presence of acid in the lumen, which was significantly lower than in the pentagastrin-stimulated groups (I-IV) and compared with groups V-VI with inhibition of acid secretion. When the acid was washed away, the pHjm was still significantly lower than in the other groups. Compared with group VII, which also received ranitidine and indomethacin, removal of the loosely adherent mucous layer resulted in a nonsignificantly lower pHjm in the presence of luminal acid and a significantly slower reestablishment of the pH gradient after the acidic period. This indicates that the loosely adherent mucus is important only if acid secretion and prostaglandin synthesis are inhibited.
In group IX (n = 5, Fig.
5), acid secretion was stimulated with
pentagastrin and the mucosa was pretreated with DIDS (0.5 mM) before
acid challenge. The loosely adherent layer was removed before DIDS was
applied to minimize interactions between DIDS and the mucus. The
pHjm was initially neutral (see Table 1) but decreased to a
lowest level of 1.4 ± 0.2 (5 min after acid application) in the
presence of luminal acid at pH 1. This value is significantly lower
than in the other pentagastrin-stimulated groups (I-IV). When the
acid had been washed away, the pHjm slowly returned within 20 min to a neutral value.
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DISCUSSION |
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The mucous layer continuously covers the gastric mucosa (1) and is believed to contribute to the preepithelial defense mechanisms in different ways. In the Necturus antrum, a luminal mucous layer has been shown to be necessary for keeping the pHjm and intracellular pH neutral in the presence of luminal acid (20). In accordance with this, an unstirred layer has been shown in which the pH gradient is formed by bicarbonate secreted from the epithelial cells, neutralizing back-diffused acid (22, 25). Moreover, we have earlier studies suggesting that acid secretion is restricted to penetrating the mucous layer from its site of formation to the stomach lumen in channels, thereby limiting the acidification of the mucous layer (16).
In an in vivo study in the rat corpus, an inverse relation between mucous gel thickness (measured by alternately focusing on the fluorescent cell surface and the gel-lumen interface) and intracellular acidification in the surface epithelium was found (7). This indicates that a thicker mucous layer would protect the underlying cells from back-diffused acid. We have recently found that the adherent gastric mucous layer can be divided into two different layers (3). The most luminal of these two layers, which we have designated the loosely adherent layer, can be removed by suction or mechanically removed with a cotton tip, leaving a thinner, still continuous, firmly adherent layer attached to the mucosa. The thicknesses of the different layers can be measured with micropipettes inserted into the mucus. The total mucus thickness (loosely adherent plus firmly adherent) was 189 ± 11 µm, and the thickness of the firmly adherent layer (measured directly after removal of the loosely adherent layer) was 80 ± 5 µm (3). The physical properties and physiological importance of the different layers are still unknown.
One purpose of the present study was to investigate the importance of
the loosely adherent mucous layer in maintaining the basal
pHjm during HCl (pH 1) applied in the lumen. The results clearly show that the loosely adherent layer is of minor importance in
maintaining the pHjm since pH at the epithelial cell
surface was not altered when the loosely adherent layer was removed
before acid pH 1 was instilled into the lumen. This seems plausible, since the loosely adherent layer most probably is removed from the
mucosal surface by ingested food, which also stimulates acid secretion.
The function of the loosely adherent layer might be to lubricate food
particles and bind bacteria. In earlier experiments in which the pH
gradient was measured through the entire mucous layer (firmly and
loosely adherent), the depth of this gradient in the mucus during acid
secretion (100 µm closest to the epithelial surface, luminal pH 2 or 3) was found to correspond quite well with the thickness of the
firmly adherent mucous layer (3, 15, 25). This supports
the finding from the present study that the loosely adherent layer is
not important for preserving a pH gradient.
Our results also support recent observations by Chu et al. (5) in a study in which the pH in the mucous layer and the mucus thickness were measured with a confocal microscope by use of different fluorescent dyes. They found that a mucous gel between 25- and 75-µm-thick provided the most alkaline surface epithelium during superfusion with pH 3 and that if the mucous gel was thicker than 100 µm it did not provide greater surface protection. However, they found an inverted pH gradient in the mucous gel covering the rat corpus mucosa during pentagastrin stimulation, with pH 5 in the lumen and pH 3.5 at the cell surface, suggesting that acid diffused from its site of secretion toward the lumen. Discrepancies between their results and ours have been thoroughly discussed in a previous article (16).
The results from the present study convincingly show that the pH
gradient is better preserved in an acid-secreting stomach than in a
resting one, which is in agreement with earlier reports (18,
26). Thus during endogenous acid secretion the gastric microcirculation supplies the surface epithelial cells with the bicarbonate needed for juxtamucosal neutralization. When DIDS was
applied luminally and acid secretion was stimulated with pentagastrin, the pHjm decreased dramatically when acid (pH 1) was
applied in the lumen. This indicates that bicarbonate is transported
transcellularly through a DIDS-sensitive mechanism. In vitro
experiments have revealed that gastric bicarbonate secretion is
dependent on luminal chloride ions, indicating the presence of an
apical Cl/HCO
/HCO
/HCO
-HCO
It has been shown that inhibition of prostaglandin synthesis with indomethacin decreases bicarbonate secretion and that prostaglandin 16,16-dimethyl E2 stimulates the alkali secretion in the fundic mucosa (9, 21). Moreover, inhibition of the prostaglandin synthesis with indomethacin in the presence of a luminal pH of 2 resulted in a decrease in the pHjm compared with that in a control group (23). In accordance with these findings, when acid secretion and prostaglandin synthesis were both inhibited in the present study (group VII), the pH at the cell surface was slightly reduced in the control situation before acid was applied in the lumen. However, in our model, the pHjm was not further reduced in the presence of luminal pH 1 by inhibition of prostaglandin synthesis, whether acid secretion was stimulated or inhibited. It is possible that the strong acid that penetrates down to the surface epithelial cells when acid secretion is inhibited conceals a small fraction of bicarbonate secretion that is prostaglandin dependent. However, these results indicate that gastric prostaglandin-dependent bicarbonate secretion plays only a minor role in neutralizing back-diffused acid.
When inhibition of acid secretion and of prostaglandin synthesis was combined with removal of the loosely adherent mucous layer (group VIII), a lower pHjm was seen in this group in the presence of luminal acid and the recovery to a neutral pH after removal of luminal acid was significantly delayed. This could, however, be due to thinning of the firmly adherent mucous layer induced by indomethacin, which we have found in a preliminary study (15). Thus not only the blood-borne load of bicarbonate but also the prostaglandin-dependent bicarbonate secretion is reduced and the firmly adherent layer is thinner, resulting in inadequate maintenance of the pH gradient. Further studies are required to elucidate the importance of the thickness of the firmly adherent layer in maintaining the pHjm.
A reduction in pHjm as we have shown here occurs during inhibition of acid secretion and with pH 1 in the lumen. Although the stomach does not normally experience a significant acid load during inhibition of acid secretion, the present study suggests that it would be more susceptible than normal to luminal acid if this was ingested. However, in this study when acid was applied for 20 min, this treatment did not seem to damage the mucosa since the pH returned to the values before acid challenge when the acid was changed to saline. We have previously shown that 51Cr-EDTA clearance from blood to gastric lumen increases during luminal pH 1 in animals not stimulated to produce acid (26). This permeability increase is abolished if acid secretion is stimulated with impromidine or pentagastrin. The increase in permeability, however, is reversed as soon as the luminal acid is changed to saline, which contradicts the theory that a sustained damage to the mucosa has occurred. Thus exposure to acid pH 1 for 20 min does not induce sustained damage or sustained reduction in pHjm. We can, however, not draw any conclusions about what effect a longer exposure to luminal acid would have on pHjm or epithelial damage.
In conclusion, the loosely adherent mucous layer does not seem to be important in maintaining the pHjm in the presence of luminal acid (pH 1). Hence an ~80-µm-thick mucous layer (the firmly adherent layer) is adequate for stabilizing a pH gradient with a neutral value at the cell surface while the pH in the lumen is 1. DIDS-sensitive bicarbonate transport from the alkaline blood during acid secretion is essential for maintenance of a neutral pHjm. Prostaglandin-stimulated bicarbonate secretion seems to play only a minor role and only when acid secretion is inhibited and the loosely adherent mucous layer is removed.
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ACKNOWLEDGEMENTS |
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We thank Annika Jägare for excellent technical assistance.
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FOOTNOTES |
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This study was supported by Grant 08646 from the Swedish Medical Research Council.
Address for reprint requests and other correspondence: M. Phillipson, Division of Physiology, Dept. of Medical Cell Biology, Biomedical Center, Uppsala Univ., PO Box 571, SE-751 23 Uppsala, Sweden (E-mail: Mia.Phillipson{at}physiology.uu.se).
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. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00223.2001
Received 30 May 2001; accepted in final form 3 October 2001.
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