1Physiological Sciences, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom; and 2Division of Physiology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
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ABSTRACT |
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acid-base transporters; cystic fibrosis transmembrane conductance regulator channel; surface pH gradient; mucus gels; trefoil peptides
Several agents, including un-ionized weak acids and ethanol, damage the gastric mucosa and cause a marked increase in the disappearance of acid from the gastric lumen. Davenport (52) and others (20) provided evidence for damage-induced transmucosal leakage of interstitial and plasma HCO3 neutralizing intraluminal acid. This leakage, which should be distinguished from metabolism-dependent transport of HCO3 from the undamaged mucosa, was later found to be important in mucosal repair by maintaining a neutral pH under the mucoid cap formed on top of the repairing epithelium (119, 146, 213). The protective mucoid cap was shown to be primarily a thick fibrin gel layer formed from leaking plasma fibrinogen along with interstitial HCO3 and distinct from the adherent mucus gel layer covering the undamaged mucosa (210).
In this article we review the current state of the gastroduodenal mucus bicarbonate barrier two decades after the first supporting experimental evidence appeared (see reviews, Refs. 12, 13, 66, and 78). Mucus is unique in the gastrointestinal tract in that the secretion, particularly in stomach, is a thick layer of gel adherent to the mucosal surface. The role of this gel layer in mucosal protection is a structural one: to create a stable, unstirred layer to support surface neutralization of acid and act as a protective physical barrier against luminal pepsin reaching the underlying epithelium. Therefore, the emphasis on mucus in this review is on the form and function of this adherent mucus gel layer. The role of mucosal HCO3 secretion is to neutralize acid diffusing into the mucus gel layer and to be quantitatively sufficient to maintain a near-neutral pH at the mucus-mucosal surface interface. The emphasis on mucosal HCO3 secretion in this review is on the mechanisms and neurohormonal control of its secretion, the establishment of a surface pH gradient, and, in particular, the stimulation of HCO3 secretion by acid in the lumen, which is of primary importance, particularly in duodenum.
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ADHERENT MUCUS GEL LAYER IN SITU |
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The paucity or absence of mucus on histological sections prepared using conventional procedures initially led to controversy as to whether a continuous layer of mucus existed over the gastric mucosal surface (166, 255). This was compounded by the misnaming, as mucus, of the mucoid cap seen on histological sections of reepithelializing gastric mucosa following acute damage (166). The mucoid cap on top of the damaged and repairing mucosa is primarily a fibrin gel with necrotic cells and remains of the adherent mucus layer from the original, undamaged mucosa (8, 210). This mucoid cap, in contrast to the adherent mucus gel, is three to four times thicker and can be preserved using standard histological fixation procedures.
An elegant method involving the use of intravital microscopy to observe adherent mucus gel layers on mucosal surfaces in vivo, initially developed for stomach, has now been applied throughout the gut of anesthetized rats (6, 24, 111, 197, 204, 238). With the use of this method, a continuous, translucent mucus gel layer can be seen on mucosal surfaces, with a mean thickness of 189 µm in corpus, 274 µm in antrum, and 170 µm in duodenum (24). What is particularly interesting is that two physical forms of mucus have been observed: a loosely adherent mucus layer that can be removed by suction and a firm adherent mucus layer that remains. This remaining firm adherent mucus is substantial and continuous in antrum, corpus, and colon, while it is very thin or absent in duodenum, jejunum, and ileum, where the primary function is absorption of nutrients (Fig. 1). In stomach in vivo, the firm adherent mucus layer presumably equates to the stable protective barrier, whereas the superficial loosely adherent layer, likely to be largely removed by the shear forces of the digestive process, would act more as a lubricant. The loosely adherent layer continually increases in thickness at a rate slowest in the stomach and greatest in the colon, where it is very thick (714 µm) and copious (24). Compatible with these observations in vivo is the recent isolation from pig stomach in vitro of two mucus secretions that differ distinctly in their gel rheology and, possibly, component mucin multimeric structure (242). There is a sloppy mucus gel that is readily broken down by low applied shear forces and an underlying firm adherent mucus gel that is resistant to applied shear and collapses only at shear forces two orders of magnitude higher.
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STRUCTURE AND STABILITY OF MUCUS LAYER |
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Mucus secretions from all regions of the gut have the same generic gel structure (8, 31, 211), and this is reflected by common structural patterns in the component gel-forming mucins. The central regions of all gel-forming mucin units have a protein core covered by a sheath of glycan chains that are flanked at both ends by nonglycosylated protein domains rich in cysteine. The cysteine-rich domains are the location of the interchain disulfide bridges between the mucin units that are polymerized end to end into large mucin multimers (7, 8, 19, 91, 155, 183). Gel-forming mucins are very large molecules (reported molecular masses of 545 x 106 Da) consisting of multimers of mucin units (23 x 106 Da). The peptide core alone of each mucin unit contains >5,000 amino acids, around which are packed glycan chains that comprise the major portion by weight of the molecule (between 50 and 80%). Until recently, progress in this field was slow, primarily because of the structural complexity of the component mucins and the difficulties of performing meaningful rheological studies of mixtures of such molecules. The structure of each of the four gel-forming mucins, MUC2, MUC5AC, MUC5B, and MUC6 (published only in part), has now been elucidated with cloning and sequencing of the mucin genes. This has led, over the past decade, to an explosion of information on the complexities of mucin structure, biosynthesis, and secretion, and there are many reviews available (8, 38, 46, 47, 83, 88, 132, 164, 183, 252). Three of the four gel-forming mucins are well expressed in the normal gastrointestinal tract. In the stomach, MUC5AC is expressed by the surface mucous cells of cardia, fundus, and antrum, and MUC6 is expressed by the mucous neck cells of fundus and of antral glands in cardia and antrum (54, 103, 105). MUC2 is expressed by goblet cells from duodenum to colon, whereas MUC6 is expressed by Brunner's glands in duodenum (103, 105).
The general features of mucus gel structure are known, although there are many questions remaining. The multimeric structure (previously referred to as polymeric structure) of the mucins is essential for gel formation (7, 19, 31, 220). Gel strength and stability have been shown to relate directly to the percentage of multimeric mucin, relative to the monomeric form, in the gel (211). In gastric ulcer and Helicobacter pylori infection, the percentage of multimeric mucin in the adherent gastric mucus layer falls, indicative of a weaker and less stable mucus gel (10, 168, 264). The large, highly hydrated multimeric mucin molecules interact noncovalently to form the mucus gel network (8, 17), but the chemical nature of these interactions is unclear. Recent rheological studies point to a complexity of different, noncovalent interactions of a variety of types and strengths between the mucin molecules (241). More than 90% of these interactions are transient (i.e., make and break over a finite time), explaining the unique flow properties of mucus gels.
What has emerged from such studies is evidence that gel-forming mucins from different secretions or even the same secretion, while possessing a common structural pattern, show many specific structural differences in their protein core, glycan side chains, antigenic properties, and negative charge (8, 38, 46, 54, 83, 132). Furthermore, histological studies suggest that there maybe different structural patterns within the adherent mucus layer itself. Laminated layers of surface mucus and glandular mucus, which stain for different glycan structures, have been observed in the adherent gastric mucus layer in situ in humans (100, 176). Alternating layers of MUC5AC and MUC6, the two gastric mucin gene products, have been reported in the mucus layer in sections of human gastric mucosa (104). Moreover, recent studies using the novel technique of high-pressure freezing/freeze substitution, which preserves intact not only the mucus gel but also the fluid luminal phase, showed a triple lamination of different mucin structures within the secreted mucus gel layer at the mouth of the gastric pits (203). In the present context, the key question for the future is whether and to what extent these subtle structural differences, between and within the different mucin secretions, influence gel structure sufficiently to effect the stability and permeability of the adherent mucus gel layer.
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TREFOIL PEPTIDES AND THE ADHERENT MUCUS LAYER |
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FACTORS INFLUENCING MUCUS LAYER THICKNESS |
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In rat stomach in vivo, mucus layer thickness, measured on unfixed mucosal sections, is increased up to threefold by topical prostaglandins, carbachol (intraperitoneal), and secretin (intravenous) (8, 9, 131, 159). Rat gastric mucus layer thickness was unchanged after exposure to acid pH 1 or 2 over 3 h in vivo (16). Direct observation in rat stomach in vivo showed no change in adherent mucus layer thickness over time in the presence of acid pH 1.7, whereas pentagastrin (intravenous), cimetidine (intraperitoneal), and prostaglandin E2 (PGE2) all increased mucus layer thickness by up to one-third (170, 171). Further evidence that exposure to luminal acid does not change gastric mucus layer thickness was provided by reports that no significant increase in thickness occurred in pentagastrin-stimulated rats in vivo, with or without inhibition of acid secretion by omeprazole (204). Central vagal stimulation by injection of thyrotropin-releasing hormone analog RX 77368 increased gastric mucus layer thickness by up to 30%, and this was unaffected by acid pH 1, indomethicin, or omeprazole (238).
In rat duodenum, in contrast to rat stomach, exposure to luminal acid does increase mucus layer thickness, and this is mediated via extrinsic sensory nerve fibers that release CGRP followed by stimulation via nitric oxide (NO) and cyclooxygenase (COX). The rate of continuous replenishment of duodenal mucus (sloppy) in rat in vivo, following its removal by suction, was increased (44%) by exposure to HCl pH 2 for 10 min and inhibited by indomethacin or NO synthase inhibitor N-nitro-L-arginine (197). More recently, rat duodenal mucus layer thickness in vivo was shown to be increased by >50% in response to luminal acid, primarily by stimulation of a capsaicin-sensitive pathway including NO, vanilloid receptors, and afferent nerves (3, 6). PGE2 (luminal or intravenous) similarly increased duodenal mucus layer thickness, but, interestingly, indomethacin also abolished the acid/capsaicin-mediated response, suggesting that COX pathways may be the common mechanism for duodenal mucus secretion. Once the acid stimulus is withdrawn, the mucus layer thickness values returned to basal levels of the order of 100 µm (3), indicating that the increase may have reflected primarily changes in sloppy mucus gel, which is subsequently removed by the shear forces of the perfusion system used. The acid-induced stimulation of duodenal mucus layer thickness in the duodenum is part of a series of mucosal protective mechanisms in response to increased luminal acidity, including increased HCO3 secretion and blood distribution (69, 94, 114).
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MUCUS AND PROTECTION AGAINST PEPSIN |
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The adherent mucus gel layer is a physical barrier to luminal pepsin accessing the underlying mucosa. The rate of diffusion of solutes through mucus gel decreases progressively with increasing molecular size (14, 16, 27, 29, 55), and it takes several hours for pepsin (pH 7.0) to permeate a thin layer of mucus gel in vitro (11, 14). The physical explanation for this is that measured rates of diffusion of macromolecules in unstirred solution are very slow, of the order of 1 x 106 cm2/s, and calculations show that it would take hours for pepsin (32 kDa) to diffuse through the adherent gastric mucus layer in vivo (11). There also may be some steric hindrance to macromolecular permeability through a 5% mucus gel. In duodenum in vivo, controlled removal of the thin mucus layer by papain digestion markedly enhanced the HCO3 secretory response to cholera toxin (85 kDa), H. pylori Vac A toxin (89 kDa), and glucagon (3.5 kDa) (68). These studies show that even the thin layer of firm mucus gel in the duodenum in vivo limits access of larger-molecular-weight toxins to the mucosa. They also provide a note of caution in secretory studies involving luminal application of such agents. Interestingly, in these studies, removal of the mucus layer also enhanced the stimulation of HCO3 by PGE2 (335 Da), but this effect is most likely explained by the binding of the relatively small amounts of secretagogue to mucin (68).
Because luminal pepsin cannot permeate the continuous adherent mucus layer within a physiologically meaningful time scale, it follows that the latter is an effective barrier, probably the major barrier in vivo, against proteolytic digestion of the underlying epithelium (14, 16). At the same time, luminal pepsin at acidic pH slowly hydrolyzes and erodes the adherent mucus layer. However, at the levels of luminal pepsin in vivo, this is normally balanced by new secretion (9, 14, 31). Lack of interest in pepsin as a mucosal damaging agent has been due primarily to the pharmaceutical success of acid inhibition in peptic ulcer treatment and the absence of a good selective inhibitor of pepsin secretion. The proteolytic activity of pepsin in gastric juice on an average protein substrate falls rapidly above pH 3 (102, 181), and it has been assumed that above this pH most, if not all, of the pepsin activity in vivo is lost. However, depending on the substrate and pepsin type, there can be significant pepsin activity well above pH 3. Thus pepsin 1, which rises fivefold in peptic ulcer disease to reach 20% of the total activity in gastric juice (243), has substantial mucolytic activity between pH 3 and 5 (14, 181). Levels of serum pepsinogen 1 and 2 have been shown to be increased in H. pylori infection and peptic ulcer disease, whereas low serum pepsinogen levels are a good indicator of atrophic gastritis (35, 201). However, the relationship between serum pepsinogen levels and luminal gastric pepsin activity has yet to be clarified experimentally. Pepsin-induced mucosal damage and activity of the secreted individual pepsin isoforms in peptic ulcer disease and gastroesophageal reflux disease, as well as how luminal pepsin activity relates to serum pepsinogen levels, all merit further study.
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PH GRADIENT AT THE GASTRIC MUCOSAL SURFACE |
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Under conditions of acid secretion and HCl (pH 1) instilled into the lumen, a pH gradient across the gastric mucus layer is maintained with a pH of >7 at the mucosal surface (Fig. 2) (184). Other workers using a similar system in rat and mouse stomach, but with confocal imaging and the fluorescent dye Cl-NERF, demonstrated a surface pH gradient with superfusion at luminal pH 3.0 (28, 44, 49). Furthermore, in this system, surface and intraglandular alkalinity were increased by luminal administration of dimethyl PGE2, a compound previously shown to stimulate both gastric and duodenal mucosal HCO3 secretion (23, 65, 235). Also, at luminal pH 3.0, the relatively alkaline surface pH 4.3 ± 0.1 was acidified by indomethacin (to pH 3.6 ± 0.2), and subsequently dimethyl-PGE2 restored surface pH to 4.2 ± 0.2 (28). The authors concluded that the preepithelial alkaline layer in the mouse stomach is regulated by endogenous COX activity. Similar increases in surface alkalinity in response to E-type prostaglandins have been observed in rat stomach (195).
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The adherent mucus layer per se is not a diffusion barrier to acid that diffuses rapidly through the gel matrix both in vitro and in vivo. Numerous studies have measured diffusion rates of H+ through fresh preparations of gastric mucus gel in vitro and have shown that after initial saturation of binding sites, such diffusion rates are retarded 4- to 10-fold compared with those in an equivalent "unstirred" layer of solution (57, 169, 236, 259). These results have been interpreted to show that mucus slows the mobility of H+ by acting as a barrier to its free diffusion. Various possible mechanisms for this effect have been reviewed (57). However, calculations from these measured rates of diffusion of H+ in vitro indicate that acid would still rapidly permeate a layer of adherent mucus gel 100200 µm thick in a matter of minutes in vivo (11). Studies in vivo confirm that the adherent mucus gel layer is not a significant permeability barrier to H+ (as opposed to a stable unstirred layer and mixing barrier). Thus acidification of juxtamucosal surface pH, as monitored by electrodes, can occur very rapidly through the mucus layer when acid is applied to the luminal side (137, 179, 184) (Fig. 2). Recently, elegant experiments in mouse stomach in vivo showed that the rate of diffusion of the low-molecular-mass (400 Da) fluorescent dye CL-NERF through the mucus is the same as that through an unstirred layer of luminal solution (29). This provides clear evidence that, in vivo, the adherent mucus layer is freely permeable to ions and small-sized molecules.
There have been suggestions that mucus undergoes a conformational change at pH 4 that affects its permeability properties with the result that it becomes more impermeable to H+ at higher levels of luminal acidity. The evidence to support this comes from numerous different studies on mucin solutions involving viscosity (34), viscous fingering (33), and light scattering (41). The evidence from in vivo studies in rat and mouse stomach and Necturus stomach in vitro does not support such pH effects on H+ permeability through mucus in vivo (29, 137, 179, 184). Furthermore, rheological results obtained with mucin solutions cannot necessarily be extrapolated to the native gel, where mucin molecules are restricted by interactions in a gel network and may not undergo the conformational changes seen in free solution, particularly where changes in ionic strength are involved. Thus the rheological characteristics of intact mucus gel are unaffected by exposure to low ionic strength or acid down to pH 1 (31, 211), yet both of these conditions result in a dramatic increase in mucin solution viscosity (17, 34, 41).
Considerable interest has been generated in the role of lipids within the adherent mucus layer providing a barrier to H+ (101, 153, 154). Evidence for a lipid barrier comes primarily from high contact angle measurements over the gastric mucosa, indicating a hydrophobic surface and the presence of lipids, including surfactants, in adherent gastric mucus. Loss of mucosal hydrophobicity, measured as sharp decreases in contact angle, and decreased phospholipid occur after exposure to known mucosal barrier breakers (e.g., bile and aspirin) (90, 154, 156). The reverse is seen with EGF, which is reported to increase mucosal resistance to acid (157). How lipids in mucus could form a barrier to acid is unclear, although monolayers or multilayers of phospholipid molecules within the mucus layer have been proposed (101, 154). Furthermore, it is uncertain to what contact angle measurements refer. Full drying times of 4050 min are necessary to obtain consistent results (223, 224), and during this process the adherent mucus gel is progressively dehydrated (11). Even if a lipid barrier does exist in the adherent mucus layer, the evidence of the free permeability to H+ through mucus in vivo (discussed above) demonstrates that it is not effective against acid.
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ROLE OF THE ALKALINE TIDE IN GASTRIC MUCOSAL PROTECTION |
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The importance of plasma/interstitial HCO3 in protecting the gastric mucosa against acid-induced damage was first demonstrated in dogs (51) and rats (135) in vivo, where parenteral administration of exogenous HCO3 prevented ulceration of the acid-exposed gastric surface. Furthermore, serosal (basolateral)-side administration of HCO3 has a similar acid-protective action in amphibian (137, 138) and rat (191) mucosa in vitro. Studied in the amphibian preparation, serosal-side administration of other buffers, e.g., HEPES, did not protect the mucosa, and pretreatment with DIDS, or removal of serosal-side Na+, prevented the protective action of serosal-side HCO3. The combined results provide strong evidence that uptake of HCO3 by basolateral Na+-HCO3 cotransport enhances alkaline secretion by the surface epithelial cells (65), resulting in an increased ability of the gastric epithelial surface to resist luminal acid. The presence of HCO3 in the serosal-side solution furthermore enhances the rapid reconstitution of epithelial integrity in damaged gastric mucosa in vitro (213).
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SECRETION OF ACID AND PEPSIN FROM GASTRIC GLANDS ACROSS THE MUCUS LAYER |
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Other studies have failed to show acid channels in the adherent mucus gel during acid secretion. With the use of confocal microscopy and the fluorescent acid-sensitive dye CL-NERF, no channels were observed in the mucus layer in secreting rat stomach in vivo (44), despite the spatial resolution of the technique and its demonstrated ability to measure differences in pH between glandular pits and the surrounding epithelium. Why channels are not seen with confocal imaging but are seen with direct microscopy is not yet clear, and comparative experiments using both methodologies in the same preparation would help resolve this. In another study in vitro, with the use of sensitive, double-barreled microelectrodes, no evidence was found for acid channels in the mucus layer of acid-secreting guinea pig mucosa (206). From this study, a model has been proposed in which protons transverse the mucus gel layer buffered by the mucin and are released from the latter by conversion of pepsinogen to pepsin at the lower pH values nearer the lumen (206, 207). There are difficulties with this model in that it would require rapid turnover of the firm mucus gel layer at a substantially much greater rate than that seen in vivo (24). Also, pepsinogen is converted to pepsin autocatalytically at acid pH, and it is likely that it will be, almost entirely, the activated enzyme that emerges from the gastric gland. Furthermore, the observed stability of the gastric mucus gel to acid in vitro and in vivo is not compatible with the postulate that it is widely impregnated with pepsin or pepsinogen, which under conditions of low pH would result in mucolysis (16, 31).
Finally, secreted mucosal HCO3 presumably diffuses freely from the surface of the gastric epithelium through the mucus gel layer. Because the alkali secretion (HCO3 export) by the gastric mucosa in the main reflects a Cl/HCO3 exchange process in the apical membrane of the surface epithelial cells (see below), an association between gastric crypt secretion, volume flow, and alkali secretion would appear unlikely.
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GASTRIC BICARBONATE SECRETION |
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Recordings of pH within the lumen of the gastric glands have provided further information on the secretion of HCO3 by the gastric mucosa. Intraglandular pH in acid-inhibited, cimetidine-pretreated sheets of frog (Rana esculenta) fundic mucosa was measured with double-barreled pH glass microelectrodes inserted into the glandular lumen (53). The fluid was found to be slightly more alkaline than the bathing solution, and, interestingly, both carbachol and gastrin increased transport of alkali into the intraglandular lumen. The authors proposed that oxyntopeptic cells contribute to the gastric alkaline secretion in this species. In another study using double-barreled pH-sensitive microelectrodes with guinea pig fundic mucosa (206, 207), there was a gradient of increasing pH along the crypt lumen from 3.0 in the parietal cell region to 4.6 in crypt outlets. However, it should be stressed that the rate of acid secretion by mammalian gastric mucosa in vitro usually is much lower (5%) than that in vivo. This difference in rates may reflect insufficient oxygenation of the circulation deprived mammalian tissues in vitro. Furthermore, oxygen-deficient mucosal cells may swell and release mucus. The pH-sensitive indicator Lysosensor yellow-blue was used for measurement of net acid transport within isolated gastric glands in a recent elegant study (182). From the transient nature of the response to carbachol, it was proposed that this secretagogue may induce intraglandular secretion of alkali and/or proteins, such as pepsinogens and mucins, from chief and other nonparietal cells, that may buffer acid in the intraglandular lumen. An only slightly acidic intraglandular pH (pH
5.3) was found upon confocal microscopy of rat fundic mucosa in vivo, and treatment with dimethyl-PGE2 increased intraglandular pH (49). E-type prostaglandins, which stimulate both gastric and duodenal alkaline secretion (65, 235), are also well-known inhibitors of gastric H+ secretion (256). These combined studies of intraglandular pH provide evidence that some HCO3 and/or acid-buffering substance originates from cells within the gastric glands, but this is unlikely to be quantitatively significant in net gastric mucosal HCO3 secretion in vivo.
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DUODENAL ALKALINE SECRETION |
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Knowledge about the HCO3 transport processes in the duodenal epithelium per se originates from numerous studies (65, 69) involving animals and humans in vivo, amphibian and mammalian mucosa in vitro, isolated mammalian duodenal enterocytes, isolated cell membranes, and, more recently, genetically modified mice. Microfluorospectrophotometric studies of mixed villous and crypt enterocytes isolated from proximal duodenum and loaded with the pH-sensitive fluoroprobe BCECF (117) confirmed previous hypotheses based on studies of amphibian mucosa in vitro (66), namely, that duodenal enterocytes possess at least three mechanisms for acid-base transport (Fig. 3). These are 1) amiloride-sensitive Na+/H+ exchange, which extrudes acid; 2) duodenal enterocytes, which import HCO3 at the basolateral membrane by Na+(n)-HCO3 cotransport and export HCO3 via an apical anion conductive pathway and Cl/HCO3 exchange; and in addition, 3) paracellular migration of HCO3, which is dependent on transmucosal hydrostatic pressure in vitro (64) and intestinal motility in vivo (172, 174). Studies of duodenum from knockout mice deficient in the cystic fibrosis transmembrane conductance regulator (CFTR) (45, 93, 107, 129, 209) provide strong evidence that CFTR is the membrane-spanning conductance transporting HCO3 as well as Cl (Fig. 3). CFTR is presently considered a principal anion channel pathway in Cl and HCO3 export in airway and intestinal epithelia, but it also exerts several cellular actions independent of channel activity (32). Endoscopic specimens mounted in Ussing chambers have been used in a study of CFTR activity in human duodenum (186). In line with findings from mouse duodenum, basal HCO3 secretion and short-circuit current were significantly lower in biopsies from patients with cystic fibrosis than in those from normal subjects. Present evidence thus strongly suggests that CFTR is the important apical conductive pathway in agonist-stimulated duodenal mucosal HCO3 secretion mediated by cAMP as well as by cGMP and intracellular Ca2+ concentration ([Ca2+]i) (22, 45, 107, 129, 209, 222). Basal HCO3 secretion, in contrast, seems mainly dependent on apical Cl/HCO3 exchange (222, 254). Recently, PAT1 (SLC26A6) was identified as a major Cl/HCO3 exchanger in the apical membrane of the duodenum (257), along with the DRA (SLC26A3) Cl/HCO3 exchanger (121, 161).
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It has been believed that intestinal secretions are of crypt origin, whereas absorptive functions reside in villi. Interestingly, recent work (21, 22) suggested involvement of the CFTR channel in secretion by duodenal villus enterocytes. Expression of CFTR in human and rat duodenum was characterized by immunofluorescence and immunoelectron microscopy by using anti-CFTR and enzyme marker antibodies. A subpopulation (2.5%) of villus enterocytes expressed very high levels of CFTR throughout the cells, with the greatest concentration apically. Thus CFTR-dependent export of HCO3 may be a property of villus as well as crypt cells. Finally, it was recently observed in clusters of rat and human duodenal enterocytes (218) that melatonin-induced [Ca2+]i signaling spread throughout the clusters, indicating that duodenal enterocytes interact and that the mucosa functions as a syncytium. This would enhance an integrated action of duodenal secretagogues.
A role for the CFTR channel in duodenal HCO3 export has been questioned on the basis of a study comparing transport of acid-base equivalents across the plasma membrane of proximal duodenal enterocytes in CFTR-deficient mice with that in normal littermates (188). The acid extrusion and the alkaline extrusion rates were unaffected by CFTR deficiency, and acid-base transport seemed mediated almost exclusively by Na+/H+ exchange, Cl/HCO3 exchange, and Na+-HCO3 cotransport. Absence of CFTR conductance in these studies might reflect the use of enterocytes rather than intact mucosa. The possibility cannot be excluded that cell isolation procedures induce cellular changes preventing migration of cytoplasmic CFTR (22, 251) to the duodenal enterocyte apical surface. The molecular expression and localization of Na+-HCO3 cotransporters (NBC) in mouse duodenum were recently studied using RT-PCR, sequence analysis, and immunohistochemistry (189). Enterocytes expressed mRNA encoding two electrogenic NBC1 isoforms and the electroneutral NBCn1. Both NBC1 and NBCn1 were localized to the basolateral membrane of duodenal villus enterocytes, whereas crypt enterocytes did not label with the anti-NBC antibodies. In membrane vesicles from rabbit duodenal enterocytes (120), pH gradient-driven Na+ uptake was partly HCO3 and DIDS sensitive and partly dependent on the Na+/H+ exchange isoform NHE1.
Na+/H+ exchange would supply intracellular HCO3 by export of H+ formed on hydration of CO2 to H+ and HCO3. The Na+/H+ exchanger isoforms NHE1 as well as NHE2 and NHE3 are expressed in mouse duodenal enterocytes, and all three isoforms were reported to contribute to regulation of intracellular pH (pHi) in these cells (187). In contrast, specific inhibition of the apical isoform NHE3 by the compound S3226 did not affect pHi in rat villus enterocytes in situ (85). However, the latter study (85) also showed that this compound causes a slowly developing rise in HCO3 secretion by duodenum in anesthetized rats. A rise in net alkaline (HCO3 minus H+) secretion could reflect inhibition of a smaller, and therefore concealed, H+ export. Luminal administration of the anion channel inhibitor 5-nitro-2-(3-phenylpropylamino)benzoic acid prevented the rise in net alkaline secretion, indicating an action on HCO3 export per se. The authors suggested interaction between NHE3 exchanger activity and the CFTR channel. Finally, entry of Cl for secretion across epithelial apical membranes predominantly depends on import of Cl by basolateral Na+-K+-2Cl cotransport (NKCC). Basal and cAMP-stimulated HCO3 secretion in duodenum from NKCC1 knockout mice was very similar to that in wild-type animals, indicating that apical export of HCO3 does not depend on basolateral Na+-K+-2Cl cotransport activity (254).
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STIMULATION OF GASTRODUODENAL BICARBONATE SECRETION BY LUMINAL ACID |
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The impaired alkaline response to acid in patients with duodenal ulcer disease (40, 108, 118, 163) has focused interest on mediation of this duodenal response. A low pH in the duodenal lumen (pH 5 in rat and
pH 3 in human) caused a marked, up to fivefold (60, 72) rise in the secretion. The response is mediated by neural reflexes and mucosal production of prostaglandins (23, 65, 235) and also, very likely, by locally produced uroguanylin (129). Several transmitters, including VIP and acetylcholine, are mediators of the efferent limb of the neural response. Chemical deafferentiation by capsaicin inhibits the rise in HCO3 secretion in response to luminal acid (114). The response to exogenous PGE2, in contrast, is not affected by the destruction of the afferent neurons. Thus this suggests that luminal acidification involves the enteric nervous system, whereas PGE2 acts directly on the HCO3-producing cells (23, 235). Recent findings suggest that prostaglandins stimulate duodenal HCO3 secretion by acting on duodenal EP3 receptors as well as EP4 receptors. Furthermore, it has been proposed (23) that stimulation via EP4 receptors is mediated by cAMP, whereas that via EP3 receptors is mediated by cAMP production as well as [Ca2+]i signaling. In addition, there is an interaction between these stimulatory pathways. In the stomach, prostaglandins stimulate HCO3 by affecting the gastric EP1 receptors (235). Affirming a role for prostaglandins and epithelial HCO3 in protection against mucosal injury, the duodenal mucosa in EP3 knockout mice has a markedly decreased ability to resist luminal acid damage (234). NO is another interesting mediator of the rise in duodenal alkaline secretion in response to luminal acid. Luminal acid stimulates the expression of inducible NO synthase in the duodenal villi, and it is proposed that this induces synthesis of NO (113).
It would seem physiologically rational that the presence of acid in the gastric lumen would result in an anticipatory rise in alkaline secretion by duodenal mucosa about to receive an acid load. However, instillation of acid into the ligated stomach or, conversely, decreasing gastric acidity by inhibition of acid secretion, does not affect duodenal HCO3 secretion (65, 70, 99).
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NEUROHUMORAL CONTROL OF BICARBONATE SECRETION |
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Orexins are involved in the central nervous systems control of appetite and behavior and appear to be involved in short-term regulation of feeding rather than long-term regulation of body weight (134, 145, 200). These peptides are present in endocrine cells and/or neurons in the intestine, but their effects on mucosal function and protection are largely unknown. Recent studies (77) have shown that close intraarterial infusion of low doses of orexin A (Fig. 5) caused a marked and dose-dependent stimulation of the duodenal HCO3 secretion in rats. However, stimulation occurred only in animals that had continuous access to their regular food. Short (overnight) deprivation of food abolished the stimulation of the duodenal HCO3 secretion. Similarly, short fasting caused a 100-fold increase in the amount of the muscarinic agonist bethanechol required for stimulation of the secretion. In contrast, the HCO3 secretory responses to VIP and melatonin were not affected (Fig. 5). An attractive explanation for the changes in sensitivity to orexin A and the muscarinic agonist would be that food constituents, either directly or indirectly by central or peripheral mechanisms, stimulate the activity or expression of signal pathways or receptors in the intestinal mucosa. It should also be noted that overnight fasting is a standard experimental procedure in studies of gastrointestinal function and pathophysiology in humans and animals. In view of these differences in response between the fed and fasted states, studies made on neuroendocrine control of mucosal protection and intestinal secretion may require reevaluation with respect to feeding status.
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DUODENAL PROTECTION AGAINST ACID |
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Studies in several species with a variety of modulators of secretion demonstrate the key importance of epithelial HCO3 secretion in duodenal mucosal protection against luminal acid. Stimulation and inhibition of alkaline secretion respectively increase and decrease the juxtamucosal pH at the duodenal mucosal cell surface (72, 136). Stimulation of mucosal HCO3 secretion by VIP, at doses not affecting mucosal blood flow, protected the duodenal mucosa in rat (175) and pig (1) against morphological damage induced by 10 mM luminal HCl and 30 mM luminal HCl, respectively. Stimulation of mucosal HCO3 secretion by glucagon significantly reduced the duodenal mucosal damage induced by 50 mM HCl in the rabbit (258). Inhibition of mucosal HCO3 secretion by parenteral administration of NH4Cl, vasopressin, or furosemide, in contrast, increased duodenal mucosal damage (258). Modest, acute hypovolemia markedly inhibited mucosal alkaline secretion in rat duodenum (125, 128). This procedure also significantly increased the morphological changes induced by 15-min exposure of the duodenal lumen to 100 mM HCl (125), although it had no effect at the lower concentration (10 mM) of acid. Furthermore, E-type prostaglandins, which increase duodenal mucosal alkaline secretion in all species tested, in vivo as well as in vitro, also increase mucosal resistance to luminal acid (64, 116, 233, 234, 235, 263). Inhibition of mucosal endogenous prostaglandin production by COX inhibitors reduces the alkaline secretion in humans (162) and in several (2, 64, 72, 233, 235) but not all (172) experimental models, and these compounds are well-known inducers of duodenal ulceration in experimental animals as well as in humans (229, 256).
An acid-protective role for the duodenal mucosal alkaline secretion is further supported by the finding that HCO3 secretion in proximal duodenum (40, 108, 118, 163), and, in particular, the rise in secretion in response to luminal acid is depressed in patients with duodenal ulcer disease. It has also been reported the pH at the surface of this epithelium in duodenal ulcer patients is lower than that in healthy subjects (190). The HCO3 secretion is reported to normalize after eradication of the bacterium Helicobacter pylori in patients with such infection (108). Interestingly, evidence has been presented that H. pylori infection inhibits antral mucosal production of NO (253), a transmitter thought to be important in mediation of the duodenal alkaline response (113). Perhaps surprisingly, E-type prostaglandin release from duodenal mucosa in patients with duodenal ulcer disease was greater than that in healthy controls (40). This could indicate that decreased sensitivity to E-type prostaglandins also may be part of the depression of the alkaline secretion in duodenal ulcer disease.
One additional mechanism of duodenal defense, namely, intracellular neutralization of acid, has been proposed from studies of pHi in apical villus cells in rat duodenum in situ. pHi was measured using pH-sensitive microelectrodes (178) or fluorescence microscopy of the duodenal surface after loading with the pH-sensitive compound BCECF-AM (4, 5). During acid perfusion, pHi decreased, whereas mucus gel thickness and blood flow increased. At the highest luminal acidity tested (pH 2.2), the recorded decrease in pHi after 5 min was from 7.10 to
6.30 with the fluorescence microscopy technique. The changes in pHi recorded with intracellular microelectrodes, and in response to a somewhat higher acidity (10 mM HC), were smaller (from pH 7.46 to pH 7.21) than those recorded with fluorescence microscopy. With both techniques, this decrease in pHi was smaller on a second brief exposure to acid. This interesting adaptation to rapid shifts in duodenal luminal acidity was sensitive to DIDS and was explained by acid-induced augmented cellular uptake of HCO3 by the enterocyte basolateral Na+-HCO3 cotransporter. Subsequent perfusion with neutral luminal solution increased pHi above baseline values (4), and, in line with the higher rates of transcellular HCO3 transport in proximal duodenum (115, 116, 214), acid-induced decreases in pHi were smaller in proximal than in distal duodenum (178). It thus would seem likely that intracellular neutralization of acid reflects the basolateral part of the processes for transcellular transport of HCO3 into the duodenal lumen (Fig. 3). It should be noted that, mainly, pHi in apical enterocytes in the duodenal villi was examined in these studies and that decreases in pHi may reflect acidification by high levels of CO2 (98, 112, 122) formed within the duodenal mucus gel during reaction between acid from the lumen and secreted HCO3.
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CONCLUSIONS |
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The numerous pH gradient studies are good experimental evidence for the existence of the mucus bicarbonate barrier in vivo and the establishment of a nearly neutral pH at the epithelial surface. The gastric epithelial cells may be slightly and transiently acidified during acute exposure to high concentrations of luminal acid, but mainly, the surface epithelium in acid-secreting gastric mucosa exports HCO3 at rates sufficient to maintain a neutral pH at the apical cell surfaces. During acid secretion, parietal cells release HCO3 into the mucosal interstitium and vasculature. This increased interstitial HCO3, the alkaline tide, is imported by the surface epithelial cells, significantly enhancing mucosal alkaline secretion and surface alkalinity. Uncertainties have been raised as to whether a more alkaline or acidic juxtamucosal pH exists at the mucosal surface at higher luminal pH values (pH 5), and more experimentation is needed to resolve this question. The two approaches to studying pH gradients are not directly comparable either, because pH-sensitive microelectrode studies, at luminal pH 13, have been conducted primarily in unstirred conditions, whereas the confocal imaging studies at pH 35 were performed in a perfused system.
In duodenum, the mucosal HCO3 secretion is currently accepted as the primary defense mechanism against acid discharge from the stomach. Thus the duodenal epithelium secretes HCO3 at higher rates (per unit surface area) than does the stomach or, for that matter, the more distal small intestine. In the first part of the duodenum, mucosal HCO3, secreted proximal to the entry of HCO3 from the pancreaticobiliary duct, maintains a pH gradient with a neutral pH at the mucus epithelial interface under all luminal acidities encountered in the healthy organ. Presence of acid in the lumen is a powerful stimulant in duodenum and causes up to a fivefold increase in duodenal HCO3 secretion as well as an increased mucus gel secretion. Furthermore, there is an impaired HCO3 secretory response to acid in patients with duodenal ulcer disease. The alkaline response to acid is mediated by neural reflexes and mucosal production of prostaglandins and, as shown recently, by locally produced uroguanylin. Melatonin released from enterochromaffin cells in the duodenal mucosa, furthermore, may be involved in control of HCO3 secretion, and a role also has been proposed for local mucosal dopamine.
Finally, this review is confined to aspects of the mucus bicarbonate barrier and this barriers role in protection against the natural endogenous aggressors acid and pepsin. Although there is an array of other aggressive factors that have been shown to be integral to the pathology of peptic ulceration, the principle as proposed by Schwartz in 1910 (208) still holds: no peptic activity, no ulcer. Furthermore, it should be stressed that the mucus bicarbonate barrier is one of many integrated components that form the complete protective mucosal barrier. It is the initial, and only, preepithelial barrier between the lumen and the gastric surface epithelium, and as discussed in this review, evidence suggests that it is sufficient for protection against luminal acid and pepsin during normal digestive processes. Mucosal protection for parietal and chief cells within the gastric crypts is different, with their cell apical membranes apparently resistant to their intracryptal secretions (37, 245). When the mucus bicarbonate barrier is overwhelmed or when it breaks down in disease, then there are a whole series of protective mechanisms that come into play, including intracellular neutralization of acid, rapid epithelial repair and maintenance, and distribution of mucosal blood flow.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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