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The Gastric Mucosal Barrier

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Abstract

The sections in this article are:

1 Electrolyte Composition of Gastric Juice
2 Electrical Characteristics of Gastric Mucosa
2.1 Comparison of Fundic and Antral Gastric Mucosa
3 Proton Permeability of Gastric Mucosa
4 Constituents of The Barrier
5 Mucus‐Bicarbonate Layer
6 Epithelial Cell Layer
6.1 Tight Junctions
6.2 Apical Cell Membranes
7 Studies With Barrier‐Breaking Agents
7.1 Aspirin and Weak Acids
7.2 Bile Acids
7.3 Alcohols
7.4 Pepsin
8 Gastric Membrane Composition
8.1 Lipid Constituents
8.2 Glycosubstances
9 Surface Hydrophobicity
10 Direct Evidence For Impermeability of Apical Membranes To Protons
10.1 Reconstituted Epithelial Cell Monolayers
10.2 Isolated Apical Plasma Membrane Vesicles
11 Regulation of Intracellular Ph
12 Gastric Microcirculation
12.1 Tissue Acid‐Base Balance
12.2 Tissue Oxygenation
12.3 Oxygen Radical Generation
13 Rapid Reepithelialization of Gastric Mucosa
14 Cytoprotection
14.1 Prostaglandins
14.2 Sulfhydryl Compounds and Other Agents
15 Conclusions
Figure 1. Figure 1.

Relationship between [H+] and [Na+] and flow rate of gastric juice in humans. Data were obtained in the unstimulated state and during stimulation with gastrin, k, Flow rate of nonparietal component of gastric juice.

From Makhlouf . In: Physiology of the Gastrointestinal Tract, © 1981, Raven Press, New York
Figure 2. Figure 2.

Constituents of the gastric mucosal barrier.

Adapted from Powell
Figure 3. Figure 3.

Demonstration of a pH gradient above frog gastric mucosa in vitro. An antimony microelectrode was positioned at an angle of 60° to the tissue and advanced toward the mucosal surface in 40 or 80 μn steps. Although originally believed to measure the pH within the mucus, the measurements probably also include any unstirred layer above the mucus . Arrows, changes in position of the electrode tip by either 40 or 80 μm.

From Takeuchi et al. . Copyright 1983 by The American Gastroenterology Association
Figure 4. Figure 4.

Changes in net Na+ and H+ flux from the gastric lumen of the rat and the effect of conjugated bile acids. Test solutions were 0.1 M phosphate buffer (pH 7) and 10 mM mixture of conjugated bile acids in this buffer with and without added lecithin and cholesterol. Filled bars, test solution was continuously mixed during incubation in the stomach. Open bars, test solution was not mixed. Bile acids in mixed or unmixed solutions significantly increased net forward diffusion of Na+ and backdiffusion of H+. Saturating this solution with lecithin and cholesterol prevented these changes in net ion fluxes. Mixing bile acid solutions resulted in significantly greater increases in the net fluxes of both ions. Results are means ±1 SE.

From Duane et al. . Copyright 1986 by The American Gastroenterology Association
Figure 5. Figure 5.

Electron micrographs of mouse gastric surface epithelial cells and effects of ethanol and urea. A: normal cells from a mouse that had received 145 mM NaCl for 2 min. Chromatin is scattered diffusely throughout the nucleus (N). The apical plasma membrane, the dark‐staining; mucous granules (G), the light‐staining mitochondria (M), and tight junctions (arrows) all appear normal (x 8,000). Inset: higher magnification of one of the tight junctions (arrow), which represents the fusion of the lateral plasma membranes of adjacent cells near their apical ends. Typical microvillus (MV) covered by the fuzzy coat is also seen (x 72,000). B: cells from a mouse that had received 25% ethanol plus 100 mM HCl for 5 min. Chromatin is clumped within the nucleus (N), mitochondria (M) are swollen, and the apical cell membrane is distorted. Mucous granules (G) and tight junction (arrow) appear normal (x 8,000). Inset: higher magnification of the tight junction (x 72,000). C: cells from a mouse that had received 900 mM urea for 15 min. These cells appear normal except for the presence of cytoplasmic vacuoles (V) and blister formation within the tight junction (arrow). Inset: tight junction has separated, forming a blister (x 72,000).

From Eastwood and Kirchner , © by Williams & Wilkins, 1974
Figure 6. Figure 6.

Net H+ loss and Na+ gain in the gastric lumen of rats of various ages in response to instillation of 10 mM (○), 50 mM (Δ), or 150 mM (•) HCl. Net ion fluxes increase after 25 days. Results are means ± 1 SE. *, Significant difference between groups.

From Tepperman et al.
Figure 7. Figure 7.

Diagram illustrating the pH gradient that exists in the stomach between the gastric fluid and a mucosal cell and equilibrium between the dissociated and undissociated forms of a weak acid (e.g., aspirin) R·COOH. A, concentration of the weak acid in the gastric lumen; B, concentration of the weak acid in the gastric mucosal cell.

From Martin . Reprinted by permission from Nature, copyright 1963, Macmillan Magazines Limited
Figure 8. Figure 8.

Changes in fluxes of Na+ and H+ across canine gastric mucosa during instillation of solutions of ethanol. A: increasing concentrations of ethanol were instilled in 100 mM HCl plus 54 mM NaCl. Concentrations of ethanol normally found in beer (B), sherry (S), and a martini cocktail [4 parts gin to 1 part vermouth (M)] are indicated. B: increasing concentrations of ethanol were instilled in 100 mM HCl or 30 mM phosphate buffer (pH 7.5). Ion fluxes from phosphate buffer were significantly (**) lower than from HCl solutions.

From Davenport
Figure 9. Figure 9.

Effects of ethanol on proton permeation in parietal cell isolated apical membrane vesicles. Parietal cell apical membrane vesicles [stimulation‐associated vesicles (SAV)] were equilibrated in an acidic (pH 6.5) solution. H+ permeation was measured by diluting the vesicles into a pH 8.0 solution containing acridine orange (first arrow). Vesicles were voltage‐clamped with a K+‐valinomycin system to prevent generation of diffusion potentials. Addition of vesicles leads to a quenching of the fluorescence signal from acridine orange [Λex (excitation wavelength) 492 nm; Λem (emission wavelength) 530 nm] as the dye is accumulated within the acidic vesicles. Recovery of the fluorescence gives the rate of H+ permeation. Nigericin, an H+‐K+ ionophore, was added at the second arrow to fully dissipate the proton gradient. Increasing concentrations of ethanol accelerated the rate of recovery of fluorescence, i.e., rate of H+ permeation. Inset: apparent rate constant for recovery of fluorescence was analyzed by simple first‐order kinetics. Rate constant for H+ permeation (KH+) is plotted against ethanol concentration (mean ± 1 SE for 12‐17 observations).

See refs. 254 and 119 for further details
Figure 10. Figure 10.

Rat gastric mucosa during the process of damage by ethanol and subsequent reepithelialization. Low‐power photomicrographs of semithin sections of rat gastric mucosa at various intervals after distension with absolute ethanol. A: control mucosa, luminal saline for 1 h. B: 1 min after ethanol exposure the surface epithelium is necrotic and lifting off the lamina propria (arrows). Deep pit and gland cells are intact. C: after 7 min of exposure to ethanol the surface epithelium is separated from the mucosa. D: 15‐min sample shows exfoliated surface, intervening layer, and early evidence of reepithelialization. E: after 30 min, much of the luminal surface is reepithelialized. F: by 60 min the restituted surface is clearly evident. Space between dead cell layer and mucosa contains fibrin and mucus. × 162.

From Ito and Lacy . Copyright 1985 by The American Gastroenterology Association
Figure 11. Figure 11.

Transmucosal potential difference recordings from chambered rat gastric mucosae damaged with 50% ethanol. All tissues were bathed in 0.3 M mannitol before ethanol was added. In control tissues, luminal bathing fluid was then 50 mM HCl in 0.2 M mannitol. A: in the test group, 5% N‐acetylcysteine (NAC) was added to the chamber in each period except the period in which 50% ethanol was applied min). B: protocol for these experiments was the same as shown at the top of A, except that 0.5% pepsin was added to the chamber in place of NAC. C: in the test group, solutions added to the chamber were identical to those in the control group. Under a stereomicroscope, the mucoid cap that formed after application of 50% ethanol was meticulously peeled off the underlying mucosa at 28 min (arrow). Results illustrated as mean ± 1 SE; double asterisks, significant difference from control group.

From Wallace and Whittle . Copyright 1986 by The American Gastroenterology Association
Figure 12. Figure 12.

Diagrammatic representation of an adsorbed monolayer of phospholipid on the gastric mucosal surface. Schematic includes 1) intercalated protein zones in plasma membrane lipid bilayer, which might also be coated with monolayer; 2) occasional bilayer formation; and 3) wetting of the monolayer external surface by mucus, argued to reduce interfacial energy and provide an aqueous phase containing micelles and dissolved molecules in equilibrium with the adsorbed monolayer. Folding of intercalated proteins is argued to provide the ideal orientation of protein domains for adsorption of phospholipid.

From Hills
Figure 13. Figure 13.

Electrical response of a peptic cell monolayer to mucosal acidification. Top panel, apical solution pH as a function of time; a decrease reflects addition of acid. R, membrane resistance. V, potential difference. Isc, short‐circuit current. With reduction of apical pH to <2.5, R increased and remained stable for >3 h. Addition of 4 mM aspirin (A, arrowhead) caused a rapid decay in R, V, and Isc.

From Sanders et al. . Reprinted by permission from Nature, copyright 1985, Macmillan Magazines Limited
Figure 14. Figure 14.

Gastric cytoprotection of prostaglandins against ethanol. One ml of absolute ethanol was given orally. Rats were killed 1 h later and stomachs were removed and opened along the greater curvature. A: control vehicle was given orally 30 min before the ethanol. Multiple and severe necrotic lesions of the body of the stomach caused by ethanol are visible. B‐D: a prostaglandin was administered 30 min before the ethanol. B: PGE2 500 μg·kg‐1 subcutaneously. C: PGE2 150 μg·kg‐1 orally. D: 16,16‐dimethyl PGA2 50 μg·kg‐1 orally. These 3 prostaglandins prevented formation of visible gastric lesions due to ethanol.

From Robert et al. . Copyright 1979 by The American Gastroenterology Association


Figure 1.

Relationship between [H+] and [Na+] and flow rate of gastric juice in humans. Data were obtained in the unstimulated state and during stimulation with gastrin, k, Flow rate of nonparietal component of gastric juice.

From Makhlouf . In: Physiology of the Gastrointestinal Tract, © 1981, Raven Press, New York


Figure 2.

Constituents of the gastric mucosal barrier.

Adapted from Powell


Figure 3.

Demonstration of a pH gradient above frog gastric mucosa in vitro. An antimony microelectrode was positioned at an angle of 60° to the tissue and advanced toward the mucosal surface in 40 or 80 μn steps. Although originally believed to measure the pH within the mucus, the measurements probably also include any unstirred layer above the mucus . Arrows, changes in position of the electrode tip by either 40 or 80 μm.

From Takeuchi et al. . Copyright 1983 by The American Gastroenterology Association


Figure 4.

Changes in net Na+ and H+ flux from the gastric lumen of the rat and the effect of conjugated bile acids. Test solutions were 0.1 M phosphate buffer (pH 7) and 10 mM mixture of conjugated bile acids in this buffer with and without added lecithin and cholesterol. Filled bars, test solution was continuously mixed during incubation in the stomach. Open bars, test solution was not mixed. Bile acids in mixed or unmixed solutions significantly increased net forward diffusion of Na+ and backdiffusion of H+. Saturating this solution with lecithin and cholesterol prevented these changes in net ion fluxes. Mixing bile acid solutions resulted in significantly greater increases in the net fluxes of both ions. Results are means ±1 SE.

From Duane et al. . Copyright 1986 by The American Gastroenterology Association


Figure 5.

Electron micrographs of mouse gastric surface epithelial cells and effects of ethanol and urea. A: normal cells from a mouse that had received 145 mM NaCl for 2 min. Chromatin is scattered diffusely throughout the nucleus (N). The apical plasma membrane, the dark‐staining; mucous granules (G), the light‐staining mitochondria (M), and tight junctions (arrows) all appear normal (x 8,000). Inset: higher magnification of one of the tight junctions (arrow), which represents the fusion of the lateral plasma membranes of adjacent cells near their apical ends. Typical microvillus (MV) covered by the fuzzy coat is also seen (x 72,000). B: cells from a mouse that had received 25% ethanol plus 100 mM HCl for 5 min. Chromatin is clumped within the nucleus (N), mitochondria (M) are swollen, and the apical cell membrane is distorted. Mucous granules (G) and tight junction (arrow) appear normal (x 8,000). Inset: higher magnification of the tight junction (x 72,000). C: cells from a mouse that had received 900 mM urea for 15 min. These cells appear normal except for the presence of cytoplasmic vacuoles (V) and blister formation within the tight junction (arrow). Inset: tight junction has separated, forming a blister (x 72,000).

From Eastwood and Kirchner , © by Williams & Wilkins, 1974


Figure 6.

Net H+ loss and Na+ gain in the gastric lumen of rats of various ages in response to instillation of 10 mM (○), 50 mM (Δ), or 150 mM (•) HCl. Net ion fluxes increase after 25 days. Results are means ± 1 SE. *, Significant difference between groups.

From Tepperman et al.


Figure 7.

Diagram illustrating the pH gradient that exists in the stomach between the gastric fluid and a mucosal cell and equilibrium between the dissociated and undissociated forms of a weak acid (e.g., aspirin) R·COOH. A, concentration of the weak acid in the gastric lumen; B, concentration of the weak acid in the gastric mucosal cell.

From Martin . Reprinted by permission from Nature, copyright 1963, Macmillan Magazines Limited


Figure 8.

Changes in fluxes of Na+ and H+ across canine gastric mucosa during instillation of solutions of ethanol. A: increasing concentrations of ethanol were instilled in 100 mM HCl plus 54 mM NaCl. Concentrations of ethanol normally found in beer (B), sherry (S), and a martini cocktail [4 parts gin to 1 part vermouth (M)] are indicated. B: increasing concentrations of ethanol were instilled in 100 mM HCl or 30 mM phosphate buffer (pH 7.5). Ion fluxes from phosphate buffer were significantly (**) lower than from HCl solutions.

From Davenport


Figure 9.

Effects of ethanol on proton permeation in parietal cell isolated apical membrane vesicles. Parietal cell apical membrane vesicles [stimulation‐associated vesicles (SAV)] were equilibrated in an acidic (pH 6.5) solution. H+ permeation was measured by diluting the vesicles into a pH 8.0 solution containing acridine orange (first arrow). Vesicles were voltage‐clamped with a K+‐valinomycin system to prevent generation of diffusion potentials. Addition of vesicles leads to a quenching of the fluorescence signal from acridine orange [Λex (excitation wavelength) 492 nm; Λem (emission wavelength) 530 nm] as the dye is accumulated within the acidic vesicles. Recovery of the fluorescence gives the rate of H+ permeation. Nigericin, an H+‐K+ ionophore, was added at the second arrow to fully dissipate the proton gradient. Increasing concentrations of ethanol accelerated the rate of recovery of fluorescence, i.e., rate of H+ permeation. Inset: apparent rate constant for recovery of fluorescence was analyzed by simple first‐order kinetics. Rate constant for H+ permeation (KH+) is plotted against ethanol concentration (mean ± 1 SE for 12‐17 observations).

See refs. 254 and 119 for further details


Figure 10.

Rat gastric mucosa during the process of damage by ethanol and subsequent reepithelialization. Low‐power photomicrographs of semithin sections of rat gastric mucosa at various intervals after distension with absolute ethanol. A: control mucosa, luminal saline for 1 h. B: 1 min after ethanol exposure the surface epithelium is necrotic and lifting off the lamina propria (arrows). Deep pit and gland cells are intact. C: after 7 min of exposure to ethanol the surface epithelium is separated from the mucosa. D: 15‐min sample shows exfoliated surface, intervening layer, and early evidence of reepithelialization. E: after 30 min, much of the luminal surface is reepithelialized. F: by 60 min the restituted surface is clearly evident. Space between dead cell layer and mucosa contains fibrin and mucus. × 162.

From Ito and Lacy . Copyright 1985 by The American Gastroenterology Association


Figure 11.

Transmucosal potential difference recordings from chambered rat gastric mucosae damaged with 50% ethanol. All tissues were bathed in 0.3 M mannitol before ethanol was added. In control tissues, luminal bathing fluid was then 50 mM HCl in 0.2 M mannitol. A: in the test group, 5% N‐acetylcysteine (NAC) was added to the chamber in each period except the period in which 50% ethanol was applied min). B: protocol for these experiments was the same as shown at the top of A, except that 0.5% pepsin was added to the chamber in place of NAC. C: in the test group, solutions added to the chamber were identical to those in the control group. Under a stereomicroscope, the mucoid cap that formed after application of 50% ethanol was meticulously peeled off the underlying mucosa at 28 min (arrow). Results illustrated as mean ± 1 SE; double asterisks, significant difference from control group.

From Wallace and Whittle . Copyright 1986 by The American Gastroenterology Association


Figure 12.

Diagrammatic representation of an adsorbed monolayer of phospholipid on the gastric mucosal surface. Schematic includes 1) intercalated protein zones in plasma membrane lipid bilayer, which might also be coated with monolayer; 2) occasional bilayer formation; and 3) wetting of the monolayer external surface by mucus, argued to reduce interfacial energy and provide an aqueous phase containing micelles and dissolved molecules in equilibrium with the adsorbed monolayer. Folding of intercalated proteins is argued to provide the ideal orientation of protein domains for adsorption of phospholipid.

From Hills


Figure 13.

Electrical response of a peptic cell monolayer to mucosal acidification. Top panel, apical solution pH as a function of time; a decrease reflects addition of acid. R, membrane resistance. V, potential difference. Isc, short‐circuit current. With reduction of apical pH to <2.5, R increased and remained stable for >3 h. Addition of 4 mM aspirin (A, arrowhead) caused a rapid decay in R, V, and Isc.

From Sanders et al. . Reprinted by permission from Nature, copyright 1985, Macmillan Magazines Limited


Figure 14.

Gastric cytoprotection of prostaglandins against ethanol. One ml of absolute ethanol was given orally. Rats were killed 1 h later and stomachs were removed and opened along the greater curvature. A: control vehicle was given orally 30 min before the ethanol. Multiple and severe necrotic lesions of the body of the stomach caused by ethanol are visible. B‐D: a prostaglandin was administered 30 min before the ethanol. B: PGE2 500 μg·kg‐1 subcutaneously. C: PGE2 150 μg·kg‐1 orally. D: 16,16‐dimethyl PGA2 50 μg·kg‐1 orally. These 3 prostaglandins prevented formation of visible gastric lesions due to ethanol.

From Robert et al. . Copyright 1979 by The American Gastroenterology Association
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Barry H. Hirst. The Gastric Mucosal Barrier. Compr Physiol 2011, Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion: 279-308. First published in print 1989. doi: 10.1002/cphy.cp060315