Gastric Mucosal Defense and Cytoprotection: Bench to Bedside

The gastric mucosa maintains structural integrity and function despite continuous exposure to noxious factors, including 0.1 mol/L HCl and pepsin, that are capable of digesting tissue. Under normal conditions, mucosal integrity is maintained by defense mechanisms, which include preepithelial factors (mucus-bicarbonate-phospholipid “barrier”), an epithelial “barrier” (surface epithelial cells connected by tight junctions and generating bicarbonate, mucus, phospholipids, trefoil peptides, prostaglandins (PGs), and heat shock proteins), continuous cell renewal accomplished by proliferation of progenitor cells (regulated by growth factors, PGE2 and survivin), continuous blood flow through mucosal microvessels, an endothelial “barrier,” sensory innervation, and generation of PGs and nitric oxide. Mucosal injury may occur when noxious factors “overwhelm” an intact mucosal defense or when the mucosal defense is impaired. We review basic components of gastric mucosal defense and discuss conditions in which mucosal injury is directly related to impairment in mucosal defense, focusing on disorders with important clinical sequelae: nonsteroidal anti-inflammatory drug (NSAID)-associated injury, which is primarily related to inhibition of cyclooxygenase (COX)-mediated PG synthesis, and stress-related mucosal disease (SRMD), which occurs with local ischemia. The annual incidence of NSAID-associated upper gastrointestinal (GI) complications such as bleeding is approximately 1%–1.5%; and reductions in these complications have been demonstrated with misoprostol, proton pump inhibitors (PPIs) (only documented in high-risk patients), and COX-2 selective inhibitors. Clinically significant bleeding from SRMD is relatively uncommon with modern intensive care. Pharmacologic therapy with antisecretory drugs may be used in high-risk patients (eg, mechanical ventilation ≥48 hours), although the absolute risk reduction is small, and a decrease in mortality is not documented. The gastric mucosa maintains structural integrity and function despite continuous exposure to noxious factors, including 0.1 mol/L HCl and pepsin, that are capable of digesting tissue. Under normal conditions, mucosal integrity is maintained by defense mechanisms, which include preepithelial factors (mucus-bicarbonate-phospholipid “barrier”), an epithelial “barrier” (surface epithelial cells connected by tight junctions and generating bicarbonate, mucus, phospholipids, trefoil peptides, prostaglandins (PGs), and heat shock proteins), continuous cell renewal accomplished by proliferation of progenitor cells (regulated by growth factors, PGE2 and survivin), continuous blood flow through mucosal microvessels, an endothelial “barrier,” sensory innervation, and generation of PGs and nitric oxide. Mucosal injury may occur when noxious factors “overwhelm” an intact mucosal defense or when the mucosal defense is impaired. We review basic components of gastric mucosal defense and discuss conditions in which mucosal injury is directly related to impairment in mucosal defense, focusing on disorders with important clinical sequelae: nonsteroidal anti-inflammatory drug (NSAID)-associated injury, which is primarily related to inhibition of cyclooxygenase (COX)-mediated PG synthesis, and stress-related mucosal disease (SRMD), which occurs with local ischemia. The annual incidence of NSAID-associated upper gastrointestinal (GI) complications such as bleeding is approximately 1%–1.5%; and reductions in these complications have been demonstrated with misoprostol, proton pump inhibitors (PPIs) (only documented in high-risk patients), and COX-2 selective inhibitors. Clinically significant bleeding from SRMD is relatively uncommon with modern intensive care. Pharmacologic therapy with antisecretory drugs may be used in high-risk patients (eg, mechanical ventilation ≥48 hours), although the absolute risk reduction is small, and a decrease in mortality is not documented. The gastric mucosa is continuously exposed to many noxious factors and substances. How the gastric mucosa maintains structural integrity and resists autodigestion by substances such as 0.1 mol/L HCl and pepsin puzzled clinicians and investigators for more than 200 years. An early hypothesis proposed by Hunter in 1772 and supported by Virchow in 1853 was that continuous circulation of alkaline blood through the mucosa neutralizes acid.1Hunter J. Digestion of the stomach after death.Philos Trans R Soc Lond. 1772; 62: 447-454Crossref Google Scholar, 2Virchow R. Historisches, kritisches und positives zur lehre der unterleibsaffektionen.Arch Pathol Anat. 1853; 5: 281-375Crossref Scopus (9) Google Scholar Subsequent work demonstrated that a large number of mucosal defense mechanisms prevent mucosal damage and maintain mucosal integrity. The discovery by Vane that the major mechanism by which aspirin and other NSAIDs produce gastric damage is inhibition of prostaglandin (PG) synthesis,3Vane J.R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.Nat N Biol. 1971; 232: 232-235Crossref Google Scholar and the concept of cytoprotection developed in the late 1970s and early 1980s by Robert et al4Robert A. Nezamis J.E. Lancaster C. et al.Cytoprotection by prostaglandins in rats Prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl and thermal injury.Gastroenterology. 1978; 77: 433-443Google Scholar, 5Robert A. Nezamis J.E. Lancaster C. et al.Mild irritants prevent gastric necrosis through “adaptive cytoprotection” mediated by prostaglandins.Am J Physiol. 1983; 245: G113-G121PubMed Google Scholar sparked tremendous interest in gastric mucosal defense. Gastric mucosal injury may occur when noxious factors “overwhelm” an intact mucosal defense (eg, Zollinger Ellison syndrome) or when the mucosal defensive mechanisms are impaired. This review focuses on conditions in which mucosal injury is directly related to impairment in mucosal defense. Conditions in which the inciting factor is an injurious agent (eg, acid, Helicobacter pylori) are covered in other reviews in this series. We first review the basic components and mechanisms that provide gastric mucosal defense and then discuss clinical conditions that occur primarily because of impairment in gastric mucosal defense. Finally, we will review the prevention and treatment of 2 important clinical conditions that result from impaired mucosal defense: NSAID-associated injury and SRMD. Defense mechanisms permit the gastric mucosa to withstand frequent exposure to damaging factors across a wide range of pH, osmolality, and temperature.6Werther J.L. The gastric mucosal barrier.Mt Sinai J Med. 2000; 67: 41-53PubMed Google Scholar, 7Montrose M.H. Yasutada A. Takeuchi K. et al.Gastroduodenal mucosal defense.in: Johnson L.R. Academic Press, New York2006: 1259-1291Google Scholar, 8Lichtenberger L.M. Gastroduodenal mucosal defense.Curr Opin Gastroenterol. 1999; 15: 463-472Crossref PubMed Scopus (13) Google Scholar, 9Tarnawski A. Cellular and molecular mechanisms of mucosal defense and repair.in: Yoshikawa T. Arakawa T. Bioregulation and its disorders in gastrointestinal tract. Blackwell Science, Tokyo, Japan1998: 3-17Google Scholar, 10Ham M. Kaunitz J.D. Gastroduodenal defense.Curr Opin Gastroenterol. 2007; 23: 607-616Crossref PubMed Scopus (26) Google Scholar, 11Szabo S. Mechanisms of gastric mucosal injury and protection.J Clin Gastroenterol. 1991; 13: S21-S34Crossref PubMed Google Scholar, 12Kobayashi K. Arakawa T. Arachidonic acid cascade and gastric mucosal injury, protection, and healing: topics of this decade.J Clin Gastroenterol. 1995; 21: S12-S17PubMed Google Scholar These include local defense mechanisms and neurohormonal mechanisms described below (Figure 1). The mucus-bicarbonate-phospholipid “barrier” constitutes the first line of mucosal defense.8Lichtenberger L.M. Gastroduodenal mucosal defense.Curr Opin Gastroenterol. 1999; 15: 463-472Crossref PubMed Scopus (13) Google Scholar, 13Allen A. Structure of gastrointestinal mucus and the viscous and gel-forming properties of mucus.Br Med Bull. 1978; 34: 28-33PubMed Google Scholar, 14Allen A. Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.Am J Physiol Cell Physiol. 2005; 288: C1-C19Crossref PubMed Google Scholar, 15Atuma C. Strugala V. Allen A. et al.The adherent gastric mucus gel layer: thickness and physical state in vivo.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G922-G929PubMed Google Scholar This barrier is formed by mucus gel, bicarbonate, and surfactant phospholipids, which cover the mucosal surface. This unstirred layer retains bicarbonate secreted by surface epithelial cells to maintain a neutral microenvironment (pH ∼7.0) at the surface epithelial cells and prevents penetration of pepsin and thus proteolytic digestion of the surface epithelium.14Allen A. Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.Am J Physiol Cell Physiol. 2005; 288: C1-C19Crossref PubMed Google Scholar, 15Atuma C. Strugala V. Allen A. et al.The adherent gastric mucus gel layer: thickness and physical state in vivo.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G922-G929PubMed Google Scholar The mucus gel contains phospholipids, and its luminal surface is coated with a film of surfactant phospholipids with strong hydrophobic properties.8Lichtenberger L.M. Gastroduodenal mucosal defense.Curr Opin Gastroenterol. 1999; 15: 463-472Crossref PubMed Scopus (13) Google Scholar, 16Hills B.A. Butler B.D. Lichtenberger L.M. Gastric mucosal barrier: hydrophobic lining to the lumen of the stomach.Am J Physiol. 1983; 244: G561-G568PubMed Google Scholar Mucus gel is secreted by apical expulsion from surface epithelial cells and contains ∼95% water and ∼5% mucin glycoproteins, products of mucin (MUC) genes. The gel-forming mucin units polymerize into large mucin multimers essential for gel formation.14Allen A. Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.Am J Physiol Cell Physiol. 2005; 288: C1-C19Crossref PubMed Google Scholar, 15Atuma C. Strugala V. Allen A. et al.The adherent gastric mucus gel layer: thickness and physical state in vivo.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G922-G929PubMed Google Scholar, 17Jordan N. Newton J. Pearson J. et al.A novel method for the visualization of the in situ mucus layer in rat and man.Clin Sci (Lond). 1998; 95: 97-106Crossref PubMed Scopus (54) Google Scholar The structure of each of the gel-forming mucins, MUC2, MUC5AC, MUC5B, and MUC6, has been elucidated.14Allen A. Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.Am J Physiol Cell Physiol. 2005; 288: C1-C19Crossref PubMed Google Scholar, 18Gendler S. Spicer A.P. Epithelial mucin genes.Annu Rev Physiol. 1995; 57: 607-634Crossref PubMed Google Scholar In the stomach, MUC5AC is expressed in the surface epithelial cells of cardia, fundus, and antrum; and MUC6 is expressed in the neck cells of the fundus and in antral glands. Alternating layers of MUC5AC and MUC6 have been demonstrated in the mucus layer in human gastric mucosa.14Allen A. Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.Am J Physiol Cell Physiol. 2005; 288: C1-C19Crossref PubMed Google Scholar, 19Ho S.B. Takamura K. Anway R. et al.The adherent gastric mucous layer is composed of alternating layers of MUC5AC and MUC6 mucin proteins.Dig Dis Sci. 2004; 49: 1598-1606Crossref PubMed Scopus (53) Google Scholar Mucus gel is cosecreted with low-molecular-weight trefoil factor family peptides (TFFs).20Newton J. Allen A. Westley B.M. et al.The human trefoil peptide, TFFl, is present in different molecular forms that are intimately associated with the adherent mucus gel in normal stomach.Gut. 2000; 46: 312-320Crossref PubMed Scopus (74) Google Scholar, 21Poulsom R. Wright N.A. Trefoil peptides: a newly recognized family of epithelial mucin associated molecules.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G211-G219Crossref PubMed Google Scholar TFFs are an integral part of the intracellular mucus secretory vesicles and may play a role in the intracellular assembly and/or packaging of mucins.20Newton J. Allen A. Westley B.M. et al.The human trefoil peptide, TFFl, is present in different molecular forms that are intimately associated with the adherent mucus gel in normal stomach.Gut. 2000; 46: 312-320Crossref PubMed Scopus (74) Google Scholar TFF2 increases the viscosity of gastric mucin and stabilizes the gel network.22Thim L. Madsen F. Poulsen S.S. Effect of trefoil factors on the viscoelastic properties of mucus gels.Eur J Clin Invest. 2002; 32: 519-527Crossref PubMed Scopus (143) Google Scholar Mucus secretion is stimulated by gastrointestinal hormones, including gastrin and secretin, as well as PGE2 and cholinergic agents.7Montrose M.H. Yasutada A. Takeuchi K. et al.Gastroduodenal mucosal defense.in: Johnson L.R. Academic Press, New York2006: 1259-1291Google Scholar, 14Allen A. Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.Am J Physiol Cell Physiol. 2005; 288: C1-C19Crossref PubMed Google Scholar Ulcerogenic substances such as aspirin and bile salts cause dissipation of the mucus gel and phospholipid layer, leading to acid back-diffusion and mucosal injury.14Allen A. Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.Am J Physiol Cell Physiol. 2005; 288: C1-C19Crossref PubMed Google Scholar, 23Darling R.L. Romero J.J. Dial E.J. et al.The effects of aspirin on gastric mucosal integrity, surface hydrophobic, and prostaglandin metabolism in cyclooxygenase knockout mice.Gastroenterology. 2004; 127: 94-104Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar The secretion of HCO3− into a stable, adherent mucus gel layer creates a pH gradient at the epithelial surface in the stomach and duodenum and provides the first line of mucosal defense against luminal acid.14Allen A. Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.Am J Physiol Cell Physiol. 2005; 288: C1-C19Crossref PubMed Google Scholar, 15Atuma C. Strugala V. Allen A. et al.The adherent gastric mucus gel layer: thickness and physical state in vivo.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G922-G929PubMed Google Scholar, 24Flemström G. Active alkalinization by amphibian gastric fundic mucosa.Am J Physiol Endocrinol Metab Gastrointest Physiol. 1977; 233: E1-E12PubMed Google Scholar pH gradient studies provided experimental evidence for the existence of the mucus-bicarbonate barrier in vivo and presence of a nearly neutral pH at the epithelial surface.15Atuma C. Strugala V. Allen A. et al.The adherent gastric mucus gel layer: thickness and physical state in vivo.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G922-G929PubMed Google Scholar The surface epithelium in acid-secreting gastric mucosa exports HCO3− at rates only 10% of the acid secretion rate. Mucus gel minimizes luminal loss of HCO3− sufficiently to maintain a neutral pH at the apical cell surfaces. Experimental studies show that Na+HCO3− cotransport at the basolateral membrane is the major mechanism for import of HCO3−. Studies of rat and rabbit gastric mucosa demonstrated expression of a Cl−/HCO3− anion exchanger in the apical membranes of gastric surface epithelial cells.25Rossmann H. Bachmann O. Vieillard-Baron D. et al.Na+/HCO3− cotransport and expression of NBC1 and NBC2 in rabbit gastric parietal and mucous cells.Gastroenterology. 1999; 116: 1389-1398Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar In the stomach, PGs stimulate HCO3− secretion via EP1 receptors.26Takeuchi K. Yagi K. Kato S. et al.Roles of prostaglandin E-receptor subtypes in gastric and duodenal bicarbonate secretion in rats.Gastroenterology. 1997; 113: 1553-1559Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Luminal acid, corticotrophin-releasing factor (CRF), melatonin, uroguanylin, and orexin A also stimulate HCO3− secretion.7Montrose M.H. Yasutada A. Takeuchi K. et al.Gastroduodenal mucosal defense.in: Johnson L.R. Academic Press, New York2006: 1259-1291Google Scholar, 14Allen A. Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.Am J Physiol Cell Physiol. 2005; 288: C1-C19Crossref PubMed Google Scholar The mucus bicarbonate barrier is the only preepithelial barrier between lumen and epithelium. When it is overwhelmed or breaks down in disease, the next series of protective mechanisms come into play, including intracellular neutralization of acid, rapid epithelial repair, and maintenance and distribution of mucosal blood flow. The next line of mucosal defense is formed by a continuous layer of surface epithelial cells (Figure 2), which secrete mucus and bicarbonate and generate PGs, heat shock proteins, TFFs, and cathelicidins. Because of the presence of phospholipids on their surfaces, these cells are hydrophobic, repelling acid- and water-soluble damaging agents.8Lichtenberger L.M. Gastroduodenal mucosal defense.Curr Opin Gastroenterol. 1999; 15: 463-472Crossref PubMed Scopus (13) Google Scholar Interconnected by tight junctions, the surface epithelial cells form a “barrier” preventing back diffusion of acid and pepsin.7Montrose M.H. Yasutada A. Takeuchi K. et al.Gastroduodenal mucosal defense.in: Johnson L.R. Academic Press, New York2006: 1259-1291Google Scholar, 6Werther J.L. The gastric mucosal barrier.Mt Sinai J Med. 2000; 67: 41-53PubMed Google Scholar, 9Tarnawski A. Cellular and molecular mechanisms of mucosal defense and repair.in: Yoshikawa T. Arakawa T. Bioregulation and its disorders in gastrointestinal tract. Blackwell Science, Tokyo, Japan1998: 3-17Google Scholar, 14Allen A. Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin.Am J Physiol Cell Physiol. 2005; 288: C1-C19Crossref PubMed Google Scholar The surface epithelial cells are metabolically and electrically coupled by gap junctions. Heat shock proteins are generated by gastric epithelial cells in response to stress, such as increased temperature, oxidative stress, and cytotoxic agents.27Tanaka D. Tsutsumi S. Arai Y. et al.Genetic evidence for a protective role of heat shock factor 1 against irritant-induced gastric lesions.Mol Pharmacol. 2007; 71: 985-993Crossref PubMed Scopus (42) Google Scholar, 28Oyaka J. Otaka M. Matsuhashi T. et al.Over-expression of 70-kDa heat shock protein confers protection against monochloramine-induced gastric mucosal cell injury.Life Sci. 2006; 79: 300-305Crossref PubMed Scopus (34) Google Scholar, 29Tarnawski A. Hollander D. Gergely H. et al.Comparison of antacid, sucralfate, cimetidine and ranitidine in protection of the gastric mucosa against ethanol injury.Am J Med. 1985; 79: 19-23Abstract Full Text PDF PubMed Google Scholar They prevent protein denaturation and protect cells against injury. Activation of heat shock protein response is one of the mucosal protective mechanisms of the antacid hydrotalcite.30Tarnawski A. Wang H. Tomikawa M. et al.Talcid triggers induction of heat shock proteins HSP-70 in gastric mucosa: a key to its mucosal protective action?.Gastroenterology. 1999; 116: A331Google Scholar Cathelicidin and β defensins are cationic peptides that play roles in the innate defensive system at mucosal surfaces preventing bacterial colonization. They have been demonstrated in gastric epithelial cells, and they accelerate ulcer healing.31Yang Y.H. Wu W.K. Tai E.K. et al.The cationic host defense peptide rCRAMP promotes gastric ulcer healing in rats.J Pharmacol Exp Ther. 2006; 318: 547-554Crossref PubMed Scopus (27) Google Scholar Surface epithelial cells secrete TFFs that regulate reepithelialization and exert mucosal protective action.32Taupin D. Podolsky D.K. Trefoil factors initiators of mucosal healing.Nat Rev Mol Cell Biol. 2003; 4: 721Crossref PubMed Scopus (314) Google Scholar Continuous cell renewal from mucosal progenitor cells maintains structural integrity of the mucosa. The epithelium is continually renewed by a well-coordinated and controlled proliferation of progenitor cells that enables replacement of damaged or aged surface epithelial cells. Complete replacement of the gastric surface epithelium usually takes 3–7 days, whereas months are required to replace the glandular cells. In gastric glands, a single stem cell undergoes division to produce committed progenitor cells, which further differentiate into an adult epithelial cell type.33Modlin I.M. Kidd M. Lye K.D. et al.Gastric stem cells: an update.Keio J Med. 2003; 52: 134-137Crossref PubMed Google Scholar The stem/progenitor cell niche is made up of proliferating and differentiating epithelial cells and surrounding mesenchymal cells.34Leedham S.J. Brittan M. Preston S.L. et al.The stomach periglandular fibroblast sheath: all present and correct.Gut. 2006; 55: 295-296PubMed Google Scholar The latter generate growth factors and thus promote mesenchymal to epithelial cross talk and signaling to maintain the niche progenitor cell survival. Restitution of the surface epithelium after superficial injury occurs within minutes by migration of preserved epithelial cells located in the neck area of gastric glands.35Svanes K. Ito S. Takeuchi K. et al.Restitution of the surface epithelium of the in vitro frog gastric mucosa after damage with hyperosmolar sodium chloride: morphologic and physiologic characteristics.Gastroenterology. 1982; 82: 1409-1426Abstract Full Text PDF PubMed Google Scholar, 36Lacy E.R. Ito S. Rapid epithelial restitution of the rat gastric mucosa after ethanol injury.Lab Invest. 1984; 51: 573-583PubMed Google Scholar This migration precedes and is independent of proliferation of progenitor cells, which occurs later—hours after injury.36Lacy E.R. Ito S. Rapid epithelial restitution of the rat gastric mucosa after ethanol injury.Lab Invest. 1984; 51: 573-583PubMed Google Scholar, 37Tarnawski A. Hollander D. Stachura J. et al.Prostaglandin protection of the gastric mucosa against alcohol injury—a dynamic time-related process The role of mucosal proliferative zone.Gastroenterology. 1985; 88: 334-359Abstract Full Text PDF PubMed Google Scholar Cell proliferation of progenitor cells is controlled by growth factors. The major growth factor receptor expressed in gastric progenitor cells is epidermal growth factor receptor (EGF-R),38Tarnawski A. Stachura J. Durbin T. et al.Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats.Gastroenterology. 1992; 102: 695-698PubMed Google Scholar and the major mitogenic growth factors that activate this receptor are transforming growth factor α (TGF-α) and insulin-like growth factor-1.39Nguyen T. Chai J. Tanigawa T. et al.Novel roles of local IGF-1 activation in rat gastric ulcer healing: promotes actin polymerization, cell proliferation, reepithelialization and induces COX-2 in a PI3K-dependent manner.Am J Pathol. 2007; 170: 1219-1228Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar PGE2 and gastrin transactivate EGF-R and trigger the mitogen-activated protein kinase pathway thereby stimulating cell proliferation and exerting a trophic action on gastric mucosa.40Pai R. Soreghan B.A. Szabo I.L. et al.Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy.Nat Med. 2002; 8: 289-293Crossref PubMed Scopus (630) Google Scholar EGF peptide itself is absent in normal gastric mucosa. However, it is present in the gastric lumen, derived from salivary and esophageal glands, and can stimulate progenitor cell proliferation in case of injury. An important new finding is the expression of survivin, an antiapoptosis protein, in gastric progenitor cells, which allows these cells to avoid apoptosis and promotes mitosis (Figure 2C).41Chiou S.K. Tanigawa T. Akahoshi T. et al.Survivin—a novel target for indomethacin-induced gastric injury.Gastroenterology. 2005; 128: 63-73Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar “Alkaline tide” occurs because stimulated parietal cells secreting hydrochloric acid into the gastric gland lumen concurrently secrete bicarbonate into the interstitium and lumen of adjacent capillary blood vessels (Figure 1). This bicarbonate is transported upward to the base of the surface epithelial cells and to the gastric lumen, where it contributes to the unstirred layer of mucus and bicarbonate. Mucosal microcirculation is essential for delivery of oxygen and nutrients and removal of toxic substances. At the level of the muscularis mucosae, most gastric arteries branch into capillaries, which enter the lamina propria and travel upward in proximity to gastric glandular epithelial cells (Figure 1, Figure 2). At the base of surface epithelial cells, capillaries converge into collecting venules.42Gannon B. Browning J. O'Brien P. et al.Mucosal microvascular architecture of the fundus and body of the human stomach.Gastroenterology. 1984; 86: 866-875PubMed Google Scholar The endothelial cells lining the microvessels generate potent vasodilators such as nitric oxide (NO) and prostacyclin (PGI2), which protect the gastric mucosa against injury and oppose the mucosal damaging action of vasoconstrictors such as leukotriene C4, thromboxane A2, and endothelin. PGI2 and NO maintain viability of endothelial cells and prevent platelet and leukocyte adherence to the microvascular endothelial cells, thus preventing compromise of the microcirculation.43Guth P.H. Current concepts in gastric microcirculatory pathophysiology.Yale J Biol Med. 1992; 65: 677-688PubMed Google Scholar When the gastric mucosa is exposed to an irritant or when acid back-diffusion occurs, a marked and rapid increase in mucosal blood flow occurs. This increase allows removal and/or dilution of the back-diffusing acid and/or noxious agents. This response seems to be essential for mucosal defense because its abolition through mechanical restriction of blood flow leads to hemorrhagic necrosis. This hyperemic response is mediated by sensory afferent nerves (see below). The increased mucosal blood flow in response to acid secretion is mediated, at least in part, by NO, generated by NO synthase. NO plays a major role in mucosal defense by modulating the mucosal circulation.43Guth P.H. Current concepts in gastric microcirculatory pathophysiology.Yale J Biol Med. 1992; 65: 677-688PubMed Google Scholar, 44Peskar B.M. 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Physiology of the gastrointestinal tract. 4th ed. Academic Press, New York2006: 817-839Crossref Scopus (7) Google Scholar Hydrogen sulfide is another endogenously generated compound that exerts a strong mucosal protective action similar to NO; it reduces tumor necrosis factor α (TNF-α) expression, decreases leukocyte adherence to vascular endothelium, and inhibits NSAID-induced gastric mucosal injury.46Fiorucci S. Antonelli E. Distrutti E. et al.Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs.Gastroenterology. 2005; 129: 1210-1224Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 47Fiorucci S. Distrutti E. 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Respondek M. et al.Protection by gastrin in the rat stomach involves afferent neurons, calcitonin gene-related peptide, and nitric oxide.Gastroenterology. 1995; 109: 89-97Abstract Full Text PDF PubMed Scopus (52) Google Scholar The nerves fibers from this plexus enter the lamina propria (accompanying capillary vessels) and end just beneath the surface epithelial cells (Figure 3B). These nerve endings can sense the luminal content and/or entry of acid into the mucosa via acid-sensing channels. Activation of these nerves directly affects the tone of submucosal