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Gastroduodenal mucosal defense

deFoneska, Arushia,b; Kaunitz, Jonathan Da,c,d,e

Current Opinion in Gastroenterology: November 2010 - Volume 26 - Issue 6 - p 604–610
doi: 10.1097/MOG.0b013e32833f1222
Stomach and duodenum: Edited by Mitchell L. Schubert

Purpose of review We have summarized recent findings related to gastroduodenal mucosal defense as well as factors contributing to defensive failure, highlighting findings that illuminate new pathophysiological mechanisms.

Recent findings Gastroduodenal bicarbonate secretion is mediated by prostaglandin E receptors and stimulated by the prostone lubiprostone. Toll-like receptor (TLR)4 signaling is protective against gastric injury. Intestinal alkaline phosphatase (IAP) is a chemosensor that regulates the duodenal mucosal surface pH. Lipopolysaccharide (LPS) increases gastric permeability; IAP secreted during fat digestion may detoxify colonic LPS. NADPH oxidase activity mediates ischemia/reperfusion-related gastric mucosal damage. Heat shock protein 70 (HSP70) protects the gastric mucosa through inhibition of apoptosis, proinflammatory cytokines, and cell adhesion molecules (CAMs). HSP90 may be a contributing factor in impaired adaptive cytoprotection. Proteinase-activated receptor-1 (PAR-1) is protective against Helicobacter-induced gastritis, mediated by the suppression of proinflammatory pathways. IKK β/NF-κB signaling decreases chronic Helicobacter-induced inflammation by inhibiting cellular apoptosis and necrosis. Activation of A2A adenosine receptors decreases inflammation and gastritis but leads to persistent Helicobacter pylori infection.

Summary Enhanced understanding of the mechanisms of gastroduodenal defense and injury provides new insight into potential therapeutic targets, contributing towards the development of better tolerated and more effective therapies.

aGreater Los Angeles Veteran Affairs Healthcare System, WLAVA Medical Center, USA

bCedars-Sinai Internal Medicine Residency, USA

cCURE: Digestive Diseases Research Center, USA

dBrentwood Biomedical Research Institute, USA

eDepartment of Medicine, UCLA School of Medicine, Los Angeles, California, USA

Correspondence to Jonathan D. Kaunitz, Bldg. 114, Suite 217, West Los Angeles VA Medical Center 11301 Wilshire Blvd. Los Angeles, CA 90073, USA Tel: +1 310 268 3879; fax: +1 310 268 4811; e-mail:

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The gastric mucosa is continuously exposed to noxious substances. For more than 200 years, investigators have been perplexed by how the gastric mucosa resists damage and auto-digestion by substances such as hydrochloric acid and pepsin. That inhibition of prostaglandin synthesis is a mechanism of gastric damage by aspirin and other nonsteriodal anti-inflammatory drugs (NSAIDs) [1] combined with the concept of cytoprotection that was developed in the late 1970s [2,3] sparked interest in understanding gastric mucosal defense.

The gastric mucosa maintains structural integrity through defense mechanisms. Specifically, the surface epithelium secretes a barrier consisting of water, mucin glycoproteins, bicarbonate, phospholipids, trefoil factor (TFF) peptides, prostaglandins, and heat shock proteins (HSPs). Gastric epithelial intracellular tight junctions and submucosal microcirculation regulated by afferent nerves and mediator release provide oxygen, bicarbonate, and nutrients while removing toxins and H+. Continuous cell renewal also provides additional lines of defense [4–6]. Duodenal mucosal defense similarly consists of premucosal, mucosal and submucosal factors, including bicarbonate secretion, prevention of intracellular acidification by the Na+/H+ exchanger, and submucosal neuronal activation and blood flow responses [5,6]. Furthermore, gastroduodenal defense involves neutralization of reactive oxygen species (ROS), cytokine release, innate and adaptive immune responses, and inhibition of apoptosis. Mucosal injury may occur however, when defense mechanisms are impaired or are overwhelmed by noxious substances such as gastric acid, NSAIDs, and Helicobacter pylori. This review provides an update on the current knowledge and recent findings related to gastroduodenal mucosal defense, highlighting recent research and future directions in the field.

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Bicarbonate secretion

The duodenal mucosa is exposed to antrally propelled gastric acid and to secreted bicarbonate. Therefore, the duodenal mucosa must adjust its defense mechanisms according to luminal pH, which can rapidly fluctuate between 2 and 7. The duodenal mucosa senses luminal acidity via epithelial ion transporters and neuronal acid sensors, which increases the absorption of luminal acid and secretion of bicarbonate, thus maintaining the acid–base balance between the stomach and duodenum [6] (Fig. 1).

Figure 1

Figure 1

Bicarbonate secretion also protects gastric epithelial cells. The mucus–bicarbonate gel that adheres to the luminal surface of the mucosa provides a zone of low turbulence that enables the development of a pH gradient. Thus, a small amount of bicarbonate may neutralize a large amount of acid, attributing pathophysiological importance to bicarbonate secretion. At the same time, gastric acid secretion is affected by luminal pH. As summarized by Akiba and Kaunitz [6], high gastric luminal pH induces antral G cells to secrete gastrin, which acts on parietal cells to increase acid secretion. A lower pH increases somatostatin release by D cells, which decreases acid secretion. Luminal acidity activates endocrine cells through capsaicin-sensitive afferent nerves and calcitonin gene-related peptide (CGRP) release by mechanisms that have not been completely elucidated. Nevertheless, Wank has reported that the calcium-sensing receptor (CaSR) serves as a luminal acid sensor in the gastric epithelium (Wank SA, unpublished observations).

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Prostaglandin control of bicarbonate secretion

Prostaglandins, particularly PGE2, are important in the regulation of gastro duodenal bicarbonate secretion. Prostaglandins enhance synthesis of endogenous prostaglandins that increase bicarbonate secretion, whereas inhibitors of prostaglandin synthesis such as NSAIDs decrease bicarbonate secretion. Prostaglandin E receptors are expressed throughout the gastrointestinal tract, including the gastroduodenum. These G protein-coupled receptors may be divided into four subtypes: EP1 through EP4. Takeuchi et al.[7•], in a study of prostaglandin-mediated pathways for bicarbonate secretion in rats and in knockout mice, reported gastric bicarbonate secretion is mediated by EP1 receptors in a pathway that increases intracellular calcium, whereas duodenal bicarbonate secretion is mediated by EP3 and EP4 receptors, in a pathway that increases intracellular 3′,5′-cyclic-adenosine monophosphate (cAMP) and calcium. Nucleotides such as cAMP and cyclic-guanosine monophosphate (cGMP) are degraded into inactive metabolites by phosphodiesterase (PDE), of which there exist 11 isoenzymes. Bicarbonate secretion was decreased by verapamil, a calcium channel inhibitor, in the stomach and duodenum and was enhanced by nonspecific phosphodiesterase inhibitors. These results suggest that the effects of PGE2 are mediated by calcium in the stomach and by calcium and cAMP in the duodenum. Takeuchi et al.[7•] also reported that PDE1 and PDE3 help regulate duodenal bicarbonate secretion and are involved in pathways activated by PGE2. Further, gastric bicarbonate secretion is stimulated by nitric oxide in a process that involves cGMP, modified by PDE1 and PDE5, and mediated by PGE2 through stimulation of EP1 receptors [7•].

Lubiprostone, a bicyclic fatty acid derived from PGE1 recently approved for the treatment of chronic constipation in adults, increases chloride secretion arguably by activating intestinal epithelial cell ClC-2 channels. Mizumori et al.[8•] demonstrated that luminal perfusion of lubiprostone stimulated ion secretion in a concentration-dependent manner in rats stimulating increased bicarbonate secretion at relatively high concentrations and increased chloride and water secretion at low concentrations. Lubiprostone-induced bicarbonate secretion was cystic fibrosis transmembrane regulator (CFTR)-dependent, whereas chloride secretion was CFTR-independent. Lubiprostone-induced bicarbonate secretion was eliminated by an EP4 receptor antagonist, whereas an EP1/EP2 receptor antagonist had no effect. Lubiprostone-induced bicarbonate secretion was not altered by indomethacin pretreatment, suggesting that lubiprostone increases bicarbonate secretion by directly activating EP4 receptors [8•]. Further, lubiprostone induced water and ion secretion during CFTR inhibition and also increased mucus secretion in airway submucosal glands via CFTR-dependent and independent pathways, suggesting that lubiprostone may improve the phenotype in patients with cystic fibrosis within and outside of the gastrointestinal tract.

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Toll-like receptors

Toll-like receptors (TLRs), involved in innate immunity, act as pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) and trigger host defense responses. The TLR4 agonist LPS and the TLR3 agonist polyinosinic:polycytidylic acid induce production of COX-2 and PGE2[9,10]. Zhang et al.[11•] demonstrated that TLR4 expression increased 4 h after ethanol injury. Mice with a loss-of-function mutation in the TLR4 gene experienced more gastric injury compared to mice without this mutation, suggesting that TLR4 signaling continues to the protective response to necrotizing injury in the stomach. TLR4 signaling is gastroprotective via production of COX-2 and PGE2. Further, TLR4-expressing cells were located in the lamina propria, either on macrophages or COX-2-expressing cells [11•]. In contrast, other studies have localized TLR4-expressing cells which were reported localized to the gastric epithelium in H. pylori-induced gastritis [12], suggesting that TLR4 acts through different pathways depending on the mechanism of injury. In noninfectious injury, rather than PAMPs, TLRs likely recognize damage-associated molecular patterns (DAMPs) such as HSPs and hyaluronan.

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Phosphodiesterase inhibitors

Vardenafil, a PDE5 inhibitor, is used to treat erectile dysfunction and pulmonary hypertension. Vardenafil increases portal flow and portal pressure in patients with cirrhosis [13]. Vardenafil offers protection of the heart, liver, colon, and brain after ischemia/reperfusion injury. Karakaya et al.[14•] recently demonstrated that vardenafil provided dose-dependent protection against indomethacin-induced gastric mucosal lesions in rats. Specifically, vardenafil decreased indomethacin induced gastric ulcers and reduced oxidative stress as measured by the lipid peroxidation product malondialdehyde (MDA) [14•]. Thus, patients treated with PDE5 inhibitors may experience gastroprotective benefits, especially at higher doses.

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Amino acids

L-glutamate, the primary nutrient conferring ‘umami’ taste and the predominant free amino acid in dietary proteins, dose-dependently increases intracellular pH and mucous gel thickness but not blood flow in the gastroduodenal mucosa. L-glutamate exerts these actions through capsaicin-sensitive afferent nerves and COX activation. Other mucosal protective effects of luminal L-glutamate include activation of gastric vagal afferent nerves leading to release of nitric oxide and 5-hydroxytryptamine (5-HT) as well as activation of the 5-HT3 receptor. L-glutamate receptors include the following G protein-coupled receptors: ‘umami’ receptor heterodimers T1R1 and T1R3, metabotropic L-glutamate receptor (mGluR) 1 and mGluR4, and the CaSR. The effects of L-glutamate on intracellular pH and mucous gel thickness were mimicked by mGluR4 agonists and inhibited by mGluR4 antagonists, whereas mGluR1/5 was only partially involved in intracellular pH regulation. Luminal L-glutamate, L-aspartate and L-leucine slightly increase bicarbonate secretion, which was robustly enhanced by addition of inosine 5′-monophosphate (IMP) leading to intracellular acidification. The synergistic effect of L-glutamate and IMP on bicarbonate secretion suggests that L-glutamate associated bicarbonate secretion is mediated by T1R1/T1R3. Finally, CaSR agonists mimicked the effects of gastric acid leading to intracellular acidification, increased bicarbonate secretion, and mucous gel thickness. Therefore, luminal L-glutamate protects the mucosa from acid induced injury and may alter the mucosa for subsequent luminal protein digestion [6,15•,16].

Trans-resveratrol, produced by plants, is a phytoalexin that protects against fungal infections. Resveratrol, present in substantial concentration in grape skin, has been proposed as an explanation of the observation that moderate consumption of red wine reduces the risk of cardiovascular disease. Further, resveratrol is currently being studied as a potential cancer chemopreventive agent. Nevertheless, treatment with resveratrol aggravates and delays healing of pre-existing gastric ulcers in mice by decreasing COX-1 and inducible nitric oxide synthase (iNOS) expression. At the same time, resveratrol increases endothelial nitric oxide synthase (eNOS) expression but delays ulcer healing because of the overall decrease in nitric oxide production. Guha et al.[17•] recently demonstrated that treatment with L-arginine, the endogenous substrate of NOS, significantly increased nitric oxide synthesis via the higher levels of eNOS induced by eNOS and improved ulcer healing.

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Newly recognized function of intestinal alkaline phosphatase

Although intestinal alkaline phosphatase (IAP) has long been known to be highly expressed in the proximal intestinal brush border, its exact function remained a mystery. Recently, several new lines of data have attributed novel functions to this enzyme [18].

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Regulation of surface pH

Enterocytes release ATP into the gut lumen, which increases duodenal bicarbonate secretion. IAP is a glycosylphosphatidylinositol-anchored ectoprotein highly expressed on the apical membrane of duodenal epithelial cells. In the presence of bicarbonate, IAP has ATPase activity, suggesting the presence of a negative feedback loop. Mizumori et al.[19•] recently demonstrated in rats that IAP inhibition increases duodenal bicarbonate secretion, coincident with increased luminal secretion of ATP. Further, luminal ATP activates the purinergic receptor P2Y1 increasing bicarbonate secretion and IAP activity, presumably by bringing the catalytic site of IAP closer to its pH optimum. ATP output into the duodenal lumen was partially CFTR-dependent and was increased by luminal acid as well as by inhibition of IAP and ecto-nucleoside triphosphate diphosphohydrolase (ENTPDase). IAP and ENTPDase are both duodenal brush border membrane proteins with ATPase activity. Nevertheless, the finding that ENTPDase inhibition is less effective at augmenting bicarbonate and ATP output than IAP inhibition suggests that IAP is the predominant ATPase in the duodenum. Enhanced IAP ATPase activity decreases ATP and bicarbonate secretion. Thus, this study also showed that IAP acts as a chemosensor in the ectopurinergic signaling pathway that regulates the pH of the protective mucous layer in the duodenum [19•].

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Regulation of inflammation

Endotoxemia from sepsis injures the gut through mechanisms that are not fully understood. Increased production of inflammatory mediators such as tumor necrosis factor (TNF)-α is an important mediator of this injury. Dial et al.[20•] recently showed that LPS, a component of bacterial cell membranes, increases gastric permeability and secretory phospholipase A2 (sPLA2) activity. Increased sPLA2 degrades phosphatidylcholine, the predominant component of the gastric mucosal barrier, to produce lysoPC. Both LPS-induced sPLA2 and lysoPC are damaging to the gastric mucosa and may contribute to subsequent inflammation [20•]. The mechanisms by which lysoPC-induced damage is prevented under normal, uninfected physiologic conditions are not fully understood.

In vitro, IAP detoxifies LPS by cleaving its phosphate esters. IAP activity is associated with decreased bowel inflammation; exposure of the intestinal wall to LPS induces IAP gene expression. Decreased IAP expression is associated with increased LPS toxicity in zebrafish and Caco-2 cells [21,22]. Nevertheless, IAP is mostly expressed in the duodenum, whereas most LPS exposure that is produced by microflora occurs in the ileum and colon. Nakano et al.[23•] recently reported that lysoPC, whose concentration in the intestinal lumen rapidly increases after a fatty meal due to hydrolysis of bile phosphatidylcholine by pancreatic phospholipase A2, increases release of bound IAP into the lumen, followed by increased IAP synthesis for restoration of bound IAP. LysoPC may also be involved in turnover of other brush border proteins [23•]. Thus, IAP released into the lumen during fat digestion and relatively resistant to pancreatic proteases may survive transit to the colon and provide an LPS detoxifying enzyme throughout the length of the colon, decreasing inflammation.

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Ischemia/reperfusion injury

Ischemia/reperfusion damages the gastric mucosa by inducing oxidative stress. Specifically, ROS such as superoxide and hydrogen peroxide induce inflammatory responses and tissue damage by fragmenting cellular DNA. In the gut, ROS can also be generated by NSAIDs, cold stress, ethanol, and H. pylori infection. NADPH oxidase found on phagocytic cells, vascular muscular cells, endothelial cells, fibroblasts, and adipocytes converts oxygen into superoxide anions. Nakagiri and Murakami [24•] recently reported that NADPH oxidase activity is increased in ischemia and ischemia/reperfusion and is involved in the resulting gastric mucosal damage. The increased NADPH oxidase activity may also induce up-regulation of COX-2, although more studies are needed to clarify this point [24•].

Peskar et al.[25•] reported that during ischemia/reperfusion, inhibitors of the cyclooxygenase and lipoxygenase pathways increased gastric mucosal damage in a dose-dependent manner. Synergism observed with the combination of cyclooxygenase and lipoxygenase pathway inhibitors suggests that both pathways are important in gastric mucosal defense during ischemia/reperfusion. PGE2 antagonized the effects of cyclooxygenase and lipoxygenase pathway inhibitors. Similarly, lipoxin A4, a lipoxygenase-derived product of arachidonate metabolism, also antagonized the effects of cyclooxygenase and lipoxygenase pathway inhibitors, and could replace PGE2 in the prevention of gastric mucosal damage caused by cyclooxygenase inhibitors during ischemia/reperfusion [25•].

CGRP, a 37 amino acid neuropeptide produced by tissue-specific alternative splicing of the calcitonin gene primary transcript, which is one of the most potent vasodilators known, is a regulator of the brain-gut axis. CGRP, released from afferent nerves, protects the mucosa by increasing blood flow. Further, intravenous CGRP inhibits gastric acid secretion through its effects on the vagus nerve [26•]. Feng et al.[27•] recently studied the effect of CGRP on gastric mucosal injury after cerebral ischemia/reperfusion in a middle cerebral artery occlusion rat model. CGRP injected intraperitoneally alleviated gastric mucosal damage induced by cerebral ischemia/reperfusion. After cerebral ischemia/reperfusion, the number of G cells and gastrin expression was higher, whereas the number of D cells and somatostatin expression was lower. Gastrin and somatostatin were involved in cerebral ischemia/reperfusion-induced disease modulated by CGRP treatment, decreasing gastrin expression while increasing somatostatin expression and mucosal protection. Other protective effects of CGRP reported include the inhibition of aquaporin-4 expression, a protein that transports water molecules and facilitates gastric acid secretion, up-regulation of basic fibroblast growth factor, an important factor involved in growth of gastric mucosa, the maintenance of normal density and permeability of blood vessels, and inhibition of mast cell degranulation [27•]. Thus, CGRP may be a potential gastric mucosal protective therapy to be used after cerebral ischemia/reperfusion.

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Trefoil factor and hypoxia inducible factor

Gastric damage caused by NSAIDs is one of the most common adverse effects associated with drug therapy. One major mechanism by which NSAIDs induce gastric damage is through inhibition of COX and prostaglandin synthesis, which decreases mucosal blood flow and tissue hypoxia. Hypoxia-inducible factor-1 (HIF-1), composed of HIF-1α and HIF-1β subunits, regulates the transcriptional response to hypoxia. During normal oxygen conditions, HIF-1α is degraded by enzymes that require oxygen as a substrate. Nevertheless, when oxygen pressure decreases, HIF-1α escapes degradation and can bind HIF-1β to form transcriptionally active HIF-1. Aspirin leads to HIF-1-mediated induction of TFF gene expression in rat and human gastric epithelial cells. Thus aspirin-induced hypoxia activated defense mechanisms in damaged tissue through induction of TFF – a secreted peptide that augments surface mucous barrier functions and promotes the multistep process of restitution, including increased blood flow, migration of cells, and restoration of barrier function. Increased TFF expression was also observed in nonhypoxic cells with overexpression of HIF-1, but was reduced in hypoxic cells when HIF-1α activity was inhibited [28•,29].

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Heat shock proteins

Heat shock proteins, especially HSP70, provide cellular protection against stressor-induced tissue damage by re-folding or degrading denatured proteins produced by these stressors. Otaka et al.[30•] recently used affinity chromatography to identify cytoskeletal myosin and actin as the first molecules bound by HSP70 after gastric mucosal injury in rats. Transcriptional up-regulation of HSPs occurs via the transcription factor heat shock factor 1 (HSF1) binding to heat shock element (HSE) located upstream of the HSP genes. In HSF1 null and HSP70 expressing transgenic mice, HSPs are protective against irritant (NSAIDs or ethanol)-induced gastric lesions; geranylgeranylacetone (GGA), an antiulcer drug, induces HSPs. Further HSP70 protects the gastric mucosa through inhibition of apoptosis, proinflammatory cytokines, and CAMs involved in leukocyte infiltration. HSPs are protective in mouse models of inflammatory bowel disease and NSAID-induced lesions of the small intestine after induction by GGA. Therefore, HSP inducers such as GGA may have therapeutic benefits in numerous diseases [31,32].

In addition to inhibiting COX and decreasing prostaglandin production, NSAIDs induce mucosal damage through ROS produced by recruited leukocytes. ROS-mediated mitochondrial damage, oxidation of lipids, proteins, and DNA leads to cellular apoptosis and mucosal injury. HSP70-overexpressing rat gastric mucosal cells were relatively resistant to indomethacin-induced apoptosis compared to control cells. Further, HSP70-overexpressing cells had lower expression of pro-apoptotic factors (Bcl-2 associated death promoter, caspase activation) and higher expression of antiapoptotic proteins (Bcl-2) compared to controls after indomethacin treatment [33•].

Portal hypertensive (PHT) gastropathy, observed in patients with portal hypertension, increases susceptibility to mucosal damage. Excessive nitric oxide production via eNOS overexpression, mediated by HSP90, occurs in PHT gastropathy and may increase susceptibility to mucosal damage. In rat models of PHT, ethanol treatment of gastric mucosa increases HSP90 expression, leading to higher degrees of mucosal damage upon subsequent ethanol exposure compared with controls. Thus, higher levels of HSP90 may contribute to impaired adaptive cytoprotection [34•].

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Helicobacter pylori

Helicobacter pylori, a gram-negative microaerophilic bacterium, colonizes the stomach in at least half the world's population. If left untreated, H. pylori causes gastritis, peptic ulcer disease, mucosal-associated lymphoma, and gastric adenocarcinoma. As reviewed by Machado et al.[35•]H. pylori increases the risk of cancer development by increasing DNA damage with decreased repair mechanism activities inducing nuclear and mitochondrial DNA mutations. Host genetic factors also increase susceptibility to H. pylori-associated diseases. Cytokine polymorphisms, for example, in the interleukin (IL)-1β and TNF-α genes, are associated with increased susceptibility to peptic ulcer disease and gastric cancer [36,37]. Protease-activated receptors (PARs) are G-protein-coupled receptors expressed on epithelial cells and leukocytes. PARs are environmental sensors that respond to tissue damage and pathogens. PAR-1, activated by serine protease thrombin, protects rat gastric mucosa after ethanol-induced damage and is increased in H. pylori infection. PAR-2, activated by cognate proteases such as trypsin, is a proinflammatory mediator in the gut. In PAR-1 and PAR-2 knockout mice 2 months after Helicobacter infection, Helicobacter colonization was reduced in PAR-1 knockouts and increased in PAR-2 knockouts. Nevertheless, Helicobacter colonization was inversely correlated with the severity of inflammation. PAR-1 knockouts had a higher serum antibody response and higher levels of NF-κB, the proinflammatory cytokine macrophage inflammatory protein (MIP)-2. PAR-1 is hence protective in H. pylori-induced gastritis, mediated by the suppression of proinflammatory pathways [38•].

The IKK β/NF-κB signaling complex regulates apoptosis in epithelial cells and affects the gastric mucosal response to external stimuli. Shibata et al.[39•] recently studied IKK β/NF-κB signaling in mice with a IKK β knockout in gastric epithelial cells and myeloid cells. In an acute Helicobacter infection, NF-κB was increased in myeloid cells. In chronic Helicobacter infection or irradiation injury, NF-κB was increased in gastric epithelial cells. Loss of IKK β in gastric epithelial cells increased apoptosis, ROS, cellular necrosis, up-regulated IL-1α, decreased transcription of antiapoptotic genes, and accelerated progression to preneoplasia. In contrast, loss of IKK β in myeloid cells decreased gastric atrophy and progression to preneoplasia. Thus, IKK β/NF-κB signaling in gastric epithelial cells decreases chronic inflammation by inhibiting cellular apoptosis and necrosis in response to stress [39•].

Interstitial adenosine levels increase in inflamed or hypoxic tissues through CD39 nucleoside triphosphate dephosphorylase and CD73 5′-ectonucleotidase mediated dephosphorylation of ATP. Adenosine activates A2A adenosine receptors on T cells, which has anti-inflammatory effects. Alam et al.[40•] recently reported the mechanisms of how purinergic signaling mediates mucosal damage in response to Helicobacter infection. Specifically, they found that activation of human T cells obtained from blood and gastric tissues increases expression of A2A adenosine receptors. Stimulation of lymphocyte A2A adenosine receptors increased production of cAMP while decreasing production of proinflammatory cytokines such as IL-2, TNF-α and INF-γ. Mice deficient in A2A adenosine receptors had significantly more inflammation of the gastric mucosa at baseline and in response to Helicobacter infection compared to wild type. Mice deficient in IL-10, an anti-inflammatory cytokine, have more inflammation associated with Helicobacter leading to spontaneous clearance of infection. Activation of A2A adenosine receptors in IL-10-deficient mice decreases inflammation while leading to persistent H. pylori infection [40•]. Thus, purinergic signaling through A2A adenosine receptors helps mitigate mucosal inflammation due to H. pylori infection but leads to persistent infection.

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The gastroduodenal mucosa is continuously exposed to noxious substances such as gastric acid, NSAIDs, and H. pylori. Structural integrity is maintained through premucosal, mucosal, and submucosal pathways that lead to secretion of a protective mucous barrier, formation of intracellular tight junctions, increased blood flow, continuous cell renewal, neutralization of ROS, immune responses, and inhibition of apoptosis. Mucosal injury may occur when defense mechanisms are impaired or overwhelmed. Understanding these pathways will lead to improved therapies for the treatment and prevention of mucosal damage.

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We thank Coleen Palileo for her editorial assistance. Supported by VA Merit Review funding, NIH/NIDDK R01 DK54221, and NIH/NIDDK P30 DK0413.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 664–665).

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33• Hirata I, Naito Y, Handa O, et al. Heat-shock protein 70-overexpressing gastric epithelial cells are resistant to indomethacin-induced apoptosis. Digestion 2009; 79:243–250. Studied the resistance of HSP70-overexpressing cells to apoptosis as a mechanism of how HSP protects against mucosal damage.
34• Tominaga M, Ohta M, Kai S, et al. Increased heat-shock protein 90 expression contributes to impaired adaptive cytoprotection in the gastric mucosa of portal hypertensive rats. J Gastroenterol Hepatol 2009; 24:1136–1141. Studied adaptive cytoprotection and the role of HSP90 in portal hypertensive rats.
35• Machado AM, Figueiredo C, Seruca R, Rasmussen LJ. Helicobacter pylori infection generates genetic instability in gastric cells. Biochim Biophys Acta 2010; 1806:58–65. Reviewed the mechanisms by which
36 El-Omar EM, Rabkin CS, Gammon MD, et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 2003; 124:1193–1201.
37 Sugimoto M, Furuta T, Shirai N, et al. Different effects of polymorphisms of tumor necrosis factor-alpha and interleukin-1 beta on development of peptic ulcer and gastric cancer. J Gastroenterol Hepatol 2007; 22:51–59.
38• Wee JL, Chionh YT, Ng GZ, et al. Protease-activated receptor-1 down-regulates the murine inflammatory and humoral response to Helicobacter pylori. Gastroenterology 2010; 138:573–582. Studied the role of PAR-1 in gastroduodenal protection against
39• Shibata W, Takaishi S, Muthupalani S, et al. Conditional deletion of IkB-kinase-b accelerates helicobacter-dependent gastric apoptosis, proliferation, and preneoplasia. Gastroenterology 2010; 138:1022–1034. Studied the role of IKK β/NF-κB signaling apoptosis and development of dysplasia in
40• Alam MS, Kurtz CC, Wilson JM, et al. A2A adenosine receptor (AR) activation inhibits pro-inflammatory cytokine production by human CD4+ helper T cells and regulates Helicobacter-induced gastritis and bacterial persistence. Mucosal Immunol 2009; 2:232–242. Studied the role of A2A adenosine receptors in mucosal defense during

heat shock proteins; Helicobacter pylori; prostaglandins; proteinase-activated receptors; purinergic signalling; toll-like receptors; trefoil factors

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