Homeostasis in the gastric mucosa and blood circulation. Part 1. Mechanisms of the adequate blood flow maintenance in the gastric mucosa]

The increase of mucosal blood flow in response to food entrance into stomach or different irritant action is the component of gastric mucosal defence barrier. Sufficient blood flow ensures normal acid-bicarbonate balance in gastric mucosa, supports the healing process and prevents superficial damages from developing into deep ones. Capsaicin-sensitive afferent nerve fibers play the large role in the blood flow regulation. The influence of these nerve fibers on the gastric blood flow is mediated by the calcitonin-gene related peptide. This peptide released from peripheral afferent terminals improves microcirculation in stomach walls. Moreover nerve impulses from afferent neurons modulate parasympathetic activity that in turn induces the increase of gastric mucosal blood flow through both choilinergic and noncholinergic mechanisms. The gastric mucosal blood flow may be also regulated by humoral and paracrine metabolites. Nitric oxide and prostaglandines are the most important low molecular weight compounds. They play the main role in the maintenance of the basal gastric mucosal blood flow and in the development of hyperemic responses to harmful agents.     

Role of mucus in gastric mucosal protection.

Even though there is no general agreement as to the mechanism of gastric mucosal protection, the consensus is that the initial brunt of luminal insults falls on the mucus layer which constitutes the only identifiable physical barrier between the gastric lumen and the mucosal surface. The continuous renewal and resilient nature of this layer efficiently counters peptic erosion of the gel, assures its viscoelastic and permselective properties, and provides a milieu for containment of the diffusing luminal acid by mucosal bicarbonate. Disturbances in this delicate balance lead to the impairment of the protective function of mucus resulting in gastric disease. Indeed, the weakening of gastric mucosal defense is intimately associated with the diminished viscoelastic qualities of mucus, decrease in hydrogen ion retardation capacity, and the extensive proteolysis of its mucin component. Although until recently the disintegration of the mucus coat was attributed exclusively to the enhanced activity of intragastric pepsin, our studies provided strong argument that a bacterial factor, namely infection by Helicobacter pylori, through the action of its protease and lipase enzymes also is highly detrimental to the integrity of gastric mucus. Hence, agents capable of interfering with the pathogenic activity of this bacteria are becoming the drugs of choice in peptic ulcer therapy.     

Some new aspects of gastric mucosal protection and damage

Much of the research on gastric mucosal protection has concerned prostaglandins. Some of the recent studies consolidate aspects first investigated a few years ago, but whose importance is now becoming established more clearly. This short review will mention some of the more recent work demonstrating the importance of prostaglandins in preventing stasis of gastric mucosal blood flow, effects on cell senescence and exfoliation, and the protection of a severe mucosal lesion by a mucus-containing plug which facilitates healing. The leukotrienes are other substances formed in the gastric mucosa from the same precursors as the prostaglandins. Their roles are not well understood, but may include participation in gastric inflammation, and in mucosal damage by nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol. The NSAIDs may damage the gastric mucosa not only by reducing the formation of protective prostaglandins, but also by increasing the metabolism of prostaglandin precursors into leukotrienes. Another factor is thromboxane A2, a substance that is damaging to the gastric mucosa but whose synthesis is inhibited by NSAIDs. The prostaglandin analogues produced for the treatment of peptic ulcer may find a major use in the protection against damage by NSAIDs. Not only may they act as 'replacement therapy' for the inhibited prostaglandins, but they protect against damage from substances that do not inhibit prostaglandin synthesis. In doses that raise the gastric pH, the prostaglandins reduce the local absorption of NSAIDs by increasing their ionisation. In rats, paracetamol protects against damage by aspirin, but whether this occurs in man is controversial. Work not previously published demonstrates that paracetamol does not affect the inhibition of prostaglandin formation by indomethacin in human isolated gastric mucosa.     

Ethanol stimulates formation of leukotriene C4 in rat gastric mucosa

Ethanol-induced gastric mucosal damage is characterized by microcirculatory changes such as stasis and plasma leakage. Sluggish blood flow and stasis have also been observed after administration of exogenous leukotriene (LT) C4. The effect of ethanol on the release of LTC4 from rat gastric mucosa was therefore investigated. It was found that intragastric instillation of ethanol increases gastric mucosal release of LTC4 in a dose- and time-dependent manner parallel to the production of gastric lesions. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) and the anti-ulcer drug carbenoxolone (CX) inhibited mucosal release of LTC4 and simultaneously protected against gastric damage caused by ethanol. It is concluded that increased formation of LTC4 and/or other 5-lipoxygenase-derived products of arachidonate metabolism may be involved in ethanol-induced gastric damage. Furthermore, inhibition of the 5-lipoxygenase pathway may be an important mechanism of action of gastric protective drugs.     

Helicobacter pylori associated gastric pathology.

Helicobacter pylori (HP), undoubtedly, the most common world-wide infection plays an important role in pathogenesis of peptic ulcer. Proof for a causal role for HP in peptic ulcer rests in two major points; 1) the majority of ulcer patients are HP infected and the prevalence of this infection for both gastric ulcer (GU) and duodenal ulcer (DU) is much higher than for gender- and age-adjusted controls and 2) the cure of HP infection dramatically reduces ulcer recurrence. Conclusions regarding the mechanisms by which HP induces peptic ulcer are restricted mainly to studies observing the consequences of its eradication by antibiotics combined with gastric inhibitors or bismuth agents. Several specific virulence factors such as cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) as well as other noxious substances including ammonia, lipopolysaccharide (endotoxin), platelet activating factor (PAF), nitric oxide (NO) and others have been implicated in gastritis and were found to be significantly more frequent in gastric cancer than in gender- and age-matched controls, especially in younger generation. Chronic inflammation, atrophic gastritis, intestinal metaplasia, impaired defense mechanisms combined with hypergastrinemia, deficiency of vitamin C in the stomach , excessive oxygen metabolites and epithelial cell proliferation have been associated with gastric cancer. This multi-step pathway originally proposed by Correa and his colleagues, long before the HP was discovered in the stomach, leads to cancer but may be reversed by eradication of HP. This is, however, a controversial issue because gastric atrophy and intestinal metaplasia may be also caused by other factors such as bile reflux, dietary irritants, and autoimmunity. The implication of HP in MALT-lymphoma is based on the observations that eradication of HP in early stage of low-grade of this tumor leads to complete remission. The significance of HP in non-ulcer dyspepsia remains questionable and requires further studies.     

Effects of reactive oxygen species action on gastric mucosa in various models of mucosal injury.

BACKGROUND: The exposure of gastric mucosa to damaging factors, such as ethanol, water restraint stress, or ischemia followed by reperfusion, produces pathological changes: inflammatory process, hemorrhagic erosions, even acute ulcers. The base of these changes is a disturbance of protective mechanisms and disrupture of gastric mucosal barrier. Previous studies pointed out the role of disturbances of gastric blood flow, mucus secretion and involvement of prostaglandins and nitric oxide formation in the pathomechanism of gastric mucosa lesions. The role of reactive oxygen species (ROS) in these processes has been little studied. Aim: The purpose of our present investigations is to explain the participation of ROS in acute gastric mucosal damage by various irritants. MATERIAL AND METHODS: Experiments were carrying out on 80 male Wistar rats. To assess gastric blood flow (GBF) laser Doppler flowmeter was used. The area of gastric lesions was established by planimetry. The levels of proinflammatory cytokines were measured by ELISA technique. The colorimetric assays were used to determine of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) as well as superoxide dismutase (SOD) activity. RESULTS: We demonstrated that 3.5 h of water immersion and restraint stress (WRS), 30 min of gastric ischemia followed by 60 min of reperfusion or intragastric administration of 100% ethanol, all resulted in appearance of acute gastric mucosal lesions accompanied by a significant decrease of gastric blood flow. These lesions are also accompanied by the significant increase of proinflammatory cytokines including interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) plasma level. Biological effects of ROS were estimated by measuring tissue level of MDA and 4-HNE, the products of lipid peroxydation by ROS, as well as the activity of SOD, the scavanger of ROS. It was established that 3.5 h of WRS, ischemia-reperfusion and 100% ethanol lead to significant increase of MDA and 4-HNE mucosal level, accompanied by a decrease of SOD activity (significant in WRS and ethanol application). CONCLUSIONS: The pathogenesis of experimental mucosal damage in rat stomach includes the generation of ROS that seem to play an important role, namely due to generation of lipid peroxides, accompanied by impairment of antioxidative enzyme activity of cells.     

Partial sleep deprivation compromises gastric mucosal integrity in rats

The gastric mucosa is most susceptible to stress that has been shown to induce mucosal damage in humans and animals. This study aims to explore the underlying mechanisms of partial sleep deprivation, as a source of psychophysiological stress, on gastric functions and its effect on mucosal integrity. Sprague-Dawley rats were partially sleep deprived (PSD) for 7 or 14 days by housing inside slowly rotating drums. Gastric tissues and plasma were sampled at the end of the sleep deprivation periods and mucosal lesion scores were evaluated. Morphological examination was performed after Hematoxylin and Eosin staining. Plasma levels of noradrenaline, adrenaline, gastrin, histamine and somatostatin were determined with enzyme immunoassays. Gastric acidity was measured with acid-base titration in pylorus ligated rats. Gastric mucosal blood flow was evaluated with Laser Doppler Flowmetry. It was found that gastric lesions were induced in about 30%-50% of the PSD rats. Gastric acidity as well as plasma levels of noradrenaline, gastrin and histamine were elevated. Gastric mucosal blood flow and plasma somatostatin level were on the contrary reduced, especially in rats with PSD for 14 days. It is concluded that partial sleep deprivation compromises gastric mucosal integrity by increasing gastric acidity, plasma levels of noradrenaline, gastrin, histamine, and decreasing gastric mucosal blood flow. These results provided experimental evidence on the gastric damaging effects of PSD and it could be one of the risk factors contributing to gastric ulcer formation.     

Ethanol stimulates formation of leukotriene C4 in rat gastric mucosa

Ethanol-induced gastric mucosal damage is characterized by microcirculatory changes such as statis and plasma leakage. Sluggish blood flow and statis have also been observed after administration of exogenous leukotriene (LT) C₄. The effect of ethanol on the release of LTC₄ from rat gastric mucosa was therefore investigated. It was found that intragastric instillation of ethanol increases gastric mucosal release of LTC₄ in a dose- and time-dependent manner parallel to the production of gastric lesions. The lipoxugenase inhibitor nordihydroguaiaretic acid (NDGA) and the anti-ulcer drug carbenoxolone (CX) inhibited mucosal release of LTC₄ and simultaneously protected against gastric damage caused by ethanol. It is concluded that increased formation of LTC₄ and /or other 5-lipoxygenase-derived products of arachidonate metabolism may be involved in ethanol-induced gastric damage. Furthermore, inhibition of the 5-lipoxygenase pathway may be an important mechanism of action of gastric protective drugs.     

Gastric microcirculatory change and development of acute gastric mucosal lesions (stress ulcer)

Concerning the pathogenesis of acute gastric mucosal lesions, gastric microcirculatory change has drawn attention as an important factor. In view of this fact, gastric mucosal blood flow and microvascular structure were investigated in normal and in burn stressed rats. Moreover, alterations in acid and pepsin activities in by morphological and biochemical procedures in order to evaluate the relationship between defensive and aggressive factors of the gastric mucosa. Gastric mucosal blood flow decreased significantly in early period after induction of stress (p less than 0.01). The incidence of ulceration showed a correlative relation with the decrease of mucosal blood flow. Reduction of blood flow in burn was due to opening of arteriovenular shunt and it appeared that this was responsible for mucosal ischemia and congestion. Following the decrease of blood flow, acid output was lower in stress than that in control. Finally, the results of these studies demonstrated the importance of defensive factors. The reduction of mucosal blood flow resulted in the sequence of events that led to formation of acute gastric mucosal lesion.     

Apoptosis in gastric mucosa with stress-induced gastric ulcers.

The maintenance of gastric mucosal integrity depends upon the interplay between epithelial cell proliferation and apoptosis (programmed cell death). The Bcl-2 family of proteins plays a central role in the regulation of apoptotic cell death by suppressing the apoptosis while some others such as Bax proteins promote this process. Stress-induced gastric ulcerations are accompanied by the fall in gastric mucosal cell proliferation but little is known about the influence of the stress on the apoptosis in gastric mucosa. In the present study, the gastric epithelial apoptosis was determined by means of expression of Bax and Bcl-2 mRNA in the gastric mucosa following acute stress. Wistar rats were exposed to mild water immersion and restraint stress (WRS) for 3.5 h and then sacrificed at 0, 2, 4, 6, 12 and 24 h after the termination of WRS. At each time interval after WRS, the gastric blood flow (GBF) and the proliferating cell nuclear antigen (PCNA) labeling were determined. The apoptosis rate in the gastric mucosa was determined by the terminal deoxynucleotidyl transferase (TDT) mediated 2-deoxyuridine 5-triphosphate (dUTP)-biotin nick end-labeling (TUNEL) staining method and the expression of Bax and Bcl-2 mRNA was analyzed by RT-PCR and southern blot hybridization. WRS produced multiple erosions accompanied by the fall in GBF and PCNA index and by a dramatic enhancement in gastric epithelial apoptosis rate reaching maximum at 4 h after exposure to WRS. Following 6 and 12 h after the end of WRS the apoptotis declined but even 24 h after WRS it failed to reach the value recorded in intact gastric mucosa. The PCNA index was still significantly inhibited at 2 h after WRS but then showed significant rise at 6 and 12 h to reach at 24 h after WRS, the level similar to that measured in intact gastric mucosa. The expression of Bax mRNA was detected in intact gastric mucosa and gradually increased in first 4 h after WRS to decline at 24 h to the level not significantly different from that observed in the intact mucosa. In contrast, the expression of Bcl-2 mRNA was almost undetectable during first 4 h but showed strong signal at 6 and 12 h to decline to the control level 24 h after WRS. We conclude that: 1. Healing of WRS lesions involves an increase in GBF and mucosal cell proliferation and 2. The enhancement in gastric epithelial apoptosis accompanies the mucosal damage induced by stress and this appears to be triggered by the shift from the cell death effector Bax to the cell death repressor Bcl-2 protein.     

The pharmacological differences and similarities between stress- and ethanol-induced gastric mucosal damage.

Stress- and ethanol-induced gastric mucosal damage are the two commonly used ulcer models in animals. They share some of the similarities but also have differences in the etiology of gastric ulceration. This article reviews the influences of various protective drugs on these two types of gastric damage in rats. Verapamil (a calcium antagonist) or N-ethylmaleimide (a sulfhydryl depletor) prevents cold restraint-, but potentiates ethanol-provoked gastric lesion formation. N-Acetylcysteine (a mucolytic agent) and acetaminophen (an antipyretic analgesic) have the opposite actions. Prostaglandins provide a much better antiulcer effect on ethanol-induced lesions. Cimetidine (a histamine H2-receptor antagonist) prevents only stress-induced mucosal damage. These differences in drug actions indicate that stress and ethanol may have dissimilar ulcerogenic mechanisms in rats. On the other hand, carbenoxolone (a mucus inducer), histamine H1-receptor antagonists, leukotriene inhibitors (FPL 55712 and nordihydroguaiaretic acid) and mast cell stabilizers (like zinc compounds, sodium cromoglycate, FPL 52694 and ketotifen), all protect against gastric mucosal damage by stress or ethanol in rats. However, the role of gastric sulfhydryls in both types of gastric lesions is still controversial. These findings imply that the two types of lesion formation share some of the ulcerogenic mechanisms. This communication attempts to analyze the various findings and to relate them to the etiology of stress and ethanol-induced gastric lesions. It also summarizes the uses, and the antiulcer mechanisms, of the drugs that have been studied utilizing these two animal ulcer models, and suggests their possible implications in man.     

The distribution of 4-hydroxynonenal-modified proteins in gastric mucosa of duodenal peptic ulcer patients

This study used monoclonal antibody specific for 4-hydroxynonenal (HNE)-histidine to evaluate immunohistochemical distribution of HNE-protein adducts in gastric mucosa biopsies of 52 peptic ulcer patients (all positive for H. pylori) and of 20 healthy volunteers (eight positive and 12 negative for H. pylori). HNE-modified proteins were present in glandular epithelium in all subjects, both patients with duodenal peptic ulcer and healthy subjects. Hence, the presence of HNE did not appear to be related to the presence of H. pylori. However, in patients with duodenal peptic ulcer accumulation of HNE-protein adducts was frequently observed also in nuclei, while in the control group such subcellular distribution of HNE was not observed at all. This study shows physiological presence of HNE in human gastric mucosa, but also suggests its role in pathology of gastric dysfunction in duodenal peptic ulcer patients manifested by accumulation of HNE-protein adducts in particular in nuclei of gastric glandular epithelium.     

Antacid talcid activates in gastric mucosa genes encoding for EGF and its receptor. The molecular basis for its ulcer healing action.

In previous studies [Gut 35 (1994) 896-904], we demonstrated that antacid talcid (TAL) accelerates gastric ulcer healing and provides better quality of mucosal restoration within the scar than the omeprazole (OME). However, the mechanisms of TAL-induced ulcer healing are not clear. Since growth factors promote cell proliferation, re-epithelization, angiogenesis and ulcer healing, we studied whether TAL and/or OME affect expression of epidermal growth factor (EGF) and its receptors (EGF-R) in both normal and ulcerated gastric mucosae. Rats with or without acetic acid-induced gastric ulcers (n = 64) received i.g. twice daily 1 mL of either: A) placebo (PLA); B) TAL 100 mg; or C) OME 50 mg x kg(-1) for 14 d. Studies of gastric specimens: 1) ulcer size; 2) quantitative histology; 3) expression of EGF mRNAs was determined by RT/PCR; 4) gastric sections were immunostained with antibodies against EGF and its receptors. In non-ulcerated gastric mucosa of placebo or omeprazole treated group, EGF expression was minimal, while EGF-R was localized to few cells in the mucosal proliferative zone. Gastric ulceration triggered overexpression of EGF and its receptor in epithelial cells of the ulcer margin and scar. In ulcerated gastric mucosa TAL treatment significantly enhanced (versus PLA and omeprazole) expression of EGF and EGF-R. OME treatment reduced expression of EGF in ulcerated mucosa by 55 +/- 2% (P < 0.01). It is concluded that: 1) treatment with TAL activates genes for EGF and its receptor in normal and ulcerated gastric mucosae; 2) since EGF promotes growth of epithelial cells and their proliferation and migration, the above actions of TAL provide the mechanism for its ulcer healing action and improved (versus OME) quality of mucosal restoration.     

The distribution of 4-hydroxynonenal-modified proteins in gastric mucosa of duodenal peptic ulcer patients

This study used monoclonal antibody specific for 4-hydroxynonenal (HNE)-histidine to evaluate immunohistochemical distribution of HNE–protein adducts in gastric mucosa biopsies of 52 peptic ulcer patients (all positive for H. pylori) and of 20 healthy volunteers (eight positive and 12 negative for H. pylori). HNE-modified proteins were present in glandular epithelium in all subjects, both patients with duodenal peptic ulcer and healthy subjects. Hence, the presence of HNE did not appear to be related to the presence of H. pylori. However, in patients with duodenal peptic ulcer accumulation of HNE-protein adducts was frequently observed also in nuclei, while in the control group such subcellular distribution of HNE was not observed at all. This study shows physiological presence of HNE in human gastric mucosa, but also suggests its role in pathology of gastric dysfunction in duodenal peptic ulcer patients manifested by accumulation of HNE-protein adducts in particular in nuclei of gastric glandular epithelium.     

Role of gastric microcirculation in the gastroprotection by glucocorticoids released during water-restraint stress in rats

Our previous investigations demonstrated that glucocorticoids released in response to stress protect gastric mucosa against stress-induced ulceration. This study was designed to determine whether gastric microcirculation is involved in the mechanism of gastroprotective glucocorticoid action. For this we evaluated the effects of deficiency of glucocorticoid production during 3 hr water-restraint stress and corticosterone replacement on the stress-induced gastric erosions, gastric microcirculation and arterial pressure in rats. The stress was produced in awake rats and gastric microcirculation and arterial pressure were evaluated in animals anesthetized in 3 hr after the onset of water-restraint stress. An in vivo microscopy technique for the direct visualization of gastric microcirculation was employed. The gastric submucosal and the superficial mucosal microvessels were monitored on television screen through a microscope and the pictures were stored by microfilming for the analysis of red blood cell velocity and vessel diameter. Gastric microcirculation was estimated on the base of both the volume blood flow velocity in submucosal microvessels and the diameter of superficial mucosal venous microvessels. Gastric erosions were quantitated by measuring the area of damage. Plasma corticosterone levels were also measured after 3 hr stress by fluorometry. Water-restraint stress induced an increase in corticosterone level, an appearance of gastric erosions, a decrease in volume blood flow velocity of submucosal microvessels, a dilatation of superficial mucosal microvessels, a decrease in arterial pressure. The deficiency of glucocorticoid production during water-restraint stress promoted the stress-induced gastric ulceration, a dilatation of mucosal microvessels, a decrease of blood flow velocity in submucosal microvessels and of arterial pressure. Corticosterone replacement eliminated the effects of deficiency of glucocorticoid production on all of the parameters under study. Thus, the stress-induced corticosterone rise decreased gastric ulceration, restricted both the reduction of blood flow velocity in submucosal microvessels and a dilatation of superficial mucosal venous microvessels during water-restraint stress. These data suggest that the gastroprotective action of glucocorticoids during stress may be provided by the maintenance of gastric blood flow.     

Ionic fluxes induced by topical misoprostol in canine gastric mucosa

We studied the dose response of ionic fluxes in canine chambered gastric segment mucosa to increasing doses of topical misoprostol (0.1, 1, 10, 100, and 1000 micrograms). The fluxes were also correlated with the simultaneous changes in focal gastric mucosal blood flow measured by laser-Doppler flowmetry. After misoprostol administration, there was a dose-dependent increase in focal gastric mucosal blood flow (Emax = 8.23 +/- 3.25 V at 10 micrograms; ED50 = 1.05 micrograms), pH, and the outputs of ions (Na+, K+, Cl-, and HCO3-) and fluid (Emax for pH and fluxes greater than or equal to 1000 micrograms). ED50 values for these outputs ranged from 215.40 to 340 micrograms (mean +/- SE = 279.08 +/- 24.27 micrograms). H+ output showed a dose-dependent decrease to zero at the 10-micrograms dose, the dose at and after which net HCO3- secretion became obvious. The slopes of the dose-response curves for the fluxes of fluid, Na+, K+, Cl-, and HCO3- were significantly different (p less than 0.01) from the slope of the curve for mucosal blood flow changes. There were no correlations between the changes in these fluxes and blood flow changes. Na+ and Cl- were the predominant cation (98.84%) and anion (98.19%), respectively, in the misoprostol-induced secretion. Misoprostol stimulates a composite alkaline gastric nonparietal secretion, predominantly Na+ and Cl-, but also containing K+ and HCO3-. Our results suggest different mechanisms for the effects on nonparietal secretion and focal gastric mucosal blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in the energy resources of rat gastric mucosa exposed to dopamine agonists and antagonists in conditions of experimental stress

Changes in adenyl nucleotide and glycogen content in rat gastric tissue under the action of stressogenic factor and injection of the dopamine blocker metoclopramide and the dopamine precursor L-DOPA were investigated with the use of the "social stress" method devised by the authors. It was established that stress induced gastric mucosal lesions and reduced the content of adenyl nucleotides and glycogen in the gastric tissue. Preliminary injection of L-DOPA potentiated the effect of stress while metoclopramide inhibited it. The data show a role of energy balance disturbances in the gastric tissue in the pathogenesis of an acute ulcer. In the authors' opinion, the disturbances seen during immobilization psychogenic stress were caused by undue stimulation of central dopamine receptors.     

Gastric mucosal integrity: gastric mucosal blood flow and microcirculation. An overview

The stomach is in a state of continuous exposure to potentially hazardous agents. Hydrochloric acid together with pepsin constitutes a major and serious threat to the gastric mucosa. Reflux of alkaline duodenal contents containing bile and pancreatic enzymes are additional important injurious factors of endogenous origin. Alcohol, cigarette smoking, drugs and particularly aspirin and aspirin-like drugs, and steroids are among exogenous mucosal irritants that can inflict mucosal injury. The ability of the stomach to defend itself against these noxious agents has been ascribed to a number of factors constituting the gastric mucosal defense. These include mucus and bicarbonate secreted by surface epithelial cells, prostaglandins, sulfhydryl compounds and gastric mucosal blood flow. The latter is considered by several researchers to be of paramount importance in maintaining gastric mucosal integrity. The aim of this paper is to review the experimental and clinical data dealing with the role of mucosal blood flow and in particular the microcirculation in both damage and protection of the gastric mucosa.