Development Of Gastric Mucosal Lesions Research Articles

Mitochondrial dysfunction induced by HIF-1α under hypoxia contributes to the development of gastric mucosal lesions.

Hypoxia is an important characteristic of gastric mucosal diseases, and hypoxia-inducible factor-1α (HIF-1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF-1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified. To evaluate the effects of hypoxia-induced HIF-1α on the development of gastric mucosal lesions. Portal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)-induced mouse models in METTL3 mutant or NLRP3-deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed. HIF-1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3-dependent dynamin-related protein 1 (Drp1) N6-methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF-1α with PX-478, inhibiting Drp1-dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi-1) treatment or METTL3 mutation alleviated this process. Furthermore, HIF-1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF-1α-induced Drp1-dependent mitochondrial fission also enhanced glycolysis. Drp1-dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC. Under hypoxic conditions, HIF-1α enhances mitochondrial dysfunction via Drp1-dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.

The occurrence, progression and development of four types of gastric mucosal atrophic lesions and their histopathological characteristics

ObjectiveTo investigate the occurrence and development of gastric mucosal atrophic lesions and their histopathological characteristics.MethodsHistopathological diagnosis and immunohistochemical staining using the EnVision two-step method were conducted on 1969 gastric mucosal atrophic lesions obtained from gastroscopic biopsy specimens. A total of 48-month three-stage endoscopic biopsy follow-ups were performed.ResultsWhen the gastric mucosal epithelium was affected by infection, chemical irritation, or immune or genetic factors, the gastric mucosal epithelium glands atrophied, the mucosa became thinner, the number of glands decreased, the intestinal epithelium progressed to metaplasia and smooth muscle fibre became hyperplasia. Such changes may lead to the proliferation and dysplasia of epithelial cells of the gastric mucosa and neoplastic hyperplasia in nature; this is referred to as gastric mucosal atrophic lesions in this study. According to this definition, the present study divided gastric mucosal atrophy into four types: (1) glandular atrophy of the lamina propria; (2) compensatory proliferative atrophy; (3) intestinal metaplasia atrophy; and (4) smooth muscle proliferative atrophy. The incidence rates of the above were 40.1% (789/1969), 14.3% (281/1969), 27.8% (547/1969) and 17.9% (352/1969), respectively. One- to 4-year follow-ups found that the changes were not significant and that the percentages of patients with disease exacerbation were 85.7% (1688/1969) and 9.8% (192/1969). The percentages of patients who developed low-grade intraepithelial neoplasia and high-grade intraepithelial neoplasia were 2.8% (55/1969) and 1.1% (21/1969), respectively; 0.7% (13/1969) of patients developed intramucosal cancer.ConclusionGastric mucosal atrophic lesions and histopathological staging are based on the morphological characteristics of gastric mucosal atrophy and the hypothesis of malignant transformation of cells during the occurrence and development of mucosal atrophy. Mastering pathological staging is beneficial to clinicians for enacting precise treatment and is important for reducing the incidence of gastric cancer.

Gastroprotective effect of dapagliflozin in ethanol-induced gastric lesions in rats: Crosstalk between HMGB1/RAGE/PTX3 and TLR4/MyD88/VEGF/PDGF signaling pathways.

Alcohol abuse may lead to the development of gastric mucosal lesions. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor, is clinically used to treat type 2 diabetes mellitus. However, studies showed protective effect of DAPA under various experimental conditions by alleviating oxidative stress and inflammation. The effect of DAPA on experimental gastric ulcer has not been studied yet. Therefore, we attempted to investigate DAPA's protective effect against ethanol (EtOH)-induced gastric lesions. Fifty-six (8-week-old) male Wistar rats were divided into seven groups. DAPA (1, 5, and 10mg/kg/day; p.o.) was given for seven days, plus a single dose of absolute EtOH (5ml/kg) on day 8. According to hematoxylin and eosin, and Alcian blue staining of gastric tissue sections, titratable acidity, and macroscopic assessments, DAPA high dose (10mg/kg) was the most protective, with lesser ulcerations, and higher mucin, relative to the lower two doses and the standard treatment omeprazole (OME). In rats pre-treated with DAPA high dose, colorimetric and ELISA analyses revealed significantly decreased oxidative stress, pro-inflammatory, and apoptosis indices and increased levels of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Western blot analysis revealed reduced pentraxin-3 (PTX3), high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and myeloid differentiation factor 88 (MyD88) expression. These results were comparable in DAPA (10mg/kg) and OME pre-treated groups. Overall, DAPA exerted a dose-dependent protective effect against EtOH-induced gastric injury. Gastroprotective effects of DAPA (10mg/kg) may be associated with influencing HMGB1/RAGE/PTX3 and TLR4/MyD88/VEGF/PDGF pathways.

The Effect of Metformin on Ethanol- and IndomethacinInduced Gastric Ulcers in Rats.

Background:Previous studies found metformin as an effective agent to suppress oxidative stress, inflammation, and apoptosis in various inflammatory diseases. The present study investigated the effect of metformin against 2 experimental gastric injury models in rats, using macroscopical, histopathological, biochemical, and immunostaining studies.Methods: After 24 hours of fasting, male Sprague-Dawley rats (280-400 g) (n = 8 per group) received indomethacin (80 mg/kg; indo ulcer group) or absolute ethanol (5 mL/kg; ethanol ulcer group) or vehicle orally by gavage. Metformin (500 mg/kg) was given orally for 3 days prior to indomethacin or ethanol challenge. Ranitidine (50 mg/kg) was given orally for 3 days before indomethacin or ethanol administration as a positive control. On day 3, the animals were euthanized 6 hours after indo or 1 hour after ethanol challenge. Gastric samples were used for macroscopic scoring, histopathological examinations, and biochemical assays. Trunk blood was collected for the assessment of interleukin-1β level.Results:In both ethanol ulcer and indo ulcer groups, metformin decreased the extent of gastric lesions macroscopically and microscopically, improved the high chemiluminescence levels, and the percentage of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells compared with untreated ulcer groups. Gastric blood flow analysis revealed significant increases in both metformin-treated ulcer groups compared to untreated ulcer groups.Conclusion:The findings of the present work demonstrated the gastroprotective effect of metformin against the development of gastric mucosal lesions induced by ethanol and indomethacin in non-diabetic, normoglycemic rats via its antioxidant and anti-apoptotic properties and partly from its ability to restore blood flow.

The gastroprotective effect of the foxtail millet and adlay processing product against stress-induced gastric mucosal lesions in rats

Foxtail millet (Setaria italica (L.) P. Beauv.) and adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) seeds have substantial benefits possesses remarkable edible and nutritive values, and ease of processing and food manufacturing. They have nutraceutical properties in the form of antioxidants which prevent deterioration of human health and have long been used in traditional Chinese medicine as a remedy for many diseases. The present study is designed to investigate the gastroprotective effect of foxtail millet and adlay processing product (APP) diet on water immersion restraint stress (WIRS) induced ulceration in rats. We examined the effects of intake of AIN-93G diet containing either foxtail millet (10, 20 and 40%, 4 weeks) or APP (15 and 30%, 5 weeks) on macroscopic ulcer index (UI), plasma calcium level, lipid peroxidation products (estimated by the thiobarbituric acid reactive substances; TBARS), non-protein sulfhydryl (NPSH), digestive enzyme activities, and histopathology were determined. The results showed that pretreatment with millet and adlay diets significantly prevented the gastric mucosal lesion development. In addition, ulcerated rats showed depletion of NPSH levels whereas treatment with millet and adlay reverted this decline in stress-induced rats. Histological studies confirmed the results. The finding suggests that millet and adlay diets promote ulcer protection by the decrease in ulcer index, TBARS values and increase NPSH concentrations. Millet and adlay diets retain the advantage of being a natural product which may protect the gastric mucosa against ulceration.

Role of polymorphisms in genes that encode cytokines and Helicobacter pylori virulence factors in gastric carcinogenesis.

The Helicobacter pylori (H. pylori) infection is a determinant factor in gastric cancer (GC) development. However, the infection outcomes are variable and depend on both host and bacterial characteristics. Some host cytokines such as interleukin (IL)-1β, IL-1Ra, IL-8, IL-10 and tumor necrosis factor-α play important roles in the host immune system response to the pathogen, in the development of gastric mucosal lesions and in cell malignant transformation. Therefore, these host factors are crucial in neoplastic processes. Certain polymorphisms in genes that encode these cytokines have been associated with an increased risk of GC. On the other hand, various virulence factors found in distinct H. pylori bacterial strains, including cytotoxin-associated antigen A, vacuolating cytotoxin, duodenal ulcer promoting gene A protein, outer inflammatory protein and blood group antigen binding adhesin, have been associated with the pathogenesis of different gastric diseases. The virulent factors mentioned above allow the successful infection by the bacterium and play crucial roles in gastric mucosa lesions, including malignant transformation. Moreover, the role of host polymorphisms and bacterial virulence factors in gastric carcinogenesis seems to vary among different countries and populations. The identification of host and bacterium factors that are associated with an increased risk of GC development may be useful in determining the prognosis of infection in patients, what could help in clinical decision-making and in providing of an optimized clinical approach.

Transient Receptor Potential Ankyrin 1 and Substance P Mediate the Development of Gastric Mucosal Lesions in a Water Immersion Restraint Stress Rat Model

Background: Activation of substance P (SP) contributes to the development and maintenance of gastric lesions, but the mechanisms underlying the release of SP and SP-mediated damage to the gastric mucosa remain unknown. Transient receptor potential ankyrin 1 (TRPA1) is expressed in SP-positive neurons in the dorsal root ganglion (DRG) and stomach of rats. We hypothesized that water immersion restraint stress (WIRS) may activate and sensitize TRPA1 in DRG neurons, subsequently inducing the release of SP from DRG and stomach cells, causing the development of acute gastric mucosal lesions (AGML). Methods: Changes in TRPA1 and SP expression in T8–11 DRG sensory neurons and the stomach in an AGML rat model were determined by reverse transcription polymerase chain reaction, western blotting and immunohistochemistry. The SP levels of serum and gastric mucosa were measured by using an enzyme-linked immunosorbent assay (ELISA). Gastric lesions were evaluated by histopathological changes. The TRPA1 antagonist HC-030031 and TRPA1 agonists allyl isothiocyanate were used to verify effect of TRPA1 and SP on AGML. Results: SP and TRPA1 in the DRG and stomach were upregulated, and the serum and gastric mucosa levels of SP were increased after WIRS, which are closely associated with AGML. The release of SP was suppressed and AGML were alleviated following a selective TRPA1 antagonist HC-030031. TRPA1 agonists AITC increased release of SP and led to moderate gastric lesions. We confirmed that WIRS induced the release of SP in the DRG, stomach, serum and gastric mucosa, and in a TRPA1-dependent manner. Conclusions: Upregulated SP and TRPA1 in the DRG and stomach and increased serum and gastric mucosa SP levels may contribute to stress-induced AGML. TRPA1 is a potential drug target to reduce stress-induced AGML development in patients with acute critical illnesses. This study may contribute to the discovery of drugs for AGML treatment.

Effect of Xiaoyao San on the brain-gut axis in rats after chronic immobilization stress

ObjectiveTo investigate the effect of Xiaoyao San on the brain-gut axis in rats exposed to chronic immobilization stress (CIS). MethodsRats were divided into control, model, and treatment groups. The rats belonging to the model and treatment groups were subjected to CIS for 21 consecutive days, during which they were administered Xiaoyao San decoction [3.854 g/(kg·d)] or vehicle by gavage, and their body weight gain, food intake and water intake were monitored. The rats were subsequently subjected to the open field test (OFT) and d-xylose absorption test, and the expression levels of neuropeptides secreted by the hypothalamus and stomach were determined by enzyme-linked immunosorbent assay (ELISA), radioimmune analysis, or real-time fluorescence quantitative polymerase chain reaction. Gastric mucosal morphology was also assessed. ResultsThe model rats exhibited complex brain-gut axis abnormalities following exposure to CIS, abnormalities signified by decreases in food intake, reductions in digestive absorption, decreases in body weight, decreases in the total distances traveled and increases in the time in the central zone during the OFT, gastric mucosal lesion development and decreases in gastrointestinal hormone secretion. These changes were reversed after treatment with Xiaoyao San, which also regulated the secretion of both peripheral (serum and stomach) and central (hypothalamus) brain-gut peptides. Specifically, the levels of neuropeptide Y (NPY) and neuropeptide Y receptor Y5, which are secreted by the hypothalamus and promote digestive function, were increased in the Xiaoyao San-treated group compared with the model group. Furthermore, the levels of pro-opiomelanocortin (POMC) and its receptor, melanocortin-4 receptor (MC4R), which are secreted by the hypothalamus and inhibit digestive function, were significantly decreased in the treatment group compared with the model group. However, the levels of ghrelin (GHRL), gastrin (GAS) and motilin (MTL), which are secreted by the stomach, were significantly increased in the serum and stomach of the treatment group compared with the serum and stomach of the model group following Xiaoyao San treatment (P < .05 vs. the model group). ConclusionXiaoyao San attenuates CIS-induced gastrointestinal dysregulation by regulating the peptides secreted by both the hypothalamus and the gastrointestinal tract (GIT), suggesting that its effects are associated with the brain-gut axis.

English

The highly selective serotonin reuptake inhibitors are successful in the treatment of depression mood and anxiety disorders. The objective of this study is to investigate the effect of fluexotine and buspirone when given orally in three dose levels (5, 10 and 15 mg/ kg) not only for eight weeks on gastric lesions and oxidative markers in normal rats' mucosal integrity, but also for four weeks on gastric mucosal lesions in rats treated with indomethacin- induced ulcers. The results of this study showed that in normal rats, the administration of fluoxetine induced gastric lesions while buspirone caused no lesions. The indomethacin administration resulted in the development of gastric mucosal lesions. Furthermore, co-administration of fluoxetine and indomethacin enhanced the development of gastric mucosal lesions that were coupled with disturbance in antioxidant status. Buspirone, in contrast, significantly decreased the development of gastric mucosal lesions in rats treated with indomethacin. In conclusion, fluoxetine caused the development of gastric mucosal lesions and aggravate the effect of indomethacin to induce ulcer, however, buspirone had a protective effect that may be attributed to its antioxidant properties. Key words: Fluoxetine, buspirone, peptic ulcer, indomethacin-induced ulcer, oxidative stress.

Effect of Cannabis sativa extract on gastric acid secretion, oxidative stress and gastric mucosal integrity in rats

Studies were conducted in pylorus-ligated rats to investigate the effect of Cannabis sativa extract on gastric acid secretion, experimental gastric ulcer and on oxidative stress and inflammatory markers in the gastric mucosa. C. sativa (5, 10 and 20 mg/kg, expressed as Δ9-tetrahydrocannabinol) was administered subcutaneously daily for 4 weeks prior to pylorus ligation and different treatments. Under basal conditions, pretreatment with cannabis extract at doses of 5 and 10 mg/kg increased gastric acid secretion and induced minimally visible gastric mucosal lesions in the 4 h pylorus-ligated rat. Malondialdehyde and nitric acid concentration increased, while reduced glutathione decreased by cannabis at doses of 5 and 10 mg/kg in gastric mucosa. TNF-α increased by cannabis extract at doses of 5 and 10 mg/kg but decreased following the high dose of 20 mg/kg. On the other hand, the gastric acid secretory responses stimulated by pentagastrin or carbachol (but not histamine) were inhibited in rats pretreated with cannabis extract. Under these conditions, cannabis decreased pepsin content after pentagastrin and carbachol but not histamine stimulation. Cannabis also decreased lipid peroxidation and nitric oxide content, and increased both reduced glutathione and catalase activity in mucosa. Moreover, cannabis decreased mucosal inflammation (level of TNF-α) and the development of gastric mucosal lesions. Cannabis administered for 1 month prior to pylorus-ligation and either acidified aspirin or ethanol (96 %) decreased the development of gastric mucosal damage in a dose-dependent manner, along with reduction in gastric acid output, gastric mucosal oxidative stress and inflammation (TNF-α). Sections of gastric mucosa stained with periodic acid Schiff showed increased mucus secretion by cannabis in basal conditions and after treatment with aspirin or ethanol. Results indicate that: (1) the effect of cannabis differs in basal conditions and after exposure of the gastric mucosa to high acid concentrations or other chemical noxious agents; (2) cannabis administered systemically exerts gastric mucosal protective effects against mucosal damage evoked by stimulation of gastric acid secretion, acidified aspirin or ethanol. These effects of cannabis are likely to involve inhibition of gastric acid and pepsin secretion, increased mucus, decreased oxidative stress and inflammation in gastric mucosa.

The protective effect of apelin against water-immersion and restraint stress-induced gastric damage.

The aim of the present study was to investigate the gastroprotective effect of apelin on water-immersion and restraint stress (WIRS)-induced gastric lesions. Male Wistar rats were divided into four groups: control, WIRS, F13A + WIRS and F13A. APJ receptor antagonist F13A was administered to rats to determine the influence of apelin on stress-induced gastric injury. WIRS administered for 6 h resulted in the development of gastric mucosal lesions accompanied by a significant increase in plasma corticosterone. WIRS increased the concentration of 4-hydroxynonenol (4-HNE) + malondialdehyde (MDA) and the expression of apelin and hypoxia inducible factor-1α (HIF-1α) in gastric mucosa. In addition, WIRS reduced the mucosal blood flow and gastric prostaglandin E(2) (PGE(2)) concentration. Plasma corticosterone, which was increased due to stress, was significantly decreased in the F13A + WIRS group. Gastric lesions and the 4-HNE + MDA concentration were also higher in the F13A + WIRS compared to the WIRS group. We conclude that apelin has a gastroprotective effect against stress-induced lesions possibly by reducing lipid peroxidation in gastric mucosa.

Protective effect of ginsenoside Re on acute gastric mucosal lesion induced by compound 48/80

The protective effect of ginsenoside Re, isolated from ginseng berry, against acute gastric mucosal lesions was examined in rats with a single intraperitoneal injection of compound 48/80 (C48/80). Ginsenoside Re (20 mg/kg or 100 mg/kg) was orally administered 0.5 h prior to C48/80 treatment. Ginsenoside Re dose-dependently prevented gastric mucosal lesion development 3 h after C48/80 treatment. Increases in the activities of myeloperoxidase (MPO; an index of neutrophil infiltration) and xanthine oxidase (XO) and the content of thiobarbituric acid reactive substances (TBARS; an index of lipid peroxidation) and decreases in the contents of hexosamine (a marker of gastric mucus) and adherent mucus, which occurred in gastric mucosal tissues after C48/80 treatment, were significantly attenuated by ginsenoside Re. The elevation of Bax expression and the decrease in Bcl2 expression after C48/80 treatment were also attenuated by ginsenoside Re. Ginsenoside Re significantly attenuated all these changes 3 h after C48/80 treatment. These results indicate that orally administered ginsenoside Re protects against C48/80-induced acute gastric mucosal lesions in rats, possibly through its stimulatory action on gastric mucus synthesis and secretion, its inhibitory action on neutrophil infiltration, and enhanced lipid peroxidation in the gastric mucosal tissue.

The immunomodulatory effects of lactic acid bacteria for improving immune functions and benefits

Probiotics have a number of beneficial health effects in humans and animals, such as reducing lactose intolerance symptoms and enhancing the bioavailability of nutrients. Probiotics help regulate intestinal microflora and immunomodulatory properties. Probiotics also decrease the prevalence of allergies in susceptible individuals, inhibit the inflammatory responses in the gut, and have antagonistic effects against intestinal and food-borne pathogens. Bacteria typically colonize the intestinal tract first and then reinforce the host defense systems by inducing generalized mucosal immune responses, including modulation of DC/NK interaction, a balanced T-helper cell response, self-limited inflammatory response, and the secretion of polymeric IgA. A lot of reports showed that lactic acid bacteria (LAB) as Lactobacillus and Bifidobacterium and their fermented products are effective at enhancing innate and adaptive immunity, prevent gastric mucosal lesion development, alleviate allergies, and put up defense against intestinal pathogen infection. In this review paper, we compared the influence of immunomodulatory effects on the function and efficacy of lactobacillus products with different strains. We also discuss the beneficial effects of several LAB strain and its derivative products for human immunity and related diseases.

Beneficial effects of Lactobacillus paracasei subsp. paracasei NTU 101 and its fermented products

It is well-known that probiotics have a number of beneficial health effects in humans and animals, including the reduction of symptoms in lactose intolerance and enhancement of the bioavailability of nutrients. Probiotics have showed to possess antimutagenic, anticarcinogenic and hypocholesterolemic properties. Further, they were also observed to have antagonistic actions against intestinal and food-borne pathogens, to decrease the prevalence of allergies in susceptible individuals and to have immunomodulatory effects. Typically, the bacteria colonise the intestinal tract first and then reinforce the host defence systems by inducing a generalised mucosal immune response, balanced T-helper cell response, self-limited inflammatory response and secretion of polymeric IgA. Scientific reports showed that the Taiwan native lactic acid bacterium from newborn infant faeces identified as Lactobacillus paracasei subsp. paracasei NTU 101 and its fermented products proved to be effective for the management of blood cholesterol and pressure, prevention of gastric mucosal lesion development, immunomodulation and alleviation of allergies, anti-osteoporosis and inhibition the fat tissue accumulation. This review article describes that the beneficial effects of this Lactobacillus strains and derivative products may be suitable for human and animals.

Vitamin E protects against stress‐induced gastric mucosal lesions in rats more effectively than vitamin C

In this study, we examined the protective effects of vitamin E (VE) against gastric mucosal lesions induced by water immersion restraint stress (WIRS) in rats in comparison with that of vitamin C (VC). The gastric mucosa of rats with 6 h of WIRS showed lesions with bleeding, decrease in nonprotein SH, VC, VE, and adherent mucus concentrations and constitutive nitric oxide synthase activity, and increase in lipid peroxide and NOx (nitrite/nitrate) concentrations and myeloperoxidase, xanthine oxidase, and inducible nitric oxide synthase activities. Either VE (0.05 or 0.5 mmol/kg) or VC (0.5 or 1.5 mmol/kg) was orally administered to rats with 6 h of WIRS just before the onset of the stress. Both doses of pre-administered VE prevented gastric mucosal lesion development and attenuated all these changes in gastric mucosal components and enzymes studied, whereas only the higher dose of pre-administered VC suppressed the changes in all parameters studied. These results indicate that orally administered VE protects against WIRS-induced gastric mucosal lesions in rats more effectively than orally administered VC. These results also suggest that the administered VE protects against gastric mucosal lesions in rats with WIRS through its antioxidant and anti-inflammatory actions in the gastric mucosa in the same way as the administered VC.

Risk factors for the development of gastric mucosal lesions in rheumatoid arthritis patients receiving long-term nonsteroidal anti-inflammatory drug therapy and the efficacy of famotidine obtained from the FORCE study

The objective of this study was to investigate the prevalence of gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA). Upper gastrointestinal endoscopy was performed on 100 RA patients treated with NSAIDs. Patient factors potentially contributing to the development of NSAID-induced gastric mucosal injury were identified by logistic regression analysis; gastric mucosal injury and ulcers were used as objective variables. Gastric mucosal injury was detected in 62 of 100 patients, and eight of these patients had ulcers. Previous history of ulcers, lifestyle, NSAID dosage, and body mass index were associated with the development of gastric mucosal injury, and the use of diclofenac and steroid dose were associated with the development of ulcers. Disease-modifying antirheumatic drugs (DMARDs) did not appear to influence the risk of NSAID-induced gastric mucosal injury. RA patients treated for long periods with NSAIDs for RA symptoms should be controlled with DMARDs, without consideration of increased doses of steroids, in terms of risk for NSAID-induced gastric mucosal injury. Simultaneously, concomitant use of histamine-2 receptor antagonists (H2RA) such as famotidine should be considered.

Risk factors for the development of gastric mucosal lesions in rheumatoid arthritis patients receiving long-term nonsteroidal anti-inflammatory drug therapy and the efficacy of famotidine obtained from the FORCE study

The objective of this study was to investigate the prevalence of gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA). Upper gastrointestinal endoscopy was performed on 100 RA patients treated with NSAIDs. Patient factors potentially contributing to the development of NSAID-induced gastric mucosal injury were identified by logistic regression analysis; gastric mucosal injury and ulcers were used as objective variables. Gastric mucosal injury was detected in 62 of 100 patients, and eight of these patients had ulcers. Previous history of ulcers, lifestyle, NSAID dosage, and body mass index were associated with the development of gastric mucosal injury,and the use of diclofenac and steroid dose were associated with the development of ulcers. Disease-modifying antirheumatic drugs (DMARDs) did not appear to influence the risk of NSAID-induced gastric mucosal injury. RA patients treated for long periods with NSAIDs for RA symptoms should be controlled with DMARDs, without consideration of increased doses of steroids, in terms of risk for NSAID-induced gastric mucosal injury. Simultaneously, concomitant use of histamine-2 receptor antagonists (H2RA) such as famotidine should be considered.

T1069 Effect of Low-Dose Administration of Lansoprazole On the Gastric Mucosal Lesions Induced By Low-Dose Aspirin in Relation to Intragastric pH in Healthy Volunteers with Different CYP2C19 Genotypes

Backgrounds and Aims: Given the major role gastric acid plays in the development of aspirininduced gastric mucosal lesions, proton pump inhibitors (PPIs) are now employed as firstline therapy in treating aspirin-related gastrointestinal disorders. Low-dose PPIs are also expected to have a similar preventive effect on aspirin-induced gastric injury. PPIs are metabolized by CYP2C19 in the liver, and their therapeutic effects are influenced by CYP2C19 genotype status. However, the effect of low-dose PPI on aspirin-induced gastric mucosal injury in relation to gastric acidity in humans has not been examined. Here, we investigated the relationship between intragastric pH and aspirin-induced gastric mucosal lesions with regard to CYP2C19 genotype status in healthy subjects receiving aspirin with and without a low-dose administration of lansoprazole. Methods: Fifteen Helicobacter pylori-negative subjects with different CYP2C19 genotype statuses (5 RMs, 5 intermediate metabolizers [IMs], and 5 poor metabolizers [PMs]) were each administered a series of three 7-day regimens of 15 mg of lansoprazole alone, 100 mg of aspirin alone, and both 15 mg of lansoprazole and 100 mg aspirin, with the order randomized among individuals. A washout period of 2 weeks or more was provided between regimens. Gastric mucosal injury was endoscopically evaluated on day 7 of each dosing period based on the modified Lanza score (MLS). 24-hour intragastric pH monitoring was started after endoscopy. Results: Median values (range) of MLS were 0 (0-1) in controls, 0 (0-1) in subjects receiving 15 mg of lansoprazole alone, 3 (0-5) in subjects receiving aspirin alone, and 0 (0-1) in subjects receiving both aspirin and 15 mg of lansoprazole. Lansoprazole increased the intragastric pH and significantly prevented aspirin-induced gastric mucosal injury (p = 0.0009 for aspirin and lansoprazole 15 mg). MLSs were negatively correlated with 24-hour intragastric pH (r = -0.740, P < 0.0001), whereas aspirin had no effect on intragastric pH. With regard to treatment with aspirin and lansoprazole 15 mg, although median values of MLS did not differ among the three genotype groups, median values of intragastric pH during treatment with this regimen were higher in PMs than in RMs and IMs (P = 0.009 for RMs, P = 0.028 for IMs). Conclusion: We observed a significant relationship between 24-hour intragastric pH and grade of aspirin-induced gastric mucosal lesions. Further, the acid inhibition attained on administration of 15 mg of lansoprazole appeared sufficient to prevent aspirin-induced gastric mucosal damage, irrespective of CYP2C19 genotype status.

M1114 Evaluation of Gastric Mucosal Blood Flow Using Contrast-Enhanced Ultrasonography During Low-Dose Aspirin Therapy and During NSAID and Low-Dose Aspirin Combined Therapy

Background: Low-dose aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are now used extensively for prevention of vascular disorders or treatment of chronic pain. The frequency of gastric mucosal lesions is expected to increase with combined use of these medicines. A histamine-2 receptor antagonist (H2RA) suppresses development of acid secretion and is expected to prevent development of gastric mucosal lesions associated with NSAIDs and low-dose aspirin. Evaluation of gastrointestinal blood flow is important for understanding the pathogenesis of various gastrointestinal diseases. Aim: we used a noninvasive examination method, transabdominal contrast-enhanced ultrasonography (low mechanical harmonic index imaging), and assessed gastric mucosal blood flow during low-dose aspirin therapy and combined therapy with low-dose aspirin and an NSAID (loxoprofen) and then investigated the effect of an H2RA (lafutidine) on gastric mucosal blood flow. Subjects and methods: The subjects were sixteen healthy volunteers without H. pylori infection. Their mean age was 24.4 years. Subjects in the placebe took low-dose aspirin (81mg) once a day for 14 days (days 1-14), 60 mg of loxoprofen three times a day for 7 days (days 8-14), and a placebo twice a day for 14 days (days 1-14). Subjects in the lafutidine followed the same protocol for low-dose aspirin and loxoprofen but took 10 mg of lafutidine twice a day for 14 days (days 1-14). We carried out contrast-enhanced ultrasonography with perflubutane on day 1, day 8, day 15 and measured gastric mucosal blood flow of the anterior wall of the gastric antrum. A time-intensity curve (TIC) for gastric mucosal blood flow was plotted from recorded ultrasonographic images. Three values were calculated from the TIC: AUC (area under the curve), TIC peak value and TIC peak time. We used these three values to measure gastric mucosal blood flow. Results: The AUC decreased significantly after taking low-dose aspirin (day 8) in both the placebo and lafutidine groups. However, no statistically significant decrease in the AUC was found between day 8 and day 15. The results for TIC peak value were the same as those for AUC. No significant extension of TIC peak time was shown between day 1, day 8 and day 15. No significant difference in AUC, TIC peak value and TIC peak time was found between the placebo and laftidine groups. Conclusion: Low-mechanical index imaging with perflubutane enables noninvasive assessment of gastric mucosal blood flow in real time. The use of this method in a daily primary care setting is expected to lead to prevention and early detection of gastric mucosal injury caused by aspirin and NSAIDs.

Effect Of Buspirone On Inflammation, Pain And Gastric Injury In Mice

Buspirone, a 5HT1A receptor partial agonist, was evaluated in various acute nociceptive pain models, on the carrgaeenaninduced paw oedema, in Porsolt's forced-swimming test, on haloperidol-induced catalepsy, on the indomethacin-induced gastric mucosal damage and on gastric acid secretion in mice. Buspirone (2, 4 or 8 mg/kg, i.p.) significantly increased the response latency in the mouse hot plate test. The anti-nociceptive activity was observed with 2 mg/kg and a maximal increase in hot-plate latency by 41.3%. Buspirone in addition markedly increased the nociceptive thresholds in the acetic-acid-induced writhing assay, in the capsaicin-induced chemogenic pain and in electrically-induced pain in mice. It displayed no antidepressant activity in the Porsolt's forced-swimming test, but at doses of 8 or 16 mg/kg, buspirone decreased the duration of catalepsy induced by haloperidol by 28.1 and 58.3%, respectively. When given 30 min prior to subplantar carrageenan injection, the drug at 8, 16 mg/kg, inhibited paw oedema response 4 h post-carrageenan by 26.3, 41.6%, respectively. Buspirone (2, 4 or 8 mg/kg, i.p.) significantly inhibited the development of indomethacin gastric mucosal lesions and gastric acid secretion in a dose-dependent manner. In conclusion, Buspirone increased pain threshold in models of thermal, chemogenic, electrical and visceral pain and displayed anti-inflammatory and gastric protective properties. The drug might prove of value for the management of inflammatory painful conditions.