Yoko Shinji

Microsomal prostaglandin E synthase (mPGES)-1, mPGES-2 and cytosolic PGES expression in human gastritis and gastric ulcer tissue

Recently, three different prostaglandin E2 synthases have been identified: microsomal prostaglandin E synthase (mPGES)-1, cytosolic PGES (cPGES), and mPGES-2; however, their role and connection to cyclooxygenase (COX)-2 in the gastric ulcer repair process remain unknown. Therefore, we examined mPGES-1, cPGES, and mPGES-2 expression and localization in the stomach in vitro and in vivo. Tissues were obtained from Helicobacter pylori (H. pylori)-infected patients and consisted of surgical resections of gastric ulcers, or biopsies of gastric ulcers or gastritis. mPGES-1 mRNA and protein expression levels were examined by real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. mPGES-1, cPGES, and mPGES-2 localization were analyzed immunohistochemically. Induction of PGES expression in response to interleukin (IL)-1β was examined in vitro in the cultured human gastric fibroblast line Hs262.St. Real-time PCR analysis of mPGES-1 mRNA expression in biopsy samples showed significantly higher expression levels in open than in closed gastric ulcer tissue. Western blot analysis showed mPGES-1 protein expression limited to open ulcer tissue, while mPGES-2 and cPGES immunoreactivities were seen in both open and closed ulcer tissue. Immunohistochemical analysis showed strong mPGES-1 expression in fibroblasts and macrophages of the ulcer bed, paralleling COX-2 expression. cPGES and mPGES-2 expression levels were seen in both fibroblasts of the ulcer bed and in epithelial cells. Furthermore, stronger cPGES and mPGES-2 immunoreactivities were seen in scattered mast cell-like cells and neuroendocrine-like cells, respectively. Induction of mPGES-1 expression in response to IL-1β was seen in cultured gastric fibroblasts in vitro, and double immunostaining showed mPGES-1 coexpression with COX-2 in fibroblasts of the ulcer bed in vivo. In conclusion, mPGES-1, cPGES, and mPGES-2 are all expressed in gastric ulcer tissue, but only mPGES-1 parallels COX-2 expression in mesenchymal and inflammatory cells of the ulcer bed, suggesting a key role for this enzyme in the ulcer repair process.

COX-1 and COX-2 conversely promote and suppress ischemia-reperfusion gastric injury in mice

Objective. Neutrophil activation followed by free radical production is a feature that is common to the various forms of gastric injury. However, the roles of cyclooxygenase (COX)-1 and -2 in neutrophil activation have yet to be clarified in the gastric mucosa. We examined the roles of both COX-1 and COX-2 in neutrophil activation and free radical production in ischemia-reperfusion (IR) injury in the gastric mucosa of mice. Material and methods. Ischemia was induced by clamping the celiac artery for 30 min, then removing the clamp for 90 min. SC-560, a selective COX-1 inhibitor; NS-398, a selective COX-2 inhibitor; or rebamipide, a mucoprotective agent, was administered to mice 60 min before ischemia. Gastric damage was evaluated histologically and by measuring myeloperoxidase (MPO) activity. Expressions of COX protein and intercellular adhesion molecule (ICAM)-1 were evaluated by Western blot analysis and ELISA, respectively. Effects of these drugs on thiobarbituric acid reactive substances (TBARS) and gastric blood flow were also evaluated. Results. COX-2 expression was induced in gastric mucosa 60 min after reperfusion, whereas COX-1 expression remained unaltered. Localization of COX-1 and ICAM-1 in IR-injured mucosa was observed mainly in endothelial cells, while COX-2 expression was detected in mesenchymal cells such as mononuclear cells, spindle-like cells and endothelial cells. SC-560 significantly decreased gastric blood flow at the reperfusion point and reduced gastric mucosal injury in IR mice. Furthermore, SC-560 pretreatment significantly reduced MPO activity, TBARS levels and ICAM-1 expression. In contrast, NS-398 significantly increased ICAM-1 expression, MPO activity and TBARS levels, and aggravated gastric damage in IR mice. Rebamipide pretreatment reduced both COX-2 expression and IR injury. Conclusions. In IR mice, COX-2 protects the gastric mucosa by down-regulating ICAM-1 expression, whereas COX-1 is involved in up-regulating reperfusion flow, thereby aggravating the mucosa.

Celecoxib Inhibits Cdx2 Expression and Prevents Gastric Cancer in Helicobacter pylori-Infected Mongolian Gerbils

Background/Aim: The aim of this study was to see whether administration of celecoxib, a selective COX-2 inhibitor, prior to the appearance of intestinal metaplasia could prevent the development of gastric cancer in Helicobacter pylori-infected Mongolian gerbils. Methods:Fifty-two Mongolian gerbilswere divided into 3 groups and given 5 biweekly doses of N-methyl-N-nitrosourea (MNU; 30 ppm). At week 12, group 2 (n = 20) and group 3 (n = 22) gerbils were then given an injection of H. pylori, while group 1 controls (n = 10) received Brucella broth alone. In addition, 7 weeks after H. pylori inoculation, at week 19, group 3 gerbils also received a 36-week administration course of celecoxib (1,500 ppm) in their diet. The incidence of gastric adenocarcinoma was determined at week 54 by histological analysis. COX-2 and Cdx2 protein expression and COX activity were evaluated for each group. The extent of intestinal metaplasia, Cdx2 and MUC2 expression, and the apoptotic index were evaluated semi-quantitatively by immunohistochemistry. Results: The incidence of gastric adenocarcinoma was: group 1, 0% (0/10); group 2, 65% (13/20), and group 3, 23% (5/22; p < 0.05). Continuous celecoxib administration significantly reduced COX activity and COX-2 protein expression, Cdx2 and MUC2 protein immunoreactivity, and the extent of Alcian blue periodic acid-Schiff-positive intestinal metaplasia in H. pylori-infected gerbils. Celecoxib also induced apoptosis in these gerbils. Significant inhibition of Cdx2 expression in group 3 gerbils was also shown by Western blot analysis. Conclusions: Prior to the first appearance of intestinal metaplasia, timely administration of celecoxib prevents gastric cancer occurrence by disrupting the progression of intestinal metaplasia into gastric carcinoma through its inhibition of Cdx2 expression in MNU-pretreated H. pylori-infected Mongolian gerbils.

Preventive therapy for non-steroidal anti-inflammatory drug-induced ulcers in Japanese patients with rheumatoid arthritis: the current situation and a prospective controlled-study of the preventive effects of lansoprazole or famotidine

Background : There is a lack of evidence for the efficacy of preventive medications for peptic ulcers (PUs) among long‐term users of non‐steroidal anti‐inflammatory drugs (NSAIDs) in Japan.

Teprenone, but not H2-Receptor Blocker or Sucralfate, Suppresses Corpus Helicobacter pylori Colonization and Gastritis in Humans: Teprenone Inhibition of H. pylori-Induced Interleukin-8 in MKN28 Gastric Epithelial Cell Lines

Background.  The role of teprenone in Helicobacter pylori‐associated gastritis has yet to be determined.

Bisphosphonate increases risk of gastroduodenal ulcer in rheumatoid arthritis patients on long-term nonsteroidal antiinflammatory drug therapy

BackgroundRheumatoid arthritis (RA) patients are at increased risk of peptic ulcers (PU) induced by nonsteroidal antiinflammatory drugs (NSAIDs). However, the impact of potential drug interactions on the development of PU has yet to be determined in a daily clinical setting. The aim was to estimate the clinical important interactions for PU presented by comedication in Japanese RA outpatients on long-term NSAID treatment.MethodsThis retrospective cohort study enrolled 196 consecutive RA outpatients on NSAID medication for at least 3 months. Potential risk factors for endoscopic PU were analyzed in RA outpatients on longterm NSAID treatment.ResultsPU incidence was 31% with bisphosphonate co-therapy and 17% without the co-therapy. PU incidence was only 5% in subjects with proton pump inhibitors (PPI) or prostaglandin E1 analogues (PG) co-therapy, 14% with histamine-H2 receptor antagonists(H2RA) co-therapy, and 27% without anti-ulcer agents. In multivariate logistic regression analysis, bisphosphonate co-therapy remained a significant risk factor for PU (OR, 2.29; 95% CI, 1.09–4.81). Other risk factors for ulcer development were advanced age (greater than 60 years) and smoking (OR, 2.58; 95% CI, 1.03–6.49 and OR, 2.71; 95% CI, 1.13–5.53, respectively.) Factors that significantly reduced the incidence of PU were H2RA or PPI/PG cotherapies (OR, 0.29; 95% CI, 0.12–0.68.).ConclusionsBisphosphonate co-therapy as well as advanced age and smoking was found to be a significant risk factor in PU, while co-therapies of standard-dose H2RA or PPI/PG proved effective in preventing PU in Japanese RA patients on long-term NSAID treatment.

Rebamipide reduces indomethacin-induced gastric injury in mice via down-regulation of ICAM-1 expression

Non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric mucosal injury occurs through subsequent events following free radical production derived from activated neutrophils. In this study, we hypothesized that rebamipide, a novel anti-ulcer agent, exerts a protective effect on NSAID-induced gastric injury through its antioxidant properties. The protective effect of rebamipide in a mouse model of indomethacin-induced gastric injury and mechanisms for this effect were investigated. Pre-treatment with rebamipide significantly inhibited indomethacin-induced gastric mucosal injury in mice. Gastric thiobarbituric acid reactive substances (TBARS) levels and myeloperoxidase (MPO) activity substantially increased 3 hr after indomethacin administration. These increases were significantly inhibited by pre-treatment with rebamipide. Furthermore, rebamipide pre-treatment notably decreased intercellular adhesion molecule-1 (ICAM-1) expression that was up-regulated in gastric tissue treated with indomethacin. Therefore, rebamipide may reduce indomethacin-induced gastric mucosal injuries through its antioxidant effect, which inhibits the neutrophil activation step following up-regulation of ICAM-1 expression on endothelial cells.

Effect of acid suppression therapy on development of gastric erosions after cure of Helicobacter pylori infection.

Helicobacter pylori eradication markedly improves histological inflammation and decreases peptic ulcer recurrence, but little is known about the subsequent development of gastric mucosal injury.

Bleeding from foveolar hyperplasia developing on a gastrointestinal stromal tumor of the stomach

A 52‐year‐old Japanese woman who presented with gastrointestinal (GI) bleeding underwent a proximal gastrectomy for a gastrointestinal stromal tumor (GIST) with a foveolar hyperplasia at the apex of the tumor, 4.5 cm in size, located in the upper body of the stomach. Although GIST are often asymptomatic and are found only incidentally, clinical symptoms such as bleeding, abdominal pain, or obstruction, occasionally lead to a premorbid diagnosis. When submucosal tumors present GI bleeding, the source of the bleeding usually is an ulceration of the mucosa over the tumor. However, in the present study, it was thought that the bleeding originated from the region of foveolar hyperplasia.

Interrelations of Nonsteroidal Antiinflammatory Drugs, H. pylori Infection, and Gastric Damage

Because 50% of elderly patients in Japan have Helicobacter pylori infection, many NSAID-induced peptic ulcers, by chance, occur in patients who happen to be H. pylori-positive. Many previous studies have reported the relation between H. pylori and NSAIDs. Chan et al. and Bianchi et al. described increased risk for ulcers in H. pylori-positive NSAID users. In contrast, recent prospective studies show that the presence of H. pylori does not increase the risk of gastric or duodenal ulcers in arthritis patients or healthy subjects taking NSAIDs. Because many H. pylori-positive patients are administered NSAIDs in Japan, it is important to determine whether these offensive factors affected the gastric mucosa additively or independently. Regarding cyclooxygenase-2 (COX-2) protein, which is the target enzyme against NSAIDs, COX-2 expressed at inflammatory sites in the gastrointestinal tract presumably plays a role in the repair process of gastric damage. H. pylori infection elevated COX-2 protein in gastric epithelium and decreased the levels of COX mRNA in the stomachs of mice with experimentally induced gastric erosions or ulcers, although COX-2 mRNA levels were undetectable in controls. Therefore, it seems to be important to determine the role of COX-2 protein in the gastric tissues to clarify the relation between H. pylori infection and NSAIDs.