Masaki Hamaguchi

Mechanisms and Roles of Neutrophil Infiltration in Stress-Induced Gastric Injury in Rats

Water-immersion and restraint stress is associated with an increase in neutrophil infiltration into the gastric mucosa, but the mechanism responsible for this infiltration is unclear. We investigated the involvement of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-α (TNF-α) in neutrophil infiltration in stress-induced gastric injury in rats. Rats were administered neutralizing antibody against ICAM-1 or TNF-α and were subjected to induction of gastric injury by 6-hr water-immersion and restraint stress. To evaluate the relationship between gastric acid and neutrophil infiltration, some rats were given cimetidine before administration of stress. Neutralizing antibodies inhibited both the lesion formation and the increase in myeloperoxidase activity induced by stress. Expression of ICAM-1 on endothelial cells was increased by stress, accompanied by an increase of TNF-α-positive cells. Antibody against TNF-α inhibited this increase in ICAM-1 expression. Cimetidine almost completely inhibited gastric lesions, but did not affect myeloperoxidase activity. In conclusion, neutrophil infiltration in stress-induced gastric injury may be mediated by ICAM-1 and TNF-α, but not gastric acid, and may play crucial roles in the progression of gastric injury.

Increased expression of cytokines and adhesion molecules in rat chronic esophagitis.

Background/Aims: Cytokines and adhesion molecules regulate many inflammatory processes in several gastrointestinal diseases. The dynamics of cytokines and adhesion molecules in reflux esophagitis are unknown in detail. We examined the expression and dynamics of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), MIP-2, GRO/cytokine-induced neutrophil chemoattractant-2α (CINC-2α), intercellular adhesion molecule-1 (ICAM-1), leukocyte function-associated antigen 1 (LFA-1; CD11a/CD18), and Mac-1 (CD11b/CD18) in rat chronic reflux esophagitis. Methods: Chronic acid reflux esophagitis was induced in Wistar rats by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus with a small piece of an 18-Fr Nélaton catheter. Rats were killed 3 or 21 days after operation. The levels of mRNA expression of cytokines and ICAM-1 were determined by real-time quantitative RT-PCR. Localization of adhesion molecules and cytokines was investigated by immunohistochemical staining, and numbers of LFA-1- or Mac-1-positive cells were quantified. Results: IL-1β, TNF-α, MCP-1, MIP-1α, MIP-2, CINC-2α, and ICAM-1 mRNA expression was significantly increased in esophageal lesions compared with normal esophagus. There were few these cytokines- or adhesion molecule-positive cells in normal esophagus. In regions of esophagitis, numerous inflammatory leukocytes in lamina propria and the submucosal layer exhibited positive reactions for these cytokines and endothelial cells were intensely stained for ICAM-1. Numbers of LFA-1- and Mac-1-positive cells were significantly increased in rat chronic esophagitis. Treatment with rabeprazole almost completely inhibited development of chronic acid reflux esophagitis and significantly decreased expression of cytokines and ICAM-1 mRNA in esophageal tissue compared with control. Conclusion: Cytokines and adhesion molecules play important roles in the pathogenesis of chronic reflux esophagitis in this rat model.

Increased expression of transforming growth factor-alpha and epidermal growth factor receptors in rat chronic reflux esophagitis

Background and Aim:  Transforming growth factor‐alpha (TGF‐α), which binds to epidermal growth factor receptors (EGF‐R), stimulates esophageal epithelial cell proliferation, enabling rapid repair after mucosal injury. The aim of the present study was to examine epithelial proliferation and dynamics of TGF‐α and EGF‐R gene and protein expression in rat chronic acid reflux esophagitis.

Roles of cyclooxygenase 2 and microsomal prostaglandin E synthase 1 in rat acid reflux oesophagitis

Background: Although prostaglandin E2 (PGE2), cyclooxygenase 2 (COX-2), and microsomal prostaglandin E synthase 1 (mPGES-1) are known to play a role in various inflammatory events, their roles in the pathogenesis of gastro-oesophageal reflux disease are not known. Aims: We examined the dynamics of COX-1, COX-2, mPGES-1, mPGES-2, cytosolic PGES (cPGES), and PGE2 synthetic activity in rat acid reflux oesophagitis and the effects of COX-2 inhibitors on the severity of oesophagitis. Methods: Acid reflux oesophagitis was induced by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus. Rats were killed on day 3 (acute phase) or day 21 (chronic phase) after induction of oesophagitis. Results: Expression of COX-2 and mPGES-1 was markedly increased in oesophagitis while modest changes in COX-1, cPGES, and mPGES-2 expression were observed. COX-2 and mPGES-1 were colocalised in epithelial cells of the basal layer, as well as inflammatory and mesenchymal cells in the lamina propria and submucosa. COX-2 inhibitors significantly reduced the severity of chronic oesophagitis but did not affect acute oesophageal lesions. COX-2 inhibitors significantly inhibited the increase in PGE2 synthesis in oesophageal lesions on both days 3 and 21. Epithelial proliferation was significantly increased in the basal layer on day 21. Inflammatory cells and epithelial cells of the basal layer exhibited reactions for EP4 in oesophagitis. Conclusion: PGE2 derived from COX-2 and mPGES-1 plays a significant role in the pathogenesis of chronic acid reflux oesophagitis, and possibly in basal hyperplasia and persistent inflammatory cell infiltration.

Comparison of the effects of rebamipide with those of cimetidine on chronic gastritis associated with Helicobacter pylori in Mongolian gerbils

Background and Aims : The effects of rebamipide on chronic gastritis associated with Helicobacter pylori have not been well‐defined. We compared these effects of rebamipide with those of cimetidine in Mongolian gerbils infected with H. pylori.

Increased expression of epidermal growth factor receptors in basal cell hyperplasia of the oesophagus after acid reflux oesophagitis in rats

Epidermal growth factor (EGF), which binds to EGF receptors (EGF‐R), stimulates oesophageal epithelial cell proliferation, enabling rapid repair after mucosal injury. In the normal human oesophageal epithelium, EGF‐R expression is present and confined to the basal layer.

Safety and Efficacy of S-1, a Novel Oral Fluorouracil Antitumor Drug, for a Chronic Renal Failure Patient Maintained on Hemodialysis

Objective: S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase, and potassium oxonate (Oxo), a reducer of gastrointestinal toxicity. S-1 has safe and potent antitumor effects in patients with gastric cancer via these respective functions. However, the plasma 5-FU concentration is suspected to accumulate in patients with renal dysfunction, because 50% of the CDHP is excreted into the urine. There are no useful data on safety and efficacy of S-1 in chronic renal failure patients maintained on hemodialysis (HD). We examined the influence of HD on the pharmacokinetics (PK) of S-1 and its therapeutic efficacy in liver metastases from gastric cancer. Methods: For the HD patient, the dose of S-1 in a single-administration study was set at 50 mg/body/day (41.7% of the recommended dose of 80 mg/m2/day). S-1 was given to the patient 24 h after HD. Blood samples were obtained before administration and 2, 4, 6, 8, and 24 h thereafter and 1, 2, 4, and 72 h after the following HD session. The PK parameters (5-FU, CDHP, Oxo, and FT) were measured, and Cmax, Tmax, AUC0–24, and T1/2 were calculated. The dose of consecutive or maintained administrations was determined. Results: Both an increase in Cmax and an elongation of T1/2 for 5-FU, CDHP, and Oxo, but not for FT, occurred in this case as compared with controls. The AUC0–24 of 5-FU in this case was similar to that of controls at the standard dose. After HD, 87.8, 54.5, 77.4, and 66.2% of 5-FU, CDHP, Oxo, and FT, respectively, were eliminated. A slight accumulation of CDHP did not alter the 5-FU PK. Consecutive or maintained S-1 oral administration at the same dose showed similar effects on all PK parameters of a single-administration test. Liver metastases almost totally regressed with no adverse events 4 weeks after S-1 treatment (50 mg/body/day three times a week). Conclusion: Adjusted doses of S-1 according to the results of PK studies may provide therapeutic safety and high efficacy in liver metastases from gastric cancer, even in chronic renal failure patients maintained on HD.

Wireless Capsule Endoscopy and Double-Balloon Enteroscopy in Japanese Patients with Obscure Gastrointestinal Bleeding

Wireless Capsule Endoscopy and Double-Balloon Enteroscopy in Japanese Patients with Obscure Gastrointestinal Bleeding Masatsugu Shiba, Kazuhide Higuchi, Natsuhiko Kameda, Kaori Kadouchi, Hirohisa Machida, Kazuki Yamamori, Hirotoshi Okazaki, Masaki Hamaguchi, Tomoko Wada, Yoshio Jinnno, Eiji Sasaki, Kenji Watanabe, Kazunari Tominaga, Toshio Watanabe, Yasuhiro Fujiwara, Shirou Nakamura, Nobuhide Oshitani, Tetsuo Aeakawa Background: Capsule endoscopy has demonstrated its clinical utility in the evaluation of small bowel pathology in several Western studies and increasingly being used in the investigation of obscure gastrointestinal bleeding. Double-balloon enteroscopy is emerging as another interesting alternative or complementary method. We aimed to evaluate the clinical utility of capsule endoscopy and compare the usefulness of double-balloon enteroscopy with capsule endoscopy. Patiens and Methods: From March 2004 through October 2004, we examined by CE 26 patients with complained of obscure GI bleeding and between June 2004 and October 2004, we used double-balloon enteroscopy on 14 patients and retrospectively evaluated the usefulness of double-balloon enteroscopy compared with capsule endoscopy. All patients had undergone non-diagnostic EGD, colonoscopy, and barium contrast radiography of the small bowel. Results: M2A capsule endoscopy disclosed abnormal small bowel findings in 23 (88%) out of 26 patients. Sixteen of them had significant pathological findings explaining their clinical disorders. Diagnostic yield was therefore 58% (15 of 26 patients). Definite bleeding sites diagnosed by capsule endoscopy in 15 patients included angiodysplasia (4), small-bowel erosion (8), small-bowel ulcer (1) small-bowel tumors (2). Double-balloon enteroscopy detected the definite sources of bleeding in 11 (79%) of the 14 patients. Patients with definite bleeding sources included small-bowel erosion (4), small-bowel ulcer (4) small-bowel tumors (2), angiodysplasias (1), small-bowel polyp (1), small-bowel hemorrhagic polyp (1) and not detectable (1). Double-balloon enteroscopy localized an additional bleeding source in comparison with capsule endoscopy in 4 patients. On the other hand, capsule endoscopy localized an additional bleeding source in comparison with double-balloon enteroscopy in 2 patients. Capsule endoscopy was well tolerated by all patients. One patient had a complication of capsule retention due to stricture of ileum. Conclusions: Many of the bleeding sources recognized by both imaging methods were small-bowel erosions or small-bowel ulcers in this study; although angiodysplasia was most popular bleeding source of obscure gastrointestinal bleeding in several Western studies. Double-balloon enteroscopy resulted in more positive findings than capsule endoscopy, although there is no significant difference in both imaging methods.

Lansoprazole inhibits the development of dextran sodium sulfate-induced colitis in rats

was not preventing the activated T cells from proliferating as the numbers were not reduced in the ASM981relative to vehicle-treated mice Conclusions:ASM981 is highly effective in a dlerapeutic setting. ASM981 has strong effects on some of the downstream systemic inthmmatory reactions in this model. The data from th~s severe chronic model of IBD together with the already impressive findings in chronic inflammatory skin disorders lead as to expect ASM981 to be effective in IBD in man