Masaharu Miyazawa

Polaprezinc attenuates the Helicobacter pylori-induced gastric mucosal leucocyte activation in Mongolian gerbils - A study using intravital videomicroscopy

We previously demonstrated that Helicobacter pylori colonization evokes gastric mucosal inflammation and an extensive increase in lipid peroxides and glutathione in Mongolian gerbils. Zinc and its derivative, polaprezinc, have been reported to be potent antioxidants in gastric mucosa.

Attenuated Apoptosis in H. pylori-Colonized Gastric Mucosa of Mongolian Gerbils in Comparison with Mice

Although gastric cancer formation with H. pylori in Mongolian gerbils was recently reported, the same inoculation procedure did not result in cancer formation in other animals such as mice. Disturbed regulation of apoptosis and cell proliferation are known to link the multistep process of carcinogenesis. The present study is designed to examine the level of gastric epithelial cell apoptosis in Mongolian gerbils colonized with the H. pylori (Sydney strain: SS1) in comparison with that in mice. Mice (C57BL/6) and Mongolian gerbils were orally inoculated with SS1 and the stomachs were examined 9 and 18 months later. MPO activity increased persistently in gerbils, but increased transiently in mice. While the levels of DNA fragmentation, caspase-3 activity, and the number of TUNEL-positive cells increased significantly in mice, such parameters were attenuated in gerbils. On the other hand, the number of PCNA-positive cells increased after SS1 inoculation only in Mongolian gerbils, suggesting the enhancement of cell turnover in H. pylori-colonized gerbils. In conclusion, the SS1-induced increase in gastric mucosal apoptosis observed in mice was attenuated significantly in Mongolian gerbils, suggesting the causative role for the higher incidence of gastric carcinogenesis in this animal.

Suppressed apoptosis in the inflamed gastric mucosa of Helicobacter pylori-colonized iNOS-knockout mice

UNLABELLED Deregulated cell turnover in Helicobacter pylori (H. pylori)-colonized gastric mucosa has been suggested to be linked to the gastric carcinogenesis pathway. We previously reported attenuation of apoptosis and enhancement of cellular proliferation in the H. pylori-colonized gastric mucosa of Mongolian gerbils as compared to that in mice, which might reflect a specific link between H. pylori colonization and carcinogenesis in the Mongolian gerbils; the difference between the two strains could be attributable to differences in the host genetic background. Inducible-type nitric oxide synthase (iNOS) is thought to participate in not only the inflammatory response, but also in the regulation of gastric mucosal cell turnover in H. pylori-colonized gastric mucosa. Thus, the present study was designed to examine gastric leukocyte activation and epithelial cell apoptosis in the gastric mucosa following H. pylori inoculation in iNOS-knockout mice. METHODS iNOS-knockout mice (iNOS(-/-)) and their iNOS(+/+) littermates were orally inoculated with the Sydney strain of H. pylori (SS1, 10(8) colony-forming units [CFU]). H. pylori infection was confirmed by microaerobic bacterial culture. The stomach of each mouse was evaluated 14 weeks and 30 weeks after the inoculation. Gastric mucosal accumulation of polymorphonuclear leukocytes (PMN) was assessed by determining the myeloperoxidase (MPO) activity and histological score based on the updated Sydney system. The level of apoptosis was determined by estimation of the cytoplasmic levels of mono- and oligonucleosomes and by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method. RESULTS The SS1-inoculated mice showed persistent H. pylori colonization for 12 weeks. While gastric mucosal PMN infiltration increased following SS1 inoculation in both iNOS(+/+) and iNOS(-/-)strains, enhanced DNA fragmentation was observed in only SS1-colonized iNOS(+/+) mice, and not in the iNOS(-/-) mice. In conclusion, although the recruitment of PMN in response to H. pylori was evoked even in the gastric mucosa of iNOS(-/-) mice, epithelial cell apoptosis induced by H. pylori was attenuated in this strain. These data suggest that iNOS may play an important role in promoting apoptosis in the H. pylori-infected inflamed gastric mucosa, and that persistent inflammation without apoptosis in iNOS(-/-) mice with H. pylori infection may be linked to preneoplastic transformation.

Treatment with a proton pump inhibitor promotes corpus gastritis in patients with Helicobacter pylori-infected antrum-predominant gastritis

Proton pump inhibitors have been reported to modify the level of Helicobacter pylori gastritis.

No difference in the level of gastric mucosal cell apoptosis and proliferation in Helicobacter pylori‐colonized p53 heterozygous knockout mice

We previously reported that attenuated epithelial apoptosis and enhanced proliferation in comparison with mice might link to the specific carcinogenesis in Mongolian gerbils and suggested that the difference in both strains might be due to a difference in genetic background. p53 is a well‐known tumour suppressor gene, mutation of which is also known to be involved in gastric cancer formation.

Proton pump inhibitor modifies inflammatory reaction in human gastric mucosa infected by Helicobacter pylori

To examine whether proton pump inhibitors modify the production of oxygen‐derived free radicals and related cytokines in the human gastric mucosa infected with H. pylori.

Ammonia aggravates stress-induced gastric mucosal oxidative injury through the cancellation of cytoprotective heat shock protein 70.

The relationship between Helicobacter pylori colonization and the formation of stress-induced gastric mucosal injury remains unknown. Since ammonia (NH(3)) is known as one of the injurious factors in H. pylori-colonized gastric mucosa, the present study is designed to investigate the level of stress-induced gastric mucosal oxidative injury with or without intragastric NH(3) overloading. To apply emotional stress, the communication box paradigm was used in the mouse model. Mice (C57BL/6, male) were pretreated with distilled water (responder-H(2)O) or 0.01% NH(3) (responder-NH(3)) through a gastric tube once a day for a week. Emotional stress was then applied to the responder mice for 3 h per day for 3 d by watching and hearing the behavior of the sender mice subjected to electric shocks to the feet (2 mA, 10 s, 50 s interval). After the communication box protocol, the tissue MPO activity, the contents of TBA-reactive substances (TBARS), and the level of gastric mucosal HSP70 were examined. Responder-NH(3) mice developed more severe gastric lesions than the responder-H(2)O subjects. MPO activity and TBARS contents were enhanced significantly in the responder-NH(3) group compared with the responder-H(2)O subjects. Although the contents of HSP70 in the gastric mucosa increased in the responder-H(2)O group compared with the control-H(2)O animals, they were significantly attenuated in the responder-NH(3) mice. Excess intragastric NH(3) was able to enhance the formation of emotional stress-induced gastric mucosal lesions. This injury may be associated with the enhanced production of oxygen free radicals from accumulated neutrophils under the NH(3)-mediated cancellation of gastric mucosal cytoprotective HSP70.

Rabeprazole treatment attenuated Helicobacter pylori-associated gastric mucosal lesion formation in Mongolian gerbils

Background and Aim: Although rabeprazole (RPZ), a proton pump inhibitor, has been reported to have a bactericidal effect on Helicobacter pylori (H. pylori), no studies have been conducted regarding the effect of RPZ on gastric mucosal lesion formation caused by this bacterium. In the present study, we investigated the effect of RPZ on H. pylori‐associated gastric mucosal lesion formation.

A Case of Severe Rectal Hemorrhage Possibly Caused by Radiation Recall after Administration of Gemcitabine

Radiation recall is an acute inflammatory reaction that can be triggered when systemic agents are administered long time after radiotherapy. Because radiotherapy is now indicated for many types of cancer, care should be taken regarding possible toxic events relating to radiotherapy in combination with radio-sensitizing agents. Gemcitabine, one such anti-cancer agent, is widely used, especially for urologic cancers. We report an intriguing case of possible radiation recall in the rectum caused by gemcitabine administration 37 years after radiation therapy. From a review of the literature, it appears that there have been no reported cases of radiation recall in the rectum with such a long interval between radiation therapy and chemotherapy. Here, we describe the case and provide a literature review.

Microvascular Leukocyte Activation and Apoptosis in Helicobacter pylori-Colonized Gastric Mucosa

Helicobacter pylori (Hp) colonization evoked gastric mucosal inflammation in Mongolian gerbils. This review summarizes the time course of H. pylori-associated gastric oxidative injury including leukocyte activation and apoptosis. After Hp inoculation the bacteria colonized to the surface epithelium, and in the venules of the gastric mucosa large numbers of leukocytes rolling on or adhering to the vascular wall were observed by intravital microscopy. Adherent leukocytes migrated into the parenchyma, and the levels of tissue myeloperoxidase activity increased. Among the several toxic factors, monochloramine (NH2Cl), which derived from both activated leukocyte and Hp urease, is important for genesis of gastric cellular injury, such as apoptosis. The sequential in vitro study of NH2Cl-induced apoptosis is summarized. Futhermore, the balance in the levels of gastric mucosal apoptosis and gastric cell proliferation and the possible relevance to gastric carcinogenesis are described.