Arata Kimura

Lansoprazole Induces Mucosal Protection through Gastrin Receptor-Dependent Up-Regulation of Cyclooxygenase-2 in Rats

Proton pump inhibitors (PPIs) are antiulcer agents that have both gastric antisecretory and mucosal protective actions. The mechanisms of PPI-induced gastric mucosal protection are not known. The present study was designed to examine the mechanism for lansoprazole-induced gastric mucosal protection in rats. Rats were given 0.5, 5, and 50 mg/kg/day lansoprazole alone or both lansoprazole (50 mg/kg/day) and a specific gastrin receptor antagonist 3R-1-(2,2-diethoxyethyl)-((4-methylphenyl)amino-carbonyl methyl)-3-((4-methylphenyl)ureidoindoline-2- one) (AG-041R) (3, 10, and 30 mg/kg/day) for 14 days. Serum gastrin concentrations were measured. The expression of cyclooxygenases (COX-1 and COX-2) in the gastric mucosa was analyzed using Western blotting and immunohistochemical staining. Another series of rats was used to examine the 1) levels of prostaglandin (PG) E2 in gastric mucosa, 2) influences of the drugs on gastric damage caused by absolute ethanol, and 3) effects of a COX-2-specific inhibitor on PGE2 in the gastric mucosa and the mucosal protection afforded by lansoprazole. Lansoprazole dose dependently increased the serum gastrin concentration and enhanced the mucosal expression of COX-2 but not that of COX-1. Lansoprazole increased gastric mucosal PGE2 and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE2 and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE2and mucosal protection. Activation of gastrin receptors by endogenous gastrin has a pivotal role in the effects of lansoprazole on COX-2 up-regulation and mucosal protection in the rat stomach.

Cyclo-oxygenase-2 inhibitors suppress epithelial cell kinetics and delay gastric wound healing in rats

Background and Aims : The present study examined the effects of NS‐398, a specific cyclo‐oxygenase‐2 inhibitor, on gastric mucosal cell kinetics and gastric wound healing following acid‐induced injury.

Influences of Helicobacter pylori on gastric angiogenesis and ulcer healing in mice.

Background and Aims: Helicobacter pylori infection is associated with peptic ulcers; however, it is unclear whether the bacterium delays ulcer healing. We investigated the influence of H. pylori on ulcer healing in mice. We also examined the influence of H. pylori infection on angiogenesis.

Roles of Reactive Nitrogen Species in Helicobacter-Related Carcinogenesis

Although data indicate an association between Helicobacter infection and gastric carcinogenesis, the precise mechanism for Helicobacter-related carcinogenesis are not yet clarified. An extract of Helicobacter stimulated inflammatory production of nitric oxide (NO) and other reactive nitrogen species. Nitrotyrosine, an adduct of active nitrogen species, increased in gastric epithelia in subjects with the infection. Studies show that reactive nitrogen species cause point mutations at CpG sites; and that such mutations in the p53 gene are frequently found in cancerous and precancerous lesions in the stomach. Thus, reactive nitrogen species including inflammatory NO might play important roles in Helicobacter-induced gastric carcinogenesis.