Hiroshi Saita

Products of neutrophil metabolism increase ammonia-induced gastric mucosal damage

Recent studies have indicated that ammonia is involved in the pathophysiology ofHelicobacter pylori-associated gastric mucosal damage.Helicobacter pylori-associated chronic active gastritis is characterized by an invasion of neutrophils. We investigated the interrelationship among hypochlorous acid (oxidant produced by neutrophil), ammonia (product ofHelicobacter pylori urease), and monochloramine (product of ammonia and hypochlorous acid) in the development of gastric mucosal damage in rats. Gastric mucosal lesions were produced by exposure of the gastric mucosa to ammonia, urea with urease, or urea withHelicobacter pylori in rats subjected to ischemia. Pretreatment with taurine (scavenger of hypochlorous acid) or antineutrophil serum significantly attenuated gastric mucosal lesions induced by the above test agents. Ammonia-induced gastric mucosal lesions were exacerbated in the presence of hypochlorous acid with concomitant generation of monochloramine. These results suggest that the ammonia, hypochlorous acid, and monochloramine triad may be important inHelicobacter pylori-mediated gastric mucosal damage.

Gastric ammonia has a potent ulcerogenic action on the rat stomach

BACKGROUND The pathophysiological mechanism by which Helicobacter pylori induces mucosal injury has not been clarified. The aim of this study was to investigate the role of urea, urease, and ammonia in rat gastric mucosal lesions using an ex vivo chamber model. METHODS Two groups of rats, normotensive rats and those subjected to ischemia, were studied. The gastric mucosa was examined histologically and macroscopically, and the transmucosal potential difference was measured. RESULTS Instillation of urea into the stomach generated ammonia in the presence of urease. The amount of ammonia was increased depending on the concentration of urea and was closely associated with the severity of the histological lesions. The exposure of the stomach to 15-60 mmol/L ammonium hydroxide induced both a reduction in transmucosal potential difference and microscopic damage to the gastric mucosa in normotensive rats. Moreover, 15-60 mmol/L ammonium hydroxide produced severe macroscopic gastric lesions in the rats subjected to ischemia. CONCLUSIONS These results show that ammonia is deleterious to the gastric mucosa and suggest the importance of urea, urease, and ammonia in the pathophysiology of gastric diseases in H. pylori-infected patients.

Generation of Ammonia and Mucosal Lesion Formation Following Hydrolysis of Urea by Urease in the Rat Stomach

We examined the morphological changes in gastric mucosa and the generation of ammonia after exposure of the rat stomach to urea in the presence of urease, in attempts to investigate a pathophysiological role of urea, urease, and ammonia system in gastric ulcer diseases. Exposure of the stomach for 20 min to 2 ml urea (0.025–0.2%) together with urease (100 IU) induced histological damages in a concentration-related manner. Either urea or urease alone did not induce any histological change in the mucosa. Instillation of urea into the stomach generated ammonia in the presence of urease; the amount of ammonia was increased depending on the concentration of urea, and was closely associated with the severity of histological damage. The exposure of the stomach to ammonia (NH4OH: 0.01–0.1%) also produced histological damages in the gastric mucosa in a concentration-related manner. The characteristics of injury induced by 0.5–1.0% ammonia were stasis of microcirculation, disruption of the surface epithelial cells, and necrosis of the mucosa. These results demonstrated that ammonia generated from the hydrolysis of urea by urease in the stomach causes damages in the gastric mucosa.

Therapeutic effects of lansoprazole on peptic ulcers in elderly patients

We studied the effects of lansoprazole on ulcer healing and Helicobacter pylori infection in elderly patients with peptic ulcers. In a group of 24 patients with gastric ulcers, the H. pylori infection rate was 100%. In the course of gastric ulcer healing with famotidine or lansoprazole alone, the H. pylori infection showed no signs of decline. The ulcer healing rates after 8 weeks were similar between the H2-receptor antagonist famotidine (73%), and the proton pump inhibitor lansoprazole (82%). When eradication of H. pylori infection was attempted by concomitant administration of lansoprazole and amoxicillin 500 mg b.i.d. for 2 weeks, the eradication rate was 33% in the group given lansoprazole 30 mg q.d. plus ampicillin 500 mg b.i.d., whereas it was 77% in the group given lansoprazole 30 mg b.i.d. plus ampicillin 500 mg b.i.d. Lansoprazole is considered to be a useful agent for the treatment of patients with peptic ulcers and H. pylori infection and its effectiveness in H. pylori eradication is improved by b.i.d. administration along with ampicillin.

Link between Helicobacter pylori-associated gastritis and duodenal ulcer.

We examined the interrelationships among the degree of fundic mucosal atrophy, the prevalence ofHelicobacter pylori in the gastric antrum, the gastric juice, and the duodenum with and without gastric metaplasia, in 20 duodenal ulcer patients and 20 non-duodenal ulcer patients. The detection rates ofH. pylori in the antrum, the gastric juice, and the duodenum were significantly higher in duodenal ulcer patients (80%, 65%, and 60%) than in non-duodenal ulcer subjects (50%, 20%, and 5%). The frequency ofH. pylori was significantly lower in the gastric juice (30%) and the duodenum (10%) in non-duodenal ulcer patients with antralH. pylori, compared with those in duodenal ulcer patients with antralH. pylori. All of seven patients with both gastric metaplasia andH. pylori infection in the duodenum had duodenal ulcer, whereas only 1 of 14 patients without either gastric metaplasia orH. pylori infection in the duodenum had duodenal ulcer. There was normal or mild atrophic mucosa in the fundus of duodenal ulcer patients withH. pylori in the antrum, whereas moderate or severe atrophic mucosa in non-duodenal ulcer patients withH. pylori gastritis. These results suggest that the preserved fundic mucosa, gastric metaplasia in the duodenum, and a greater load ofH. pylori to the duodenum through the gastric juice may be prerequisites for the formation of duodenal ulcers.

Effects of 16, 16-Dimethyl-Prostaglandin E2 on Ammonia- and Ethanol-Induced Mucosal Lesions in the Rat

The effect of necrotizing agents, such as ammonia and ethanol, on the gastric mucosa was compared. Intragas-tric administration of ammonia (0.6–1.0%) and ethanol (60–100%) produced hemorrhagic necrosis of gastric mucosa in a concentration-dependent manner. In the anesthetized rat, the macroscopic lesions induced by ethanol were significantly inhibited by pretreatment with 3 or 10 μg/kg of 16,16-dmPGE2, but the lesions induced by ammonia were not inhibited by either 3 or 10 μg/kg of 16,16-dmPGE2 in the anesthetized rat. The decrease of gastric transmucosal potential difference and mucosal blood flow produced by ethanol (100%) were significantly attenuated by 16,16-dmPGE2; however, those produced by ammonia (1%) were not inhibited by 16,16-dmPGE2 in the anesthetized rat. In conscious rats, ammonia-induced lesions were not inhibited by pretreatment with 3 μg/kg of 16,16-dmPGE2 but they were significantly reduced by the pretreatment of 10 μg/kg of 16,16-dmPGE2. These results show that 16,16-dmPGE2 afforded little protection against ammonia-induced gastric lesions in the anesthetized rat and suggest that a different mechanism is involved in the development of gastric mucosal lesions between those induced by ethanol and those induced by ammonia.

Helicobacter pylori has an ulcerogenic action in the ischemic stomach of rats.

Helicobacter pylori (H. pylori) is now accepted as an important cause of chronic active gastritis. There also seems to be an association between the colonization of H. pylori in the gastric mucosa and peptic ulceration. However, it has not demonstrated that the instillation of H. pylori into the stomach produces the ulcerative gastric lesions in animals or humans. We carried out an experiment to study whether or not H. pylori has an ulcerogenic action in the ischemic stomach of rats, using an ex vivo gastric chamber. The rat stomachs were exposed to 1 ml of H. pylori solution (200 IU of urease/ml) and 1 ml of urea (400 mg/dl) for 60 min after the creation of ischemia in the stomach (by withdrawal of 3 ml of blood). The exposure of the stomach to both H. pylori and urea resulted in severe hemorrhagic gastric mucosal lesions with a marked decrease in potential difference (PD) with a concomitant increase in ammonia concentration in rats with ischemia, whereas gastric lesions and a fall in PD were hardly observed in rats without ischemia. These results have demonstrated that H. pylori has an ulcerogenic action on the stomach subjected to mucosal ischemia.

Factors influencing Helicobacter pylori eradication with 2 week combination therapy of lansoprazole and amoxycillin: Intragastric distribution of colonization and gastric mucosal atrophy

In Japan, gastric ulcers are often accompanied by marked gastric mucosal atrophy. We evaluated the dual therapy of double‐dose lansoprazole and amoxycillin for Helicobacter pylori eradication in Japanese ulcer patients and investigated the effects of intragastric distribution of H. pylori colonization and gastric mucosal atrophy on eradication with this combination therapy. Seventy‐six H. pylori‐positive ulcer patients received lansoprazole (30 mg) plus amoxycillin (500 mg) twice daily for 2 weeks (LA‐60 group), lansoprazole (30 mg once daily) plus amoxycillin (500 mg twice daily) for 2 weeks (LA‐30 group) or lansoprazole (30 mg once daily) for 6 or 8 weeks (LPZ group). Infection was evaluated by light microscopy, culture and biopsy urease tests. Helicobacter pylori colonization was classified as localized to the corpus (localized type) or involving the antrum and corpus (whole type). Fundic mucosal atrophy was graded according to endoscopic and histological features. Eradication was achieved in 67.6% in the LA‐60 group, 31.6% in the LA‐30 group, and 0% in the LPZ group, and moderate or severe histological gastritis was improved in the LA‐60 group. Eradication was better in localized‐type colonization (92%) than whole‐type (56%), and better with fundic mucosal atrophy (84%) than without, but poor in both whole‐type colonization and scanty mucosal atrophy (47%). The LA‐60 therapy achieves better eradication in Japanese ulcer patients with localized H. pylori colonization and/or gastric mucosal atrophy, which are likely to be important predictors for the successful eradication with dual therapy.

Role of mucosal microcirculation in gastric lesions induced by lateral hypothalamic lesions in rats

To evaluate the pathophysiology underlying gastric mucosal lesions induced by lateral hypothalamic (LH) lesions, we investigated the changes in acid secretion, gastric mucosal blood flow, gastric mucus and mucosal integrity in the corpus during the 4 h period and 48 h after the production of bilateral electrolytic LH lesions in male Sprague‐Dawley rats. Gastric mucosal lesions were macroscopically produced 24 h (63%) and 48 h (83%) after LH lesions, although there were no visible lesions at 7 h. Gastric acid secretion was significantly increased 48 h after LH lesions, compared with that in the control group. Gastric mucosal blood flow and transmucosal potential difference (PD) in the LH lesion group immediately decreased after LH lesions and did not recover during 4 h and at 48 h. On the contrary, in the control group, gastric mucosal blood flow decreased after the brain surgery but soon recovered, and there was no significant change in PD. LH lesions resulted in the reduction of intramucosal mucus to 50% 3 h after LH lesions. Moreover, we exposed the stomach to 10 mmol/L taurocholic acid (TCA) 3 h after LH lesions to examine the disruption in gastric mucosal defensive function in rats with LH lesions. The recovery of the reduced PD by TCA was slow and gastric mucosal lesions were easily formed in the LH lesion group. These results suggest that gastric mucosal ischaemia after lesioning of LH immediately results in the disruption of mucosal defensive function before the formation of visible gastric lesions, and predisposes to the formation of gastric mucosal lesions by a delayed increase in acid secretion.