Hiroshi Dekigai

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.

Mechanism of Helicobacter pylori-associated gastric mucosal injury

Helicobacter pylori infection is associated with gastric mucosal damage and the infiltration of neutrophils. Myeloperoxidase from neutrophils produces hypochlorous acid, which yields monochloramine in the presence of ammonia produced by urease enzyme ofHelicobacter pylori. The target cells of gastric mucosal damage are gastric mucosal cells and endothelial cells. We therefore tested the hypothesis that ammonium, hypochlorous acid, and monochloramine damage the target cells. We studied thein vitro cytotoxic effects of ammonium chloride, sodium hypochlorite, monochloramine, and activated neutrophils on the target cells. Cytotoxicity was measured by a51Cr-release assay. Ammonium chloride, sodium hypochlorite, and monochloramine were toxic to labeled cells in a concentration dependent manner. The toxicity of these agents was in the order monochloramine>sodium hypochlorite>>ammonium chloride. Incubation of labeled cells with activated neutrophils,Helicobacter pylori, and urea resulted in cytolysis. These cytotoxicities were significantly inhibited by the scavenger of hypochlorous acid, taurine. Monochloramine is more toxic to the target cells than ammonium chloride. Although ammonium chloride at neutral pH by itself has little direct damaging effect on the gastric mucosa, it is damaging to the gastric mucosa through a reaction with hypochlorous acid, suggesting that it plays a role inHelicobacter pylori-associated gastric 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.

Geranylgeranylacetone promotes induction and secretion of thioredoxin in gastric mucosal cells and peripheral blood lymphocytes

Thioredoxin (TRX) is a redox-active protein which is induced by oxidative stresses and shows a variety of biological activities including cytoprotection against oxidative stress. We recently reported that geranylgeranylacetone (GGA), an anti-ulcer drug, induces TRX in rat hepatocytes. In this study, we demonstrate that GGA promotes induction and secretion of TRX in rat gastric mucosal cells and human peripheral blood lymphocytes (PBLs). Western blotting and a sensitive sandwich ELISA showed that TRX was induced by GGA in the cell lysates and culture supernatants of rat gastric mucosal RGM-1 cells and human PBLs. LDH releasing assay showed that GGA protected rat gastric mucosal RGM-1 cells from ethanol-induced cytotoxicity. Moreover, exogenous recombinant wild type TRX decreased 51Cr release from primary cultured rat gastric mucosal cells incubated with ethanol or hydrogen peroxide in a dose-dependent manner, whereas recombinant mutant TRX (C32S/C35S), in which the two cysteines were replaced with serines in its active site, did not. These results indicate that GGA promotes the induction and secretion of TRX in a variety of types of cells and suggest that induced or secreted TRX may play an important role in the cytoprotective action of GGA on gastric mucosal cells.

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.

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.

Three Elderly Cases Suffering from Renal Cell Carcinoma with Pancreatic Metastasis.

悪性腫瘍の膵転移は決して稀なものではないが, 胃ガン, 血液悪性疾患, 胆道系悪性腫瘍, 肺癌が多いとされており, また, 原発巣がどこであれ, 生前に診断されることは比較的まれとも言われている. 一方, 腎臓癌の転移に関しては, 肺, 骨, 他方の腎, 脳などに多いとされ, 膵臓への転移はま稀である. 我々は, 膵臓に転移した高齢者腎臓癌の3症例を経験したので報告する. 症例1は, 80歳の女性で, 21年前に左腎臓癌で手術を受けている. 5年前に腹部腫瘤を指摘され, 本院にて手術を実施した. 術中所見, および組織診にて膵臓に転移した腎臓癌と判明した. 本例は, 特に化学療法などを実施していないが, 現在まで元気に過ごされている. 症例2は, 78歳の女性で, 2年前に右腎臓癌にて手術を受けている. その後の外来通院中に, 膵臓への多発性転移を指摘されている. 症例3は, 78歳の男性で, 7年前に右腎臓癌を指摘されたが, 手術を拒否. その後, 肺転移, 骨転移が出現している. 1年前より膵頭部に腫瘤が認められるようになり, 軽度ながら, 胆道系, 膵管系の拡張も出現してきている. 症例2, 3は膵腫瘍の組織診が得られていないが, 臨床経過やその他の検査成績より腎臓癌の転移と考えた.

A Case Report of Anomalous Pancreaticobiliary Duct Connection with Choledocholithiasis and Acute Pancreatitis

Abstract: A 25‐year‐old man was admitted to hospital with epigastric pain. He had had a history of episodic abdominal pain since early childhood. An anomalous pancreaticobiliary duct connection was seen by endoscopic retrograde cholangiopancreatography. In many cases, this type of abnormality is caused by an anomaly in the ventral pancreas. In this case, however, the common bile duct, with calculi, was joined to the pancreatic duct which did not arise from the ventral pancreas but from the dorsal pancreas. The pancreatic duct arising from the ventral pancreas was absent in this case. The patient underwent a prophylactic cholecystectomy, a transduodenal sphincteroplasty, a choledocholithotomy, a partial resection of the common bile duct, and a hepaticojejunostomy, performed by a Roux‐en‐Y anastomosis. His postoperative recovery was satisfactory. An anomalous pancreatobiliary duct connection allows pancreatic juices and bile to mix. This is considered to be an etiological factor in pancreatitis and choledocholithiasis.