Kiyoshi Okamura

Indomethacin blocks the anorexic action of interleukin-1

It has been reported recently that the central nervous system actions of interleukin-1 are mediated by the prostaglandin system in the brain. The present study was therefore performed in order to examine the hypothesis that indomethacin, an inhibitor of prostaglandin biosynthesis, might alleviate the interleukin-1-induced suppression of food intake in rats. The i.p. injection of interleukin-1 (2 micrograms/rat) resulted in a significant decrease in food intake. The pre-injection of indomethacin (0.5 mg/rat), however, completely blocked the anorexic action of the monokine, while indomethacin on its own did not affect food intake. These results suggested that indomethacin might be clinically useful for improvement of the anorexic state of patients with acute infectious diseases.

Interleukin-1 inhibits the secretion of gastric acid in rats: possible involvement of prostaglandin.

To examine the hypothesis that interleukin-1 may inhibit the secretion of gastric acid, the present study was carried out using pylorusligated rats. Based upon three lines of evidence, we report here that interleukin-1, both endogenously released and exogenously administered, suppresses gastric acid secretion and that the interleukin-1-induced inhibition of acid output is possibly mediated by prostaglandin. First, lipopolysaccharide, a potent stimulant of the release and production of endogenous interleukin-1, caused the suppression of gastric acid, and this response was dose-related. Second, the intraperitoneal injection of interleukin-1 resulted in a dose-related inhibition of gastric acid output. Third, the administration of indomethacin completely blocked the suppression of gastric acid secretion induced by interleukin-1. These results demonstrated for the first time that IL-1 might be involved in the regulation of gastric secretion.

Inhibition of gastric pepsin secretion by peripherally or centrally injected interleukin-1 in rats

The present study was carried out to investigate the effects of Interleukin-1 (IL-1) on gastric pepsin secretion in conscious pylorus-ligated rats. The intraperitoneal (ip) injection of IL-1 resulted in a dose-related inhibition of gastric pepsin output. The intracerebroventricular (icv) injection of IL-1 similarly reduced pepsin secretion at 100 times smaller doses than ip IL-1, suggesting that this inhibitory action of IL-1 is mediated by the central nervous system (CNS). In addition, it was found that the antisecretory action of IL-1, both peripherally and centrally administered, lasted throughout the periods observed (2 hr through 8 hr after injection). These results strongly indicate that IL-1 is involved in the CNS regulation of gastric secretion, especially under certain pathophysiological conditions which activate the immune system to release various cytokines including IL-1.

Multicentric development of pancreatic intraductal carcinoma through atypical papillary hyperplasia

We report a case of multiple intraductal carcinomas of the pancreas associated with diffuse atypical papillary hyperplasia. A 67-year-old Japanese man with a complaint of epigastric pain was examined by endoscopic retrograde pancreatography, which demonstrated multiple dilated branches of the pancreatic duct in the body and tail of the pancreas. Histologic examination on the resected pancreas showed diffuse atypical papillary hyperplasia in multiple dilated ducts associated with multiple intraductal carcinomas. Histologic features are described and multicentric carcinogenesis through atypical papillary hyperplasia is discussed.

Cytotoxicity of Simvastatin to Pancreatic Adenocarcinoma Cells Containing Mutant ras Gene

Simvastatin (SV), a 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor, inhibits the synthesis of mevalonic acid. The dose‐dependent (0.1–100 μg/ml) cytotoxicity of SV towards human (MIAPaCa‐2, Panc‐1, HPC‐1, HPC‐3, HPC‐4, PK‐1, PK‐9) and hamster (T2) pancreatic carcinoma cell lines was determined by MTT assay. At up to 20 μg/ml of SV, the effect was reversible and was restored by 60 μg/ml mevalonic acid. Point mutation of Ki‐ras at codon 12 in each cell line was detected by means of the modified polymerase chain reaction. The concentration of SV necessary to achieve 50% cytotoxicity was about 10 μg/ml, and at this concentration of SV, DNA synthesis assayed in terms of [3H]thymidine uptake, isoprenylation of p21ras examined by Western blotting and cell progression from G1 to S phase of the cell cycle analyzed by flow cytometry were all inhibited. Isoprenylation inhibitors of p21ras, such as SV, are expected to be useful for the treatment of pancreatic cancer.

Lipopolysaccharide-induced inhibition of gastric acid and pepsin secretion in rats.

We used male Wistar rats to determine the effects of lipopolysaccharide (LPS) on gastric secretion. After pylorus ligation, 24-h fasted rats received i.p. injections of different doses of LPS dissolved in sterile saline. The amounts of gastric acid and pepsin secreted were determined 2, 4 or 8 h after injection. Small doses of LPS (10-1000 ng/rat) significantly inhibited the release of both gastric secretants as compared with control animals, and this inhibitory effect of LPS on gastric secretion was dose-related. The gastric antisecretory effect of LPS was still evident 8 h after injection, indicating that this action of LPS was long-lasting. These results suggest that LPS might be involved in the regulation of gastric secretion under certain pathophysiological conditions such as acute bacterial infections.

Central nervous system action of basic fibroblast growth factor: Inhibition of gastric acid and pepsin secretion

To examine the effects of basic fibroblast growth factor (bFGF) on gastric secretion, the present study was carried out using pylorus-ligated rats. Intracisternally injected bFGF inhibited the secretion of both gastric acid and pepsin, and this gastric antisecretory action of bFGF was a dose-related response. On the other hand, the intraperitoneal injection of bFGF did not change gastric secretion. These results strongly suggested for the first time that bFGF, a growth factor that promotes the proliferation of various cell types, might also be a chemical messenger that is involved in the central regulation of gastric secretion. This biological action of bFGF may be considered as a novel nonmitogenic activity of this growth factor.

Gastric antisecretory and antiulcer actions of interleukin-1 : evidence for the presence of an immune-brain-gut axis

Increasing evidence suggests that interleukin-1 (IL-1), a cytokine mainly produced by activated monocytes/macrophages, has various biological actions in addition to its immunological activities. In the present study, we examined the effects of IL-1 on gastric secretion and gastric ulcer formation in rats. Gastric secretion was assessed in conscious pylorus-ligated rats weighing approximately 200 g. The peripheral injection of IL-1 resulted in a dose-related inhibition of gastric acid output. The central injection of IL-1 similarly reduced gastric acid secretion at 100 times smaller doses than peripherally injected IL-1, suggesting that this gastric antisecretory action of IL-1 is mediated by the central nervous system. In addition, it was found that this inhibitory effect of IL-1, either peripherally or centrally administered, was still evident at 8 h after injection, indicating the long-lasting property of this IL-1 action. On the basis of these antisecretory actions of IL-1, we determined whether or not pretreatment with IL-1 would prevent experimentally induced gastric ulcer formation. As expected, the central administration of IL-1 dose-dependently suppressed the development of gastric mucosal lesions induced by water-immersion restraint stress, a well-established ulcerogenic procedure. These results clearly demonstrated that IL-1 has potent antisecretory and antiulcer effects that are mediated by the central nervous system. Moreover, these findings suggest that there may exist an “immune–brain–gut” axis, which is involved in the regulation of gastric secretion and mucosal homeostasis, especially under certain pathophysiological conditions that activate the immune system to release various cytokines including IL-1.

Prevention by interleukin-1 of intracisternally injected thyrotropin-releasing hormone (TRH)-induced gastric mucosal lesions in rats

We have recently found that interleukin-1 (IL-1) acts in the central nervous system to potently inhibit gastric acid and pepsin secretion in rats. In the present study, we examined the effects of IL-1 on the development of gastric mucosal lesions induced by intracisternal (i.c.) thyrotropin-releasing hormone (TRH), a neuropeptide known to centrally stimulate gastric secretion. Pretreatment with i.c. injected IL-1 (10 ng/rat) significantly suppressed the severity of TRH-induced gastric erosions. On the other hand, the same dose of i.c. injected IL-1 failed to exert a cytoprotective action for the gastric mucosa against orally administered absolute ethanol. These results suggest that IL-1 has an anti-ulcer effect mainly through its inhibitory action on gastric secretion.

Site-Specific Formation of Gastric Ulcers by the Electric Stimulation of the Left or Right Gastric Branch of the Vagus Nerve in the Rat

The present study was conducted to investigate the role of the parasympathetic nervous system innervating the stomach in gastric ulcer formation, with special reference to its neuroanatomic characteristics in rats. First, the effects of electric vagal stimulation on the gastric mucosa were examined. The electric stimulation of the left or right gastric branch of the vagus nerve caused gastric mucosal lesions to develop. Interestingly, however, gastric lesions were found on the anterior wall in the rats that had received electric stimulation to the left gastric branch of the vagus nerve and on the posterior wall in the rats that had received stimulation to the right gastric branch. Next, the cells of origin projecting to the left or right gastric branch of the vagus nerve were identified by means of a horseradish peroxidase retrograde tracer method. The left and right gastric branches were found to be innervated by the left and right dorsal motor nuclei of the vagus nerve in the medulla oblongata, respectively. It has been reported that the left and right dorsal motor nuclei of the vagus nerve separately innervate the anterior or posterior gastric wall. The present results, therefore, suggest that the long-lasting excitation of neurons in the dorsal motor nucleus facilitates the site-specific formation of gastric ulcers through the left or right gastric branch of the vagus nerve.