Shigeru Kitamori

Interleukin-1: A cytokine that has potent antisecretory and anti-ulcer actions via the central nervous system

The present study was performed to determine if interleukin-1 (IL-1) acts as a chemical messenger in the central nervous system (CNS) regulation of gastric secretion and ulcer formation, using male Wistar rats. The central injection of IL-1 dose-dependently inhibited gastric acid secretion in pylorus-ligated rats at 100 times smaller doses than the peripheral injection of the cytokine. The action of IL-1 was long-lasting because its antisecretory effect was still evident at 8 hr after injection. Furthermore, it was observed that pretreatment with central IL-1 dose-dependently suppressed the development of gastric ulcers induced by water-immersion restraint stress, a well-established ulcerogenic procedure. These results clearly suggested for the first time that IL-1, a cytokine produced by activated monocytes/macrophages, acts centrally in the brain to exert gastric antisecretory and anti-ulcer actions.

Evidence that gastric antisecretory action of lipopolysaccharide is not due to a toxic effect on gastric parietal cells

We have recently found that bacterial lipopolysaccharide (LPS) or endotoxin at minute doses inhibits the secretion of gastric acid and pepsin in rats. The present study was performed to determine whether this antisecretory action of LPS was a reversible biological response or a result of the destruction of gastric parietal cells by endotoxin. The intraperitoneal injection of LPS into pylorus-ligated rats resulted in a dose-related (40–4000 ng/kg) decrease in gastric acid secretion, with maximal inhibition being observed at a dose of 4000 ng/kg. The stomach then was examined both macroscopically and microscopically for the presence or absence of mucosal lesions or damaged gastric parietal cells. No morphological changes in the gastric mucosal, structure including parietal cells were observed even in the rats injected with 4000 ng/kg of LPS. Next, basal gastric acid output was compared in the rats that had received LPS (4000 ng/kg, intraperitoneal) or saline alone 24 hr before. There was no significant difference in gastric, acid secretion between the saline- and LPS-pretreated groups, indicating that the secretory capacity of gastric parietal cells returned to the control level at 24 hr after the injection of a maximal antisecretory dose of LPS. These results clearly suggest that the LPS-induced inhibition of gastric secretion results not from its toxic or destructive effect on the gastric secretory mechanism but from its reversible biological effect on gastric physiology.

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.

The gastric antisecretory action of lipopolysaccharide is blocked by indomethacin

We have recently found that bacterial lipopolysaccharide (LPS) at minute doses inhibits the secretion of gastric acid and pepsin in rats. The present study was performed to examine the mechanism by which LPS exerts its antisecretory action. The i.p. injection of LPS resulted in a dose-dependent (40-4000 ng/kg) decrease in gastric acid output in pylorus-ligated rats. However, preinjection of indomethacin (2-10 mg/kg s.c.), an inhibitor of prostaglandin biosynthesis, prevented the LPS-induced inhibition of gastric secretion in a dose-related manner, while these concentrations of indomethacin by themselves did not affect gastric acid output. These results suggest that LPS requires an intact prostaglandin system to exhibit its inhibitory action on gastric secretion.

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.

Central basic fibroblast growth factor inhibits gastric ulcer formation in rats

We have recently reported that basic fibroblast growth factor (bFGF) acts in the brain to inhibit the secretion of gastric acid and pepsin, two major aggressive factors in the pathogenesis of gastric ulcer formation. In the present study, we determined whether or not bFGF has an anti-ulcer action via the central nervous system, using male Wistar rats. The intracisternal injection of bFGF dose-dependently (0.1-1.0 microgram(s)/rat) inhibited the severity of gastric ulcers induced by water-immersion restraint stress or central thyrotropin-releasing hormone. The same doses of peripherally injected bFGF failed to protect the gastric mucosa from these ulcerogenic procedures. These results suggest for the first time that bFGF has a mucosal protective effect through a mechanism involving the central nervous system. It is speculated that this anti-ulcer action of bFGF is, at least in part, dependent upon its gastric antisecretory effect.

Gastric Lesions Induced by Kainic Acid Injection into the Dorsal Motor Nucleus of the Vagus Nerve in Rats

Kainic acid injection into the dorsal motor nucleus of the vagus nerve (DMN) induced lesions in the glandular stomach of rats. A decrease in mucus production seemed to play an important role in the pathogenesis of the kainic acid-induced gastric lesions. On the other hand, by means of horseradish peroxidase tracing method, the original cells projecting to the DMN were identified in the central nucleus of the amygdala, several hypothalamic nuclei and the insular cortex. Considering that kainic acid is a long-acting neuronal excitant, it was suggested that the continual stimulation of DMN neurons facilitated gastric ulcer formation.

Basic fibroblast growth factor (bFGF) acts centrally in the brain to inhibit gastric emptying in rats

In the present study, we evaluated the central nervous system action of basic fibroblast growth factor (bFGF) on gastric emptying of a liquid meal in conscious rats using a Phenol red method. Intracisternal injection of bFGF dose-dependently inhibited gastric emptying, while intraperitoneal injection of bFGF at the same doses failed to alter gastric emptying. These results suggest for the first time that bFGF acts in the central nervous system to delay gastric emptying.

Site-Specific Formation of Thyrotropin-Releasing Hormone-Induced Gastric Ulcers through the Vagal System

The left and right dorsal motor nuclei (DMN) separately innervate the anterior and posterior gastric walls through the left and right gastric branches of the vagus nerve (GBVN) in rats. The present study was carried out to investigate the effects of selective centrally originated excitation of the unilateral vagal system on the gastric area in which vagus-induced gastric ulcers developed. Since intracisternally injected thyrotropin-releasing hormone (TRH) stimulates neurons in the bilateral DMNs to produce gastric ulcers, selective stimulation of the unilateral vagal system was produced by contralateral gastric branch vagotomy before intracisternal injection of TRH. Intracisternal injection of TRH (2 micrograms/rat) into left gastric branch-vagotomized rats resulted in lesion formation only on the posterior gastric wall and not on the anterior wall. In contrast, in right gastric branch-vagotomized rats TRH-induced gastric lesions were observed only on the anterior gastric wall and not on the posterior wall. These results suggest that selective stimulation of the left or right DMN induces site-specific ulcer formation through the left or right GBVN. Next, gastric acid secretion was determined in pylorus-ligated rats to examine a role of acid hypersecretion in site-specific ulcer formation caused by TRH. Of interest was that gastric acid secretion in unilaterally vagotomized rats given TRH intracisternally was significantly smaller than that in sham-operated rats given intracisternal saline, although the former rats developed gastric ulcers, whereas the latter did not. It is therefore speculated that gastric hyperacidity plays a less important role in the peripheral mechanisms of TRH-induced site-specific gastric ulceration.