Differentiation of the gastric mucosa. II. Role of gastrin in gastric epithelial cell proliferation and maturation

Gastrin is the principal hormonal inducer of gastric acid secretion. The cellular targets for gastrin in the stomach are the acid-secreting parietal cell and histamine-producing enterochromaffin-like (ECL) cell. Gastrin is also a growth factor, with hypergastrinemia resulting in increased proliferation of gastric progenitor cells and a thickened mucosa. This review presents insights into gastrin function revealed by genetically engineered mouse models, demonstrating a new role for gastrin in the maturation of parietal and ECL cells. Thus, gastrin regulates many aspects of gastric physiology, with tight regulation of gastrin levels required to maintain balanced growth and function of gastric epithelial cells.     

Abnormal gastric morphology and function in CCK-B/gastrin receptor-deficient mice.

Mice lacking the cholecystokinin (CCK)-B/gastrin receptor have been generated by targeted gene disruption. The roles of this receptor in controlling gastric acid secretion and gastric mucosal growth have been assessed. The analysis of homozygous mutant mice vs. wild type included measurement of basal gastric pH, plasma gastrin concentrations as well as quantification of gastric mucosal cell types by immunohistochemistry. Mutant mice exhibited a marked increase in basal gastric pH (from 3.2 to 5.2) and about a 10-fold elevation in circulating carboxyamidated gastrin compared with wild-type controls. Histologic analysis revealed a decrease in both parietal and enterochromaffin-like (ECL) cells, thus explaining the reduction in acid output. Consistent with the elevation in circulating gastrin, antral gastrin cells were increased in number while somatostatin cells were decreased. These data support the importance of the CCK-B/gastrin receptor in maintaining the normal cellular composition and function of the gastric mucosa.     

CCK2 receptor antagonists: pharmacological tools to study the gastrin-ECL cell-parietal cell axis

Gastrin-recognizing CCK2 receptors are expressed in parietal cells and in so-called ECL cells in the acid-producing part of the stomach. ECL cells are endocrine/paracrine cells that produce and store histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. The ECL cells are the principal cellular transducer of the gastrin-acid signal. Activation of the CCK2 receptor results in mobilization of histamine (and pancreastatin) from the ECL cells with consequent activation of the parietal cell histamine H2 receptor. Thus, release of ECL-cell histamine is a key event in the process of gastrin-stimulated acid secretion. The oxyntic mucosal histidine decarboxylase (HDC) activity and the serum pancreastatin concentration are useful markers for the activity of the gastrin-ECL cell axis. Powerful and selective CCK2 receptor antagonits have been developed from a series of benzodiazepine compounds. These agents are useful tools to study how gastrin controls the ECL cells. Conversely, the close control of ECL cells by gastrin makes the gastrin-ECL cell axis well suited for evaluating the antagonistic potential of CCK2 receptor antagonists with the ECL-cell HDC activity as a notably sensitive and reliable parameter. The CCK2 receptor antagonists YF476, YM022, RP73870, JB93182 and AG041R were found to cause prompt inhibition of ECL-cell histamine and pancreastatin secretion and synthesis. The circulating pancreastatin concentration is raised, was lowered when the action of gastrin on the ECL cells was blocked by the CCK2 receptor antagonists. These effects were associated with inhibition of gastrin-stimulated acid secretion. In addition, sustained receptor blockade was manifested in permanently decreased oxyntic mucosal HDC activity, histamine concentration and HDC mRNA and CGA mRNA concentrations. CCK2 receptor blockade also induced hypergastrinemia, which probably reflects the impaired gastric acid secretion (no acid feedback inhibition of gastrin release). Upon withdrawal of the CCK2 receptor antagonists, their effects on the ECL cells were readily reversible. In conclusion, gastrin mobilizes histamine from the ECL cells, thereby provoking the parietal cells to secrete acid. While CCK2 receptor blockade prevents gastrin from evoking acid secretion, it is without effect on basal and vagally stimulated acid secretion. We conclude that specific and potent CCK2 receptor antagonists represent powerful tools to explore the functional significance of the ECL cells.     

Relationship of ECL cells and gastric neoplasia.

The enterochromaffin-like (ECL) cell in the oxyntic mucosa has a key role in the regulation of gastric secretion since it synthesizes and releases the histamine regulating the acid secretion from the parietal cell. Gastrin is the main regulator of the ECL cell function and growth. Long-term hypergastrinemia induces ECL cell hyperplasia, and if continued, neoplasia. ECL cell carcinoids occur in man after long-term hypergastrinemia in conditions like pernicious anemia and gastrinoma. There is also accumulating evidence that a proportion of gastric carcinomas of the diffuse type is derived from the ECL cell. Furthermore, the ECL cell may, by producing substances with angiogenic effects (histamine and basic fibroblast growth factor), be particularly prone to develop malignant tumors. Although the general opinion is that gastrin itself has a direct effect on the oxyntic mucosal stem cell, it cannot be excluded that the general trophic effect of gastrin on the oxyntic mucosa is mediated by histamine or other substances from the ECL cell, and that the ECL cell, therefore, could play a role also in the tumorigenesis/carcinogenesis of gastric carcinomas of intestinal type.     

Helicobacter pylori and hormones.

Helicobacter pylori affects gastric acid secretion via several mechanisms. One of these is by changing gastric regulatory physiology. The infection elevates plasma gastrin levels and decreases gastric mucosal expression of the inhibitory peptide somatostatin. These changes may be due to products of H. pylori itself or inflammatory cytokines released in H. pylori infection: acid secretion is inhibited less by a low intra-gastric pH, infusions of cholecystokinin and gastric distention in infected persons. Eradication of H. pylori rapidly decreases basal acid secretion and gastrin-releasing, peptide-stimulated acid secretion. There are now reports that maximally-stimulated acid secretion, a measure of the parietal cell mass, falls significantly six and 12 months after eradication of H. pylori from duodenal ulcer patients. This might be due to withdrawal of the trophic effect of gastrin. However H. pylori can also decrease gastric acid secretion, both through the mechanisms described in Dr. Cave''s paper and by causing gastric mucosal atrophy with loss of parietal cells. The net effect on acid presumably depends on which mechanism predominates. The processes involved may be crucial determinants of clinical outcome. For example, infection with little atrophy and high acid secretion is associated with duodenal ulcers, while infection with atrophy and low acid secretion increases the risk of gastric cancer of the intestinal-type.     

Gastric acid secretion in aquaporin-4 knockout mice

The aquaporin-4 (AQP4) water channel has been proposed to play a role in gastric acid secretion. Immunocytochemistry using anti-AQP4 antibodies showed strong AQP4 protein expression at the basolateral membrane of gastric parietal cells in wild-type (+/+) mice. AQP4 involvement in gastric acid secretion was studied using transgenic null (-/-) mice deficient in AQP4 protein. -/- Mice had grossly normal growth and appearance and showed no differences in gastric morphology by light microscopy. Gastric acid secretion was measured in anesthetized mice in which the stomach was luminally perfused (0. 3 ml/min) with 0.9% NaCl containing [(14)C]polyethylene glycol ([(14)C]PEG) as a volume marker. Collected effluent was assayed for titratable acid content and [(14)C]PEG radioactivity. After 45-min baseline perfusion, acid secretion was stimulated by pentagastrin (200 microg. kg(-1). h(-1) iv) for 1 h or histamine (0.23 mg/kg iv) + intraluminal carbachol (20 mg/l). Baseline gastric acid secretion (means +/- SE, n = 25) was 0.06 +/- 0.03 and 0.03 +/- 0.02 microeq/15 min in +/+ and -/- mice, respectively. Pentagastrin-stimulated acid secretion was 0.59 +/- 0.14 and 0.70 +/- 0.15 microeq/15 min in +/+ and -/- mice, respectively. Histamine plus carbachol-stimulated acid secretion was 7.0 +/- 1.9 and 8.0 +/- 1.8 microeq/15 min in +/+ and -/- mice, respectively. In addition, AQP4 deletion did not affect gastric fluid secretion, gastric pH, or fasting serum gastrin concentrations. These results provide direct evidence against a role of AQP4 in gastric acid secretion.     

Hypergastrinemia increases gastric epithelial susceptibility to apoptosis

Plasma concentrations of the hormone gastrin are elevated by Helicobacter pylori infection and by gastric atrophy. It has previously been proposed that gastrin acts as a cofactor during gastric carcinogenesis and hypergastrinemic transgenic INS-GAS mice are prone to developing gastric adenocarcinoma, particularly following H. pylori infection. We hypothesised that the increased risk of carcinogenesis in these animals may partly result from altered susceptibility of gastric epithelial cells to undergo apoptosis. Gastric corpus apoptosis was significantly increased 48 h after 12Gy gamma-radiation in mice rendered hypergastrinemic by transgenic (INS-GAS) or pharmacological (omeprazole treatment of FVB/N mice) methods and in both cases the effects were inhibited by the CCK-2 receptor antagonist YM022. However, no alteration in susceptibility to gamma-radiation-induced gastric epithelial apoptosis was observed in mice overexpressing progastrin or glycine-extended gastrin. Apoptosis was also significantly increased in gastric corpus biopsies obtained from H. pylori-infected humans with moderate degrees of hypergastrinemia. We conclude that hypergastrinemia specifically renders cells within the gastric corpus epithelium more susceptible to induction of apoptosis by radiation or H. pylori. Altered susceptibility to apoptosis may therefore be one factor predisposing to gastric carcinogenesis in INS-GAS mice and similar mechanisms may also be involved in humans.     

Stomachs of mice lacking the gastric H,K-ATPase alpha -subunit have achlorhydria, abnormal parietal cells, and ciliated metaplasia

The H,K-ATPase of the gastric parietal cell is the most critical component of the ion transport system mediating acid secretion in the stomach. To study the requirement of this enzyme in the development, maintenance, and function of the gastric mucosa, we used gene targeting to prepare mice lacking the alpha-subunit. Homozygous mutant (Atp4a(-/-)) mice appeared healthy and exhibited normal systemic electrolyte and acid-base status but were achlorhydric and hypergastrinemic. Immunocytochemical, histological, and ultrastructural analyses of Atp4a(-/-) stomachs revealed the presence of chief cells, demonstrating that the lack of acid secretion does not interfere with their differentiation. Parietal cells were also present in normal numbers, and despite the absence of alpha-subunit mRNA and protein, the beta-subunit was expressed. However, Atp4a(-/-) parietal cells had dilated canaliculi and lacked typical canalicular microvilli and tubulovesicles, and subsets of these cells contained abnormal mitochondria and/or massive glycogen stores. Stomachs of adult Atp4a(-/-) mice exhibited metaplasia, which included the presence of ciliated cells. We conclude that ablation of the H,K-ATPase alpha-subunit causes achlorhydria and hypergastrinemia, severe perturbations in the secretory membranes of the parietal cell, and metaplasia of the gastric mucosa; however, the absence of the pump appears not to perturb parietal cell viability or chief cell differentiation.     

Histamine metabolism of gastric carcinoids in Mastomys natalensis.

Pharmacological inhibition of gastric acid secretion and subsequent hypergastrinemia in Mastomys natalensis is an experimental model well suited for the study of gastric carcinoid formation. The genetic susceptibility of Mastomys to develop such tumors is a feature reminiscent of the situation in patients with the MEN-1 Zollinger Ellison syndrome, in whom tumor-induced hypergastrinemia, promotes the development of gastric carcinoids. Chronic hypergastrinemia, induced by the irreversible H2-receptor antagonist loxtidine will cause carcinoid formation in Mastomys already after four to six months. As in humans, gastric carcinoids in Mastomys are mainly composed of enterochromaffinlike (ECL) cells and have low malignant potential. Administration of exogenous gastrin to normal young animals increases the expression of histidine decarboxylase (HDC) mRNA in the oxyntic mucosa within 30 minutes. Endogenous hypergastrinemia, induced by short-time loxtidine treatment (three to 29 days) enhances the expression of HDC mRNA, histamine contents and ECL cell numbers in the oxyntic mucosa. Long-term loxtidine treatment (seven to 21 months) results in sustained hypergastrinemia and tumor formation. Tumor-bearing animals exhibited an increase in HDC mRNA and histamine content in the oxyntic mucosa as well as increased urinary excretion of the main histamine metabolite, tele-methylimidazole acetic acid (MeImAA). Subsequent to cessation of loxtidine treatment for two weeks, all parameters of histamine metabolism were normalized in tumor-bearing animals. These results indicate that gastric carcinoids developing during hypergastrinemia are well-differentiated neoplasms whose histamine synthesis and metabolism is regulated by plasma gastrin.     

Pathobiology and management of hypergastrinemia and the Zollinger-Ellison syndrome.

Gastrin is both stimulatory and trophic to the cells of the gastric fundus--parietal and peptic cells, and enterochromaffin-like (ECL) cells which are major intermediaries of the gastrin effect. Gastrin (from the antrum) and acid (from the fundus) represent the interactive positive and negative limbs of a feedback loop. The nature and extent of sub-loops, perhaps involving the vagus, acetylcholine, histamine, and other peptides and cell products are at present unclear or unknown. Loss of either gastrin or acid has predictable consequences. Absent acid, as in pernicious anemia or as a result of omeprazole, leads to hypergastrinemia. In rats, such hypergastrinemia (gastrin > 1,000 pg/ml) causes fundic ECL hyperplasia and, eventually, carcinoids; in humans with pernicious anemia, hypergastrinemia causes ECL-cell hyperplasia, which may progress to carcinoids that are reversible upon withdrawal of gastrin, illustrated by three cases described here. Loss of gastrin by antrectomy for duodenal ulcer leads to fundic involution and marked reduction in basal acid output, maximal acid output, and fundic histamine. An uncontrolled excess of gastrin, as from a gastrinoma outside the negative feedback loop, causes acid and pepsin hypersecretion with upper GI mucosal damage, the Zollinger-Ellison syndrome. This paper summarizes the abnormal regulation of gastrin and the biology, natural history, diagnosis, and management of ZE syndrome by medical and surgical means.     

Omeprazole and ranitidine, antisecretagogues with different modes of action, are equally effective in causing hyperplasia of enterochromaffin-like cells in rat stomach

Female rats were treated for 28 days with high doses of the gastric acid secretion inhibitors omeprazole and ranitidine. Omeprazole, which is long-acting, was given orally once daily. Ranitidine, which is short-acting, was given by continuous infusion (via osmotic minipumps, implanted subcutaneously). The aim was to produce a similar degree of acid inhibition with the two drugs. The inhibition of acid secretion over the day and night was more pronounced in the omeprazole-treated rats (maximal inhibition 100%, minimum 85%) than in those receiving ranitidine (mean 70%). In both groups, there was a great increase in plasma gastrin, somewhat greater after omeprazole than after ranitidine. The gastrin concentration in the antrum was almost doubled by both treatments and there was a moderate increase in the number of antral gastrin cells in the omeprazole-treated rats. The number of enterochromaffin-like (ECL) cells (per visual field) increased in the oxyntic mucosa to the same extent (greater than 100%) in the ranitidine- and omeprazole-treated rats. Apart from the gastrin cells in the antrum and the ECL cells in the corpus no other gastric endocrine cell type seemed to respond to treatments with antisecretagogues. We conclude that, regardless of the type of antisecretagogue used, effective and long-term suppression of gastric acid secretion results in sustained hypergastrinemia and increased number of ECL cells. Conceivably therefore, the ECL cell hyperplasia reflects the trophic effect of gastrin.     

Differentiation of the gastric mucosa. I. Role of histamine in control of function and integrity of oxyntic mucosa: understanding gastric physiology through disruption of targeted genes

Many physiological functions of the stomach depend on an intact mucosal integrity; function reflects structure and vice versa. Histamine in the stomach is synthesized by histidine decarboxylase (HDC), stored in enterochromaffin-like (ECL) cells, and released in response to gastrin, acting on CCK(2) receptors on the ECL cells. Mobilized ECL cell histamine stimulates histamine H(2) receptors on the parietal cells, resulting in acid secretion. The parietal cells express H(2), M(3), and CCK(2) receptors and somatostatin sst(2) receptors. This review discusses the consequences of disrupting genes that are important for ECL cell histamine release and synthesis (HDC, gastrin, and CCK(2) receptor genes) and genes that are important for "cross-talk" between H(2) receptors and other receptors on the parietal cell (CCK(2), M(3), and sst(2) receptors). Such analysis may provide insight into the functional significance of gastric histamine.     

Altered influence of CCK-B/gastrin receptors on HDC expression in ECL cells after neoplastic transformation

Gastrin is one of the main factors controlling enterochromaffin-like (ECL) cell endocrine function and growth. Long-standing hypergastrinemia may give rise to ECL cell carcinoids in the gastric corpus in man and in experimental models. We have analysed the expression and function of CCK-B/gastrin receptors in normal ECL cells and in ECL cell tumours (gastric carcinoids) of the African rodent Mastomys natalensis. Hypergastrinemia induced by short-term (5 days) histamine2-receptor blockade (loxtidine) resulted in increased histidine decarboxylase (HDC) mRNA expression in the gastric oxyntic mucosa. This increase was significantly and dose-dependently reversed by selective CCK-B/gastrin receptor blockade (YM022). Long-term (12 months) hypergastrinemia, induced by histamine2-receptor blockade, gave rise to ECL cell carcinoids in the gastric oxyntic mucosa. CCK-B/gastrin receptor mRNA was only slightly elevated while HDC mRNA expression was eight-fold elevated in ECL cell carcinoids and was not influenced by CCK-B/gastrin receptor blockade. Thus CCK-B/gastrin receptor blockade of hypergastrinemic animals reduces the HDC mRNA expression in normal mucosa but not in ECL cell carcinoids. These results demonstrate that HDC mRNA expression in neoplastic ECL cells is not controlled by CCK-B/gastrin receptors.     

Physiological significance of ECL-cell histamine.

In the oxyntic mucosa of the mammalian stomach, histamine is stored in ECL cells and in mucosal mast cells. In the rat, at least 80 percent of oxyntic mucosal histamine resides in the ECL cells. Histamine is a key factor in the regulation of gastric acid secretion. Following depletion of ECL-cell histamine by treatment with alpha-fluoromethylhistidine (alpha-FMH), basal acid secretion was reduced, and gastrin-stimulated acid secretion was abolished. Vagally-induced acid secretion (by insulin injection or pylorus ligation) was unaffected by alpha-FMH treatment but inhibited by an H2 antagonist. These results suggest that gastrin stimulates acid secretion via release of ECL-cell histamine, whereas vagally-induced acid secretion--although histamine-dependent--does not rely on ECL-cell histamine. Gastrin is known to have a trophic effect on the oxyntic mucosa. By combining long-term hypergastrinemia with continuous infusion of alpha-FMH, we were able to show that gastrin-evoked trophic effects in the stomach do not depend on ECL-cell histamine.     

Parietal cell hyperstimulation and autoimmune gastritis in cholera toxin transgenic mice

The stimulation of gastric acid secretion from parietal cells involves both intracellular calcium and cAMP signaling. To understand the effect of increased cAMP on parietal cell function, we engineered transgenic mice expressing cholera toxin (Ctox), an irreversible stimulator of adenylate cyclase. The parietal cell-specific H(+),K(+)-ATPase beta-subunit promoter was used to drive expression of the cholera toxin A1 subunit (CtoxA1). Transgenic lines were established and tested for Ctox expression, acid content, plasma gastrin, tissue morphology, and cellular composition of the gastric mucosa. Four lines were generated, with Ctox-7 expressing approximately 50-fold higher Ctox than the other lines. Enhanced cAMP signaling in parietal cells was confirmed by observation of hyperphosphorylation of the protein kinase A-regulated proteins LASP-1 and CREB. Basal acid content was elevated and circulating gastrin was reduced in Ctox transgenic lines. Analysis of gastric morphology revealed a progressive cellular transformation in Ctox-7. Expanded patches of mucous neck cells were observed as early as 3 mo of age, and by 15 mo, extensive mucous cell metaplasia was observed in parallel with almost complete loss of parietal and chief cells. Detection of anti-parietal cell antibodies, inflammatory cell infiltrates, and increased expression of the Th1 cytokine IFN-gamma in Ctox-7 mice suggested that autoimmune destruction of the tissue caused atrophic gastritis. Thus constitutively high parietal cell cAMP results in high acid secretion and a compensatory reduction in circulating gastrin. High Ctox in parietal cells can also induce progressive changes in the cellular architecture of the gastric glands, corresponding to the development of anti-parietal cell antibodies and autoimmune gastritis.     

PACAP stimulates gastric acid secretion in the rat by inducing histamine release

Previous studies have shown that pituitary adenylate cyclase-activating peptide (PACAP) stimulates enterochromaffin-like (ECL) cell histamine release, but its role in the regulation of gastric acid secretion is disputed. This work examines the effect of PACAP-38 on aminopyrine uptake in enriched rat parietal cells and on histamine release and acid secretion in the isolated vascularly perfused rat stomach and the role of PACAP in vagally (2-deoxyglucose) stimulated acid secretion in the awake rat. PACAP has no direct effect on the isolated parietal cell as assessed by aminopyrine uptake. PACAP induces a concentration-dependent histamine release and acid secretion in the isolated stomach, and its effect on histamine release is additive to gastrin. The histamine H2 antagonist ranitidine potently inhibits PACAP-stimulated acid secretion without affecting histamine release. Vagally stimulated acid secretion is partially inhibited by a PACAP antagonist. The results from the present study strongly suggest that PACAP plays an important role in the neurohumoral regulation of gastric acid secretion. Its effect seems to be mediated by the release of ECL cell histamine.     

Lessons from the gastrin knockout mice

The gastrointestinal hormone, gastrin, was discovered a century ago as the second hormone in history. Subsequently, gastrin peptides have been identified and the genes encoding the hormone as well as its receptor have been cloned in several mammalian species including the mouse. This has facilitated the development of gastrin and gastrin receptor deficient mice as models for genetic dissection of the role of gastrins in maintaining gastric homeostasis and control of acid secretion. The gastrin knockout mice are achlorhydric due to inactivation of the ECL and parietal cells. Moreover, this achlorhydria is associated with the development of intestinal metaplasia and bacterial overgrowth, which ultimately lead to development of gastric tumors. Outside the stomach, gastrin deficiency alters pancreatic islet physiology and is associated with a moderate fasting hypoglycemia in the fasting state. But lack of gastrin does not impair islet regeneration. The association between progastrin, progastrin-derived processing intermediates and colorectal carcinogenesis has also been examined through genetic or chemical cancer induction in several mouse models, although the clinical relevance of these studies still remains to be proven. While others have focused on models of increased gastrin production, the present review will describe the lessons learned from the gastrin deficient mice. These mice help understand how dysregulation of gastrin secretion may be implicated in human disease.     

Properties of isolated gastric enterochromaffin-like cells.

The gastric enterochromaffin-like cell (ECL) has been studied in gastric fundic glands by confocal microscopy and as a purified cell preparation by video imaging of calcium signaling and measurements of histamine release. Regulation of gastric acid secretion is largely due to alterations of histamine activation of the H2 receptor on the parietal cell and can be divided into central neural regulation, with direct actions of neuronally released mediators and into peripheral regulation by substances released from other endocrine cells. Gastric neuronal stimulation of acid secretion by alteration of ECL cell function is probably mediated by pituitary adenylate cyclase activating peptide (PACAP) receptors on the ECL cell, which activate calcium signaling and histamine release. Peripheral stimulation of acid secretion via the ECL cell is largely mediated by gastrin stimulation of calcium signaling and histamine release. Gastric neuronal inhibition of ECL cell function is probably mediated by galanin inhibition of calcium signaling, and histamine release and peripheral inhibition of ECL cell function is mainly due to somatostatin release from D cells.     

Lack of histamine alters gastric mucosal morphology: comparison of histidine decarboxylase-deficient and mast cell-deficient mice

Histamine plays an important role in the regulation of gastric acid secretion; however, its role in maintenance of gastric morphology remains unclear. To clarify the necessity of histamine for gastric mucosal development and maintenance, we evaluated two different kinds of mice that lacked either mast cells (one of the gastric histamine-producing cell types) or histidine decarboxylase (HDC; a histamine-synthesizing enzyme). Measurements of stomach weight, intragastric pH, mucosal histamine levels, as well as serum gastrin and albumin levels were performed in mice. Gastric mucosal appearance was examined by immunohistochemical techniques. Although gastric mucosal histamine levels in mast cell-deficient mice were half of those observed in the wild-type mice, intragastric pH, serum gastrin levels, and gastric morphology at 12 mo were unchanged compared with the wild-type mice. In contrast, HDC-deficient mice possessed no detectable gastric histamine, but did exhibit hypergastrinemia, as well as marked increases in intragastric pH and stomach weight compared with the wild-type mice. Histological analysis revealed that 9-mo-old HDC-deficient mice demonstrated hyperplasia in the oxyntic glandular base region, as well as increased numbers of parietal and enterochromaffin-like cells. These results indicate that enterochromaffin-like cell-derived histamine is potentially involved in gastric mucosal morphology regulation.