Developmental gene expression of gastrin receptor in rat stomach

Gastrin, which is present in fetal plasma, may have important roles in the development of gastric mucosa, since it is not only a potent stimulator of gastric acid secretion but also a growth promoting factor. Gastrin regulates various cellular functions via its receptors on cell membrane. Therefore, in order to elucidate a role for gastrin in the development of gastrointestinal system during gestation, Northern blot analysis was performed. The results of the study suggested that gastrin receptor is mainly present on parietal cells. Furthermore, proton pump and gastrin receptor gene expressions in parietal cells were strongly stimulated by the administration of exogenous gastrin. In conclusion, gastrin may be involved in the developmental change of parietal cells through its receptors.     

Bromodeoxyuridine-immunohistochemistry on cellular differentiation and migration in the fundic gland of Xenopus laevis during development

Summary Cellular differentiation and migration in the fundic glands of adult and larval Xenopus laevis have been examined using bromodeoxyuridine-immunohistochemistry. In the adult fundic gland, cumulative labeling with bromodeoxyuridine revealed a proliferative cell zone between the surface mucous cells and mucous neck cells, in what is referred to as the neck portion of the gland. The labeling-index of mucous neck cells had rapidly increased by week-5. The labeling-index of oxynticopeptic cells showed a more delayed increase until week-7, coincident with the decrease in the labeling of mucous neck cells. In the immature fundic glands of larvae, the labeled proliferating cells were randomly distributed throughout the developing gastric mucosa. During metamorphosis, the labeling-index of immature epithelial cells was highest at stage 63. Following administration of bromodeoxyurdine at this, stage, there was no significant loss of labeled epithelial cells during the metamorphosing period. Furthermore, there was no significant difference in the labeling-indices among the epithelial cells, such as surface mucous cells/generative cells, mucous neck cells, and oxynticopeptic cells, 7 days after administration. Cellular differentiation and migration pathways of epithelial cells in the fundic gland of adult X. laevis and its larvae are discussed.     

Gastrin and interleukin-1beta stimulate growth factor secretion from cultured rabbit gastric parietal cells

The hormone gastrin stimulates proliferation of the gastric mucosa. Inflammation of the stomach is also associated with increased proliferation. The proliferative response is important in the reparative response to injury but can be deleterious by predisposing to the development of cancer. Parietal cells, but not the cells in the proliferative zone of the gastric glands, express the appropriate gastrin receptor. Parietal cells may mediate the trophic effects of gastrin by secreting other growth factors. The role of parietal cells in the proliferative responses has been examined in this study. Rabbit parietal cells were cultured with gastrin or the cytokine interleukin-1beta for 18 hours. The conditioned medium from gastrin or IL-1beta stimulated parietal cells increased proliferation of HeLa cells in an epidermal growth factor-receptor dependant manner. Gastrin and IL-1beta stimulated the secretion of heparin-binding epidermal growth factor and amphiregulin but not transforming growth factor-alpha from parietal cells. Combinations of gastrin and IL-1beta on growth factor secretion were synergistic. The protein kinase C inhibitor staurosporine abolished these stimulatory effects of gastrin and IL-1beta. Divergent effects on histamine-stimulated acid secretion were observed; 18 hours pre-treatment with gastrin enhanced acid secretion by 50% but IL-1beta inhibited acid secretion in both control and gastrin pre-treated parietal cells. The acid-secreting parietal cell plays a central role in the regulation of mucosal proliferation in gastric inflammation. Secretion of paracrine growth factors by parietal cells may be an important point of integration between the endocrine and inflammatory stimuli in determining mucosal responses to injury and inflammation.     

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.     

Identification and Characterization of a Specific Receptor for Cholecystokinin on Isolated Fundic Glands from Guinea Pig Gastric Mucosa Using a Biologically Active 125I-CCK-8 Probe

Abstract

Specific binding sites for cholecystokinin (CCK) have been identified and characterized in fundic glands isolated by collagenase treatment from guinea pig gastric mucosa using a biologically active ¹²⁵I-labeled derivative of the C-terminal octa-peptide of CCK (¹²⁵IIE-CCK-8). The time course of binding to these glands was rapid, temperature dependent and saturable. At 24, 30 and 37° C, half-maximal binding was reached at 5 min and full binding at 30 min. The addition of a large excess of CCK-8 after 15 and 30 min of binding at 24° C caused a prompt and rapid decline in radioligand bound showing that the interaction was reversible. There was a progressive decline in the amount of ¹²⁵IIE-CCK-8 bound to fundic glands with increasing concentrations of CCK-8 and other structurally related peptides. Gastrin II displaced 50% of the radioligand at 1.6nM, CCK-8 at 3.2nM, gastrin I at 16nM, and desulfated-CCK-8 and pentagastrin at 59nM. Secretin did not displace the radioligand from fundic glands at 1.0uM. The binding was also tissue specific as glands isolated from the antral mucosa did not contain specific binding sites for ¹²⁵IIE-CCK-8. This data provides evidence for specific receptors for CCK on gastric fundic glands that may be involved in the control of acid and pepsinogen secretion.     

Synergistic action of gastrin and ghrelin on gastric acid secretion in rats

Gastrin and ghrelin are secreted from G cells and X/A-like cells in the stomach, respectively, and respective hormones stimulate gastric acid secretion by acting through histamine and the vagus nerve. In this study, we examined the relationship between gastrin, ghrelin and gastric acid secretion in rats. Intravenous (iv) administration of 3 and 10 nmol of gastrin induced transient increases of ghrelin levels within 10 min in a dose-dependent manner. Double immunostaining for ghrelin and gastrin receptor revealed that a proportion of ghrelin cells possess gastrin receptors. Although (iv) administration of gastrin or ghrelin induced significant gastric acid secretion, simultaneous treatment with both hormones resulted in a synergistic, rather than additive, increase of gastric acid secretion. This synergistic increase was not observed in vagotomized rats.These results suggest that gastrin may directly stimulate ghrelin release from the stomach, and that both hormones may increase gastric acid secretion synergistically.     

Glycoprotein hormone alpha-subunit in human stomach

To demonstrate the immunoreactive alpha-subunit of human chorionic gonadotropin (hCG) or glycoprotein hormones in non-neoplastic gastric mucosa, and to clarify the nature and significance of alpha-subunit-immunoreactive cells, immunohistochemical studies were performed on gastric mucosa using polyclonal antibodies for hCG alpha and beta, hLH beta, hFSH beta, hTSH beta, and gastrin, and a monoclonal antibody for hCG alpha. Surgically resected stomachs were classified as follows: nearly normal (Group A); antral gastritis (Group B); fundic gastritis with pseudopyloric glands (Group C); and intestinal metaplasia (Group D). Cells immunoreactive for the alpha-subunit were present in the pyloric glands and to a lesser extent in the fundic glands (Groups A and B). Almost all alpha-subunit-immunoreactive cells were nonreactive for the beta-subunits of the four glycoprotein hormones. alpha-subunit-immunoreactive cells corresponded to gastrin-containing cells in the pyloric glands, but were unrelated to gastrin in the fundic glands. In fundic gastritis, alpha-subunit-immunoreactive cells appeared to increase (Group C), and many hyperplastic foci were observed in atrophic glands with hyperplasia of the argyrophilic cells (Groups C and D). Isolated hCG alpha or the alpha-subunit of glycoprotein hormones may be present in the endocrine cells of gastric mucosa, and alpha-subunit-immunoreactive cells in the fundic glands seem to proliferate in fundic gastritis.     

Topography of somatostatin cells in the stomach of the rat: Possible functional significance

Summary Somatostatin cells in the stomach of the rat have a characteristic shape and distribution. In the antral mucosa they occur together with gastrin cells and enterochromaffin cells at the base of the glands. In the oxyntic mucosa they are scattered along the entire glands with some predominance in the zone of parietal cells. Throughout the gastric mucosa the somatostatin cells possess long and slender processes that emerge from the base of the cell and end in clublike swellings. Such processes appear to contact a certain proportion of neighbouring gastrin cells in the antral mucosa and parietal cells in the oxyntic mucosa.Exogenous somatostatin given by intravenous infusion to conscious rats counteracted the release of gastrin stimulated by feeding, elevated antral pH or vagal excitation. Gastrin causes parietal cells to secrete HCl and endocrine cells in the oxyntic mucosa to mobilise and synthesise histamine. Somatostatin is known to block the response of the parietal cells to gastrin. In contrast, somatostatin did not block the response of the histamine-storing endocrine cells to gastrin, perhaps because these endocrine cells lack receptors to somatostatin. Conceivably, somatostatin in the gastric mucosa has a paracrine mode of action. The observations of the present study suggest that somatostatin may affect some, but not all of the various cell types in the stomach. Under physiological conditions this selectivity may be achieved in the following ways: 1) Communication may be based on direct cell-to-cell contact. 2) Only certain cell types are supplied with somatostatin receptors.     

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.     

Demonstration of a specific receptor site for glucagon-37 (oxyntomodulin/bioactive enteroglucagon) in rat oxyntic glands

In this work, we show directly the existence of specific binding sites for Glucagon-37 (G-37) in isolated oxyntic glands from rat fundic mucosa. The binding of 125I-Glucagon-37 was inhibited by G-37 with a dissociation constant KD = 2.6 X 10(-9) M (high affinity binding capacity = 85 fmol/mg of protein) and by pancreatic Glucagon (G-29) with a KD = 2.2 X 10(-8) M. These results confirm the tissue specificity of G-37, evidenced in vitro on the cyclic AMP production by the same glands and in vivo on the inhibition of gastric acid secretion. They suggest that these activities are related to the G-37-binding on this novel receptor site for Glucagon-related peptides, which is distinct from receptors for the main stimulants of acid secretion, such as Gastrin, Histamine or cholinergic agents.     

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.     

Effect of starvation on endocrine cells in the rat stomach

The influence of food deprivation on gastric G- and D-cells and on parietal cells was studied in the rat. In fed controls and groups of rats fasted for 12 and 96 h G-, D- and parietal cell densities, somatostatin and gastrin concentration in antral and fundic specimens and serum gastrin were compared. Gastrin in antral mucosa, serum gastrin, G-cell density as well as antral D-cell density decreased in long-term fasted rats by 52%, 90%, 58% and 42%, respectively. Fundic D-cell density remained unchanged. After 96 h starvation somatostatin concentration slightly increased in antral mucosa (+35%; P less than 0.05), but decreased in fundic mucosa (-40%; P less than 0.05). Parietal cell density was not influenced by prolonged fasting. These findings demonstrate that changes in D-cell morphology and mucosal somatostatin content are not parallel and that the rat gastric D-cell is less dependent on food in the gastric lumen than the G-cell. The unaltered fundic D-cell density reflects the functional activity of gastric D-cell which has also been shown to be independent of the presence or absence of food.