Number Of G-cells Research Articles

Inflammation and Gli2 Suppress Gastrin Gene Expression in a Murine Model of Antral Hyperplasia

Chronic inflammation in the stomach can lead to gastric cancer. We previously reported that gastrin-deficient (Gast−/−) mice develop bacterial overgrowth, inflammatory infiltrate, increased Il-1β expression, antral hyperplasia and eventually antral tumors. Since Hedgehog (Hh) signaling is active in gastric cancers but its role in precursor lesions is poorly understood, we examined the role of inflammation and Hh signaling in antral hyperplasia. LacZ reporter mice for Sonic hedgehog (Shh), Gli1, and Gli2 expression bred onto the Gast−/− background revealed reduced Shh and Gli1 expression in the antra compared to wild type controls (WT). Gli2 expression in the Gast−/− corpus was unchanged. However in the hyperplastic Gast−/− antra, Gli2 expression increased in both the mesenchyme and epithelium, whereas expression in WT mice remained exclusively mesenchymal. These observations suggested that Gli2 is differentially regulated in the hyperplastic Gast−/− antrum versus the corpus and by a Shh ligand-independent mechanism. Moreover, the proinflammatory cytokines Il-1β and Il-11, which promote gastric epithelial proliferation, were increased in the Gast−/− stomach along with Infγ. To test if inflammation could account for elevated epithelial Gli2 expression in the Gast−/− antra, the human gastric cell line AGS was treated with IL-1β and was found to increase GLI2 but decrease GLI1 levels. IL-1β also repressed human GAST gene expression. Indeed, GLI2 but not GLI1 or GLI3 expression repressed gastrin luciferase reporter activity by ∼50 percent. Moreover, chromatin immunoprecipitation of GLI2 in AGS cells confirmed that GLI2 directly binds to the GAST promoter. Using a mouse model of constitutively active epithelial GLI2 expression, we found that activated GLI2 repressed Gast expression but induced Il-1β gene expression and proliferation in the gastric antrum, along with a reduction of the number of G-cells. In summary, epithelial Gli2 expression was sufficient to stimulate Il-1β expression, repress Gast gene expression and increase proliferation, leading to antral hyperplasia.

Receptors Responsive to Protein Breakdown Products in G-Cells and D-Cells of Mouse, Swine and Human

Monitoring the luminal content in the stomach is of vital importance for adjusting the gastric activities, including the release of gastric hormones such as gastrin. Our previous studies have shown that in mice the gastrin-secreting G-cells express receptor types which are responsive to amino acids. Since the pig is considered as more suitable model for studying gastro-physiological aspects relevant for men, in this study we have analyzed the distribution of G-cells and D-cells in the gastric antrum of men, swine, and mouse and the expression of receptor types which may render these cells responsiveness to protein breakdown products. The results indicate that the number of G-cells per antral invagination was significantly higher in swine and human compared to mice and also the distribution pattern of G-cells differed between the species. The molecular phenotyping revealed that the receptors GPRC6A and CaSR were also expressed in G-cells and in a subpopulation of D-cells from swine and men. As an additional receptor type, the peptone-receptor GPR92, was found to be expressed in G-cells and a subpopulation of D-cells; this receptor type may be particular suitable for sensing protein breakdown products and thus be a key element to adjust the activity of G-cells and D-cells according to the progress of the digestive processes in the stomach. In search for elements of an intracellular signaling cascade it was found that G-cells express the G-protein subunit Gαq as well as the phospholipase C subtype PLCβ3; in contrast, D-cells expressed the subtype PLCβ2 and neither Gαq. These results indicate that there are significant species differences concerning the number and distribution pattern, but not concerning the molecular phenotype of the gastric endocrine cells. However, G-cells and D-cells significantly differ from each other regarding the repertoire of receptors and signaling elements.

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca(2+), whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca(2+) homeostatic capacity. Luminal nutrients, such as Ca(2+) and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca(2+), amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca(2+), peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca(2+) homeostasis should be reviewed for effects outside traditional Ca(2+)-regulating tissues in view of the broader distribution and function of CaR.

Effects of intra-gastric beta-casomorphin-7 on somatostatin and gastrin gene expression in rat gastric mucosa

To investigate the in vivo effect of beta-casomorphin-7 on the regulation of gastric somatostatin and gastrin messenger RNA in rat gastric mucosa. Somatostatin and gastrin mRNA were quantified by RT-PCR and in situ hybridization (ISH) in 24 rats. The rats were divided into three treatment groups: basal diet + physiological saline (n=8), basal diet + beta-casomorphin-7 (7.5 x 10(-7)mol) (n=8), and basal diet + poly-Gly-7 (containing equal mol of N with 7.5 x 10(-7) mol beta-casomorphin-7) (n=8). After oral administration for 30 days, rats were killed by exsanguinations. After intra-gastric administration of beta-casomorphin-7 for 30 d, gastrin mRNA increased by 52.8% (P<0.05, n=8), and somatostatin mRNA levels decreased by 30.7% compared with the controls (P<0.01, n=8). No significant differences in the expression of the two genes were observed in the poly-Gly-treated group, although gastrin mRNA expression was elevated by 35.6% as against the control group (P=0.15, n=8). The long-term oral administration of a casomorphin solution significantly decreased the even gray of D-cells, but did not lower the number of D-cells both in the antrum and fundus. Interestingly, the number of G-cells increased in the antrum and fundus, but its average density was augmented only in the antrum. Beta-casomorphin-7 is capable of modulating gene expression of the regulatory peptides from G and D cells. Data from in situ hybridization studies indicate that beta-casomorphin-7 affects gastrin gene expression indirectly by means of the paracrine action of somatostatin, and depends on its intrinsic molecular function.

Gastric body partition to avoid ulcerogenic risk and hypergastrinemia

For treatment of giant perforated peptic ulcers, we hypothesized that partitioning of the gastric body instead of the antrum would prevent hypergastrinemia and minimize ulcerogenic risk. By maintaining part of the acid-secreting gastric body in continuity with the excluded distal stomach, gastrin-secreting cells in the antrum would still be inhibited by gastric acid secretion from the gastric body. We studied (1) gastric body partition with gastrojejunostomy in 8 critically ill patients with giant perforated peptic ulcers and (2) the influence of gastric partition on serum gastrin in 18 dogs with gastric antral partition + gastrojejunostomy, or gastric body partition + gastrojejunostomy, or gastrotomy. No patient developed major postoperative complications. Serum gastrin levels were normal in 6 patients but showed an abnormal increase in 2 patients 1 month after gastric body partition. Serum gastrin levels had returned to the normal range at postoperative follow-up after 2 years. In the animal study, serum gastrin levels and the number of G-cells in the excluded antrum and acid-secreting parietal cells in the gastric body were increased when evaluated on day 60 postoperatively or after antral partition, compared with preoperative data in the same group. These changes did not occur in the group undergoing partition of the gastric body and the group undergoing gastrostomy. Postoperative serum gastrin levels, and the number of G-cells and parietal cells also was significantly greater in the antral partition group than in the other 2 groups. No ulcer was found in any dog in the gastric body partition and gastrostomy groups, but ulcers occurred in 4 dogs in the antral partition group, all of whom died of ulcer perforation. Gastric body partition + gastrojejunostomy is a simple, dependable procedure for patients with perforated giant peptic ulcers. This procedure does not require extreme expertise and can be performed in a very short time, even by a trainee general surgeon in emergency.

Antral G-cell in gastrin and gastrin-cholecystokinin knockout animals

The antral hormone gastrin is the key regulator of gastric acid secretion, mucosal growth and differentiation. Gastrin is synthesized in the endocrine G-cells in the antroduodenal mucosa. We have now examined the way in which the loss of gastrin alone or gastrin plus cholecystokinin (CCK) affects the antral G-cell. Immunohistochemistry, radioimmunoassay and quantitative real-time polymerase chain reaction techniques were employed to examine the expression of genes belonging to the G-cell secretory pathway in gastrin and gastrin-CCK knockout mice. Transmission electron microscopy was used to examine the ultrastructure of the G-cells. The number of G-cells increased but the secretory granules were few and abnormally small in the G-cells of both mouse models compared with wildtypes. Thus, gastrin is not necessary for the formation of G-cells as such but the lack of gastrin reduces the number and size of their secretory granules suggesting that gastrin is vital for the formation and/or maintenance of secretory granules in G-cells.

Precursor Lesions in Patients With Multiple Endocrine Neoplasia Type 1--Associated Duodenal Gastrinomas

The identification of precursor lesions has a great impact on the understanding of tumorigenesis. Precursor lesions of endocrine tumors are known to occur in the setting of the MEN1 syndrome. The aim of this study was to test the hypothesis that MEN1-associated duodenal gastrinomas originate from diffuse preneoplastic gastrin cell changes. Precursor lesions may precede the development of duodenal gastrinomas because, in contrast to sporadic gastrinomas, these tumors are usually multiple. The distribution of endocrine cells in the nontumorous duodenal tissue was analyzed qualitatively and quantitatively for 25 patients operated on for a duodenal gastrinoma. MEN1 status was assessed clinically and by polymerase chain reaction-based mutational analysis. Fourteen of 25 patients with gastrinoma had proliferative, hyperplastic lesions consisting of gastrin cells in the nontumorous duodenal mucosa, similar to the gastric enterochromaffin-like cell lesions observed in chronic atrophic gastritis. All patients with Zollinger-Ellison syndrome with proven MEN1 had such proliferative gastrin cell lesions, and all patients with Zollinger-Ellison syndrome without precursor lesions were MEN1 negative. Duodenal gastrinomas in MEN1, but not sporadic duodenal gastrinomas, are associated with proliferative gastrin cell changes within the nontumorous mucosa. It is likely that these lesions precede the development of MEN1-associated duodenal gastrinomas.

Effects of Ostertagia ostertagi and omeprazole treatment on feed intake and gastrin-related responses in the calf

Infection with the bovine abomasal nematode, Ostertagia ostertagi, results in a loss of acid-secreting parietal cells and an increase in gastric pH. The effects of an experimental infection with Ostertagia and/or daily treatment with omeprazole (OMP) at 2 mg kg −1 bodyweight for four consecutive days (experiment days 24–27, inclusive) on voluntary feed intake, blood and tissue gastrin concentrations, abomasal G-cell numbers, gastric pH, and blood cholecystokinin (CCK) and pepsinogen concentrations were investigated in the calf. Ostertagia-infected calves demonstrated a significant drop in feed intake between days 24 and 27 post-infection (38%; P<0.001) and in G-cell numbers (42%; P<0.05) and significant increases in abomasal pH ( P<0.001), fundic mucosal weight (99%; P<0.01), and blood gastrin ( P<0.05) and pepsinogen ( P<0.0001). OMP treatment of worm-free animals resulted in a significant drop in intake between days 24 and 27 (30%; P<0.001) and in G-cell numbers (17%; P<0.05) and significant increases in abomasal pH ( P<0.01) and blood gastrin ( P<0.001). OMP treatment of Ostertagia-infected animals with an existing hypergastrinaemia had no effect on feed intake, abomasal pH, blood gastrin or pepsinogen or abomasal G-cell numbers. Blood CCK concentrations were also unaffected by either Ostertagia infection or OMP treatment. These data suggest that: (a) the depression in feed intake associated with OMP in worm-free calves was not due to a side effect of drug treatment; (b) inappetance in Ostertagia-infected animals is closely associated with the parasite-induced hypergastrinaemia; and (c) the elevation in abomasal pH was a major factor responsible for the elevated blood gastrin concentrations seen in parasitised and OMP-treated animals.

Gastrinaemia, Tissue Gastrin Concentration and G Cell Density in the Antral Mucosa of Swine With and Without Gastric Ulcer of the Pars Oesophagea

Gastric ulcer of the pars oesophagea (GUPO) of the stomach, which occurs spontaneously in swine, is of unknown aetiology. Because gastrin is a potent secretagogue linked to acid secretion, this study was designed to investigate, in pigs with or without GUPO, (1) basal and food-stimulated serum gastrin concentrations, (2) the concentration of tissue gastrin, and (3) gastrin-producing (G) cell density in the antral mucosa. Sixty-four pigs (32 with, and 32 without ulceration) were studied. Antral mucosa was obtained immediately after slaughter for assessment of G-cell number and tissue gastrin concentration. The presence or absence of GUPO was not significantly associated with either of the parameters measured.

Effect of long-term omeprazole treatment on antral G and D cells in children.

Long-term omeprazole therapy is associated with hypergastrinemia. In the antrum, gastrin secretion from G cells is inhibited in a paracrine manner by somatostatin secreted from D cells. Omeprazole may alter the ratio of G to D cells; however, there are limited data concerning such an effect in humans and none in children. The authors studied the effect of long-term omeprazole therapy on antral G- and D-cell numbers in children. Six children received omeprazole for 4 to 7 years for erosive reflux esophagitis. Endoscopic antral biopsy specimens obtained at baseline and at 1, 4, and 7 years of omeprazole administration were immunostained to assess G and D cell numbers per antral gland. The G- and D-cell numbers were also assessed in an age-matched control group consisting of 24 healthy children from six different age groups. The mean G-cell number per unit area showed a significant increase at 4 years (85 +/- 5.7 years) and at 7 years (89 +/- 6.8 years) on omeprazole compared with baseline (56 +/- 4.8 years) ( P < 0.01). D-cell numbers did not change. The ratio of G to D cells increased progressively, and the change from baseline was significant at 7 years taking omeprazole ( P < 0.02). In the control group, G- and D-cell numbers did not differ significantly within the six age groups. Long-term omeprazole therapy is associated with a significant increase in G-cell numbers and in the ratio of G to D cells in children. These changes reflect the effect of omeprazole because there was no change in these parameters in the age-matched control group.

The role of gastrin in ulcer pathogenesis

Duodenal ulcer patients are characterized by an antrum-predominant, body-sparing, non-atrophicHelicobacter pylori (H. pylori) gastritis, which results in increased gastrin release and increased acid secretion. The increased gastrin release is caused by the infection impairing the acid-mediated inhibitory control of gastrin release. The elevated levels of the gastrin stimulate the healthy uninflamed, non-atrophic acid-secreting region of the stomach to secrete excess amounts of acid. The increased gastrin also exerts trophic effects on the oxyntic mucosa, causing hyperplasia of both the enterochromaffin-like cells and the parietal cells. These trophic changes in the mucosa further enhance its ability to secrete acid. The increased acid secretion results in an increased duodenal acid load, causing gastric metaplasia of the duodenal bulb and eventually the development of ulceration.In H. pylori -infected subjects without duodenal ulceration, a different pattern of gastritis is seen. This includes atrophy of the antrum, which reduces the number of G-cells and thus the degree of hypergastrinaemia induced by the antral infection. There are usually also varying degrees of inflammation and atrophy of the acid-secreting mucosa, which impair its ability to secrete acid in response to gastrin stimulation. The combined effects of the atrophy of the antrum and the inflammation of the antrum of the body mucosa therefore prevent H. pylori -induced acid hypersecretion and may result in varying degrees of hypochlorhydria.The particular pattern of gastritis that a subject develops in response to H. pylori infection and their likelihood of developing a duodenal ulcer is likely to be determinded by host genetic factors plus dietary factors.

Effect of Helicobacter pylori infection on antral gastrin and somatostatin cells and on serum gastrin concentrations.

ObjectivesHelicobacter pylori infection induces selective reduction of the number of antral D-cells and results in abnormal regulation of serum gastrin secretion. The purpose of this study was to investigate the relationship between H. pylori infection and the numbers of G-cells and D-cells.MethodsThe numbers of antral G-cells and D-cells, the ratio of G-cells to D-cells and fasting serum gastrin concentrations were compared between 37 patients with (29 with duodenal ulcers and 8 with gastric ulcers) and 33 without H. pylori infection (22 with duodenal ulcers and 11 with gastric ulcers). Serum gastrin concentrations were measured using the radioimmunoassay technique. Antral mucosal biopsy specimens were examined using immunohistochemical staining with antibodies specific for gastrin and somatostatin and the numbers of G-cells and D-cells per gastric gland were counted.ResultsFasting serum gastrin concentrations were significantly higher in patients with H. pylori infection compared to patients without infection (80.3±23.5 vs 47.6±14.1 pg/ml, p<0.001). The number of G-cells per gastric gland was similar in infected and uninfected patients (7.1±3.1 vs 7.3±3.9, respectively, p>0.5). The number of D-cells was significantly lower in patients with H. pylori infection than in uninfected patients in both duodenal and gastric ulcer patients (1.3±0.4 vs 2.5±1.6, respectively, p<0.001). The ratio of G-cells to D-cells was also significantly higher in infected patients compared with uninfected patients for both gastric and duodenal ulcers (5.7±2.7 vs 3.5±1.9, respectively, p<0.001).ConclusionsThese results strongly suggest that Helicobacter pylori infection induces reduction of the number of antral D-cells. The resulting relative hypofunction of the inhibitory action of D-cells against G-cells may be responsible for increased serum gastrin secretion.

The G-cells in the dog: a light and electron microscope immunocytochemical study.

An immunohistochemical study has been performed to analyse the distribution of gastrin cells in the gastrointestinal tract of the dog. This study revealed that G-cells immunoreactive for gastrin were almost exclusively present in the pyloric antral mucosa, mainly in the middle third of the pyloric mucosa. The calculated number of G-cells per surface unit area was 8.5 x 10(3)-1.2 x 10(4) cells cm-2. Some gastrin-immunopositive cells were found in the first 10 mm of the proximal duodenum, mainly in the villous region. The fundic area of the dog stomach, the oesophagus, small intestine, caecum, colon, rectum, salivary glands, liver and pancreas were all immunonegative for gastrin. At the ultrastructural level, three different types of granules (150-400 nm) were evident in G-cells: electron-dense, electron-lucent and intermediate forms. Most of them were located in the subnuclear region of the cell. The effect of fixation of the antral mucosa at different pH levels was studied. In samples fixed with acid solutions, most of the G-cell granules were of the electron-dense type and were strongly immunopositive for gastrin. Fixation of samples at a basic pH resulted in most of the gastrin granules losing their contents into the cytoplasm, and the positive reaction to gastrin was then located in the cytoplasm and at the periphery of the electron-lucent granules.

Alteration in gastric nerve fibers containing gastrin-releasing peptide in relation to the gastrin-producing cell population after truncal vagotomy in a rat model

The fine structural alteration in the gastric nerve fibers containing gastrin-releasing peptide (GRP) was studied in relation to the dynamics of gastrin-producing cells (G-cells) after truncal vagotomy in a rat model. The circulating gastrin levels were markedly elevated from the 1st day after vagotomy and the number of G-cells with positive immunoreaction for G17 and G34(1-15) was significantly increased in the vagotomized group. On the 3rd day after vagotomy, the G-cells showed conspicuous ultrastructural changes characterized by hypertrophy of the Golgi complexes and increased numbers of secretory granules. The GRP-positive nerve fibers formed a fine network in the gastric wall and were densely distributed in the oxyntic mucosa close to the blood vessels and showing varicosities composed of either small clear or GRP-positive large vesicles containing an electron-dense core. In the oxyntic mucosa of the vagotomized rats, axonal swelling of the nerves occurred on the 3rd day, and a depletion of GRP immunoreactivity was evidenced by a markedly decreased number of large-cored vesicles on the 7th day, when the serum GRP levels were also found to be markedly elevated. These findings indicate that the alteration in gastric nerve fibers containing GRP after truncal vagotomy may be related to hypergastrinemia and antral G-cell hyperplasia in the rat gastric mucosa.

Chronic systemic treatment with epidermal growth factor induces hypergastrinaemia in Goettingen minipigs.

Epidermal growth factor (EGF) is an inhibitor of gastric acid secretion. The impact of chronic systemic treatment with EGF on intragastric pH and serum gastrin concentrations has not been investigated previously. Goettingen minipigs were treated with human recombinant EGF (hEGF) or placebo for 4 weeks. Once a week the acidity and protein concentration of gastric juice were determined, and serum gastrin concentrations measured. After 4 weeks, tissue specimens were obtained from the gastric antrum and immunostained for gastrin- and somatostatin-producing G- and D-cells. Furthermore, the development of antibodies against hEGF was evaluated. Subcutaneously administered hEGF, 30 micrograms/kg/day for 4 weeks, included a fourfold increase in basal serum gastrin concentration, increased the number of antral G-cells, and decreased the density of antral D-cells. The acidity of gastric fluid was reduced, and the protein concentration increased. All animals developed low-titred antibodies towards hEGF. The antibodies did not influence the extent to which the individual animal responded to the EGF treatment.

Antral G-cell and D-cell numbers in Helicobacter pylori infection: Effect of H. pylori eradication

Background: It has recently been recognized that Helicobacter pylori infection is associated with abnormalities in the regulation of gastrin secretion. We investigated whether there was a relationship between H. pylori infection and G-cell and D-cell numbers. Methods: The numbers of antral G cells and D cells were compared between 20 patients with duodenal ulcer and 24 volunteers, 12 with and 12 without H. pylori infection. The effect of eradication of H. pylori infection on G-cell number was also evaluated. Antral mucosal biopsy specimens were examined using immunohistochemical techniques specific for the presence of gastrin and somatostatin. Results: The number of G cells was significantly (P < 0.02) less in patients with duodenal ulcer than in either infected or uninfected controls (3.7 0.3 vs. 6.2 ± 0.6 and 5.3 ± 0.5 G cells per gland for infected and uninfected controls, respectively). The ratio of G-cells to D-cells was similar in duodenal ulcer patients (2.2) and uninfected controls (2.0). It was found that, although eradication of the H. pylori infection results in a dramatic reduction in stimulated gastrin secretion, it is not associated with a change in the numbers of antral G cells or D cells in patients with duodenal ulcer. Conclusions: It is concluded that H. pylori infection-associated increase in gastrin secretion appear to be related to local factors regulating G-cell function.

Gastrin and gastrin-related responses to infection with Ostertagia ostertagi in the half

The effects of a single challenge with 60,000 infective Ostertagia ostertagi larvae on blood and gastrointestinal mucosal gastrin concentrations, gastrin-producing G-cell numbers in the pyloric mucosa and growth of different parts of the gut were investigated in 16, two-and-a-half-month-old calves. Infected calves exhibited a rise in abomasal pH which was accompanied by a 145 per cent increase in wet weight of the fundic mucosa (P<0·05) and a significant rise in blood total gastrin concentrations (P<0·01). Circulating little gastrin (G-17) was unaffected. Pyloric mucosal total gastrin concentrations remained unaltered in the infected calves until day 28 when levels fell to 36·9 per cent of control group values (P<0·01). Pyloric mucosal G-cell numbers declined during the experiment in the infected group. It is suggested that release of previously stored tissue gastrin and not a change in Gcell numbers contributes to the hypergastrinaemia associated with ostertagia infection in the calf.

Effect of Experimental Hypochlorhydria on the Histological Differentiation of Adenocarcinomas in the Canine Stomach

Hypochlorhydria is considered to be a risk factor for gastric cancer, both clinically and experimentally. In humans, the hypo‐acidic condition appears to be closely associated with the development of differentiated‐tyne gastric carcinomas. We investigated relationships between antral pH and histological types of gastric cancer using an animal model. A total of 7.65 g of N‐ethyl‐N′‐nitro‐N‐nitrosoguanidine (ENNG) was orally administered to male beagle dogs. Subsequently, the dogs were divided into four groups and underwent four surgical interventions designed to create various conditions in the antrum. Antral pM was recorded at the time of killing after an observation period ranging from 16 to 33 months. The number of gastrin‐secreting cells (G‐cells) was counted after immunohistochemical staining. Carcinomas were found in the antrum of 12 of the 21 dogs that had survived. Although limited doses of ENNG, such as those used in this study, have been reported to produce only undifferentiated adenocarcinomas, differentiated adenocarcinomas were found in seven of these 12 dogs. Antral pH and the number of G‐cells were significantly higher in these seven dogs than in the other five dogs, which had developed only undifferentiated adenocarcinomas. Bile inflow showed no significant effect on the development of differentiated adenocarcinomas. Neither atrophic gastritis nor intestinal metaplasia was seen in any of the dogs. These results suggest that the hypo‐acidic condition itself may play a role in the development of differentiated adenocarcinomas.

Effect of Helicobacter pylori eradication on antral gastrin- and somatostatin-immunoreactive cell density and gastrin and somatostatin concentrations.

The density of antral gastrin (G)- and somatostatin (D)-immunoreactive cells and the contents of antral gastrin and somatostatin were investigated in endoscopic antral biopsy specimens from patients with duodenal ulcer before and after eradication of Helicobacter pylori. After H. pylori eradication both antral somatostatin concentration (p = 0.0002) and antral D-cell density (p = 0.01) increased significantly. Conversely, although the number of G-cells was unchanged, antral (p = 0.0002) and serum (p = 0.001) gastrin contents decreased significantly. The number of oxyntic D-cells did not change significantly. These results strongly suggest that the hypergastrinaemia observed in H. pylori-positive patients may be due to a deficiency in antral somatostatin, which normally inhibits the synthesis and release of gastrin.

Response of the antral mucosa of the rat stomach to 2,3,7,8-tetrachlorodibenzo- p-dioxin

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) produces a striking hypergastrinemia in rats that is thought to mediate the antiatrophy effect of TCDD on the oxyntic gland mucosa of the stomach. However, effects of TCDD on the antral mucosa, which is the origin of most physiologically released gastrin and is not a target for the trophic action of gastrin, has yet to be thoroughly investigated. Also gastrin release from gastrin-containing cells (i.e., G-cells) in the antral mucosa is inhibited by the paracrine secretion of somatostatin from D-cells in the antrum. Our purpose was to determine if the antral mucosa is affected by the trophic influence of TCDD and if alterations in antral mucosa levels of gastrin or somatostatin cause the hyper-gastrinemia. TCDD (100 μg/kg, Day 14 post-treatment) had a trophic effect on the antral mucosa. This was demonstrated histologically and by significant increases in antral wet weight and antral mucosa height. In contrast, pair-fed control rats that lost the same amount of body weight developed antral mucosa atrophy. With respect to serum and antral levels of gastrointestinal hormones, TCDD produced a 7- to 10-fold increase in serum gastrin concentrations that was not detected until Day 14 post-treatment. In contrast, serum gastrin concentrations in pair-fed control rats were comparable to those of control rats. The number of G-cells in the antral mucosa was not affected by either TCDD treatment or paired-feed restriction. These findings demonstrate that hypergastrinemia in TCDD-treated rats is not caused by reduced feed intake or antral G-cell hyperplasia. A major finding was that antral mucosa levels of both gastrin and somatostatin were decreased significantly in TCDD-treated rats. However, the temporal development and dose-decreased of these TCDD effects on antral hormone levels were quite different than those for hypergastrinemia. TCDD-induced decreases in antral levels of gastrin and somatostatin were detected 1 week earlier than hypergastrinemia. Also, the ED50 of TCDD on Day 14 post-treatment for the decrease in antral mucosa content and concentration of gastrin (29 and 22 μg/kg, respectively) and somatostatin (24 and 19 μg/kg, respectively) was less than that for hypergastrinemia (46 μg/kg). These time- and dose-dependent differences demonstrate that hypergastrinemia in TCDD-treated rats is not a consequence of reduced antral levels of gastrin or somatostatin. We conclude that the antral mucosa, an epithelial tissue not responsive to the proliferative effect of gastrin, is nevertheless a target for the trophic influence and gastrointestinal hormone-altering effects of TCDD.