Enterochromaffin-like Cell Density Research Articles

The gastric mucosa 25 years after proximal gastric vagotomy

Objective. Vagotomy causes inhibition of basal and post-prandial acid secretion in humans, but the knowledge about the trophic effect of the vagal nerves is limited. Vagotomy is known to induce hypergastrinemia and we aimed to study the long-term effects of proximal gastric vagotomy (PGV) on the oxyntic mucosa and the enterochromaffin-like (ECL) cell density in particular. Material and methods. Eleven patients operated with PGV because of duodenal ulcer and age- and sex-matched controls were examined 26 to 29 years postoperatively by gastroscopy with biopsies from the antrum and oxyntic mucosa. Neuroendocrine cell volume densities were calculated after immunohistochemical labeling of gastrin, the general neuroendocrine cell marker chromogranin A (CgA) and the ECL cell marker vesicular monoamine transporter 2 (VMAT2). Gastritis was graded and Helicobacter pylori (H. pylori) status was determined by polymerase chain reaction of gastric biopsies. Fasting serum gastrin and CgA were measured. Results. Serum gastrin was higher in the PGV group compared to controls (median 21.0 [interquartile range (IQR) = 22.0] pmol/L vs 13.0 [IQR = 4.0] pmol/L, p = 0.04). However, there was neither a significant difference in serum CgA or in CgA (neuroendocrine) nor VMAT2 (ECL cell) immunoreactive cell volume density in the oxyntic mucosa. There was significantly more inflammation and atrophy in H. pylori-positive patients, but PGV did not influence the grade of gastritis. Conclusion. Despite higher serum gastrin concentrations, patients operated with PGV did not have higher ECL cell mass or serum CgA. Vagotomy may prevent the development of ECL cell hyperplasia caused by a moderate hypergastrinemia.

Long‐term, open‐label trial: safety and efficacy of continuous maintenance treatment with pantoprazole for up to 15 years in severe acid‐peptic disease

To date, the safety and tolerability of proton pump inhibitors (PPIs) have been demonstrated in studies of up to 10 years. To report on the tolerability, safety and efficacy of up to 15 years' continuous treatment with pantoprazole in patients with severe acid-peptic disease. Following healing of endoscopically confirmed peptic ulcer or reflux oesophagitis during 4-12 weeks' treatment with pantoprazole (40-80 mg/day), adult patients received open-label maintenance treatment with pantoprazole (40-160 mg/day) for up to 15 years in a single centre combined study (10-year initial study; 5-year extension study). Safety assessments were carried out using endoscopy, clinical examination, clinical laboratory investigations, serum gastrin determination, gastric mucosal histology and mucosal endocrine cell quantification. The safety set comprised 142 patients. At 12 weeks, healing rates were 95.8%. During long-term treatment, mean fasting gastrin levels rose from baseline to moderate levels throughout the study. Mean enterochromaffin-like cell density showed a moderate initial increase during the first 3 years, remaining stable thereafter. These changes were not associated with any clinically relevant changes of the gastric mucosa. Patients with successful Helicobacter pylori eradication showed long-term regression of antral and corpus gastritis during continued pantoprazole treatment. Daily pantoprazole maintenance therapy for up to 15 years for severe acid-peptic disease is effective and well tolerated, with no identified safety concerns. The longest study to date, these data provide reassuring evidence for the long-term safety of pantoprazole.

Five-year follow-up of patients treated for 1 year with octreotide long-acting release for enterochromaffin-like cell carcinoids

Background. Gastric carcinoids type 1 (GC1) are neuroendocrine tumors (NETs) arising from the enterochromaffin-like (ECL) cells in patients with chronic atrophic gastritis (CAG). The treatment of GC1 has been endoscopic polypectomy or surgical tumor excision and antrectomy. One year treatment with somatostatin analogs (SSAs) diminished tumor load and ECL cell density. The effect persisted 1 year after treatment was discontinued. However, the optimal SSA dose and treatment duration are unknown. Objectives. The aim of the present work was to study macroscopic and histopathological changes in the stomach and serum markers gastrin and chromogranin A (CgA) in GC1 patients 5 years after 1 year of octreotide long-acting release (LAR) treatment. Material and methods. Five patients with GC1 were included 5 years after the initial year of octreotide LAR treatment. All patients underwent upper gastrointestinal endoscopy including tumor and mucosal biopsies from oxyntic mucosa, chest and abdominal computer tomography and octreotide scintigraphy. Fasting serum gastrin and CgA were also measured. Results. At 5 years, one patient had a highly malignant gastric tumor, one patient had an increased number of GCs, regional and distant metastases and three patients had an increased number of GCs. Serum gastrin and CgA increased to pre-treatment levels after 1 year of follow-up and were unchanged at the 5-year follow-up. Conclusions. The disease had progressed in all five GCs patients treated with octreotide for 12 months at 5 years of follow-up. This suggests that, if started, octreotide treatment should not be discontinued in these patients.

Effects on the rat oxyntic mucosa of the histamine2-antagonist loxtidine and the H+, K(+)-ATPase inhibitor omeprazole.

The present study examined whether histamine could affect the growth of the enterochromaffin-like (ECL) cell and the parietal cell. The effects of the unsurmountable histamine H2-receptor antagonist loxtidine (80 mg/kg) and the H+, K(+)-ATPase inhibitor omeprazole (100 mumol/kg) were compared in female Sprague-Dawley rats. Both drugs were given by gavage once daily for 3 months. Omeprazole induced a more pronounced and sustained hypergastrinaemia than loxtidine. In spite of marked hypergastrinaemia during most of the day, even in the loxtidine-treated rats, the weights of the stomach and oxyntic mucosa were elevated only in the omeprazole-treated rats. The ECL cell density was slightly higher in the loxtidine- than in the omeprazole-treated rats. Both treatments elevated the gastrin-stimulated histamine release from the vascularly perfused stomach. The parietal cell density was unaffected by omeprazole treatment, whereas it tended to be reduced in the loxtidine-treated rats. Simultaneous administration of loxtidine and omeprazole reduced the sustained hypergastrinaemia induced by omeprazole given alone. The present study may indicate that histamine inhibits the growth of the ECL cell, but further studies are needed to elucidate if histamine has any trophic effect on the parietal cells.

Changes in gene expression of gastric mucosa during therapeutic acid inhibition

Long-term therapy with potent acid inhibitors is a common treatment for gastro-esophageal reflux disease. Administration of proton pump inhibitors (PPIs) causes profound and continuous hypochlorhydria by inhibition of the proton pump in gastric parietal cells. Long-term hypergastrinaemia increases mucosal thickness and enterochromaffin-like cell density in oxyntic mucosa. The aim of this study was to see whether this very common clinical intervention induces significant changes in the gastric mucosal gene expression pattern. Seven patients suffering from gastro-esophageal reflux disease were included in this study. Endoscopic biopsies were taken from the corpus mucosa before and toward the end of a 3-month treatment with the PPI esomeprazole. Microarray analysis identified 186 differentially expressed genes. A high proportion of genes with changed gene expression levels during PPI treatment are involved in proliferation, apoptosis, and stress response. This study identified many genes that were not previously known to be affected by inhibition of gastric acid secretion. Further characterization of the functional roles of genes whose expression is modulated by potent acid inhibition may give new insight into the biological responses to potent acid inhibition, including the mucosal response to the moderately increased gastrin levels encountered in clinical practice.

Molecular characterization of rat gastric mucosal response to potent acid inhibition

Potent acid inhibition with proton pump inhibitors (PPIs) is widely used in clinical medicine, especially for gastroesophageal reflux disease. PPIs cause profound changes in the intragastric environment with near-neutral pH and increase serum concentration of the gastric secretagogue hormone gastrin. Long-term hypergastrinemia increases mucosal thickness and enterochromaffin-like cell density in gastric corpus mucosa and results in development of gastric carcinoids in experimental animals. Our aim was to study responses to potent acid inhibition by characterizing genome-wide gene expression changes in gastric corpus mucosa in rats dosed with the PPI omeprazole. Nine rats received 400 micromol/kg omeprazole daily for 10 wk. Seven rats received vehicle only. Analysis of gastric corpus with microarrays representing 11,848 genes identified 134 genes with changed gene expression levels in omeprazole-dosed rats. Several of the identified genes were previously known to be affected by potent acid inhibition. Of the 62 genes with known functions that changed gene expression levels after PPI dosing, 27 are known to be involved in proliferation and apoptosis and immune, inflammatory, and stress responses. Our study indicates that microarray analysis can detect relevant gene expression changes in the complex gastric tissue, and that cellular processes involved in cell growth and defense responses are strongly affected by PPI dosing. Many genes are identified that were not previously known to be affected by inhibition of gastric acid secretion or that have unknown biological functions. Characterization of the roles of these genes may give new insight into molecular responses to treatment with PPIs.

Neuroendocrine tumor markers and enterochromaffin-like cell hyper/dysplasia in type 1 diabetes.

Parietal cell antibodies (PCAs) are found in 20% of type 1 diabetic patients, denoting autoimmune gastritis and pernicious anemia, which may predispose to enterochromaffin-like (ECL) cell hyper/dysplasia and gastric carcinoid tumors. We evaluated whether chromogranin A (CgA), 5-hydroxyindole acetic acid (5-HIAA), and neuron-specific enolase (NSE) contribute to screening for ECL cell hyper/dysplasia. Sera from 93 type 1 diabetic patients (53 men and 40 women, 31 PCA(+) and 62 PCA(-), aged 45 +/- 13 years) were analyzed for PCAs by indirect immunofluorescence and for CgA, NSE, and gastrin by radioimmunoassay. Urinary 5-HIAA was tested by high-performance liquid chromatography. Corpus atrophy and ECL cell proliferation were assessed in gastric biopsies. PCA(+) patients had higher gastrin (P < 0.0001) and CgA levels (P = 0.003) and were more prone to autoimmune gastritis (odds ratio [OR] 17, P < 0.0001) and ECL cell hyper/dysplasia (OR = 23, P = 0.005) than PCA(-) subjects. ECL cell hyper/dysplasia was present in seven PCA(+) patients who showed higher CgA levels (P < 0.0001) than subjects without ECL cell hyper/dysplasia, but NSE and 5-HIAA levels were similar. CgA levels correlated with gastrinemia (r = 0.50, P < 0.0001), PCA titer (r = 0.42, P = 0.001), and 5-HIAA levels (r = 0.38, P = 0.012). Logistic regression identified the CgA level (beta = 0.01, P = 0.027) as an independent risk factor for ECL cell hyper/dysplasia when PCA, CgA, 5-HIAA, NSE, gastrin, sex, and age were tested. Multivariate linear regression demonstrated that CgA level was determined by ECL cell density (r = 0.59, P < 0.0001) and gastrin level (r = 0.67, P = 0.02). One PCA(+) patient with elevated gastrin, CgA, and 5-HIAA levels had a gastric carcinoid tumor. PCA(+) patients, particularly those with high gastrin and CgA levels, risk developing ECL cell hyper/dysplasia. The determination of CgA, but not NSE and 5-HIAA, may complement histology in evaluating ECL cell mass.

Treatment of ECL cell carcinoids with octreotide LAR

Background: Patients with chronic atrophic gastritis (CAG) and hypergastrinaemia are at risk of developing hyperplasia of the enterochromaffin‐like (ECL) cells and ECL‐cell‐derived tumours. The effect of the somatostatin analogue octreotide on ECL cell carcinoids is examined. Methods: Five patients with hypergastrinaemia and ECL cell carcinoids were enrolled in a 1‐year study of octreotide LAR (long‐acting release) 20 mg given at monthly intervals. Biopsies from tumours and from flat oxyntic mucosa were done at the start and 3, 6 and 12 months thereafter. Sections were stained with haematoxylin‐erythrosin, immunostained with chromogranin A (CgA) and doublestained with CgA and Ki‐67. Serum gastrin and CgA were measured. Results: The number of visible tumours was reduced by more than 50 %. Sections from both tumours and flat mucosa showed a reduced number of CgA immunoreactive cells. Mean serum gastrin decreased from 421 to 186 pM (normal <40 pM); P > 0.05, and serum CgA from 73 to 25 ng/ml (normal <30 ng/ml); P < 0.001. Conclusions: During treatment the patients were still markedly hypergastrinaemic, whereas the serum CgA showed normalization. A diminished tumour load and reduced ECL cell density were found, indicating an antiproliferative effect of octreotide directly on the ECL cells.

Helicobacter pylori effects on gastritis, gastrin and enterochromaffin-like cells in Zollinger-Ellison syndrome and non-Zollinger-Ellison syndrome acid hypersecretors treated long-term with lansoprazole.

Helicobacter pylori is said to cause atrophy of the gastric corpus and enterochromaffin-like cell proliferation in gastro-oesophageal reflux disease (GERD) patients treated long-term with a proton pump inhibitor. To determine the effect of H. pylori infection on gastritis, enterochromaffin-like cell density and hyperplasia, mucosal atrophy and serum gastrin in patients with gastric hypersecretion (basal acid output gt; 15 mmol/h) with either hypergastrinemia (Zollinger-Ellison syndrome) or normal gastrin (non-Zollinger-Ellison syndrome) before and during long-term treatment with lansoprazole. Lansoprazole was individually titrated to reduce basal acid output to < 5 mmol/h (< 1 mmol/h in post-surgical Zollinger-Ellison syndrome). Gastric corpus biopsies were obtained every 6 months before treatment and up to 8 years later. H. pylori was present in corpus biopsies in approximately 50%, causing active gastritis which resolved rapidly in 15 subjects after elimination of H. pylori. Patchy mild/moderate corpus atrophy was present at entry in two and at the end in four out of 60 patients, one being H. pylori-positive. Intestinal metaplasia (< 10%) was seen in six isolated biopsies (1% of total). H. pylori did not affect serum gastrin, enterochromaffin-like cell density or hyperplasia. Enterochromaffin-like cell density was twice as high in Zollinger-Ellison syndrome as in non-Zollinger-Ellison syndrome patients (241 vs. 126 cells/mm2, P < 0.001). Enterochromaffin-like cells remained normal in the non-Zollinger-Ellison syndrome hypersecretors regardless of H. pylori status. Corpus enterochromaffin-like cell increases were related to serum gastrin elevation, but neither H. pylori nor long-term treatment with lansoprazole alone or together had any effect on enterochromaffin-like cell density or hyperplasia. Corpus acute gastritis resulted from H. pylori infection, but did not result in mucosal atrophy despite long-term proton pump inhibitor treatment and promptly resolved with loss of H. pylori.

Spontaneous ECLomas in cotton rats (Sigmodon hispidus): tumours occurring in hypoacidic/hypergastrinaemic animals with normal parietal cells.

We have identified cotton rats with a high female-predominant occurrence of spontaneous gastric carcinomas localized to the oxyntic mucosa, classified as malignant enterochromaffin-like (ECL) omas. The present study was made to further characterize these ECLomas and surrounding oxyntic mucosa, both morphologically using histochemical and immunohistochemical methods, and for gene expression by northern blot analysis. Among eight female cotton rats, three had an irregularly thickened oxyntic mucosa, increased stomach weight and a high serum gastrin level. Histopathological examination showed adenomatous hyperplasia of the thickened oxyntic mucosa with areas of an invasive neoplastic tumour. Immunohistochemistry, using the general neuroendocrine cell marker chromogranin A (CgA) and the specific ECL cell marker histidine decarboxylase (HDC), showed a considerably increased ECL cell density. These ECL cells displayed active proliferation, with hyperplasia, dysplasia and neoplasia. Parietal cells were not found in the tumour tissue. Parietal cell density was only slightly reduced in the surrounding oxyntic mucosa. The antral mucosa was histopathologically normal with a normal number of gastrin-immunoreactive cells. Likewise, somatostatin-immunoreactive cells did not show any differences in the antral and oxyntic mucosa between rats with pathological and normal oxyntic mucosa. Northern blot analysis revealed increased expression of CgA and HDC mRNA in the thickened oxyntic mucosa, whereas H(+)/K(+) ATPase mRNA was similar in the oxyntic mucosa of those with thickened and normal oxyntic mucosa. Gastrin mRNA in the antral mucosa was high in animals with thickened oxyntic mucosa. Somatostatin mRNA expression was similar in the antral mucosa of control animals and animals with a thickened oxyntic mucosa. We conclude that the spontaneous gastric carcinoma occurring in female cotton rats is an ECLoma developing secondary to hypergastrinaemia due to reduced intragastric pH. The mechanism for reduced acidity is not known, but is not gastric atrophy.

Quantitation of glandular gastric changes in rats given a proton pump inhibitor for 3 months with emphasis on sampling scheme selection.

Proton pump inhibitors and H2-receptor antagonists suppress gastric acid secretion and secondarily induce hypergastrinemia. Sustained hypergastrinemia has a trophic effect on stomach fundic mucosa, including enterochromaffin-like (ECL) cell hypertrophy and hyperplasia. Histomorphometric quantitation of the pharmacologic gastric effects was conducted on 10 male and 10 female rats treated orally with LY307640 sodium, a proton pump inhibitor, at daily doses of 25, 60, 130, or 300 mg/kg for 3 mo. Histologic sections of glandular stomach, stained for chromogranin A, were evaluated by image analysis to determine stomach mucosal thickness, mucosal and nonmucosal (submucosa and muscularis) area, gastric glandular area, ECL cell number/area and cross-sectional area. Total mucosal and nonmucosal tissue volumes per animal were derived from glandular stomach volumetric and area data. Daily oral doses of compound LY307640 sodium caused slight to moderate dose-related mucosal hypertrophy and ECL cell hypertrophy and hyperplasia in all treatment groups as compared with controls. All observed effects were prominent in both sexes but were generally greater in females. The morphometric sampling schemes were explored to optimize the data collection efficiency for future studies. A comparison between the sampling schemes used in this study and alternative schemes was conducted by estimating the probability of detecting a specific percentage of change between the male control and high-dose groups based on Tukey's trend test. The sampling scheme analysis indicated that mucosal thickness and mass had been oversampled. ECL cell density quantitation efficiency would have been increased by sampling the basal mucosa only for short-term studies. The ECL cell size sampling scheme was deemed appropriate for this type of study.

Gastric mucosal histamine storing cells

Gastric mucosal histamine content, enterochromaffin-like cell density, and mast cell density were studied in 13 subjects under omeprazole therapy, 13 partially gastrectomized subjects with a Billroth II reconstruction, 10 partially gastrectomized subjects with a Roux-en-Y reconstruction, and 9 control subjects. Histamine content was significantly greater both in the subjects with higher gastrinemic levels (omeprazole-treated subjects) and those with more abundant enterogastric reflux (Billroth II subjects) than in controls. Enterochromaffin-like cell density was significantly greater in the omeprazole subjects than in each of the other groups. Mast cell density was significantly greater in Billroth II subjects than in controls. Serum gastrin levels, mucosal histamine content, and enterochromaffin-like cell density were positively correlated. Gastrin was not correlated to mast cell density. These results support the existence of different control pathways for enterochromaffin-like and mast cells. Moreover, they suggest that enterochromaffin-like cells and mast cells are involved in the regulation of gastric secretion and in gastric mucosal injury-repair mechanisms, respectively, due to histamine release.

Gastrin mediates the increase in gastric cell growth in uremic rats

In a rat model of chronic renal failure, we recently reported that hypergastrinemia was associated with increased stomach weight and parietal cell and enterochromaffin-like (ECL) cell density. In this study, the role of gastrin in mediating trophic effects of uremia on the gastric mucosa was examined by chronic immunoneutralization of endogenous gastrin in the sub-total nephrectomy uremic rat model. Three weeks after surgery, the rats were uremic (azotemic and hypertensive). Uremic rats had a significant increase in corpus mucosal height (17%), parietal cell density (14%), ECL cell density (27%), and basal gastric mucosal blood flow (63%). These effects were specifically inhibited by chronic administration of gastrin-specific monoclonal antibody (5 mg ip every other day) in the 3-wk postoperative period. Uremic rats also had an increase in stomach weight (23%), corpus mucosal area (8%), arterial blood pressure, and serum creatinine and a decrease in body weight. Gastrin immunoneutralization did not alter these effects. The findings suggest that elevated levels of endogenous circulating gastrin in uremic rats mediate, in part, the trophic response observed in the gastric mucosa.

Detection of Cholecystokinin B/Gastrin Receptor mRNA Expressing Cells in the Stomach of Hypergastrinemic Rats.

Enterochromaffin-like (ECL) cells, which are numerous in the oxyntic mucosa of the rat stomach, proliferate in the presence of hypergastrinemia. We investigated the distribution of cells expressing gastrin receptor (GR) in Sprague-Dawley rats in which hypergastrinemia was induced by partial gastric corpectomy. The ECL cell density was determined by immunohistochemical staining for histamine. The expression of GR mRNA was investigated using digoxigenin-labeled complementary RNA probes. The labeling index of the generative cell zone was determined by 3H-thymidine autoradiography. The ECL cell density and the labeling index in the generative cell zone increased in association with increased plasma levels of gastrin after 24 weeks (p<0.05). The expression of GR mRNA was seen not only in ECL, generative, parietal and chief cells, but also in stromal cells of hypergastrinemic rats. The expression of GR mRNA became more marked in the oxyntic mucosa as plasma levels of gastrin increased, and it was suggested that GR mRNA expression acts as one indication in the development of ECL cell hyperplasia.

Uremia in the rat affects gastric cell growth and differentiation

The aim of this study was to determine if hypertrophy of different tissues seen in uremic rats included gastrointestinal hypertrophy and an increase in parietal cell mass that might explain the increased acid secretion we previously reported. Chronic renal failure was induced by subtotal nephrectomy. Despite a lower total body weight, uremic rats had a significantly greater stomach weight (33%), corpus area (13%), corpus mucosal height (19%), and parietal (32%) and enterochromaffin-like (ECL, 54%) cell density, but a 16% decrease in mucous neck cell region height. These findings suggest that uremia leads to gastric stem cell stimulation with differentiation favoring parietal and ECL cells over mucous cells. In addition, in uremic rats there was an increase in height of the duodenal mucosa, but not of the ileal or transverse colon mucosa. In conclusion, the present study shows that uremia in the rat promotes hypertrophy of the stomach with cell differentiation favoring parietal cells over mucus cells. The increase in parietal cell mass may explain the increased acid secretion in these rats.

Hyperplastic manifestations of enterochromaffin-like cells in the stomach of rats with congenital moderate hypergastrinemia.

The effect of moderate congenital hypergastrinemia on the enterochromaffin-like (ECL) cells was investigated in Zucker rats 4 and 18 months of age by combining autoradiography after tritiated thymidine injection and selective immunocytochemistry. In both age groups the serum gastrin concentration was 200% higher in obese (fa/fa) than in lean (Fa/Fa; Fa/fa) littermates. In 4-month-old obese rats there was a 120% increase (p < 0.05) in the ECL cell labeling index and also a moderate increase in the ECL cell density (p < 0.05) compared with lean controls. In 18-month-old obese rats the hyperplasia was quantitatively more prominent, with both linear and micronodular ECL cell hyperplasia. At this stage, the ECL cell labeling indices in obese and in lean animals were similar. These data support the hypothesis that moderate hypergastrinemia initially accelerates the ECL cell proliferation rate, leading to diffuse ECL cell hyperplasia. In similar conditions, at the latter stage, linear and micronodular ECL cell hyperplasia also develop in most of the hypergastrinemic animals.

Effect of pantoprazole on 24-h intragastric pH and serum gastrin in humans.

Pantoprazole, a novel proton pump inhibitor, is a potent inhibitor of gastric acid secretion. In this review, data are presented from nine controlled, prospective, clinical pharmacodynamic investigations. The effects of oral and intravenous doses of pantoprazole (administered for 5-7 days) on continuously monitored 24-h intragastric pH and serum gastrin are discussed: oral pantoprazole 20 to 80 mg/day (given in the morning before breakfast) induced a dose-related increase in both the 24-h intragastric pH and the serum gastrin profile. The effects of pantoprazole doses of 60 and 80 mg were not significantly different from those of the 40 mg dose. It was concluded that oral pantoprazole at 40 mg/day is the optimal antisecretory dose for the treatment of acid-related diseases. In two comparative studies, this dose of pantoprazole (administered before breakfast) proved to be significantly more effective than ranitidine 300 mg (given in the evening) and omeprazole 20 mg (given in the morning). Administration of oral and intravenous pantoprazole (40 mg) was found to be equipotent at increasing 24-h intragastric pH, but this finding requires further evaluation. The approximately 2-4-fold rise in median serum gastrin concentrations following several days' administration of pantoprazole 40 mg is of a comparable magnitude to that of other proton pump inhibitors. It seems unlikely that this moderate hypergastrinaemia during pantoprazole treatment should influence the human enterochromaffin-like (ECL) cell density in a clinically relevant way, but data during long-term therapy are necessary to confirm this conclusion.

Time-dependent changes in enterochromaffinlike cell kinetics in stomach of hypergastrinemic rats

Background: Hypergastrinemia has been claimed to cause first hyperplasia and then dysplasia/neoplasia of enterochromaffinlike (ECL) cells in rat stomach. The growth is thought to reflect an accelerated self replication rate of mature ECL cells. The cytokinetics and the histidine decarboxylase (HDC) activity of the ECL cells were investigated during sustained hypergastrinemia. Methods: Hypergastrinemia was evoked by omeprazole (400 μmol · kg−1 · day−1 orally) for up to 1 year. Immunocytochemistry for histamine was used to determine the ECL cell density and combined with [H3]thymidine autoradiography to establish the labeling index (LI), i.e., the proportion of the ECL cells that has incorporated [H3]thymidine. Results: The ECL cell density increased progressively for 10–20 weeks in response to the hypergastrinemia and remained at a plateau for the remainder of the study. The hyperplasia was diffuse with additional micronodules at 52 weeks. The ECL cell LI was maximally elevated after 1–2 weeks and declined to control values after 10–20 weeks of treatment. In contrast, the HDC activity remained elevated for the duration of the study. Conclusions: The ECL cell hyperplasia reflects the transiently elevated ECL cell LI during the early phase but is not associated with an accelerated rate of mitosis during the 10–52 weeks period. Even though with time gastrin seems to loose its ability to sustain a high ECL cell LI it retains its ability to maintain a high HDC activity.

Effect of nicotine on the enterochromaffin like cells of the oxyntic mucosa of the rat

Smoking has an unfavourable effect on peptic ulcer disease. The pathophysiological mechanisms underlying this effect are not known. The enterochromaffin like (ECL) cell is the cellular source of histamine participating in the regulation of acid secretion. The ECL cell is under functional and trophic control of gastrin and the vagus nerves. Nicotine may affect acid secretion through vagal pathways. Furthermore, nicotine may also stimulate neuroendocrine cells. The present study examined if chronic nicotine administration could stimulate the function and growth of the ECL cell. Rats inhaled nicotine vapour at a concentration of approximately 6.2 μmol/m 3, 20 hours/day, 5 days/week for 11 weeks. Steady state plasma nicotine concentration was 461.8 (137.5 (SD)) nmol/l. The ECL cell density, histamine content and histidine decarboxylase activity of the oxyntic mucosa were similar to the controls. We also examined the effect of acute nicotine stimulation on the acid output and histamine release from the totally isolated vascularly perfused rat stomach. Nicotine did not stimulate acid secretion or histamine release. Thus no evidence could be provided to support the hypothesis that nicotine exerts its negative effects on peptic ulcer disease by stimulating the ECL cell.

The enterochromaffin-like (ECL) cell. Physiological and pathophysiological role.

Histamine has a central role in the regulation of gastric acid secretion. This histamine is produced by and released from the enterochromaffin-like (ECL) cell which accordingly has a key-regulatory role in the oxyntic mucosa. Gastrin and the vagal nerves stimulate the formation and release of histamine from the ECL cell. Moreover, gastrin and the vagal nerves also stimulate the proliferation of the ECL cell. An increased ECL cell density may partly explain the increased acid secretion in patients with duodenal ulcer, particularly in patients with Zollinger-Ellison syndrome. The reduced potency of histamine-2 blockers in patients with Zollinger-Ellison syndrome is probably due to increased histamine release by an elevated ECL cell mass. Prolonged and profound hypergastrinemia may lead to ECLomas. Moreover, a proportion of diffuse gastric carcinomas may originate from ECL cells.