The mechanism of histamine secretion from gastric enterochromaffin-like cells.
Enterochromaffin-like (ECL) cells play a pivotal role in the peripheral regulation of gastric acid secretion as they respond to the functionally important gastrointestinal hormones gastrin and somatostatin and neural mediators such as pituitary adenylate cyclase-activating peptide and galanin. Gastrin is the key stimulus of histamine release from ECL cells in vivo and in vitro. Voltage-gated K(+) and Ca(2+) channels have been detected on isolated ECL cells. Exocytosis of histamine following gastrin stimulation and Ca(2+) entry across the plasma membrane is catalyzed by synaptobrevin and synaptosomal-associated protein of 25 kDa, both characterized as a soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein. Histamine release occurs from different cellular pools: preexisting vacuolar histamine immediately released by Ca(2+) entry or newly synthesized histamine following induction of histidine decarboxylase (HDC) by gastrin stimulation. Histamine is synthesized by cytoplasmic HDC and accumulated in secretory vesicles by proton-histamine countertransport via the vesicular monoamine transporter subtype 2 (VMAT-2). The promoter region of HDC contains Ca(2+)-, cAMP-, and protein kinase C-responsive elements. The gene promoter for VMAT-2, however, lacks TATA boxes but contains regulatory elements for the hormones glucagon and somatostatin. Histamine secretion from ECL cells is thereby under a complex regulation of hormonal signals and can be targeted at several steps during the process of exocytosis. (+info)
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. (+info)
Transmembrane protein tyrosine phosphatase IA-2 (ICA512) is expressed in human midgut carcinoids but is not detectable in normal enterochromaffin cells.
A potential upregulation of receptor type protein tyrosine phosphatase IA-2 (ICA512) expression was detected by differential display and investigated in midgut carcinoid tumours. Normal intestine tissue and tumour tissue from 13 midgut carcinoid patients were studied by in situ hybridisation using an IA-2 ribonucleotide probe and confocal microscopy using specific IA-2 antibodies. Previously, it had been shown that IA-2 is located in the secretory granules of virtually all neuroendocrine cells. However, we found that IA-2 was not detectable in resting normal enterochromaffin (EC) cells of the small intestine, while high expression of IA-2 mRNA and protein was confirmed in both primary and metastatic carcinoid tissue. This difference in expression was not observed with chromogranin A or serotonin, two secretory granule hormones known to be expressed in EC cells, indicating that IA-2 was seemingly not necessary for the basal production and packaging of these hormones. When comparing patients receiving biotherapy before operation with untreated patients, we found expression of IA-2 to be lower in tumours from patients that had been treated with a combination of alpha-interferon and the somatostatin analogue, octreotide. There was no correlation between IA-2 expression and proliferation rates as measured by immunohistochemistry with antibodies against the Ki 67 antigen. Furthermore, we show that IA-2 is co-localised with serotonin in carcinoid tumours as well as in the pancreatic tumour cell line, BON1, which is interesting as serotonin secretion rate is presumably higher in tumour cells than in resting EC cells. Taken together, these findings may indicate a role for IA-2 in the later stages of the regulated secretory process. (+info)
Cure of Helicobacter pylori infection in atrophic body gastritis patients does not improve mucosal atrophy but reduces hypergastrinemia and its related effects on body ECL-cell hyperplasia.
BACKGROUND: The effects of H. pylori eradication on atrophic body gastritis are controversial. AIM: To investigate the effect of triple therapy on atrophic body gastritis in H. pylori-positive patients and its effect on morpho-functional gastric parameters. METHODS: Thirty-five consecutive atrophic body gastritis patients with histological/serological evidence of H. pylori infection were treated. Before and 6 and 12 months after H. pylori eradication the patients were evaluated for fasting gastrinemia and pepsinogen I, basal and peak acid output, and detailed histological assessment including the ECL cell proliferative patterns. RESULTS: Six months after treatment, 25 out of 32 patients were cured (78%). Cure of infection was associated with improvement in both basal (basal acid output mean 0.23 +/- 0.14 mmol/h vs. 1.75 +/- 0.7 mmol/h, P < 0.005) and stimulated acid secretion (peak acid output mean 3.0 +/- 1.06 mmol/h vs. 16.6 +/- 4.1 mmol/h, P=0.0017) as well as with reduction in hypergastrinemia (mean gastrin levels 444.1 +/- 110.7 pg/mL vs. 85.3. +/- 28 pg/mL; P < 0.005). In contrast, the eradication had no effect on body corporal atrophy and intestinal metaplasia, or pepsinogen I levels (mean 16.6 +/- 2.9 ng/mL vs. 14.2 +/- 2.1 ng/mL, N.S.). These results were confirmed at 12 months after eradication. A statistical inverse correlation was obtained (r=-0.3635, P < 0.05) between the corporal chronic infiltrate score and peak acid output values. A total of 53% of atrophic body gastritis patients showed a regression in severity of body ECL cell hyperplastic change. CONCLUSION: Cure of H. pylori infection in patients with atrophic gastritis reverses some adverse effects on gastric function and ECL cell hyperplasia. H. pylori infection may be cured in atrophic body gastritis patients with partial reversion of its negative consequences on acid secretion and body ECL cell hyperplasia. (+info)
Neurogenic appendicopathy--role of enterochromaffin cells in its pathogenesis.
One hundred cases of neurogenic appendicopathy were histochemically studied for schwann cells and enterochromaffin cells. The early phase, labelled as neuro-appendicopathy (29 cases) showed minimum to moderate number of extraepithelial enterochromaffin cells without neurogenous hyperplasia. In 53 cases, there was intra and submucosal neural hyperplasia with increase in the extraepithelial enterochromaffin cells, representing the active phase. The late phase known as obliterative neurogenic appendicopathy, showed extraepithelial enterochromaffin cells and schwann cell proliferation of variable grades (18 cases). The origin of extraepithelial enterochromaffin cells is related to proliferating nerve plexus, rather than epithelial enterochromaffin cells. (+info)
Octreotide inhibits the enterochromaffin-like cell but not peroxisome proliferator-induced hypergastrinemia.
The peroxisome proliferator ciprofibrate induces hypergastrinemia and as a consequence, enterochromaffin-like (ECL) cell hyperplasia. The mechanism for the gastrin cell stimulation is unknown. The somatostatin analog octreotide LAR (long-acting release) was used to see if the stimulating effects of ciprofibrate could be attenuated. Female Fischer rats were dosed with ciprofibrate (50 mg/kg body weight per day) alone or combined with octreotide LAR (10 mg/30 days) for 60 days. Plasma gastrin and histamine, gastric endocrine cell densities and mRNA abundances were measured. Ciprofibrate increased gastrin mRNA abundance (P<0.05), gastrin cell number (P<0. 001) and cell area (P<0.01), and induced hypergastrinemia (P<0.001). These rats had profound ECL cell hyperplasia, confirmed by an increase in chromogranin A (CgA) and histidine decarboxylase (HDC) mRNA, density of neuroendocrine and ECL cells and plasma histamine levels (all P<0.001). Octreotide LAR did not affect ciprofibrate stimulation of gastrin cells, but all parameters of ECL cell hyperplasia were reduced (P<0.001). Octreotide LAR also significantly inhibited basal ECL cell function and growth. Ciprofibrate stimulates gastrin cell activity by a mechanism unaffected by octreotide, but octreotide does inhibit basal and gastrin-stimulated ECL cell function and growth. (+info)
Complete identification of endocrine cells in the gastrointestinal tract using semithin-thin sections to identify motilin cells in human and animal intestine.
The present (Wiesbaden) classification of gut endocrine cells relies mainly on ultrastructure and the results of silver impregnation. Correlation with hormone production requires parallel immunology but conventional immune cytochemistry is, in most cases, difficult or at present impossible. The serial, semithin-thin-section technique offers an alternative, which provides absolute correlation between cell type and hormone production. The successful use of the technique is illustrated here by localization of motilin in the enterochromaffin cells of the small intestine. (+info)
Sampling strategies for analysis of enterochromaffin-like cell changes in Zollinger-Ellison syndrome.
To investigate the optimum number of biopsy specimens to be obtained for enterochromaffin-like (ECL) cell monitoring in hypergastrinemic patients and ECL cell regional variations potentially influencing the results, qualitative ECL cell changes were assessed in 149 patients with Zollinger-Ellison syndrome using jumbo biopsy specimens and a systematic sampling procedure of 4 areas each from the lesser or greater curvature of the gastric body. Of 1,176 specimens examined, 1,101 were adequate. The correlation was excellent between different sites within the greater or lesser curvature. In contrast, a normal ECL cell pattern was more frequent in the lesser curvature, whereas linear hyperplasia was more frequent in the greater curvature. Dysplastic lesions and carcinoid tumors in endoscopically unremarkable mucosa were detected in 3.4% and 1.2% of biopsy specimens, respectively, and were equally distributed between the lesser and greater curvature. Their chances of being diagnosed were related to the number of specimens examined. Extensive sampling of both the lesser and greater curvature is recommended for early diagnosis of dysplastic and/or carcinoid lesions in patients at risk. In contrast, limited sampling in the greater curvature seems to be adequate in patients with no risk for carcinoid development. (+info)