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Digestive Diseases and Sciences Sep 1994This review examines recent concepts of gastric mucosal cell biology in relation to acid inhibition. Powerful acid-inhibitory drugs have been associated with the... (Review)
Review
This review examines recent concepts of gastric mucosal cell biology in relation to acid inhibition. Powerful acid-inhibitory drugs have been associated with the production of enterochromaffin-like (ECL) cell proliferation and the induction of ECL-cell carcinoids in rats. The ECL-cell lineage and its renewal is discussed, and the factors that regulate ECL-cell proliferation are reviewed. Current methods in use for assessing genotoxicity in gastric mucosa are scrutinized; the much discussed claim that antisecretory drugs induce unscheduled DNA synthesis is examined, and the methodology that is the basis for these claims is found defective and wanting. The nature of ECL-cell proliferation in rats receiving lifelong treatment with H2-receptor antagonists or acid pump inhibitors is explored, and their relationship to ECL-cell proliferation and ECL-cell carcinoids discussed. It is concluded that aged rats are very prone to developing endocrine proliferations, and this may be related to the multiple endocrine neoplasia syndrome found in humans. There is no evidence at present that long-term antisecretory therapy causes significant ECL-cell proliferation in humans.
Topics: Animals; Anti-Ulcer Agents; Carcinoid Tumor; Cell Division; Cell Movement; Enterochromaffin Cells; Gastric Acid; Gastric Mucosa; Humans; Rats; Stomach Neoplasms
PubMed: 8082489
DOI: 10.1007/BF02088113 -
Scandinavian Journal of... 1991On the basis of clinical observations and experimental animal studies it has been established that gastrin has a trophic effect on the oxyntic mucosa. On the other hand,... (Review)
Review
On the basis of clinical observations and experimental animal studies it has been established that gastrin has a trophic effect on the oxyntic mucosa. On the other hand, histamine, being at least as efficient as gastrin as an acid secretagogue, has experimentally been reported not to have such trophic effect. However, during the last few years both endogenously and exogenously induced hypergastremia have been shown to have a specific trophic effect on the enterochromaffin-like (ECL) cell and a less pronounced and later detectable general trophic effect on the oxyntic mucosa. Moreover, in the rat (the species in which most of the trophic studies have been done) the acid-stimulatory effect of gastrin may be solely explained by stimulation of histamine release from ECL cells. Therefore, it seemed natural to evaluate whether the general trophic effect of gastrin could also be caused by histamine or another substance released from the ECL cells. In this review we challenge the concept that maximal pentagastrin-stimulated acid secretion only reflects the parietal cell mass, since the acid-stimulatory effect of gastrin is mediated by histamine release. Therefore, maximal pentagastrin-stimulated acid secretion reflects both the ECL cell mass and the parietal cell mass. With regard to the possible trophic effect of histamine, we show that the doses previously used have been inadequate. Furthermore, histamine has been reported to have a trophic effect on the parietal cell in the dog; some patients with hyperhistaminemia have an increased maximal histamine-stimulated acid secretion, suggesting an increase in the parietal cell mass; and there is parietal cell hyperplasia in the oxyntic mucosa surrounding the histamine-producing carcinoids in mastomys.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Histamine; Histamine Antagonists; Parietal Cells, Gastric; Rats; Receptors, Cholecystokinin; Vagus Nerve
PubMed: 2042030
DOI: 10.3109/00365529109093191 -
The Yale Journal of Biology and Medicine 1992The enterochromaffin-like (ECL) cells represent the predominant endocrine cell population in the acid-producing part of the stomach of both experimental animals and man.... (Review)
Review
The enterochromaffin-like (ECL) cells represent the predominant endocrine cell population in the acid-producing part of the stomach of both experimental animals and man. These cells actively produce and store histamine in addition to an anticipated but as yet unidentified peptide hormone and are under the control of gastrin. An acute gastrin stimulus causes exocytosis of the cytoplasmic granules/vesicles (and release of histamine and activation of the histamine-forming enzyme, histidine decarboxylase), while a more sustained gastrin stimulus causes first hypertrophy and then hyperplasia of the ECL cells in the rat (at most, a fivefold increase in the cell number). These effects can be demonstrated following infusion of gastrin or following an increase in the concentration of circulating gastrin of endogenous origin. The growth of the ECL cells reflects an accelerated self-replication rate. As studied in the rat, the self-replication rate is accelerated quite soon after induction of hypergastrinemia (blockade of acid secretion), the rate is maximally elevated within two weeks and then declines to control values at ten and 20 weeks despite the sustained hypergastrinemia. Lifelong hypergastrinemia in rats is associated not only with ECL-cell hyperplasia but also with an increased incidence of ECL-cell carcinoids. Recently, we could show that alpha-fluoromethylhistidine, which is a suicide inhibitor of histidine decarboxylase, effectively depletes the ECL cells of histamine and that the histamine-depleted ECL cells respond to gastrin with hyperplasia in a manner identical to normal ECL cells. Other factors beside gastrin seem to participate in the control of ECL-cell function and proliferation. Although exogenous somatostatin is known to suppress the activity of the ECL cells, we have failed to obtain evidence that the somatostatin cells in the oxyntic mucosa play a role in the physiological control of the ECL cells. The vagus, however, is important for the ability of the ECL cells to respond to gastrin. This conclusion is based on the observation that vagal denervation suppresses the hyperplastic response of the ECL cells to gastrin. Porta-cava shunting, on the other hand, greatly enhances the responsiveness of the ECL cells to gastrin. The mechanism behind this effect is unknown.
Topics: Animals; Enterochromaffin Cells; Humans
PubMed: 1341077
DOI: No ID Found -
Journal of Gastroenterology 2002
Comparative Study
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Anti-Ulcer Agents; Benzimidazoles; Enterochromaffin Cells; Gastrins; Humans; Omeprazole; Parietal Cells, Gastric; Rabeprazole; Rats
PubMed: 11931540
DOI: 10.1007/s005350200028 -
Endocrinologie 1977
Topics: Acetylserotonin O-Methyltransferase; Animals; Brain; Chromaffin System; Enterochromaffin Cells; Eye; Harderian Gland; Melatonin; Retina
PubMed: 847374
DOI: 10.1203/00006450-199404000-00002 -
The Journal of Pathology Dec 1988As endocrine tumours in a number of organs may arise in a background of hyperplasia, the density of endocrine cells in appendices from ten patients with carcinoid... (Comparative Study)
Comparative Study
As endocrine tumours in a number of organs may arise in a background of hyperplasia, the density of endocrine cells in appendices from ten patients with carcinoid tumours was compared with that in appendices from ten age- and sex-matched control patients. Crypt and lamina propria endocrine cells were quantified separately. The density of argentaffin endocrine cells in the crypts was significantly higher in appendices with carcinoid tumours when compared with the controls. No difference was found in non-argentaffin endocrine cells, and no difference was found in either argentaffin or argyrophil endocrine cells in the lamina propria. While it is possible that carcinoid tumours induce an increase in the number of enterochromaffin (EC) cells in the background mucosa, it is considered more likely that EC cell hyperplasia predisposes to the development of carcinoid tumours of the appendix.
Topics: Adolescent; Adult; Appendiceal Neoplasms; Appendix; Carcinoid Tumor; Cell Count; Child; Endocrine Glands; Enterochromaffin Cells; Female; Humans; Hyperplasia; Intestinal Mucosa; Male; Middle Aged
PubMed: 3225716
DOI: 10.1002/path.1711560409 -
Neuroendocrinology 2009Neuroendocrine tumors (NETs) of the gastrointestinal (GI) system are increasing in incidence with minimal improvement in prognosis. Although the cell of origin has been... (Comparative Study)
Comparative Study
BACKGROUND
Neuroendocrine tumors (NETs) of the gastrointestinal (GI) system are increasing in incidence with minimal improvement in prognosis. Although the cell of origin has been identified as the enterochromaffin (EC) cell, its secretory and proliferative regulation has not been defined at a mechanistic level. To date, the BON cell line has been the most widely used in vitro EC cell model despite its pancreatic origin. Using whole-genome mathematical analysis as well as secretory and proliferative studies, we compared the BON cell line to the small intestine (SI) EC cell-derived NET cell line, KRJ-I, to assess individual cell line validity and applicability for the investigation of GI-NET disease.
METHODS AND RESULTS
Principal component analysis and ANOVA of KRJ-I and BON transcriptomes (U133 Plus 2) identified substantially different (<10%) overlap in transcripts with minimal (R(2) = 0.24) correlation in gene expression profiles. RT-PCR detected large variability (>12%) in neuroendocrine (NE) marker transcripts in the BON cell line and the absence of Tph-2, DDC, TGFbetaR2, and M3 transcripts in KRJ-I. The KRJ-I cell line secreted serotonin (5-HT) in response to isoproterenol (EC(50) = 100 nM), noradrenaline (EC(50) = 1.7 nM), and pituitary adenylate cyclase (PACAP, EC(50) = 0.03 nM). Cholecystokinin (IC(50) = 430 nM), somatostatin (IC(50) = 400 nM), acetylcholine (IC(50) = 3.7 nM), and gamma-aminobutyric acid A (GABA(A), IC(50) = 2 nM) all inhibited 5-HT release, while gastrin and bombesin had no effect. 5-HT secretion in the BON cell line was stimulated by isoproterenol (EC(50) = 900 nM), noradrenaline (EC(50) = 20 nM), cholecystokinin (EC(50) = 130 nM), PACAP (EC(50) = 0.12 nM), bombesin (EC(50) = 15 nM), and acetylcholine (EC(50) = 0.2 nM). It was inhibited by somatostatin (IC(50) = 300 nM) but not GABA(A). KRJ-I responded with proliferation to connective tissue growth factor (CTGF, EC(50) = 0.002 ng/ml), transforming growth factor-alpha (TGFalpha, EC(50) = 0.63 ng/ml) and transforming growth factor-beta (TGFbeta, EC(50) = 0.63 ng/ml). Epidermal growth factor (EGF) and somatostatin had no significant effect. BON cell proliferation was stimulated only by EGF and TGFalpha (EC(50) = 15.8 and 10 ng/ml). TGFbeta (IC(50) = 0.16 ng/ml), MZ-4-147 (IC(50) = 0.5 nM), and BIM23A761 (IC(50) = 0.06 nM) all inhibited proliferation. CTGF and somatostatin had no effect.
CONCLUSION
KRJ-I and BON cell lines demonstrate substantial differences in gene level transcripts, inconsistent receptor profile expression, wide variability in NE marker transcript levels, and significantly differential proliferative and secretory responses. Given the EC cell origin of KRJ-I, these results provide evidence that the BON cell line does not represent an EC cell system and is not a valid study model of (carcinoid) EC cell-derived NET.
Topics: Cell Line, Tumor; Dose-Response Relationship, Drug; Enterochromaffin Cells; Growth Inhibitors; Humans; Intercellular Signaling Peptides and Proteins; Neuroendocrine Tumors
PubMed: 19295186
DOI: 10.1159/000209330 -
Experimental Physiology Sep 1994
Review
Topics: Animals; Base Sequence; Enterochromaffin Cells; Gastric Acid; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Histamine; Molecular Sequence Data; Neurons, Afferent; Pyloric Antrum; Somatostatin
PubMed: 7818855
DOI: 10.1113/expphysiol.1994.sp003795 -
Alimentary Pharmacology & Therapeutics 1994Both receptor antagonists and acid pump inhibitors are clinically useful suppressants of acid secretion. The latter class of drugs, the substituted benzimidazoles,... (Review)
Review
Both receptor antagonists and acid pump inhibitors are clinically useful suppressants of acid secretion. The latter class of drugs, the substituted benzimidazoles, inhibit acid secretion more effectively and, therefore, provide superior symptom relief and healing in all acid-related diseases. The H2-receptor antagonists competitively block the action of histamine on the H2-receptors of parietal cells. This histamine is released from enterochromaffin-like cells (ECL cells) due to gastrin, acetylcholine or epinephrine stimulation. In addition, parietal cells have M3-receptors which can function independently of H2-receptors. Hence, there is no single common pathway for parietal cell stimulation. Stimulation of acid secretion by parietal cells requires activation of the acid pump, the gastric H+,K(+)-ATPase. The target site for the benzimidazoles is the activated gastric H+,K(+)-ATPase, and, in particular, the cysteines of the pump that are exposed to the acid space of the secretory canaliculus of the parietal cells. Pantoprazole in its protonated form selectively reacts with cysteines present in both the fifth and sixth membrane segments of the ATPase, explaining its mechanism of inhibiting proton transport by this enzyme.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Benzimidazoles; Cells, Cultured; Enterochromaffin Cells; Gastric Acid; H(+)-K(+)-Exchanging ATPase; Histamine H2 Antagonists; Histamine Release; Humans; Omeprazole; Pantoprazole; Parietal Cells, Gastric; Proton Pump Inhibitors; Sulfoxides
PubMed: 7514042
DOI: 10.1111/j.1365-2036.1994.tb00211.x -
Gastroenterology Oct 2023
Topics: Humans; Enterochromaffin Cells; Duodenum; Serotonin
PubMed: 37178735
DOI: 10.1053/j.gastro.2023.05.008