Expression of Toll-like receptor-3 is enhanced in active inflammatory bowel disease and mediates the excessive release of lipocalin 2.

Anti-microbial peptides might influence the pathogenesis and course of inflammatory bowel disease (IBD). We sought to clarify the role of the anti-microbial glycoprotein lipocalin 2 (LCN2) in the colon by determining its localization and regulation in IBD. Following a microarray gene expression study of colonic biopsies from a large IBD population (n = 133), LCN2 was localized using immunohistochemistry and in-situ hybridization. Moreover, we examined the regulation of LCN2 in HT-29 cells with a panel of pattern recognition receptors (PRRs) and sought evidence by immunohistochemistry that the most relevant PRR, the Toll-like receptor (TLR)-3, was indeed expressed in colonic epithelium in IBD. LCN2 was among the 10 most up-regulated genes in both active ulcerative colitis (UCa) and active Crohn's disease (CDa) versus healthy controls. LCN2 protein was found in both epithelial cells and infiltrating neutrophils, while mRNA synthesis was located solely to epithelial cells, indicating that de-novo synthesis and thus regulation of LCN2 as measured in the gene expression analysis takes place in the mucosal epithelial cells. LCN2 is a putative biomarker in faeces for intestinal inflammation, different from calprotectin due to its epithelial site of synthesis. LCN2 release from the colonic epithelial cell line HT-29 was enhanced by both interleukin (IL)-1ß and the TLR-3 ligand poly(I:C), and TLR-3 was shown to be expressed constitutively in colonic epithelial cells and markedly increased during inflammation.

Adipocytes express a functional system for serotonin synthesis, reuptake and receptor activation.

AIMS: Serotonergic pathways in the central nervous system (CNS) are activated in the regulation of food intake and body weight. We hypothesized that adipocytes, like other cells of mesenchymal origin, possess serotonin receptors and thus could be regulated by peripherally circulating serotonin. METHODS: In vivo studies: four Sprague-Dawley rats were given daily serotonin (5HT) injections subcutaneously (s.c., 25 mg/kg) for 5 days; four controls received saline. In a long-term study, 12 rats were given serotonin s.c. for 4 months, 10 controls received saline. Body weight was registered throughout the studies, and visceral adipose tissue and plasma were collected and analysed. Adipocytes were isolated from normal rat visceral abdominal adipose tissue and analysed for the expression of serotonin receptors, the serotonin transporter (5HTT/SERT), activation of serotonin synthesis (tryptophan hydroxylase 1, Tph1) and secretion and serotonin-induced leptin regulation by RT-PCR and protein analyses. RESULTS: Hyperserotoninergic rats had significantly lower body weight (-7.4 and -6.8%) and plasma leptin levels (-44 and -38%) than controls, after both short- and long-term serotonin treatment, respectively, whereas plasma ghrelin levels were unaffected. Compared to controls, serotonin induced a 40-fold upregulation of 5HTT mRNA in visceral adipose tissue after 5 days of treatment. In vitro experiments showed that adipocytes express serotonin receptors, Tph1 and 5HTT, synthesize and secrete serotonin and that serotonin regulates leptin in mature adipocytes. CONCLUSIONS: These findings show that serotonin may regulate adipocyte function in a direct manner via the blood circulation and/or paracrine and autocrine mechanisms, and not only indirectly via the CNS as previously assumed.

Gastric neuroendocrine carcinoma associated with atrophic gastritis in the norwegian lundehund.

In humans and rodents the association between atrophic gastritis, hypergastrinemia and gastric neoplasia is well-documented. Gastric tumours are rare in dogs, but the Norwegian Lundehund (puffin dog) appears predisposed to the development of gastric neoplasia associated with chronic atrophic gastritis. The present study describes 8 Lundehunds with gastric neoplasia. Seven of these animals had concurrent chronic atrophic gastritis characterized by reduction in parietal cells and hyperplasia of neuroendocrine cells. Four of the tumours displayed neuroendocrine (enterochromaffin-like cell; ECL) differentiation, suggesting that hypergastrinemia secondary to fundic atrophy may be important in carcinogenesis. The Norwegian Lundehund may therefore represent a further animal model for the study of the role of gastrin in the induction of gastric neoplasia.

Long slender cytoplasmic extensions: a common feature of neuroendocrine cells?

We have recently developed a new method for visualisation of gut mucosal cells and demonstrated that enterochromaffin (EC) and enterochromaffin-like (ECL) cells possess cytoplasmic extensions. The aim of the present study was to characterise the morphology of D- and G-cells. The D-cells in the stomach differed morphologically from intestinal D-cells, suggesting two distinct subpopulations of D-cells. Some D-cells appeared to be interconnected. No cell-to-cell contact between parietal and D-cells was found. Both D- and G-cells possessed long cytoplasmic extensions corresponding with our previous descriptions of EC and ECL cells. We propose that all neuroendocrine cells have the ability to develop cytoplasmic extensions, enabling them to signal to their target cells in a neurocrine manner.

Gene expression analysis and clinical diagnosis.

BACKGROUND: A new basis for diagnostic tests is being provided by the vast amount of data on gene expression that are now becoming available through large-scale measurement of mRNA abundance. The insights gained from these resources are most likely going to provide both a better basic understanding of disease mechanisms, and to identify molecular markers for more precise diagnoses and for prediction of prognosis and treatment response. METHODS: Some quantitative RT-PCR assays are utilized today for diagnosis of both malignant and non-malignant disease, but the use of gene expression measurements in clinical medicine can be expected to increase dramatically. CONCLUSIONS: There are important technical issues that must be adequately solved in order to obtain robust assays, such as standardized protocols with appropriate quality controls that ensure reliable data for the specific samples being analysed and good inter-laboratory reproducibility.

Neuroendocrine cells in pancreatic duct adenocarcinoma: an immunohistochemical study.

Pancreatic ductal adenocarcinomas can display disseminated neuroendocrine (NE) cells. Controversies exist as to their relative incidence, histogenesis, hormone production, and the prognostic implications of their presence. These issues were elucidated by means of a broad immunohistochemical (IHC) investigation of the resected specimens from 47 patients. Chromogranin A (CgA) was chosen as the major NE marker. In addition, the sensitivity of the conventional IHC procedure was increased by means of the TSA (Tyramide Signal Amplification) technique. In tumours with CgA immunoreactive (IR) cells, detected by the conventional or the TSA methods, these NE cells were further IHC analyzed, using antisera raised against a broad spectrum of neurohormonal peptides, serotonin, and IGF-1. The IHC observations were correlated with clinical and histopathological data, the nuclear IR for the Ki67 antigen (proliferation) of the neoplastic cells, and their IR against the p53 protein. Distinct CgA IR cells were found in 5 out of 47 (11%) tumours when studied by the conventional method, and in 9 out of 47 (19%) when examined by the TSA technique. Corresponding figures, if tumours with only questionable IR against CgA were also included, were 14 (30%) and 23 (50%), respectively. Out of the 9 cases with unequivocal CgA IR, only 3 displayed an IR to an additional hormone or growth factor; this hormone turned out to be somatostatin (only minimal foci). Insulin and glucagon cells also appeared exceptionally. The NE differentiation was found to be unrelated to proliferation, p53 protein expression, and to the survival of the patients. It occurred mainly (7 out of 9) in poorly differentiated adenocarcinomas. Thus, the plain NE immunoprofile of the CgA IR cells, together with the increased IR observed when the TSA technique was used, indicates that the NE cells in these adenocarcinomas are only poorly differentiated. When the CgA IR cells exceptionally become highly differentiated, they can express islet hormones. Using strict structural and IHC criteria, a NE differentiation occurs in less than 20 % of cases; its clinico-pathological significance seems to be non relevant.

Rebound acid hypersecretion after long-term inhibition of gastric acid secretion.

BACKGROUND: Rebound acid hypersecretion develops after the use of acid inhibitors. AIM: To estimate the duration of hypersecretion and to elucidate the role of the enterochromaffin-like (ECL) cell in rebound acid hypersecretion. METHODS: Patients waiting for anti-reflux surgery who had used a proton pump inhibitor daily > 1 year were included. All patients discontinued taking acid inhibiting drugs after the operation. Basal and pentagastrin stimulated acid output was measured at 4, 8, 16 and 26 weeks postoperatively. Oxyntic mucosal biopsies were collected before and 26 weeks after the operation for counting of histidine decarboxylase (HDC) immunoreactive cells. Serum chromogranin A (CgA) and gastrin were measured before and at 4, 8, 16 and 26 weeks after the operation. RESULTS: Pentagastrin stimulated acid secretion was higher at 4 and 8 weeks than at 26 weeks after the operation. Gastrin and CgA were significantly reduced at 4 and 8 weeks, respectively. The number of HDC immunoreactive cells was reduced by 60% at 26 weeks postoperative. DISCUSSION: Rebound acid hypersecretion lasts more than 8 weeks, but less than 26 weeks after long-term proton pump inhibition. CONCLUSION: The findings indicate that not only the parietal cell mass, but also ECL cell mass and activity are involved in the mechanism of acid hypersecretion.

Spontaneous enterochromaffin-like cell carcinomas in cotton rats (Sigmodon hispidus) are prevented by a somatostatin analogue.

Among inbred female cotton rats (Sigmodon hispidus) 25-50% of the animals develop spontaneous gastric carcinomas; the corresponding figure for male cotton rats is approximately 1%. Animals with carcinomas have hypergastrinaemia and gastric hypo-anacidity and the tumours are derived from enterochromaffin-like (ECL) cells. The mechanism behind the hypo-anacidity is unknown. Carcinomas are found in all female cotton rats with hypergastrinaemia lasting more than 4 months and this represents an excellent animal model for studying gastric carcinogenesis. In this study, the somatostatin analogue octreotide was given to female cotton rats to prevent carcinoma development caused by hypergastrinaemia. Twelve female cotton rats were given monthly injections of long-acting octreotide (5 mg i.m.) for 6 months. A control group of 20 animals was not given injections. Of the 20 control animals, 13 developed hypergastrinaemia and histologically invasive carcinomas or dysplasia. Of the 12 animals in the octreotide group, five developed hypergastrinaemia. None of these five animals developed histological cancer (P<0.05), whereas three had dysplasia. However, octreotide did not affect plasma gastrin concentration or antral gastrin mRNA abundance significantly. Dysplasia of the oxyntic mucosa in hypergastrinaemic animals was accompanied by a marked increase in chromogranin A-immunoreactive cells and cells positive for Sevier-Munger staining. The malignant tissue also contained groups of cells with Sevier-Munger staining. In conclusion, octreotide prevented ECL cell carcinomas in hypergastrinaemic cotton rats without lowering the gastrin concentration.

Chromogranin A and pancreastatin-like immunoreactivity in normal pregnancies.

Placenta is a neuroendocrine organ, and we therefore wanted to study the occurrence of the general neuroendocrine marker chromogranin A (CgA) and its split product pancreastatin. CgA and pancreastatin-like immunoreactivity (PST-LI) were determined by ELISA and RIA methods, respectively, in homogenates from term placentas, sera from pregnant women, nonpregnant women, umbilical cords, and in amniotic fluids. In placental homogenates, the mean level of CgA was 7.1 +/- 8.6 pmol/g wet wt (mean +/- SD), whereas PST-LI was not detectable. CgA immunoreactivity was demonstrated by immunofluorescence studies of isolated trophoblasts and decidual cells from term placentas. In trophoblasts, CgA was colocalized with human chorionic gonadotropin (hCG) and human placental lactogen. By Northern blotting, a distinct band corresponding to CgA messenger RNA (mRNA) was demonstrated in the placental cell line, whereas, in placental homogenates, a mRNA band of a slightly larger size was found. Median CgA level in maternal sera at term tended to be higher (median: 469 pmol/L, range 61-980 pmol/L, P < 0.1) than at 6-11 weeks (286 pmol/L, 61-653 pmol/L) or in sera from nonpregnant women (306 pmol/L, 204-469 pmol/L). In umbilical cord sera, median CgA level was significantly higher (898 pmol/L, 102-2245 pmol/L, P < 0.05) than in term sera. Median serum level of PST-LI was significantly higher at term (38 pmol/L, 0-131 pmol/L) than at 6-11 weeks (9 pmol/L (0-85 pmol/L, P < 0.05), than in nonpregnant women (6 pmol/L, 0-52 pmol/L, P < 0.05), and in umbilical cord sera (12 pmol/L, 0-76 pmol/L, P < 0.05). In amniotic fluid, median CgA value was significantly higher at term (1163 pmol/L, 714-1673 pmol/L) than at 14-17 weeks (551 pmol/L, 82-980 pmol/L, P < 0.01), whereas median level of PST-LI was significantly higher at 14-17 weeks (32 pmol/L, 6-97 pmol/L) than at term (0 pmol/L, 0-15 pmol/L, P < 0.01). To our knowledge, this is the first report describing the presence of CgA and PST-LI in placenta and amniotic fluid and the occurrence CgA mRNA in placental tissue and in a placental cell line. The presence of CgA in placenta may indicate a physiological role in pregnancy.

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.

The effect of the peroxisome proliferator ciprofibrate on the gastric mucosa and particularly the gastrin cell.

The peroxisome proliferator ciprofibrate induces hypergastrinemia without inhibiting acid secretion. The present study was carried out to assess the effect of ciprofibrate on serum gastrin and gastrin (G) cells in different strains of rats and to compare the effect of ciprofibrate with other lipid-reducing agents (lovastatin and simvastatin) which have a different mechanism of action. Serum gastrin was determined by a radioimmunoassay method, G cell density by histomorphometry after immunostaining for G cells, and gastrin, somatostatin and histidine decarboxylase (HDC) mRNA abundance by Northern blot analysis. Ciprofibrate (100 mg/kg/day for three weeks) induced a marked hypergastrinemia (P < 0.01) in male and female Fischer rats as well as in female Wistar rats. Simvastatin and lovastatin did not affect serum gastrin. Antral G cell density increased significantly in female Wistar rats (P < 0.05) and non-significantly in the other rats after ciprofibrate. Both gastrin and somatostatin mRNA abundance in antral mucosa increased markedly and significantly (P < 0.01) after ciprofibrate treatment. The present study shows that the peroxisome proliferator ciprofibrate induces hypergastrinemia secondary to an increased storage and synthesis of antral gastrin. Since somatostatin mRNA abundance also increased, the present study suggests that ciprofibrate and possibly other peroxisome proliferators in sufficient concentrations have a stimulatory effect on endocrine cells.

Histamine release in the isolated vascularly perfused stomach of the rat: regulation by autoreceptors.

1. In the isolated vascularly-perfused stomach of the rat, gastrin 1-17 (520 pmol 1(-1)) increased acid output from basal values of 13.7 +/- 2.7 to 92.5 +/- 11.4 mumol h-1 and venous histamine output from 10.1 +/- 2.3 to 54.7 +/- 7.9 nmol h-1 (mean +/- s.e.mean). 2. The H1 receptor agonist 2-methylhistamine (10 mumol 1(-1)) increased acid output to 21.6 +/- 2.9 mumol h-1 (P less than 0.05) and reduced basal histamine output to 4.0 +/- 0.8 nmol h-1 (P less than 0.05). Gastrin-stimulated acid secretion and vascular histamine output was not significantly affected by 2-methylhistamine (10 mumol 1(-1)). 3. The H2 receptor agonist, impromidine, dose-dependently increased basal acid secretion, reaching a maximal value of 145.5 +/- 11.7 mumol h-1 with impromidine (10 mumol 1(-1)), and maximal gastrin-stimulated acid secretion to 167.4 +/- 15.1 mumol h-1 with impromidine (10 mumol 1(-1)). Impromidine dose-dependently inhibited basal and gastrin-stimulated vascular histamine output. 4. The H3 receptor agonist R-a-methylhistamine, (1 and 10 mumol 1(-1)) minimally increased basal acid secretion. R-a-methylhistamine (10 mumol 1(-1)) did not significantly affect maximal gastrin-stimulated acid secretion. Basal and gastrin-stimulated vascular histamine outputs decreased to 4.0 +/- 0.8 (P less than 0.05) and 24.7 +/- 4.7 nmol h-1 (P = 0.05) with R-a-methylhistamine (10 mumol 1(-1)). 5. The H2 receptor antagonist ranitidine (2 mumol 1(-1)) did not inhibit basal acid secretion, but acid outputs with gastrin and all histamine agonists were reduced. Ranitidine did not affect histamine release in the basal state, with gastrin or with any histamine agonist tested. 6 We conclude that gastric histamine release in the rat is regulated via a histamine H2 receptor sensitive to the histamine agonists tested, but not to ranitidine. It is unlikely that the inhibition of histamine release is secondary to increased gastric acidity.

Carbachol stimulation of gastric acid secretion and its effects on the parietal cell.

1. The acid secretagogue effect of gastrin is mainly mediated by the release of enterochromaffin-like (ECL) cell histamine, but the mechanism of muscarinic stimulation of acid secretion remains unclear. The results of studying aminopyrine uptake in isolated parietal cells, and histamine release in isolated ECL cells suggest that muscarinic agents may act both directly on the parietal cell and indirectly via histamine release from ECL cells. 2. We examined parietal and ECL cell responses to the muscarinic agent carbamylcholine (carbachol) in conscious rats and in rat isolated vascularly perfused stomachs. 3. Intravenous carbachol stimulated acid secretion in conscious gastric fistula rats and increased H+K+ ATPase mRNA abundance, indicating activation of parietal cells. In these experiments there was no increase in portal venous histamine, or in oxyntic mucosal histidine decarboxylase (HDC) enzyme activity and HDC mRNA abundance. 4. In rat isolated stomachs stimulated with carbachol in the dose range 10 nM(-1) mM only the 1 microM concentration increased venous histamine significantly. 5. We concluded that the muscarinic agent carbachol stimulates acid secretion and H+K+ ATPase mRNA in vivo by a direct effect on the parietal cell, that does not depend on the release of ECL cell histamine.

Personal review: is profound acid inhibition safe?

Inhibitors of gastric acid secretion, particular proton pump inhibitors, are effective drugs in the treatment and prophylaxis of acid-related diseases. Proton pump inhibitors are therefore prescribed widely, often for minor complaints. Gastric acidity kills swallowed microorganisms, and acid secretion must be of biological importance because it is maintained in phylogenesis. Acid secretion is controlled by feedback mechanisms, mainly via gastrin. A decrease in acidity always causes an increase in plasma gastrin. The trophic effect of gastrin leads to hyperplasia and neoplasia of the enterochromaffin-like (ECL) cell. ECL cell derived tumours in man were previously regarded as rare, and also as rather benign. It is now clear that the ECL cell gives rise to a significant proportion of gastric carcinomas. Moreover, ECL cell carcinoids secondary to hypergastrinaemia may develop into highly malignant tumours. Treatment with a proton pump inhibitor is followed by rebound acid hypersecretion and decreased efficiency of H2-blockers, thus such treatment may induce a type of physical dependence. It is therefore reasonable to be cautious and not to treat younger (< 50 years) patients for long periods of time with profound inhibitors of gastric acid secretion. Chromogranin A in the blood is a sensitive marker of the ECL cell mass, and it could be used to survey patients on long-term proton pump inhibitors.

Review article: the pharmacological inhibition of gastric acid secretion--tolerance and rebound.

During the last decade our understanding of the regulation of gastric acid secretion has changed considerably. The recognition that gastrin acts mainly by releasing histamine from the enterochromaffin-like (ECL) cell is of major importance. It is now necessary to review and seek new explanations for the development of tolerance and for the post-treatment acid hypersecretion that may be observed when treatment with acid-secretory inhibitors is discontinued. Tolerance and rebound related to H2-receptor antagonists has previously been explained as upregulation of gastrin and/or histamine H2-receptors, and/or an increased parietal cell mass. Experimental evidence for these theories is scarce. On the other hand, tolerance can now be explained by a gastrin-induced increase in ECL cell-derived histamine at the parietal cell H2-receptor competing with the antagonist. The lack of tolerance to proton pump inhibitors may be explained by their mode of action, being non-competitive and acting at the H+, K+-ATPase rather than at stimulatory receptors. Post-treatment rebound acid hypersecretion can be understood as gastrin upregulating and/or stimulating growth of the ECL cell, leading to increased amounts of releasable histamine post-treatment. Novel experimental data strongly support this view of the development of tolerance and post-treatment rebound acid hypersecretion.

In single doses ranitidine effervescent is more effective than lansoprazole in decreasing gastric acidity.

BACKGROUND: A rapid and reproducible decrease of gastric acidity is preferable in patients with penetrating/perforating peptic ulcers and in on-demand treatment of some patients with dyspepsia. The present study was done to compare the effect of single doses of ranitidine effervescent with that of the proton pump inhibitor lansoprazole. METHOD: Twelve healthy young volunteers were studied by 11-h intragastric continuous pH recording after the intake of ranitidine 150 or 300 mg effervescent tablets or lansoprazole 30 mg capsules. Trial medications were taken with 200 mL water, and the subjects remained fasting apart from 250 mL fluid at 4 h. RESULTS: Ranitidine effervescent, both 150 and 300 mg, induced a rapid and persisting increase in gastric pH in most of the subjects, whereas a single dose of lansoprazole 30 mg did not affect intragastric pH in five of the twelve subjects. CONCLUSION: The histamine H2-blocker ranitidine given as an effervescent formulation is superior to the proton pump inhibitor lansoprazole in inducing a rapid decrease of gastric acidity.

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.

Review article: the use of gastric acid-inhibitory drugs--physiological and pathophysiological considerations.

All vertebrates secrete gastric acid. Acid denatures the proteins in the food and thus makes them more accessible to proteolytic enzymes, and it kills swallowed micro-organisms. Gastric acid plays an important pathogenetic role in peptic ulcer disease and reflux oesophagitis. In these diseases, drugs that inhibit secretion of gastric acid will heal the lesions and suppress the symptoms. However, both reflux oesophagitis and peptic ulcer tend to recur when the acid-inhibitory treatment is stopped. Therefore, these patients often require long-term treatment with acid-inhibitors. In this overview the potential risks of long-term profound inhibition of acid secretion, raising the pH above 4 for a considerable time, resulting in reduced killing of micro-organisms and secondary hypergastrinaemia, are discussed. Gastrin regulates both the function (production and release of histamine) and growth of the enterochromaffin-like (ECL) cell. Hitherto, the role that this cell plays in gastric carcinogenesis appears to have been underestimated.

Oxyntic lesions may be provoked in the rat both by the process of acid secretion and also by gastric acidity.

BACKGROUND: Gastric ischaemia appears to be a common pathogenetic factor for stress ulcers. These ulcers occur predominantly in the oxyntic mucosa, suggesting that the acid secretory process or its stimulation is involved in the pathogenesis. METHODS: We examined separately the role of the acid secretory process and gastric luminal acidity in the pathogenesis of gastric lesions using the isolated vascularly perfused acid-secreting rat stomach. RESULTS: Pentagastrin-stimulated acid secretion induced submucosal bleeding in the oxyntic mucosa whether accompanied by perfusion of the gastric lumen with saline or a phosphate buffer at pH 7.0. On the other hand, acidity, whether endogenous or introduced by luminal perfusion, induced erosions in both the oxyntic and antral mucosa. CONCLUSION: It is concluded that the acid secretory process itself contributes to the particular vulnerability of the oxyntic mucosa to ischaemia. Histamine released upon stimulation of gastric acid secretion or shortage of energy due to the requirements for acid secretion may both contribute to this vulnerability. Furthermore, these findings suggest that inhibition of gastric acid secretion should be superior to antacids in preventing stress ulcers.

The effect of tripotassium dicitrato bismuthate on the rat stomach.

BACKGROUND: Bismuth has been used as symptomatic treatment of dyspepsia for many years. It promotes healing of peptic ulcers and reduces their recurrence. The beneficial effect of bismuth on duodenal ulcer disease is thought to be due to an effect on Helicobacter pylori, although it has a rather weak bactericidal effect on H. pylori in vitro. Eradication of H. pylori in duodenal ulcer patients by a combination of bismuth, tetracycline and metronidazole has been reported to increase the density of somatostatin-producing D cells in the antrum. A reduced D cell density in the antral mucosa of duodenal ulcer patients could explain their exaggerated gastrin release. AIMS/METHODS: To test the possibility that bismuth could affect the neuroendocrine cells independently of the presence of H. pylori or not, we gave rats a diluted tripotassium dicitrato bismuthate solution by gastric gavage for 14 days. RESULTS: Tripotassium dicitrato bismuthate treatment did not affect maximal pentagastrin-stimulated acid secretion or histamine release in isolated rat stomachs or the density of argyrophil cells in the oxyntic and antral mucosa. However, it significantly reduced the duodenal concentration of gastrin and calcitonin gene-related peptide, and the density of G cells in the antrum and duodenum. CONCLUSION: The effect of tripotassium dicitrato bismuthate on the G cell may be of significance for its beneficial effect on duodenal ulcer disease.