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I M Modlin

Publications and source records attributed to I M Modlin.

At least 55 records · Page 3Linked to original sources
PubMed1998

Telenzepine-sensitive muscarinic receptors on rat pancreatic acinar cells.

To identify the muscarinic subtype present on the rat pancreatic acinar cell, we examined the effects of different muscarinic receptor antagonists on amylase secretion and proteolytic zymogen processing in isolated rat pancreatic acini. Maximal zymogen processing required a concentration of carbachol 10- to 100-fold greater (10(-3) M) than that required for maximal amylase secretion (10(-5) M). Although both secretion and conversion were inhibited by the M3 antagonist 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP) (50% inhibition approximately 6 x 10(-7) M and 1 x 10(-8) M, respectively), the most potent inhibitor was the M1 antagonist telenzepine (50% inhibition approximately 5 x 10(-10) M and 1 x 10(-11) M, respectively). Pirenzepine, another M1 antagonist, and the M2 antagonist methoctramine did not reduce amylase secretion or zymogen processing in concentrations up to 1 x 10(-5) M. Analysis of acinar cell muscarinic receptor by PCR revealed expression of both m1 and m3 subtypes. The pancreatic acinar cell has a distinct pattern of muscarinic antagonist sensitivity (telenzepine >> 4-DAMP > pirenzepine) with respect to both amylase secretion and zymogen conversion.

Animals↗
PubMed1998

A polyamine pathway-mediated mitogenic mechanism in enterochromaffin-like cells of Mastomys.

We have previously demonstrated that in Mastomys species proliferation of gastric enterochromaffin-like (ECL) cells is predominantly regulated by gastrin and by transforming growth factor-alpha (TGF-alpha) in the naive and neoplastic state, respectively. In this study we examined whether these intracellular mitogenic responses are mediated by polyamines and ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine biosynthesis. An ECL cell preparation of high purity was used to measure the effect of the polyamine derivatives putrescine, spermidine, and spermine on DNA synthesis by bromodeoxyuridine uptake. Both putrescine and spermidine augmented gastrin-stimulated, but not basal, DNA synthesis in naive cells. This proliferative response correlated with an increase in ODC activity that was partially inhibited (20%) by difluoromethylornithine (DFMO), an inhibitor of ODC (IC50, 30 pM). In contrast, all polyamines increased both basal and TGF-alpha-stimulated DNA synthesis as well as ODC activity in tumor ECL cells. DFMO completely inhibited the proliferative response of TGF-alpha (IC50, 3 pM). Thus polyamine biosynthesis is involved in proliferation of ECL cells and in particular the mitogenesis of tumor cells, suggesting a role for this pathway in the regulation of ECL cell transformation.

Animals↗
PubMed1998

A century of Helicobacter pylori: paradigms lost-paradigms regained.

The investigation of gastric bacteria properly began in the latter half of the nineteenth century when microscope resolution had sufficiently advanced. Whilst a bacterial etiology was demonstrated for dysentery, tuberculosis and syphilitic ulcers, problems in the isolation and culture of pure strains circumvented a role for bacteria in gastric pathology. Furthermore, dogma and the intellectual chorus were in harmony advocating that gastric acid was critical in ulcer disease. The consideration of a role for a pathogen or pepsin was regarded as whimsical in the context of mucosal ulceration. Indeed, the effects of acid inhibitory agents were held as gospel truth whilst the use of antibiotics or metallic ions were deemed to be quackery or at least ill judged. Nonetheless, spiral-shaped bacteria had been identified in both mucosa and gastric contents of patients as early as 1889. Elegant studies had documented the infectivity of these organisms, and suggested but not proven a causative role in gastric disease. The prescient identification by Doenges of organisms associated with gastritis in both man and monkey, was buried by the observations of Palmer, and an opportunity for early progress lost. It required two decades and Antipodean pathological perspicacity to elucidate the warren of previous archaic gastric bacterial misinformation. The subsequent marshalling of clinical and pathological data established the fatal flaw in the mucosa to be bacteria and not only acid on the mucus shore. It is now widely apparent that Helicobacter is ubiquitous, pathological and, a century after its initial discovery, still remains a paradox of as yet incompletely determined biological consequence. It is of note that an organic helical configuration has twice in this century provided biological information of unique import.

Gastrointestinal Diseases↗
PubMed1998

Gastrin and the enterochromaffin-like cell: an acid update.

Gastrin is synthesized and secreted mostly in a heptadecapeptide form from neurocrine G cells located in the antrum. The biologically active sequence of the molecule is a C-terminal pentapeptide, which has been conserved across many species. Transcriptional regulation of gastrin mRNA synthesis is positively regulated by transforming growth factor-alpha (TGF-alpha) and inhibited by somatostatin (SST). The inactive precursor form is converted to the active molecule by several post-translation processing steps which include cleavage, C-terminal amidation, glycosylation, phosphorylation and sulfation. Aberrations in processing steps generate incompletely processed forms, particularly glycosylated progastrin, which may act as autocrine growth factors for gastrointestinal neoplasms. Gastrin release is stimulated by luminal aromatic amino acids and inhibited by a decrease in luminal pH. Other gastrin agonists include beta-adrenergic agents, acetylcholine, gastrin-releasing peptide (bombesin), TGF-alpha, and possibly the gastric pathogen, Helicobacter pylori. The principal peptide inhibitor of gastrin release is SST. The major physiological roles of gastrin include stimulation of acid secretion, regulation of mucosal cell lineage and mucosal cell proliferation. The fundic enterochromaffin-like (ECL) cell is the principal cellular transducer of the gastrin-acid signal. Activation of its gastrin/CCKB receptor results in histamine synthesis and release with consequent activation of the fundic parietal cell H2 receptor. An increase in luminal pH caused by acid inhibitory pharmacotherapy agents (particularly proton pump inhibitors) results in hypergastrinemia and ECL cell hyperplasia. Gastric carcinoids however appear occur in patients with multiple endocrine neoplasia type I syndrome, suggesting that an associated genomic defect is necessary. Gastrin is thus both a potent gastrointestinal trophic and histamine secretory agent. As a hormone it is a paradigm in the elucidation of both cellular secretory and growth factor induced cell proliferation.

Enterochromaffin-like Cells↗
PubMed1997

Gastrin receptor expression and function during rapid transformation of the enterochromaffin-like cells in an African rodent.

The enterochromaffin-like cell (ECL) cells of the stomach are principally regulated by gastrin via a gastrin/CCK(B) receptor (G[R]) which modulates both histamine secretion and cell proliferation. In the African rodent (mastomys) hypergastrinemia generated by the histamine-2 receptor antagonist (loxtidine) results in ECL cell hyperplasia and neoplasia at 8 and 16 weeks respectively. The expression, structure and function of the G(R) during transformation is however unknown. We utilized a pure (approximately 90%) preparation of ECL cells to evaluate alterations in the G(R) utilizing immunocytochemistry, Western blot analysis, reverse transcription polymerase chain reaction (RT-PCR), 5-bromo-2-deoxyuridine uptake and phosphorylation site analysis. Although the expression of ECL cell G(R) was upregulated at both mRNA (PT-PCR) and protein (Western analysis) level, its affinity to gastrin was decreased in the hyperplastic phase and lost during transformation. The coding sequence of the G(R) of mastomys tumor ECL cells was identical to that of normal ECL cells, parietal cells and the brain. However, the mRNA sequence of the third introcytoplasmic loop of the G(R) was significantly different to other species. In addition, the G(R) exhibited phosphorylation site on serine residue(s). We have thus noted a direct correlation between hypergastrinemia and G(R) alteration and function during ECL cell transformation. It is possible that the unique mastomys gastrin receptor mediated ECL cell transformation involves the novel phosphorylation sites and a divergence in the introcytoplasmic domain.

Animals↗
PubMed1997

An analysis of 8305 cases of carcinoid tumors.

BACKGROUND: Carcinoid tumors are unusual and most reports are anecdotal or limited in number. A series of 2837 cases was published in 1975. No recent large series is available. METHODS: The authors evaluated 5468 cases identified by the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI) from 1973 to 1991 together with 2837 carcinoid cases previously registered by 2 earlier NCI programs. To the authors' knowledge, the 8305 carcinoid tumors analyzed represent the largest current epidemiology series to date. RESULTS: The most frequent sites for carcinoids were the gastrointestinal (GI) tract (73.7%) and the bronchopulmonary system (25.1%). Within the GI tract, most occurred in the small bowel (28.7%), appendix (18.9%), and rectum (12.6%). For all sites, age-adjusted incidence rates were highest in African American males (2.12 per 100,000 population per year). Associated noncarcinoid tumors were frequent in conjunction with small intestinal (16.6%), appendiceal (14.6%), and colonic carcinoids (13.1%). The highest percentage of nonlocalized lesions were noted for pancreatic (76.1%), colonic (71.2%), and small intestinal carcinoids (70.7%) and this corresponded to their poor 5-year survival rates (34.1%, 41.6%, and 55.4%, respectively). The best 5-year survival rates were recorded for appendiceal (85.9%), bronchopulmonary (76.6%), and rectal carcinoids (72.2%). These exhibited invasive growth or metastatic spread in only 35.4%, 27.2%, and 14.2% of cases, respectively. CONCLUSIONS: Carcinoids appear to have increased in incidence in the past 20 years. In part, this may be due to different surgical rules of the various registries, improved diagnostic technology, and increased awareness. A cumulative analysis of all types of carcinoid tumors in the SEER group indicates that in 45.3% metastases are already evident at the time of diagnosis. The overall 5-year survival rate of all carcinoid tumors regardless of site was 50.4% +/- 6.4%.

Black or African American↗
PubMed1997

The pivotal role of John S. Edkins in the discovery of gastrin.

John Sydney Edkins was born in London in 1863. After gaining two open scholarships, he attended Caius College, Cambridge and studied physiology under the tutelage of J.N. Langley and M. Foster. During this period he published on the chemical nature of pepsinogen with Langley. After qualifying as a medical doctor, he worked in Manchester before returning to London, where he succeeded E. Klein as Head of Physiology at St. Bartholomew's. For financial reasons he also worked part time at Bedford College for Women. In 1902 Bayliss and Starling overturned Pavlov's doctrine of the nervous regulation of gastrointestinal function by discovering the pancreatic secretagogue secretin-the first identifiable chemical messenger. Edkins applied a similar rationale to the stomach and in a classic series of experiments noted that injection of a pyloric mucous membrane extract resulted in gastric acid and pepsin secretion in anesthetized cats. In 1905 he named this putative active agent "gastrin." Although his ideas were initially accepted, the discovery of histamine in 1910 and the identification that extracts from other tissues had a similar physiologic effect raised serious questions regarding the validity of the existence of gastrin. Somewhat discouraged, Edkins pursued the teaching and training of women physiologists at Bedford College, where he later became Chairman of Physiology. Outside of science he successfully pursued other interests and became President of the British Croquet Association. The demonstration that gastrin was a unique antral stimulant of acid secretion by Komarov in 1938 was followed by the purification and elucidation of its chemical structure by Gregory and Tracy in 1964. Their work allowed final validation of Edkins' original hypothesis. Edkins died in London in 1940, not only fated to predecease the vindication of his hypothesis but unable to witness the evolution of his discovery into a paradigm for the hormonal regulation of secretory and proliferative cellular activity.

Animals↗
PubMed1997

The diagnosis and management of adult intussusception.

BACKGROUND: While intussusception is relatively common in children, it is a rare clinical entity in adults, where the condition is almost always secondary to a definable lesion. DATA SOURCES: Thirteen cases of intussusception occurring in individuals older than 16 were encountered at our institute between 1981 and 1994. RESULTS: Presenting signs/symptoms included recurrent bowel obstruction, intermittent pain, and red blood per rectum. Correct preoperative diagnosis was made in six patients using colonoscopy, flexible sigmoidoscopy, upper gastrointestinal (GI) series and computed tomography (CT). At surgery the lead point was identified in the small intestine in eight cases, in the colon in four cases, and one small intestinal intussusception was considered idiopathic. Twelve patients underwent laparotomy and one patient was both diagnosed and treated by colonoscopy alone. CONCLUSIONS: Adult intussusception is an unusual cause of bowel obstruction. The likelihood of neoplasia, particularly in the colon as a cause, is high. Operative management is thus almost always necessary.

Adolescent↗
PubMed1997

Approaches to the diagnosis of gut neuroendocrine tumors: the last word (today).

Because SRS identifies 90% of hepatic metastatic disease and the addition of other studies (ultrasonography, C.T. MRI, and selective mesenteric angiography) identities only 4% more, the identification of a primary lesion with SRS obviates for the most part the use of further investigations. If SRS is negative, additional studies should only be undertaken if surgery is contemplated. Because SRS may only localize 60%-70% of primary gut NETs, an additional 10%-15% may be identified by undertaking additional studies. The most sensitive test, STIR-MRI, should be undertaken next, but because it is not widely available, pancreatic protocol CT scan is almost as effective in identification of a primary lesion. If a primary gastrinoma cannot be identified by SRS or STIR-MRI, endoscopic ultrasonography should be undertaken because duodenal gastrinomas are often minute and multicentric. A similar strategy applies for insulinomas because up to 40% cannot be located by SRS and the majority are located in the pancreatic head. Thus, STIR-MRI followed by endoscopic ultrasonography is the most appropriate course. Although calcium provocation-angiography is highly effective in the identification of insulinomas, it is significantly more invasive and should be used only as a last resort. Of particular interest is the observation that in the study of gastrinomas, SRS altered clinical management in almost 50% of patients. This reflected the ability of SRS not only to identify the primary tumor location but clarify equivocal localization results generated by conventional imaging studies. It thus seems that the simplicity, superior sensitivity, high specificity, and cost-effectiveness of SRS mandate that it be the imaging modality in patients with gastrinomas. Because the cost of an SRS is $1800 and may obviate the need for multiple other topographic studies that are at least as expensive, the fiscal dictates further warrant the use of this study as the initial topographic investigation. These observations are probably applicable to all gut NETs, although the likelihood of primary identification in the instance of insulinoma patients may be somewhat less. The timely and cost-effective establishment of the type of NET, its primary site, and the detection metastatic spread will enable determination of the appropriate management strategy.

Algorithms↗
PubMed1997

Helicobacter pylori lipopolysaccharide stimulates histamine release and DNA synthesis in rat enterochromaffin-like cells.

BACKGROUND & AIMS: Helicobacter pylori alterations in gastric acid output and mucosal proliferation may involve the enterochromaffin-like (ECL) cell. To test whether H. pylori affects ECL cell histamine secretion and proliferation, the effect of lipopolysaccharide (LPS) on ECL cell function in vitro was investigated. METHODS: Using a rat ECL cell preparation of high purity (+/-95%), basal and stimulated histamine secretion and DNA synthesis were measured by enzyme immunoassay and bromodeoxyuridine (BrdU) uptake, respectively. RESULTS: Escherichia coli LPS (10(-12) to 10(-6) mol/L) had no effect on basal and stimulated histamine secretion at concentrations of > 10(-6) mol/L. H. pylori LPS stimulated basal and gastrin-stimulated histamine secretion. These effects were completely inhibited by somatostatin (10(-10) mol/L) but not by the gastrin receptor antagonist L365,260 at 10(-6) mol/L. E. coli LPS had a weak stimulatory effect on ECL cell BrdU uptake at 10(-6) mol/L but had no effect on gastrin-stimulated BrdU uptake. H. pylori LPS did not stimulate basal synthesis but significantly increased (1.5-fold) gastrin-stimulated BrdU uptake. CONCLUSIONS: H. pylori influences both ECL cell proliferation and secretion in vitro. An interaction between H. pylori LPS and ECL cells may contribute to the reported abnormalities in acid secretion and gastric pathobiology noted in H. pylori infections.

Animals↗
PubMed1997

Trefoil peptides: mitogens, motogens, or mirages?

Healing of mucosal damage occurs in two phases: restitution of mucosal integrity followed by remodeling with recreation of mucosal architecture. Models of these phenomena include cryoprobe-induced ulcers, NSAID lesions, and surgical anastomosis. Three trefoil peptides are expressed constitutively by epithelial cells in specific regions of the GI tract: pS2 (gastric), spasmolytic polypeptide (SP, gastric and Brunner's glands), and intestinal trefoil factor (ITF, goblet cells). Altered expression occurs in reparative epithelium and adjacent mucosa. In cryoprobe ulceration, rSP mRNA abundance doubles within 2 h, with rITF mRNA becoming detectable after 2-3 days. TGF-alpha and EGF mRNAs do not increase as rapidly as rSP or to the same extent as rITF. Indomethacin lesions of gastric mucosa show increased SP immunoreactivity deep in damaged glands within hours. Surgical anastomotic damage increases rITF mRNA levels at the ulcer edge and sometimes rSP mRNA and peptide in para-anastomotic crypts. Initially, trefoil peptides were viewed as mitogens. However, they are in fact motogens, able to promote cell migration, and may possibly be morphogens. Interactions occur between trefoils and other wound healing peptides (FGFs and EGF). Trefoil peptides appear to be of considerable importance to mucosal healing and might constitute a biologic target of therapeutic relevance.

Animals↗
PubMed1997

Octreotide acetate inhibits motility in the rabbit distal colon.

Octreotide, the long-acting somatostatin analogue, has been reported to modulate gastrointestinal motility in both animals and humans. A role in colonic peristalsis and a possible clinical application in common disorders, such as chronic constipation and irritable bowel syndrome, have not been evaluated. It has been previously suggested that octreotide promotes the descending relaxation of the peristaltic reflex arc. We hypothesized that this effect may involve inhibition of the motility index (MI) of the distal colon. To test this proposal, we studied peristalsis in isolated rabbit colons and also in the intact distal colons of anesthetized rabbits undergoing octreotide administration. Left colons of New Zealand white rabbits were harvested, placed in an isolated organ chamber and perfused with Krebs-Ringer bicarbonate solution via the inferior mesenteric artery. In a separate preparation, the colons were left in situ. Motility was quantified with a 6-port continuous infusion manometry catheter. The MI (mm Hg/min) was calculated by integration of the area of the digitalized signal (8/s), which reflected high-pressure peaks of different magnitudes. High-pressure waves were defined as > 20 mm Hg. Octreotide was infused via the inferior mesenteric artery in the isolated specimen or the lateral ear vein in the anesthetized animals in concentrations of 10(-12) to 10(-6) M. Octreotide inhibited high-pressure waves in a dose-dependent manner. These effects resulted in a decreased MI, with the maximum inhibition of 24.6% at 10(-11) M (p < 0.05 by ANOVA). At that concentration, the number of peaks > 20 mm Hg were reduced by 62.2%. The data indicate that octreotide decreases the MI by inhibition of high-pressure waves in the distal rabbit colon. These findings are consistent with the proposal that somatostatin may augment descending relaxation of the peristaltic reflex arc. This effect is independent of neural modulation.

Animals↗
PubMed1997

A 40-year analysis of 265 gastric carcinoids.

OBJECTIVES: Gastric carcinoid tumors were previously regarded as rare, benign neoplasms. Few data are available on the epidemiology of this lesion. METHODS: We have analyzed the End Results Group (1950-1969), the Third National Cancer Survey (1969-1971) and the Surveillance, Epidemiology, and End Results (SEER, 1973-1991) databases of the National Cancer Institute. The three files consist of 8305 carcinoid cases collectively, including 265 gastric carcinoids. RESULTS: The percentage of gastric carcinoids among all gastric malignancies has increased from 0.3% to 0.54%. The black:white ratio declined from 0.36 to 0.17 as well as the male:female ratio from 0.9 to 0.57. The age-adjusted incidence rates have increased in white females but are much higher for the black population. Gastric carcinoids are associated with other malignant neoplasms in 7.8% of cases. The 5-yr survival rates for localized lesions, with regional and with distant metastases, were 48.6%, 39.9%, and 10%, respectively. CONCLUSIONS: Gastric carcinoids have increased in incidence over the last 20 yr. This may represent either improved diagnostic techniques, increased awareness, or a real change in incidence. Poor 5-yr survival rates indicate that gastric carcinoid tumors exhibit an aggressive biological behavior.

Age Distribution↗
PubMed1996

The effect of vagotomy on enterochromaffin-like cells in Mastomys natalensis.

The effect of vagotomy on the development of ECL cell tumours was analyzed during drug-induced hypergastrinemia in Mastomys natalensis, a rodent prone to develop ECL cell tumours. Untreated animals were compared with animals receiving the histamine2-receptor blocker loxtidine (LOX) and with animals subjected to unilateral subdiaphragmatic vagotomy prior to loxtidine treatment (VAG+LOX). Loxtidine (2g/l) was administered in drinking water for 48 weeks to allow multiple ECL cell carcinoids to develop. Plasma gastrin levels were increased in LOX animals (94 +/- 31 pmol/l) and in VAG+LOX animals (181 +/- 59 pmol/l) compared to controls (45 +/- 4 pmol/l). Corpus weight and oxyntic mucosal thickness was almost doubled in all loxtidine-treated animals and the density of mucosal endocrine cells was increased by 65% in the LOX group and by 135% in VAG+LOX animals. No significant differences in mucosal thickness and endocrine cell density were seen when denervated and intact parts of the stomach were compared. In the VAG+LOX animals endocrine cell neoplasia was seen in 60% and dysplasia in 40% of animals compared to 40% neoplasia, 45% dysplasia and 15% hyperplasia in LOX animals. The frequency of neoplastic and dysplastic lesions did not differ between denervated and intact parts of the stomach. Untreated animals showed no neoplastic or dysplastic lesions. It is concluded that unilateral vagotomy has no protective effect on the development of ECL-cell tumours in Mastomys during hypergastrinemia, as opposed to previous studies in the rat.

Animals↗
PubMed1996

Regulation of mastomys ECL cell function by transforming growth factor alpha.

Little progress has been made in the understanding of the pathobiology of gastric neoplasia over the past 4 decades. This reflects the paucity of information available regarding the biology of gastric mucosal cell proliferation. More recently it has become apparent that growth factor regulation of cell proliferation is of considerable relevance in initiating mucosal mitogenesis. We have recently identified the histamine secreting enterochromaffin-like (ECL) cell as a pivotal cellular regulator of gastric acid secretion. In addition to its critical role in initiating acid secretion, we have proposed that the ECL cell may produce agents responsible for the regulation of mucosal cell proliferation. We have therefore hypothesized that such a function may be subserved by production of transforming growth factor alpha (TGFalpha). TGFalpha is known to play a significant role both in normal physiology and in the transformation of naive cells into a neoplastic form. We therefore proposed that increased levels of gastrin induced by low acid states might stimulate TGFalpha secretion and that this agent might be capable of regulating ECL cell DNA synthesis and cell proliferation. We used the mastomys rodent to generate an in vivo hypergastrinemia model using long-term histamine-2 receptor blockade (loxtidine 1 mg/kg/day). In order to evaluate the cell-specific effects, we developed a pure isolated ECL cell system from the mastomys stomach. This utilized pronase digestion (1.0 mg/ml) and EDTA exposure (1 mM) of the mucosa followed by particle size separation with countercurrent elutriation and density purification on a Nycodenz step gradient. ECL cells were obtained with a purity of 90-95%. Histamine secretion from ECL cells was measured by radioimmunoassay (RIA). TGFalpha content was measured by RIA, and TGFalpha expression was measured by RNAse probe protection assay. DNA synthesis was quantified by measuring bromo-deoxyuridine (BrdU) incorporation into cultured cells. TGFalpha levels were increased in fundic mucosa after 16 weeks of hypergastrinemia from 4.3 +/- 0.6 to 32.6 +/- 2.6 fmole/mg protein, P < 0.05). TGFalpha message was identified in the ECL cells by RNAse probe protection assay, and was fourfold amplified in ECL cell tumors after 16 weeks of exposure to hypergastrinemia. Gastrin stimulated (10 nM) histamine secretion in isolated naive ECL cells was inhibited by TGFalpha (IC50 5 x 10 (-9) M). DNA synthesis was stimulated by gastrin (EC50 2 X 10 M) and TGFalpha (EC50 5 x 10(-9) M). These data are consistent with the proposal that elevated gastrin levels are associated with ECL cell TGFalpha production and that TGFalpha stimulates ECL cell DNA synthesis.

Animals↗
PubMed1996

Overexpression of transforming growth factor-alpha alters differentiation of gastric cell lineages.

Overexpression of transforming growth factor-alpha (TGF-alpha) in the gastric fundic mucosa of metallothionein promoter/enhancer-TGF-alpha(MT-TGF-alpha) transgenic mice produces a phenotype of foveolar hyperplasia similar to that observed in Ménétrier's disease. We have investigated the dynamics involved in the alterations of gastric mucosal morphology in the MT-TGF-alpha mouse model. The fundic mucosa of MT-TGF-alpha mice and nontransgenic littermates was evaluated in animals treated with cadmium sulfate. To mark the mucosal proliferative zone, 8-bromodeoxyuridine (BrdU) was administered 2 hr prior to killing. Gastric mucosa was examined by diastase-resistant, periodic acid-Schiff-positive (DR-PAS) staining and immunohistochemistry for H/K-ATPase an BrdU. MT-TGF-alpha mice demonstrated increased numbers of DR-PAS-staining mucous cells and lower parietal cell numbers per gland unit. While the proliferative zone in nontransgenic mice was located in the upper half of the gland, the zone in MT-TGF-alpha mice was located in the basal region. Overexpression of TGF-alpha in MT-TGF-alpha mice leads to an alteration in the development of mucosal lineages from the fundic progenitor zone, which is biased towards the predominant differentiation of foveolar mucous cells.

Animals↗
PubMed1996

Somatostatin receptor regulation of gastric enterochromaffin-like cell transformation to gastric carcinoid.

BACKGROUND: Although somatostatin is recognized as an inhibitor of neuroendocrine cell secretion, its effect on cell proliferation has not been well defined. Generation of low acid and hypergastrinemia through irreversible H2-receptor blockade (loxtidine) in the African rodent mastomys results in gastric carcinoids (ECLomas) within 4 months. This study was undertaken to evaluate and characterize the precise somatostatin receptor (SSTR) subtype on the mastomys enterochromaffin-like (ECL) cell and to define its role in the regulation of ECL cell secretion and proliferation. METHODS: A pure preparation (approximately 90%) of ECL cells was derived by a combination of pronase digestion and density gradient separation. We assessed the effect of somatostatin (10(-15) to 10(-7) mol/L) on gastrin-stimulated ECL cell histamine secretion and DNA synthesis (bromodeoxyuridine uptake). SSTR2 subtype was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) using gene specific primers and mRNA isolated from normal and hypergastrinemia-induced ECLoma. The polymerase chain reaction product was confirmed by Southern analysis, subcloned, and sequenced. RESULTS: Somatostatin inhibited both gastrin-stimulated histamine secretion (IC50, 5 x 10(-13) mol/L) and DNA synthesis (IC50, 10(-10) mol/L). SSTR2 was identified in the mastomys' brain, and both normal and tumor ECL cells and comparison of the brain and ECL cell SSTR2 nucleotide sequences revealed homology of 99%. CONCLUSIONS: The SSTR2 is expressed by the mastomys' ECL cell and ECLoma. Receptor activation inhibits both ECL cell secretory and proliferative functions.

Animals↗