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1.  Human Islet Amyloid Polypeptide Transgenic Mice: In Vivo and Ex Vivo Models for the Role of hIAPP in Type 2 Diabetes Mellitus 
Experimental Diabetes Research  2008;2008:697035.
Human islet amyloid polypeptide (hIAPP), a pancreatic islet protein of 37 amino acids, is the main component of islet amyloid, seen at autopsy in patients with type 2 diabetes mellitus (DM2). To investigate the roles of hIAPP and islet amyloid in DM2, we generated transgenic mice expressing hIAPP in their islet beta cells. In this study, we found that after a long-term, high-fat diet challenge islet amyloid was observed in only 4 of 19 hIAPP transgenic mice. hIAPP transgenic females exhibited severe glucose intolerance, which was associated with a downregulation of GLUT-2 mRNA expression. In isolated islets from hIAPP males cultured for 3 weeks on high-glucose medium, the percentage of amyloid containing islets increased from 5.5% to 70%. This ex vivo system will allow a more rapid, convenient, and specific study of factors influencing islet amyloidosis as well as of therapeutic strategies to interfere with this pathological process.
doi:10.1155/2008/697035
PMCID: PMC2386890  PMID: 18497871
2.  Enteric neuronal plasticity and a reduced number of interstitial cells of Cajal in hypertrophic rat ileum 
Gut  1998;42(6):836-844.
Background—Partial obstruction of the ileum causes a notable hypertrophy of smooth muscle cells and enteric neurones in the proximally located intestine. 
Aims—To study the expression of neuromessengers in the hypertrophic ileum of rat as little is known about neuromessenger plasticity under these conditions. To investigate the presence of interstitial cells of Cajal (ICC) in hypertrophic ileum. 
Methods—Ileal hypertrophy was induced by circumferential application of a strip of plastic film for 18-24 days. Immunocytochemistry, in situ hybridisation, nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry, and ethidium bromide staining were used to investigate the number of enteric neurones expressing neuropeptides and nitric oxide synthase, and the frequency of ICC. 
Results—In the hypertrophic ileum several neuronal populations showed changes in their expression of neuromessengers. Myenteric neurones expressing vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide, and galanin were notably increased in number. In submucous ganglia the number of VIP immunoreactive neurones decreased while those expressing VIP mRNA increased. NADPH diaphorase positive submucous neurones increased dramatically while the number of neuronal type nitric oxide synthase expressing ones was unchanged. The number of ICC decreased notably in hypertrophic ileum. 
Conclusion—Enteric neurones change their levels of expression of neuromessengers in hypertrophic ileum. ICC are also affected. The changes are presumably part of an adaptive response to the increased work load. 


Keywords: enteric nerves; interstitial cells of Cajal; hypertrophy; neuropeptides; nitric oxide; neuronal plasticity
PMCID: PMC1727150  PMID: 9691923
3.  Epithelial barrier formation by airway basal cells 
Thorax  1997;52(3):213-217.
BACKGROUND: Epithelial shedding processes in airway inflammation and defence may produce damaged areas where basal cells are the main remaining epithelial cell type. The present study examines the capacity of basal cells to form an epithelial barrier structure after loss of columnar epithelial cells. METHODS: A technique was developed which allows selective removal of columnar epithelial cells from isolated airways. A drop of tissue adhesive glue was applied on the mucosal surface shortly after excision of guinea pig trachea and human bronchus. Gentle removal of the glue, together with attached columnar cells, left a single layer of cobbled, solitary basal cells. The tissue was kept in culture media. Morphological changes of the basal cells were monitored by immuno-histochemistry and scanning and transmission electron microscopy at several time points. RESULTS: After 20 minutes the basal cells had undergone extensive flattening and established contact with each other. The basement membrane thus became covered by a poorly differentiated epithelium in both guinea pig and human airways. Abundant interdigitating cytoplasmic protrusions were observed at cell borders. CONCLUSIONS: Basal cells promptly flatten out to cover the basement membrane at loss of neighbouring columnar cells. These data may explain why the epithelial barrier function may be uncompromised in desquamative airway diseases. Furthermore, they suggest the possibility that sacrificial release of columnar epithelial cells and prompt creation of a barrier structure constitute important roles of basal cells in airway defence against severe insults. 



PMCID: PMC1758525  PMID: 9093334
4.  Pituitary adenylate cyclase activating polypeptide and nitric oxide synthase are expressed in the rat ciliary ganglion 
AIMS—To study the distribution in the rat ciliary ganglion of neurons synthesising and storing the recently discovered neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) and neuronal nitric oxide synthase (NOS), the neuronal marker of the novel gaseous transmitter nitric oxide.
METHODS—Neurons expressing PACAP and neuronal NOS mRNA were identified in the rat ciliary ganglion by in situ hybridisation with radiolabelled oligonucleotide probes. Immunocytochemistry was used to demonstrate immunoreactive neuropeptides and NOS.
RESULTS—Immunocytochemistry demonstrated immunoreactivity for PACAP and NOS in a small number of neuronal cell bodies. In situ hybridisation revealed that NOS and PACAP were expressed in numerous ganglion cell somata. The well established ciliary messengers vasoactive intestinal peptide and neuropeptide Y were found in a large number of neuronal cell bodies.
CONCLUSION—These results demonstrate that PACAP and NOS are synthesised and stored in the ciliary ganglion. These findings further illustrate the mixed nature of the ciliary ganglion and may provide a basis for the understanding of the diverse physiological functions of this ganglion.


PMCID: PMC1722144  PMID: 9135387
5.  Role of macrophage migration inhibitory factor (MIF) in allergic and endotoxin-induced airway inflammation in mice. 
Mediators of Inflammation  2000;9(1):15-23.
Macrophage migration inhibitory factor (MIF) has recently been forwarded as a critical regulator of inflammatory conditions, and it has been hypothesized that MIF may have a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Hence, we examined effects of MIF immunoneutralization on the development of allergen-induced eosinophilic inflammation as well as on lipopolysaccharide (LPS)-induced neutrophilic inflammation in lungs of mice. Anti-MIF serum validated with respect to MIF neutralizing capacity or normal rabbit serum (NRS) was administered i.p. repeatedly during allergen aerosol exposure of ovalbumin (OVA)-immunized mice in an established model of allergic asthma, or once before instillation of a minimal dose of LPS into the airways of mice, a tentative model of COPD. Anti-MIF treatment did not affect the induced lung tissue eosinophilia or the cellular composition of bronchoalveolar lavage fluid (BALF) in the asthma model. Likewise, anti-MIF treatment did not affect the LPS-induced neutrophilia in lung tissue, BALF, or blood, nor did it reduce BALF levels of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-1alpha (MIP-1alpha). The present data suggest that MIF is not critically important for allergen-induced eosinophilic, and LPS-induced neutrophilic responses in lungs of mice. These findings do not support a role of MIF inhibition in the treatment of inflammatory respiratory diseases.
PMCID: PMC1781742  PMID: 10877450
6.  Effects of topical budesonide on epithelial restitution in vivo in guinea pig trachea. 
Thorax  1995;50(7):785-792.
BACKGROUND--Continuous epithelial shedding and restitution processes may characterise the airways in diseases such as asthma. Epithelial restitution involves several humoral and cellular mechanisms that may potentially be affected by inhaled anti-asthma drugs. The present study examines the effect of a topical steroid on epithelial restitution in vivo in the guinea pig. METHODS--The airway epithelium was mechanically removed from well defined areas of guinea pig trachea without surgery and without damage to the basement membrane or bleeding. An anti-inflammatory dose of budesonide (1 mg) was administered repeatedly to the tracheal surface by local superfusion 24 hours before, at (0 hours), and 24 hours after the denudation. Migration of epithelial cells, formation of a plasma exudation-derived gel, and appearance of luminal leucocytes were recorded by scanning electron microscopy. Cell proliferation was visualised by bromodeoxyuridine immunohistochemistry and tissue neutrophils and eosinophils by enzyme histochemistry. RESULTS--Immediately after creation of the denuded zone ciliated and secretory cells on its border dedifferentiated, flattened out, and migrated speedily (mean (SE) 2.3 (0.3) micron/min) over the basement membrane. After 48 hours the entire denuded zone (800 microns wide) was covered by a tightly sealed epithelium; at this time increased proliferation was observed in new and old epithelium and subepithelial cells. Budesonide had no detectable effect on epithelial dedifferentiation, migration, sealing, or proliferation. Immediately after denudation and continuously during the migration phase plasma was extravasated creating a fibrinous gel rich in leucocytes, particularly neutrophils, over the denuded area. Budesonide had no effect on either the gel or the leucocyte density. CONCLUSIONS--These observations suggest that topical glucocorticoids may not interfere with a fast and efficient restitution of the epithelium in the airways.
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PMCID: PMC474655  PMID: 7570417
7.  Ontogeny of ECL cells in the rat. 
ECL cells produce histamine and chromogranin A, and are restricted to the oxyntic mucosa of the stomach. ECL cell ontogeny has been studied in some detail in the rat. Using histidine decarboxylase immunostaining, the first ECL cells can be demonstrated at embryonic day 17. Immunoreactive histamine and chromogranin A appear one day later. At embryonic day 20, the vesicular monoamine transporter type 2 is also present in the ECL cells. Neonatally the ECL cell proliferation is slow; however, one to three weeks postnatally there is a rapid growth of ECL cells to populate the basal half of the glands. Gastrin is known to be an important stimulator of ECL cell activity and growth in the adult rat. As revealed in recent mouse gene knock out models gastrin does not seem to play a role in the early ECL cell differentiation and development.
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PMCID: PMC2578991  PMID: 10461348
8.  Physiological significance of ECL-cell histamine. 
In the oxyntic mucosa of the mammalian stomach, histamine is stored in ECL cells and in mucosal mast cells. In the rat, at least 80 percent of oxyntic mucosal histamine resides in the ECL cells. Histamine is a key factor in the regulation of gastric acid secretion. Following depletion of ECL-cell histamine by treatment with alpha-fluoromethylhistidine (alpha-FMH), basal acid secretion was reduced, and gastrin-stimulated acid secretion was abolished. Vagally-induced acid secretion (by insulin injection or pylorus ligation) was unaffected by alpha-FMH treatment but inhibited by an H2 antagonist. These results suggest that gastrin stimulates acid secretion via release of ECL-cell histamine, whereas vagally-induced acid secretion--although histamine-dependent--does not rely on ECL-cell histamine. Gastrin is known to have a trophic effect on the oxyntic mucosa. By combining long-term hypergastrinemia with continuous infusion of alpha-FMH, we were able to show that gastrin-evoked trophic effects in the stomach do not depend on ECL-cell histamine.
PMCID: PMC2578996  PMID: 10461351
9.  Changes in neuroendocrine elements in bronchial mucosa in chronic lung disease in adults. 
Thorax  1995;50(5):551-554.
BACKGROUND--It is not clear whether there is any association between metaplasia of the bronchial epithelium and changes in the distribution of neuroendocrine cells. This study examined, by immunohistological techniques, the distribution of neuroendocrine cells and juxtamucoscal nerve fibres in bronchial biopsies showing metaplastic changes. METHODS--Bronchial biopsies from 12 subjects with epithelial metaplasia associated with bronchiectasis and diffuse pulmonary fibrosis were examined by conventional light microscopy and immunohistological techniques for protein gene product 9.5 (PGP), chromogranin A and B (CAB), serotonin, vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), calcitonin (CT), and gastrin releasing peptide (GRP). RESULTS--Regions of non-metaplastic epithelium contained numerous PGP and serotonin immunoreactive cells. Sub-populations of these cells displayed CAB, CGRP, CT, and GRP immunoreactivity. Metaplastic epithelium contained only a few weakly stained PGP, serotonin, CAB, GRP, CT and CGRP immunoreactive cells in six cases. Metaplastic epithelium was characterised by a high number of CAB-containing cells in six cases and in these biopsies prominent PGP-containing nerve bundles were seen in the subepithelial layer beneath the metaplastic epithelium. CONCLUSIONS--The distribution patterns of neuroendocrine cells and neuronal elements vary between areas of normal and metaplastic epithelium and within areas of metaplastic epithelium. Neuronal hyperplasia was associated with an increase in the number of CAB-containing cells within the metaplastic epithelium.
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PMCID: PMC1021228  PMID: 7541167
10.  The biology and physiology of the ECL cell. 
The enterochromaffin-like (ECL) cells, which are the predominant endocrine cell type in the acid-producing part of the vertebrate stomach, are characterized by numerous, electron-lucent vesicles and few electron-dense granules in the cytoplasm. The biological and physiological significance of the ECL cells remains poorly understood. They produce and store histamine and pancreastatin and are thought to produce an as yet unidentified peptide hormone. The most important clue to their function is their willingness to respond to changes in circulating gastrin. The present review presents current knowledge of the biology and physiology of the rat stomach ECL cells. Examination of serially sectioned ECL cells has revealed that the cytoplasmic vesicles almost invariably contain an electron-dense core, suggesting that perhaps the distinction between granules and vesicles is artificial. We propose a life cycle of the secretory organelles in the ECL cells with a progressive development from granules to vesicles. The results showed that the gastrin-evoked release of histamine and pancreastatin was accompanied by loss of vesicles, and that synthesis of histamine and pancreastatin was accelerated by sustained infusion of gastrin, a treatment that was associated with renewal of vesicles. The events described are instrumental in bringing about a change in the "steady state" or "equilibrium" of the ECL cells, from a non-stimulated, resting state to a gastrin-stimulated, active state. This change is attained within six to eight hr. The next "steady state" change is that from "normal-sized" but active ECL cells to "hypertrophic" ECL cells. The increase in cell size is complete after about one week. The gastrin-evoked increase in the ECL cell self-replication rate is maximal after about 10 days, after which time there is a gradual return back to pre-stimulation values. The ECL cell density increases fairly slowly and does not reach maximum (four-fold increase) until after 20 weeks hypergastrinemia. The activity of the histamine-forming enzyme, histidine decarboxylase, is elevated by gastrin and remains elevated for as long as the gastrin stimulus is maintained (the longest time studied was 20 weeks). The physiological significance of the ECL cells is probably related to their capacity to produce and store histamine and an as yet unidentified peptide hormone. The ECL cells are thought to be the source of histamine necessary for the gastrin-evoked acid response. In addition, preliminary evidence suggests that the ECL cells and the anticipated ECL cell hormone play a role in bone formation.
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PMCID: PMC2588926  PMID: 7502521
11.  The biology and pathobiology of the ECL cells. 
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.
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PMCID: PMC2589758  PMID: 1341077
12.  Histamine containing endocrine cells in the human stomach. 
Gut  1990;31(4):383-388.
Histamine and chromogranin A-immunoreactive cells were studied in the mucosa of the human stomach. Cells reacting to both histamine and chromogranin A-antibodies (histamine containing endocrine cells), were demonstrated by double immunostaining and found to be restricted to the oxyntic mucosa. Histamine containing cells that did not stain with chromogranin A-antibodies were numerous throughout the stomach. Of the histamine immunoreactive cells in the oxyntic gland area 22% reacted with antibodies against chromogranin A. Histamine containing endocrine cells constituted 44% of the total number of endocrine cells in the oxyntic mucosa. These findings suggest that the histamine containing endocrine cells in the human stomach are identical with the so called enterochromaffin like cells.
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PMCID: PMC1378409  PMID: 2186979
13.  Serum gastrin concentration affects the self replication rate of the enterochromaffin like cells in the rat stomach. 
Gut  1990;31(3):274-278.
The influence of antrectomy and antrum exclusion on the enterochromaffin like cell kinetics in the gastric mucosa of the rat was studied using a combination of histamine immunocytochemistry and autoradiography after in vivo labelling with tritiated thymidine. In all experimental groups, the enterochromaffin like cells were found to incorporate the DNA precursor, thus indicating an ability to divide. The serum gastrin concentration was raised by antrum exclusion and reduced by antrectomy. After antrum exclusion, the enterochromaffin like cell proliferation rate increased as indicated by a doubling of the labelling index and by the resulting enterochromaffin like cell hyperplasia (after six weeks). After antrectomy, the enterochromaffin like cell labelling index decreased to reach 25% of the control value; at this time the enterochromaffin like cell density had not decreased significantly. The observed correlation between the enterochromaffin like cell labelling indices and the serum gastrin concentration supports the hypothesis that enterochromaffin like cell proliferation is influenced by serum gastrin.
PMCID: PMC1378265  PMID: 2323588
14.  A mixed endocrine adrenal tumour causing steatorrhoea. 
Gut  1987;28(10):1298-1301.
A 60 year old man developed steatorrhoea, weight loss, mild diabetes mellitus, labile hypertension and limb cramps. Raised plasma concentrations of catecholamines, particularly noradrenaline and a computed tomography-scan showing an adrenal tumour strongly suggested a pheochromocytoma. Adrenoreceptor blockade reversed the symptoms, decreased faecal fat, and increased duodenal trypsin to normal concentrations. After adrenalectomy the patient was asymptomatic and there was no steatorrhoea. The blood glucose concentrations became normal. Immunocytochemistry revealed the tumour cells to store large amounts of enkephalin and somatostatin reactive material and moderate amounts of immunoreactive beta-endorphin and dynorphin.
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PMCID: PMC1433439  PMID: 2890560
15.  Achlorhydria: hypergastrinaemia: carcinoids--a flawed hypothesis. 
Gut  1987;28(9):1189-1192.
PMCID: PMC1433224  PMID: 3678974
16.  Peptide-containing nerve fibres in the gut wall in Crohn's disease. 
Gut  1983;24(8):724-733.
Neurones containing VIP, substance P, or enkephalin were studied by immunocytochemistry in intestinal specimens from 27 patients with Crohn's disease. Also several endocrine cell systems in the gut were examined. The results were compared with those from a control group of 26 patients. The relative frequency of various endocrine cells did not differ overtly from that in controls. Vasoactive intestinal polypeptide and substance P nerve fibres were distributed in all layers of the gut wall, including the submucosal and myenteric plexuses, whereas enkephalin fibres were restricted to the smooth muscle layer and the myenteric plexus. The distribution and frequency of the peptide-containing nerve fibres were the same in Crohn's disease patients as in control patients. A proportion of these nerve fibres, however, were notably coarse in the Crohn's disease patients. This was particularly apparent in the afflicted parts of the intestine although it was noted also in non-afflicted parts. The concentration of VIP and substance P (expressed as pmol/g wet weight) did not, however, exceed that of the control group.
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PMCID: PMC1420237  PMID: 6192043
17.  Enteropathy of coeliac disease in adults: increased number of enterochromaffin cells the duodenal mucosa. 
Gut  1982;23(1):42-48.
Twenty-nine adult patients with coeliac disease and 39 patients with a normal duodenal morphology were studied with respect to the 5-ht containing enterochromaffin cells. Their number in duodenal biopsies was assessed by fluorescence histochemistry and they were examined by immunohistochemistry for peptides known or believed to occur in enterochromaffin cells. Antisera used were raised against substance P, motilin, and leu-enkephalin. In addition, the concentration of 5-HT was determined chemically. In adult coeliac disease there was a significant increase in the number of duodenal enterochromaffin cells compared with the control group. The concentration of 5-HT in the duodenal mucosa was also greatly increased. Substance P was found in a minority population of enterochromaffin cells. These cells were very few and did not increase in number in coeliac disease. Motilin cells were distinct from enterochromaffin cells. No enkephalin immunoreactive cells were found in the biopsies.
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PMCID: PMC1419593  PMID: 7056495
18.  Duodenal endocrine cells in adult coeliac disease. 
Gut  1979;20(7):547-552.
Using immunohistochemical techniques we studied duodenal biopsies from 18 patients with coeliac disease and 24 patients with normal duodenal morphology. We had access to antisera against the following gastrointestinal peptides: cholecystokinin (CCK), gastric inhibitory peptide (GIP), gastrin-17, glucagon-enteroglucagon, motilin, neurotensin, pancreatic peptide (PP), secretin, somatostatin, substance P and vasoactive intestinal peptide (VIP). The somatostatin, GIP, CCK, and glucagon cells were increased in number in coeliac disease. The number of motilin cells was slightly increased, while secretin cells were reduced. Cells storing gastrin-17, substance P, or neurotensin were rare in all patients regardless of diagnosis. No PP immunoreactive cells were found and VIP was localised to neurons only. In biopsies from patients having a mucosa with ridging of villi the number of the various endocrine cell types did not differ from that in the control group.
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PMCID: PMC1412522  PMID: 385455

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