Ultrastructural investigations of the enterochromaffin-like (ECL) cells in three different rat strains (Sprague-Dawley, Fischer 344, Wistar) after treatment with the H+,K(+)-ATPase inhibitor pantoprazole.

The purpose of the present study was the evaluation of ultrastructural characteristics of the enterochromaffin-like (ECL) cells in the fundic mucosa of three different rat strains without treatment and after treatment with the H+, K(+)-ATPase inhibitor pantoprazole. In the study, 20 one year old female Sprague Dawley (SD), Fischer 344 (F) and Wistar (W) rats each were treated orally for three months with 4 mg pantoprazole/kg/d or with the vehicle only. The control animals showed close conformity of ECL cell density and morphology in all three strains. Treatment with pantoprazole led to a significant increase in serum gastrin concentration and GPC density in all strains. However, the electron microscopically determined ECL cell density was markedly increased in the SD strain only. Ultrastructurally all treated rats showed activation of the ECL cells, and enhanced histamine release. The SD and F strains had an enhanced proportion of large ECL cell granules, with the F rats also showing an increased granule density. In contrast, the treated W rats were found to have a lower granule density and a higher proportion of small and medium sized granules compared to their controls.     

Effects of short-term treatment with an H+,K(+)-ATPase inhibitor (B8301-078) on enterochromaffin-like (ECL) cells in rat fundic mucosa.

In the present study, female Sprague-Dawley rats were treated orally over 2, 14, and 29 days with 50 mg/kg/day of the H+, K(+)-ATPase inhibitor B8301-078, a substituted benzimidazole. The endocrine cells in the fundic mucosa were quantified by light microscopy with the aid of Grimelius silver staining and examined by electron microscopy. After 2 days of treatment, the number of argyrophilic Grimelius-positive cells (GPC) was clearly reduced compared to the controls, whereas after 14 and 29 days, hyperplasia was observed. Electron microscopy showed that there was only an apparent decrease in GPC density after 2 treatments. This reduction was due to the massive degranulation of the enterochromaffin-like (ECL) cells and the resultant decrease in stainability with silver. After 14 and 29 days the granular depletion was less pronounced. The cells were, therefore, detectable again by light microscopy.     

The effects of prolonged administration of cimetidine or pirenzepine on gastric mucosal cell kinetics, serum gastrin levels and acid secretory responses in rats

60 days' treatment of rats with cimetidine 160 mg/kg/die per os produced a significant increase in total gastrin cell number, gastrin cell density of antral mucosa as well as parietal cell density of fundic mucosa as compared with controls. By contrast, the same parameters significantly decreased in rats treated for 60 days with pirenzepine 16 mg/kg/die per os. Under the same conditions, immunoreactive serum gastrin levels were found to be significantly enhanced in cimetidine-treated rats, but not significantly changed in rats treated with pirenzepine. 48 hours after drug withdrawal, gastric secretory responses to pentagastrin were found to be significantly increased in cimetidine-treated rats and decreased in pirenzepine-treated rats. These results suggest that a feed-back reaction to cimetidine-induced prolonged hypochlorhydria mediates hyperactivity of the gastrin cell system which, in turn, induces parietal-cell hyperplasia. The hyperplasia accounts for hypersecretive responses in cimetidine-treated rats. The inhibitory activity displayed by pirenzepine on the same parameters may be due to the blockade of vagal trophic influences on gastric mucosal cells and/or to the release of inhibitory factors such as somatostatin.     

胃泌素对大鼠胃粘膜环氧合酶及生长因子表达的影响

目的：探讨胃泌素对大鼠胃粘膜环氧合酶（COX）及生长因子表达的影响。方法：雄性SD大鼠皮下注射胃泌素1 μg/kg、10 μg/kg或100 μg/kg，Western blot和免疫组化检查胃粘膜COX-1、COX-2、肝细胞生长因子（HGF）和肝素结合表皮生长因子样生长因子（HB-EGF）表达。评价胃泌素受体拮抗剂YM022对COX-1、COX-2、HGF和HB-EGF表达的影响。结果：胃泌素剂量依赖性地增加大鼠胃粘膜COX-2和HB-EGF表达，而对COX-1和HGF表达无明显影响；YM022阻断胃泌素诱导的COX-2和HB-EGF表达。 结论： 胃泌素调节大鼠胃粘膜COX-2和HB-EGF蛋白表达，提示COX-2和HB-EGF参与与胃泌素相关联的胃粘膜增生和胃癌等的发病过程。     

Histogenesis of a duodenal carcinoid

A duodenal carcinoid with a diameter of 9 mm was cut serially into 5 microns thin sections from one end to the other. Every fourth section was stained with the argyrophil method of Grimelius, while representative sections in between were used for immunohistochemical analyses. The tumor displayed an argyrophil reaction and was chromogranin A immunoreactive and S-100 protein negative. Furthermore, the majority cell population was gastrin-immunoreactive, while minor cell populations stained for somatostatin and serotonin. The serial sectioning revealed that the tumor arose from differentiated endocrine cells located in the mucosal crypts. In the duodenal mucosa in the vicinity of the tumor the epithelial crypts exhibited an increased number of endocrine cells, preferentially displaying gastrin immunoreactivity. The results indicate that in this particular case the carcinoid tumor arose from hyperplastic and differentiated endocrine cells in the epithelial crypts of the duodenal mucosa.     

Gastrin has a specific proliferative effect on the rat enterochromaffin-like cell, but not on the parietal cell: a study by elutriation centrifugation

Gastrin has a general growth-promoting effect on gastric oxyntic mucosa, and a more pronounced one on the enterochromaffin-like (ECL) cell. Whether gastrin has a proliferative effect on the parietal cell lineage beyond the general effect is uncertain. Hypergastrinaemia was evoked in rats using pantoprazole (group II: 100 micromol kg-1, group III: 400 micromol kg-1) for 45 days. Plasma gastrin was 43 +/- 8 pmol L-1 (control), 283 +/- 54 pmol L-1 (group II) and 577 +/- 63 pmol L-1 (group III). Gastric mucosal cells were isolated and fractionated by elutriation centrifugation. Total cell number, percentage and number of ECL and parietal cells, and histamine were determined in each fraction. The number of mucosal cells increased 1.5-fold in both hypergastrinaemic groups. Enterochromaffin-like cell content was 2.6 +/- 0.5% (control), 6.0 +/- 0.6% (group II) and 9.0 +/- 0.8% (group III). Histamine concentration in oxyntic mucosal cells rose similarly. The size of the ECL cells was 8.5 +/- 0.1 microm (control), 10.8 +/- 0.2 microm (group II) and 12.1 +/- 0.2 microm (group III), and the increased size was confirmed by shifted distribution in elutriation fractions. Histamine per ECL cell increased with cell size. The number of parietal cells increased parallel to the total number of mucosal cells (1.5-fold). Parietal cell size and percentage, assessed by image analysis and distribution in elutriation fractions, were unchanged after pantoprazole dosing. Gastrin has a pronounced, concentration-dependent specific trophic effect on ECL cells and a general proliferative effect on gastric mucosa, including parietal cells.     

以有限元法仿真分析闭合式上颌窦提升的黏膜形变

背景：如何避免闭合式上颌窦提升种植治疗中医源性上颌窦黏膜穿孔等并发症成为近年研究的热点。 目的：以有限元法比较闭合式上颌窦提升种植治疗中不同上颌窦黏膜厚度对黏膜穿孔的影响。 方法：在ANSYS有限元分析软件的SHELL63单元中分别建立0.3,0.5,0.8 mm厚度上颌窦黏膜与4.2 mm直径种植体的有限元模型,模拟闭合式上颌窦提升手术抬高黏膜,根据大变形非线性理论计算3种厚度上颌窦黏膜中心Von Mises最大应力值,并进行统计学分析。 结果与结论：通过对3种厚度上颌窦黏膜提升1-5 mm的形变与应力分析,发现上颌窦黏膜高变形区发生在黏膜顶端中心,在黏膜提升1-4 mm时,最大应变值曲线变化温和,在大于4 mm高度后曲线斜率明显增加;在上颌窦黏膜提升5 mm之内,0.3,0.5,0.8 mm 3种厚度黏膜中心最大Von Mises应力值差异无显著性意义(P > 0.05)。提示上颌窦黏膜提升高度大于4 mm之后,黏膜弹性拉伸大幅增加,增大了穿孔的概率;对于上颌窦黏膜厚度为0.3-0.8 mm需要进行闭合式上颌窦提升治疗的患者,其所面对的黏膜穿孔风险是无差别的;而上颌窦黏膜厚度小于0.3 mm的患者,要更加慎重地选择上颌窦提升方案以防止黏膜穿孔的发生。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

The role of the antrum and the vagus nerve in the formation of gastric mucosal histamine

1. The effects of the vagus nerve and of antral gastrin on the rate of histamine formation (histamine forming capacity, HFC, i.e. histidine decarboxylase activity) in the parietal cell region of the gastric mucosa has been investigated in the following stomach preparations: gastric fistula, denervated Heidenhain pouch, antral resection with gastrojejunostomy, gastrojejunostomy with exclusion of the duodenum and in the intact stomach. The determinations of mucosal HFC were made on fasting rats and on re-fed animals when the effect of feeding was studied.2. In fasting rats with a gastrojejunostomy and the antrum intact the mucosal HFC of the innervated stomach was about 4 times higher than in the corresponding preparation with the antrum resected. In the innervated main stomach the mucosal HFC was about twice as high as in the denervated pouch, indicating that the vagus and endogenous antral gastrin each contribute to maintaining mucosal HFC in the fasting state.3. Acidifying the stomach caused a substantial lowering of the mucosal HFC presumably by inhibiting antral gastrin release, whereas acid in the stomach did not interfere with the elevation of mucosal HFC evoked by injection of gastrin.4. Injection of gastrin elevated mucosal HFC in the innervated main stomach and in the denervated pouch to approximately equal levels. With the dose of gastrin employed there was about a fourfold increase in the HFC of the pouch mucosa.5. In antrectomized rats enhanced vagal influence, evoked by insulin injection or by feeding, raised the mucosal HFC. In rats with the antrum intact and the stomach acidified, insulin injection produced an increased HFC. Thus, a vagal effect on mucosal HFC exists independent of participation of antral gastrin.6. The stable choline esters carbachol and methacholine act directly on the parietal cell without involving mucosal HFC. The vagus nerve and gastrin, however, are assumed to provide secretory stimulation by means of accelerated histamine formation.7. The interrelation between increased histamine formation and hydrochloric acid secretion is discussed.     

Oxidant defense mechanisms in the human colon

Reactive oxygen metabolites have been implicated as important mediators of inflammation-induced intestinal injury associated with ischemia (and reperfusion), radiation, and inflammatory bowel disease. Because the colonie mucosa may be subjected to significant oxidant stress during times of acute and chronic inflammation, knowledge of the oxidant defense mechanisms in the colon is of biologic and potential clinical importance. Therefore, the objective of this study was to quantify the specific activities of superoxide dismutase (SOD), catalase, and GSH peroxidase in the normal human colon. We found low, but significant, amounts of all three enzymes in the mucosa, submucosa, and muscularis/serosa of the human colon. However, the mucosal levels of SOD (3.6±0.3 units/mg protein), catalase (11±3 units/ mg), and GSH peroxidase (15.2±0.8 mU/mg) represented only 8%, 4%, and 40%, respectively, of those values determined for human liver. Colonic epithelial cells derived from mucosal biopsies exhibited significantly higher specific activities for SOD (12±0.5 units/mg) and catalase (26±6 units/mg) when compared to whole mucosa, suggesting most of the mucosal activity was associated with the epithelial cells and not the lamina propria. In a comparative study, we found that a human colonic carcinoma cell line (CaCo-2) contained significantly lower SOD (6 ±0.5 units/mg) and catalase (6±0.6 units/mg) activities when compared to colonic epithelial cells. Taken together, our data suggest that: (1) the colonic mucosa is relatively deficient in antioxidant enzymes when compared to liver, and (2) most of the protective enzyme activity is localized within the epithelium and not the mucosal interstitium.This work was supported by a grant from the NIH (DK 39168).     

Gastrin has a specific proliferative effect on the rat enterochromaffin‐like cell,but not on the parietal cell: A study by elutriation centrifugation

Gastrin has a general growth‐promoting effect on gastric oxyntic mucosa, and a more pronounced one on the enterochromaffin‐like (ECL) cell. Whether gastrin has a proliferative effect on the parietal cell lineage beyond the general effect is uncertain. Hypergastrinaemia was evoked in rats using pantoprazole (group II: 100 μmol kg^–1, group III: 400 μmol kg^–1) for 45 days. Plasma gastrin was 43 ± 8 pmol L^–1 (control), 283 ± 54 pmol L^–1 (group II) and 577 ± 63 pmol L^–1 (group III). Gastric mucosal cells were isolated and fractionated by elutriation centrifugation. Total cell number, percentage and number of ECL and parietal cells, and histamine were determined in each fraction. The number of mucosal cells increased 1.5‐fold in both hypergastrinaemic groups. Enterochromaffin‐like cell content was 2.6 ± 0.5% (control), 6.0 ± 0.6% (group II) and 9.0 ± 0.8% (group III). Histamine concentration in oxyntic mucosal cells rose similarly. The size of the ECL cells was 8.5 ± 0.1 μm (control), 10.8 ± 0.2 μm (group II) and 12.1 ± 0.2 μm (group III), and the increased size was confirmed by shifted distribution in elutriation fractions. Histamine per ECL cell increased with cell size. The number of parietal cells increased parallel to the total number of mucosal cells (1.5‐fold). Parietal cell size and percentage, assessed by image analysis and distribution in elutriation fractions, were unchanged after pantoprazole dosing. Gastrin has a pronounced, concentration‐dependent specific trophic effect on ECL cells and a general proliferative effect on gastric mucosa, including parietal cells.     

Effect of <Emphasis Type="Italic">Cannabis sativa</Emphasis> extract on gastric acid secretion,oxidative stress and gastric mucosal integrity in rats

Studies were conducted in pylorus-ligated rats to investigate the effect of Cannabis sativa extract on gastric acid secretion, experimental gastric ulcer and on oxidative stress and inflammatory markers in the gastric mucosa. C. sativa (5, 10 and 20 mg/kg, expressed as Δ⁹-tetrahydrocannabinol) was administered subcutaneously daily for 4 weeks prior to pylorus ligation and different treatments. Under basal conditions, pretreatment with cannabis extract at doses of 5 and 10 mg/kg increased gastric acid secretion and induced minimally visible gastric mucosal lesions in the 4 h pylorus-ligated rat. Malondialdehyde and nitric acid concentration increased, while reduced glutathione decreased by cannabis at doses of 5 and 10 mg/kg in gastric mucosa. TNF-α increased by cannabis extract at doses of 5 and 10 mg/kg but decreased following the high dose of 20 mg/kg. On the other hand, the gastric acid secretory responses stimulated by pentagastrin or carbachol (but not histamine) were inhibited in rats pretreated with cannabis extract. Under these conditions, cannabis decreased pepsin content after pentagastrin and carbachol but not histamine stimulation. Cannabis also decreased lipid peroxidation and nitric oxide content, and increased both reduced glutathione and catalase activity in mucosa. Moreover, cannabis decreased mucosal inflammation (level of TNF-α) and the development of gastric mucosal lesions. Cannabis administered for 1 month prior to pylorus-ligation and either acidified aspirin or ethanol (96 %) decreased the development of gastric mucosal damage in a dose-dependent manner, along with reduction in gastric acid output, gastric mucosal oxidative stress and inflammation (TNF-α). Sections of gastric mucosa stained with periodic acid Schiff showed increased mucus secretion by cannabis in basal conditions and after treatment with aspirin or ethanol. Results indicate that: (1) the effect of cannabis differs in basal conditions and after exposure of the gastric mucosa to high acid concentrations or other chemical noxious agents; (2) cannabis administered systemically exerts gastric mucosal protective effects against mucosal damage evoked by stimulation of gastric acid secretion, acidified aspirin or ethanol. These effects of cannabis are likely to involve inhibition of gastric acid and pepsin secretion, increased mucus, decreased oxidative stress and inflammation in gastric mucosa.     

Mucosal gastrin receptor. I. Assay standardization and fulfillment of receptor criteria.

Using iodinated gastrin with demonstrable biological activity, this study has shown that optimal specific gastrin binding occurs in rat gastric mucosal 270--30,000 g membrane preparations after an incubation period of 30 min at 30 degrees C (pH 7.4) with a protein concentration of 150--200 micrograms per assay tube. The gastrin binding was shown to be saturable with an equilibrium Ka of approximately 0.25 X 10(10) M-1 and an equilibrium Kd of approximately 4 X 10(10) M. The binding capacity was approximately 4 fmol/mg protein. Specific gastrin binding was shown to be present in the oxyntic gland and duodenal mucosa and to be absent from the antral mucosa, liver, spleen, and kidney. In order to decrease the specific binding of gastrin by 50% the competitors in order of potency are 15-Leu G-17 greater than cholecystokinin greater than caerulein greater than pentagastrin; secretin did not display a response similar to the other four competitors tested, indicating that its inhibition may be non-competitive. Fasting decreased the binding capacity of the gastrin receptor and refeeding brought the receptor levels back to control range; this result parallels the decrease seen in serum gastrin after fasting and the return to normal levels with refeeding. This suggests that rat gastric mucosal gastrin receptors may exhibit autoregulation. This study is the first to meet all the criteria for establishing the existence of a mucosal gastrin receptor.     

Localization of Gastrin Activity in the Gastric Antrum1

Gastrin activity was determined in sections, cut parallel to the surface, of the antral mucosa and submucosa of cats and dogs and in the aboral corpus mucosa of dogs and man. The maximal gastrin activity in the antrum was found in the basal 2/3 of the gland crypt region of the mucosa. The superficial 1/3 of the antral mucosa of the cat contained no gastrin activity, whereas in the dog traces of activity were found in this part of the mucosa. Extracts from the submucosa of the cat antrum contained no gastrin activity, but in the submucosa of 1 dog out of 3 low activity was found. The results suggest that the gastrin cells are localized predominantly in the region of the middle and basal parts of the gland crypts of the antral mucosa in the dog and cat. In the corpus mucosa immediately oral to the visualized antrum-corpus boundary, no gastrin activity was found in 3 dogs and activity was present in only 4 of 14 doudenal ulcer patients. Thus the gastrin cells do not seem to be present in the corpus mucosa of dog or man, but the occasional finding of gastrin activity in the most aboral part of the acid secreting gastric mucosa of man speaks in favour of a dentate, or sometimes notchy, antrum-corpus boundary.     

Gastric enterochromaffin-like cell hyperplasia and neoplasia in the rat: an indirect effect of the histamine H2-receptor antagonist, BL-6341

Oral administration of BL-6341 hydrochloride, a long-acting histamine H2-receptor antagonist, to rats for 2 years at doses of 10, 55 or 300 mg/kg/day resulted in several changes in the fundic (oxyntic) mucosa of the glandular stomach. The most significant alteration was a proliferation of argyrophil endocrine cells that was demonstrated to be enterochromaffin-like (ECL) cells. The ECL cell proliferation consisted of a continuum of changes involving diffuse hyperplasia, focal adenomatous hyperplasia, and carcinoid tumor formation at the highest dose level of 300 mg/kg. At 55 mg/kg only ECL cell hyperplasia occurred, and at the low dose of 10 mg/kg there were no remarkable proliferative changes. The reference compound, cimetidine (950 mg/kg), produced a degree of ECL cell proliferation that was slightly less, but not significantly different than, that observed with 55 mg/kg of BL-6341. Dose-related elevations of serum gastrin were observed with BL-6341, while cimetidine produced hypergastrinemia that was generally intermediate between that produced by the middle and low doses of BL-6341. The hypergastrinemia resulted from the pharmacologic inhibition of acid secretion, which is the negative feedback mechanism controlling the production of gastrin. Only the 300 mg/kg dose of BL-6341 produced a significant, sustained (24 hours) hypergastrinemia and carcinoid tumors. The chronic, sustained hypergastrinemia was considered to be the primary cause of the ECL cell carcinoid neoplasia. All genetic toxicology tests performed with BL-6341 were negative. It was concluded that the demonstrated hypergastrinemia represents an indirect, hormonal, epigenetic mechanism of tumorigenesis.     

Effects of Helicobacter pylori infection on the link between regenerating gene expression and serum gastrin levels in Mongolian gerbils

Although regenerating gene (Reg) protein is reported to have a trophic effect on gastric epithelial cells, its involvement in human gastric diseases is not clear. We have recently shown that both gastrin and gastric mucosal inflammation enhance Reg gene expression in the fundic mucosa in rats. This study was designed to clarify whether Reg protein is involved in Helicobacter pylori-induced gastritis and whether Reg gene expression is linked to serum gastrin levels in this condition. Mongolian gerbils were inoculated with an H. pylori strain isolated from a gastric cancer patient. Four weeks later, some of the gerbils with H. pylori infection were eradicated by lansoprazole, amoxicillin, and clarithromycin. The time courses of changes in Reg gene expression, serum gastrin levels, gastric acidity, and histopathologic factors were examined. Four weeks after H. pylori infection, gastritis started spreading to the fundic mucosa, and gastric acidity started reducing. Serum gastrin levels and Reg mRNA expression in the fundus were significantly increased 6 weeks after infection. Reg mRNA expression in the fundus correlated significantly with both serum gastrin levels and the severity of fundic mucosal inflammation. After H. pylori eradication, serum gastrin levels and fundic mucosal inflammation were normalized, and the increase in Reg mRNA expression was abolished. The Reg gene is associated with hypergastrinemia and fundic mucosal inflammation and may be involved in H. pylori-induced gastritis.     

Gastrointestinal endocrine cells in metaplasia of the gastric mucosa and duodenum

Grimelius reaction and immunohistochemical PAP method were used to study endocrine cells producing gastrin (G-cells), somatostatin (D-cells) and gamma-endorphin (GER-cells) in gastric and duodenal mucosa of 95 males with atrophic gastritis with intestinal and pyloric metaplasia. The number of cells was counted per 1 mm2 of the mucosa. In the cases of marked intestinal metaplasia the number of G-, GER- and especially D-cells in the pyloric region non-metaplastic epithelium decreases and is approaching to its number in the duodenum of the control group. In the foci of marked pyloric metaplasia of gastric corpus the number of G- and GER-cells is almost the same as in the zones of gastric metaplasia of duodenum, and is approximating their number in the pyloric region of controls, thus allowing the designation of pyloric metaplasia as a complete one.     

Effects of acid inhibition on somatostatin-producing cells in the rat gastric fundus

Somatostatin plays a role in the regulation of gastric acid secretion. Omeprazole, a potent inhibitor of gastric acid secretion, has been reported to cause either a significant decrease or increase in the formation of gastric somatostatin-producing cells. Therefore, we determined in the present study distribution patterns of somatostatin mRNA and protein in fundus mucosa of rats after long-term inhibition of gastric acid secretion. Female Sprague-Dawley rats were given 0, 20 and 100 mg/kg/day omeprazole, respectively, as gastric instillations during 2 months. Serum gastrin levels were significantly higher in the third group than in the other groups. The omeprazole-treated groups also showed an increase in the number of somatostatin-containing cells in fundus mucosa. Moreover, the intensity of somatostatin-positivity was higher in the treated groups than in the control group. We also observed an increase in the number of cells containing somatostatin mRNA in fundus mucosa of omeprazole-treated rats. These results suggest that long-term inhibition of acid secretion does not inhibit but stimulate somatostatin production in mucosa of rat gastric fundus.     

Reduction of alachlor-induced olfactory mucosal neoplasms by the matrix metalloproteinase inhibitor Ro 28-2653

Chronic exposure to the chloracetanilide herbicide alachlor has been shown to cause olfactory mucosal neoplasms. Genomic analysis of olfactory mucosa from rats given alachlor (126 mg/kg/d) for from 1 day to 18 mo suggested that matrix metalloproteinases MMP-2 and MMP-9 were upregulated in the month following initiation of treatment. The present studies were designed to confirm this latter finding and to explore the potential role of MMPs in alachlor-induced olfactory carcinogenesis. Zymographic analysis of olfactory mucosal extracts confirmed that MMP-2 activity is higher in the olfactory mucosa of alachlor-treated rats. Therefore, rats were fed alachlor (126 mg/kg/d in the diet for 1 year) either with or without the MMP-2/MMP-9 inhibitor Ro 28-2653 (100 mg/kg daily by gavage for the first 2 months of alachlor treatment). The number of olfactory mucosal neoplasms was reduced by 25% after 1 year of alachlor treatment in rats that received both alachlor and Ro 28-2653. The morphology of alachlor-induced olfactory tumors was similar whether or not Ro 28-2653 had been given; the MMP inhibitor itself had no impact on olfactory mucosal histology. These data confirm that olfactory mucosal MMP-2 activity is increased following short-term alachlor exposure and show that administration of an MMP-2/9 inhibitor reduced the incidence of olfactory neoplasms in alachlor-treated rats, thereby implicating MMP-2 activity as a mediator of alachlor-induced carcinogenicity.     

Antral G cells in rats during dosing with a PPARa agonist: a morphometric and immunocytochemical study

Gastrin-producing G cells constitute one of the major populations of neuroendocrine cells in the antral mucosa of the stomach. The peroxisome proliferator-activated receptor (PPAR) alpha-agonist ciprofibrate is used as a lipid-lowering drug. Recently, ciprofibrate has been shown to induce hypergastrinemia in rats without reducing gastric acidity, which indicates a direct stimulatory effect on the G cell. Gastrin probably plays an important role in gastric tumorgenesis, and long-term dosing with ciprofibrate results in enterochromaffin-like (ECL) cell carcinoids in the oxyntic mucosa of rats. In this study, we aimed to examine changes of neuroendocrine granules in G cells following ciprofibrate dosing and relate them to changes induced by the proton pump inhibitor pantoprazole. Furthermore, we wanted to study peroxisomes in G cells. Rats received ciprofibrate 80 mg/kg/day or pantoprazole 200 mg/kg/day in 4 weeks. Antral mucosal specimens were processed for conventional staining procedures and immunocytochemistry for both the light and electron micro-scope. Specimens were immunolabeled for gastrin and peroxisome-specific proteins. Electron micrographs were analyzed planimetrically. This study shows that hypergastrinemia induced by ciprofibrate is accompanied by a decrease in granule number per cell and a relative increase in electron-dense granules. These changes were quite similar to those induced by pantoprazole, indicating signs of G-cell activation in general. However, distinctions concerning granule size and composition and both hypertrophy and hyperplasia of G cells are presented. Finally, demonstration of peroxisomes in G cells was only achieved by using the highly sensitive tyramide signal amplification technique in immunostaining for the peroxisome-specific protein PMP-70. Therefore, neither morphological nor quantitative changes of peroxisomes in G cells were detected.     

Apoptosis resistance in ulcerative colitis: high expression of decoy receptors by lamina propria T cells

Intestinal mucosa is constantly exposed to normal environmental antigens. A significant number of intestinal mucosal T cells are being deleted through apoptosis. In contrast, T cells from inflamed mucosa of ulcerative colitis patients did not undergo apoptosis. In this study, we determined whether the apoptosis of normal mucosal T cells was induced by antigen receptor stimulation and further determined pathways that mediated the apoptosis. Freshly isolated lamina propria T cells were stimulated with CD3 mAb and apoptosis was determined by Annexin V staining. Normal mucosal T cells underwent apoptosis upon CD3 mAb stimulation whereas the T cells from inflamed mucosa did not. The apoptosis in normal T cells was blocked by TRAIL-R1:Fc and an inhibiting CD95 antibody. Interestingly, decoy receptor (DcR)1, DcR2, and DcR3 that compete with death receptor (DR)4/5 and CD95 were highly expressed by the T cells from inflamed mucosa, but much lower by T cells from normal mucosa. Our data suggest that normal mucosal T cells are constantly deleted in response to environmental antigens mediated through DR4/5 and CD95 pathways and mucosal T cells from ulcerative colitis resist to undergoing apoptosis due to highly expression of DcR1, DcR2, and DcR3.