Morphofunctional state of the gastric parietal and gastrin-producing cells in chronic gastroduodenitis in children

Morphofunctional studies of parietal and gastrin-producing cells in 30 children with chronic gastroduodenitis with (10 patients) or without (20) recurrent erosions in the pyloroduodenal region showed functional inhibition of G cells and hyperplasia of P cells in the antral part of the stomach in children with recurring erosions. In these children, the increased surface area and density of parietal cells, the increased perimeters of secretory canaliculi's membranes, and the consequent elevated gastric juice acidity were probably due to P-cell hyperplasia in the gastric antrum and G-cell hyperplasia in the duodenal bulb. In children, gastroduodenitis with recurrent erosions should be considered a pathogenetic variant of duodenal ulcerous disease.     

Gastroduodenal incretory cells in duodenal ulcer with different levels of gastric secretion

Immunomorphological PAP method was used in 20 patients with duodenum ulcer and in 10 control individuals to study gastrin (G)-, somatostatin (D)- and calcitonin-gene-related peptide (CGRP) cells in biopsies of the stomach and duodenum. The gastrin and pepsinogen level in the blood, basal and acid production stimulated by pentagastrin were also studied. All patients are subdivided into two groups by their acid production: those with hypersecretion and those with normal secretion. The group with hypersecretion was not homogeneous: some patients had deficiency of D-cells (sometimes in combination with G-cell hyperplasia) and others had a relative and absolute decrease of the number of CGRP cells in combination with foci of parietal cells in pylorus. These patients showed a tendency to the hypergastrinemia and significant hyperpepsinogenemia I in the blood. Stomach hyperplasia in the duodenum, multiple duodenal ulcers, erosive gastroduodenitis and ulcers in close relatives occurred more frequently in these patients. G- and CGRP cells are found to be similar in the form and localization. It is not excluded that G-cell contains, apart from gastrin 1-17, calcitonin-gene related peptide.     

G-cell hyperplasia in chronic hypercalcemia. An immunocytochemical and morphometric analysis

The distribution of antropyloric G cells was mapped immunocytochemically and quantitated morphometrically in chronically hypercalcemic and normocalcemic patients. In the normocalcemic (control) patients, the G-cells were sparse in number and confined to the lower third of the antropyloric mucosa, where they were distributed singly or in small clusters within the glands. The absolute G cell (AGC) counts were 5.8 +/- 0.26 (mean +/- SE) per 0.25 sq mm of mucosa. The hypercalcemic patients showed a marked increase in their antropyloric G-cell population. The cells were uniformly distributed throughout the lower two-thirds of the mucosal thickness and were present in large numbers in practically every gland. The AGC counts in these hypercalcemic patients were 48.2 +/- 13.0, a statistically significant increase. These observations indicate that in man chronic hypercalcemia of diverse etiology is associated with antropyloric G-cell hyperplasia. The physiologic significance of this finding and its role in the pathogenesis of peptic ulcer disease needs to be elucidated.     

实验性狗溃疡病手术后G细胞密度及功能的变化研究

目的 研究实验性狗溃疡病手术后G细胞密度和功能的变化。方法 给成年杂种狗分别施行胃大部切除、胃空肠吻合术(DPG-BⅡ)或保留幽门括约肌胃段切除术(PPSG)或高选择性迷走神经切断术(HSV)。以中和滴定法测定胃酸;以放射免疫法测定血清胃泌素;用免疫组化方法检测G细胞数量和功能。结果 三种手术均能有效抑制胃酸分泌。DPG-BⅡ和PPSG术后血清胃泌素降低,而HSV术后血清胃泌素升高。三种手术后胃窦或残留胃窦、十二指肠和空肠的G细胞数密度增加、功能增强。结论 溃疡病术后G细胞呈代偿性增生和功能增强,胃泌素水平不随胃酸降低而相应降低。     

Multicentric gastric carcinoids complicating pernicious anemia. Origin from the metaplastic endocrine cell population

We report three cases of multicentric carcinoid tumors of the stomach in patients with long-standing pernicious anemia and severe atrophic gastritis (type A). The tumor nodules arose in nonantral gastric mucosa showing marked intestinal metaplasia. Diffuse endocrine cell hyperplasia was present in both fundus and antrum. Antral G-cell hyperplasia was observed. A widely accepted pathogenesis of this syndrome suggests that the proliferating cell type is the argyrophilic, enterochromaffinlike cell native to the gastric body and fundus. Our findings conflict with this view, in that focal argentaffin staining was also present within tumor cells, as well as immunoreactivity for serotonin and substance P (more characteristic of small-intestinal enterochromaffin or Kulchitsky's cells and small-intestinal carcinoids). Findings in these cases at least suggest an alternative possibility: the tumors may derive from small-intestinal-type metaplastic endocrine cells within the atrophic mucosa, rather than the hypertrophic native endocrine cell population.     

Duodenal microgastrinoma producing the Zollinger-Ellison syndrome

A 1.5-mm gastrinoma of the duodenal wall was discovered during dissection of a duodenal ulcer in a patient in whom the Zollinger-Ellison (ZE) syndrome was later suspected due to gross autopsy findings. Multiple duodenal ulcers and gastric rugal hypertrophy were noted, and hyperplasia of the parietal cells associated with a duodenal gastrinoma was confirmed by immunohistochemical studies. In many cases of ZE syndrome, a primary neoplasm cannot be localized by angiography, computed tomography, ultrasound, or palpation at exploratory laparotomy. If a neoplasm cannot be identified, many cases will be attributed to islet cell hyperplasia, or antropyloric gastrin cell (G cell) hyperplasia. This case confirms that the primary neoplasm may be grossly undetectable and still produce the clinicomorphologic manifestations of this syndrome.     

G-cell density in the antral mucosa: a feasibility study

In this work a new method for gastrin-secreting cell (G-cell) density measurement was employed in order to test the hypothesis that G-cell density of the antral mucosa can be estimated with an acceptable degree of error. The zone of antral mucosa where most G-cells are located was demarcated, its area was measured and the G-cells within this area were counted. The variation in the e error of the estimate according to normal distribution theory, and the size of the sampling expected to yield G-cell density values with a given error were assessed. Our data indicate that a very large surface of the G-cell zone should be explored in order to estimate G-cell density with an acceptable degree of error. G-cell density measurement appears not to be feasible on biopsy specimens or, for routine diagnosis, on gastrectomy specimens.     

Smooth muscle cell proliferation but not neointimal formation is dependent on alloantibody in a murine model of intimal hyperplasia

Transplant coronary artery disease is the pre-eminent cause of late cardiac allograft failure. It is primarily characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). Although the pathogenesis of TIH is predominately immune driven, the specific role of alloantibodies in the disease process remains undefined. In this study we investigated the contribution of alloantibodies to the development of TIH in a murine model. Orthotopic, carotid artery transplantation was performed between B10A(2R) (H-2(h2)) donor mice and B-cell deficient muMT(-/-) knockout or wild-type C57BL/6 (H-2(b)) recipients in the absence of immunosuppression. Grafts were harvested at 35 days and subjected to planimetry and immunohistochemistry. Alloantibodies were detectable in wild-type recipients within 7 days of transplantation and recipients developed marked TIH at 35 days. Allografts harvested from B-cell deficient recipient mice also developed TIH, which was comparable in severity with wild-type recipients. However, whereas allografts from wild-type recipients showed marked intimal smooth muscle cell (SMC) proliferation, the neointima in B-cell deficient recipients lacked SMCs. Post-transplantation administration of anti-donor serum to muMT(-/-) recipients restored neointimal SMC population but did not influence the severity of TIH. Significant neointimal formation occurs in the absence of alloantibodies but lacks a SMC component. Therefore, SMC migration and proliferation is antibody dependent.     

Critical Roles of Notch and Wnt/β-Catenin Pathways in the Regulation of Hyperplasia and/or Colitis in Response to Bacterial Infection

Notch and Wnt/β-catenin signals play essential roles in intestinal development and homeostasis. Citrobacter rodentium induces transmissible murine colonic hyperplasia (TMCH) and various degrees of inflammation, depending upon the genetic background. We aimed at delineating the role of the Notch and Wnt/β-catenin pathways in the regulation of colonic crypt hyperplasia and/or colitis following C. rodentium infection. During TMCH, relative levels of the Notch intracellular domain (NICD) increased significantly, along with increases in Jagged-1 and Hes-1 coinciding with the progression and regression phases of hyperplasia. Blocking of Notch signaling with dibenzazepine (DBZ) for 5 days before the onset of hyperplasia also blocked Wnt/β-catenin signaling. Targeting the Notch pathway for 5 days after the onset of hyperplasia failed to inhibit Wnt/β-catenin-regulated crypt hyperplasia. Chronic DBZ administration for 10 days blocked both Notch and Wnt signaling, disrupted the intestinal barrier, and induced colitis. Core-3(-/-) mice, which are defective in mucin secretion and are susceptible to experimental triggers of colitis, also exhibited significant colitis in response to C. rodentium plus DBZ. Chronic DBZ administration in these mice did not result in depletion of the putative stem cell marker doublecortin-like kinase-1 (DCLK1) in the crypts. Dietary bael (Aegle marmelos) extract (4%) and curcumin (4%) restored signaling via the Notch and Wnt/β-catenin pathways, thereby promoting crypt regeneration, and also replenished the mucus layer, leading to amelioration of C. rodentium- and DBZ-induced colitis in NIH:Swiss mice. Thus, the balancing act between cell proliferation and mucus production to restore barrier integrity seems to depend upon the interplay between the Wnt/β-catenin and Notch pathways in the TMCH model.     

Antropyloric G-cell hyperplasia in hypercalcemic rabbits bearing the VX2 carcinoma.

The number of distribution and the numbers of G cells in the antropyloric region of the rabbit stomach were mapped employing immunoperoxidase localization and morphometric quantitation and compared to similar analyses in hypercalcemic rabbits bearing the VX2 carcinoma. In normal animals, G cells were confined to the lower third of the antropyloric mucosa, where they were randomyly distributed within the mucosal glands. In contrast, tumor-bearing animals showed an extension of these cells into the middle third of the antropyloric mucosa. The absolute counts of G cells in control rabbits were 5.3 +/- 0.78 (mean +/- SE) per unit area, while those in hypercalcemic tumor-bearing rabbits were 11.9 +/- 0.46, a statistically significant increase. It is concluded that rabbits bearing VX2 carcinoma have G-cell hyperplasia.     

Electron microscopic studies of endocrine hyperplasia in duodenal adenomas in familial adenomatous polyposis

Summary Electron microscopical studies on endocrine cell hyperplasia of duodenal adenomas from five patients with familial adenomatous polyposis were performed. All the endocrine cell types normally found in the duodenal mucosa were identified. A constant feature was proliferation of duodenal-enterochromaffin cells but an increase in the number of all other endocrine cell types apart from pyloricgastrin cells and somatostatin cells, was also observed. Certain types of intestinal endocrine cells (the intestinal enterochromaffin cell and the glicentin cell) are rare cells in the normal duodenal mucosa. The finding of these cells may indicate increased biological aggressivity.     

A Morphometric Study of Antral G-Cell Density in a Sample of Adult General Population: Comparison of Three Different Methods and Correlation with Patient Demography, Helicobacter pylori Infection, Histomorphology and Circulating Gastrin Levels

Helicobacter pylori infection has been linked to hypergastrinemia and either decreased or normal G-cell content in the antral mucosa. To clarify this controversial issue, we quantitatively determined antral G-cell content on the same biopsy specimens with three different methods and examined whether these methods are intercorrelated and the relation of these methods to plasma gastrin concentrations, demography, the occurrence of H. pylori infection and chronic gastritis. Gastric antral mucosal biopsy sections from 273 adults (188 with and 85 without H pylori infection) from a general population sample were examined immunohistochemically for G-cells using cell counting, stereology (point counting) and computerized image analysis. Gastritis was scored according to the updated Sydney system. Basal plasma gastrin concentrations were measured by radioimmunoassay. The three methods for G-cell quantification were poorly correlated and the results showed no correlation with basal plasma gastrin concentrations. The antral G-cell density and scores for H. pylori colonization were positively related to age. Neither the scores for chronic inflammation, nor the scores for inflammatory activity, atrophy or intestinal metaplasia were consistently related to the antral G-cell content. In conclusion, the results of three techniques for G-cell quantification in the gastric antral mucosa were poorly intercorrelated and none of the methods correlated with plasma gastrin concentrations. Age and scores for H pylori colonization seem to be determinants of the G-cell density. That common morphometric techniques correlate poorly is of utmost importance to bear in mind when quantitative morphological studies are planned, compared or interpreted.     

Sustainability of forestomach hyperplasia in rats treated with ethyl acrylate for 13 weeks and regression after cessation of dosing.

In a chronic study conducted by the National Toxicology Program (NTP), gavage administration of 100 or 200 mg ethyl acrylate (EA)/kg/day, 5 days/week, to F344 rats and B6C3F1 mice resulted in a significant dose-dependent increase in the incidence of squamous cell papillomas and carcinomas of the forestomach of both sexes of rats and mice. No increase in the incidence of tumors was observed at any other site in these rats. Chemically-induced cell proliferation is currently thought to play a role in the development and progression of chemically-induced neoplasia. Therefore, a stop-study was initiated where 100 or 200 mg EA/kg (in corn oil) was administered daily, 5 days/week, for 13 weeks. Rats sacrificed at the end of the treatment regimen had severe epithelial hyperplasia of the forestomach. No lesions were observed in the glandular stomach or liver of EA-treated rats. Forestomach hyperplasia induced by EA included upward and downward cell proliferation. However, forestomachs of rats treated for 13 weeks and sacrificed 8 weeks after the last EA dose exhibited a significant decline in the incidence and severity of forestomach mucosal hyperplasia. Histopathologic evaluation of forestomachs of EA-treated rats (13 weeks) which were allowed a 19-month-recovery (with no exposure to EA) showed further decline in the incidence and severity of mucosal cell hyperplasia. These results indicate that gavage administration of EA to rats results in extensive and sustained forestomach mucosal hyperplasia. The sustainability of forestomach hyperplasia is apparently dependent on the continued exposure of rats to ethyl acrylate, and regressed after cessation of dosing. Furthermore, although enough post-treatment time was allowed for tumors to develop after cessation of EA administration, forestomachs exhibited a nearly complete recovery with no increased incidence of papillomas or carcinomas. It, therefore, remains to be determined what duration of exposure or other factors are critical for reversibility or progression of EA-induced forestomach mucosal hyperplasia to neoplasia.     

Duodenal ulcer with gastrin cell hyperplasia--a special form of peptic ulcer

Pap test was used to study gastric and duodenal G and D cells, blood gastrin levels, basal and stimulated acid production, clinical manifestations, and morphological characteristics of the mucosa in 39 patients with duodenal ulcer and 13 controls. The findings enable the authors to outline a special form of peptic ulcer that is characterized by gastrin cellular hyperplasia concurrent with relative pyloric D cell deficit, gastric metaplasia in the duodenum and gastric hypersecretion. Such patients have more frequently multiple ulcers, predominantly 0(I) blood group, complication-aggravated course of the disease, and ulcer history in close relatives. Moreover, it has been demonstrated that incidence of gastric metaplasia is due to gastric hypersecretion; hyperplasia of duodenal gastrin cells is associated with incidence of gastric metaplasia in patients with peptic ulcer.     

In vivo boosting of lung natural killer and lymphokine-activated killer cell activity by interleukin-2: comparison of systemic, intrapleural and inhalation routes.

Natural killer (NK) cells are thought to play a role in host defence against malignancy and infection, in immunoregulation and as precursor cells in a generation of lymphokine-activated killer (LAK) cells which can lyse NK-resistant tumour cells. As the lung is a major site for malignancy and infection and as there are large numbers of lymphoid cells including NK cells in the interstitial compartment of the lung, we evaluated the capacity of interleukin-2 (IL-2), a lymphokine capable of augmenting NK activity in vitro, to augment lung NK cell activity in vivo, using different routes of IL-2 administration. We compared both systemic (i.v. and i.p.) and local (intrapleural and inhalation) routes of IL-2 administration (50,000 U/daily for 5 days) using CBA mice, assessing NK and LAK cell activity in the spleen (systemic) and in the lung. The target cells used for these studies were the YAC-1 (NK-sensitive) and P815, NO36 and HA56 (NK-resistant, LAK-sensitive) cell lines. Splenic NK activity was increased by 1.4-1.9-fold for i.v./i.p., respectively, compared with controls with both systemic routes of administration, and lung NK activity was increased 3.2-fold and 3.8-fold (i.v./i.p, respectively, P less than 0.05), to levels which were comparable to systemic (splenic) NK activity following the same therapy. Intrapleural IL-2 administration similarly enhanced lung NK activity (3.3-fold) and splenic NK activity (1.3-fold; P less than 0.05 versus controls for both). Surprisingly, inhaled IL-2 suppressed both splenic and lung NK cell activity (84 +/- 8% and 78 +/- 10% suppression, respectively, P less than 0.05). LAK cell activity was also enhanced in the lung by 1.8-8-fold in response to i.v., i.p. and intrapleural IL-2, whereas inhaled IL-2 was ineffective in generating LAK cell activity. These results suggest that the systemic and intrapleural administration of IL-2 effectively boost pulmonary NK and LAK activity whereas inhalation of IL-2 does not. Thus, in clinical situations where boosting of local lung NK or LAK cell activity is desired, these routes of IL-2 administration may be effective.     

Sex related differences in serum gastrin concentrations and G- and D-cell populations of the gastric mucosa in guinea-pigs (experimental RIA and immunocytochemical study)

In the present study antral G-cells which secrete gastrin and antral and fundic D-cells which secret somatostatin, an inhibitor of gastric acid secretion were revealed immunocytochemically and the population size estimated along with serum gastrin levels in ten male and eight female guinea pigs. Serum gastrin, antral G-cells, antral D-cells and fundic D-cells were 41.90 +/- 6.10 SD pg/ml, 210 +/- 18.03 SD cells/cm, 128.20 +/- 17.64 SD cells/cm and 121 +/- 17.91 SD cells/cm respectively in males and 35 +/- 4.62 SD pg/ml, 176 +/- 13.80 SD cells/cm, 108.40 +/- 6.90 SD cells/cm and 106.8 +/- 6.50 SD cells/cm respectively in females. The differences in serum gastrin levels, antral G-cell population and antral D-cell population between the two sexes were statistically significant (P less than 0.05, P less than 0.001, P less than 0.01). It is possible that endogenous androgens induce a relative hyperplasia and endogenous oestrogens a relative hypoplasia of G-cells. Antral D-cell differences may reflect an adaptive hormonal mechanism to the possible different states of gastric secretory functions.     

Autoimmune gastritis. A clinicopathologic study of 25 cases

The histopathological diagnosis of autoimmune gastritis (AG) in its early stages can be a diagnostic challenge. Even some advanced cases with complete atrophy of the corpus mucosa may be difficult to recognize. To establish the diagnosis of autoimmune gastritis, several histological features should be assessed and combined with immunostains for enterochromaffin cell-like (ECL) cells and G-cells. The main histological criteria include a mononuclear infiltrate within the lamina propria, foci of destruction of oxyntic glands, intestinal metaplasia (IM), pyloric metaplasia, and parietal cell pseudohypertrophy. These criteria were evaluated in our series of 25 patients with achlorhydria and/or megaloblastic anemia. Some of our patients presented with nonspecific gastrointestinal symptoms. The age ranged between 46 and 79 years; one male patient was only 31 years old. Histologically, the corpus mucosa displayed in all cases chronic inflammation with focal complete IM and advanced pyloric metaplasia. In 4 patients, oxyntic glands were destructed in some sites. There was a pancreatic metaplasia of acinar type in 2 patients and a minimal focal pseudohypertrophy of parietal cells in the 31-year-old man. A tubular adenoma with a low-grade dysplasia was found in one female patient. Immunohistochemically, chromogranin-A highlighted linear or nodular hyperplasia of ECL cells in 19 patients, and adenomatoid ECL hyperplasia in one case (80%). In the remaining cases hyperplasia of ECL cells could not be recognized from their normal count. In 13 cases (52%) a few ECL cells were seen also in IM. Regarding associated pathology, in one woman with nodular ECL cell hyperplasia, a gastric carcinoid was removed endoscopically. The reaction with gastrin antibody revealed in 11 cases (44%) a small number of G cells in IM in the corpus mucosa. In 18 patients, antral mucosa was examined as well. In 8 patients, the mucosa was normal; in 10 cases, a mild chronic inactive gastritis was diagnosed, and in 15 patients G-cell hyperplasia was found. In accordance with other studies, we show that the diagnosis of AG may be established microscopically in endoscopic specimens of the gastric body mucosa when histologic features and immunohistochemical detection of ECL and G cell hyperplasia are combined.     

动脉粥样硬化大鼠血管损伤后局部组织学结构的变化

目的建立大鼠颈总动脉球囊损伤模型，了解血管成形术后再狭窄的发生规律及病理机制。方法在大鼠动脉粥样硬化病变的基础上，使用2F球囊导管损伤大鼠左侧颈总动脉，观察术后不同时期内膜、中膜增生的动态改变；对血管壁增殖的细胞进行鉴定；观察血管壁平滑肌细胞表型标志物SMα—actin表达的变化。结果损伤后7天薪生内膜开始形成，至3月时内膜增厚达最大，管腔明显狭窄，损伤动脉壁可见细胞大量增殖，大部分为平滑肌细胞。损伤早期血管壁表达SMα—actin减少，至损伤后期逐渐恢复至原有水平。结论应用球囊导管可以成功建立大鼠血管损伤动物模型，损伤后新生内膜增生导致管腔狭窄，平滑肌细胞的表型改变、迁移及增殖是内膜过度增生的病理基础。     

Features of the destructive and reparative processes of the liver in various types of acute experimental peritonitis

In experiments on 135 albino rats, present-day techniques were used to examine the time-course of hepatic destructive and reparative processes during various courses of acute experimental peritonitis (AEP). The magnitude of destructive changes in the liver was found to be directly related to the severity of peritoneal lesion, degree of intoxication, and immunologic reactivity of the body. Within the first 4-5 days of AEP, the liver was regenerated mainly by intracellular hyperplasia. On days 3-4 the mitotic activity of hepatocytes markedly increased, reaching its maximum on day 5 of the experiment. Destructive and suppurative changes predominated over reparative ones in the organ in AEP treated with the immunodepressant azathioprine. In contrast, the administration of the cellular immunity stimulant, levamisole++, to the experimental animals was followed by drastically increased mononuclear infiltration, hepatic stromal cell proliferation and reparative hepatocyte regeneration.     

Sex related differences in serum gastrin concentrations and G- and D-cell populations of the gastric mucosa in guinea-pigs (experimental RIA and immunocytochemical study).

In the present study antral G-cells which secrete gastrin and antral and fundic D-cells which secret somatostatin, an inhibitor of gastric acid secretion were revealed immunocytochemically and the population size estimated along with serum gastrin levels in ten male and eight female guinea pigs. Serum gastrin, antral G-cells, antral D-cells and fundic D-cells were 41.90 +/- 6.10 SD pg/ml, 210 +/- 18.03 SD cells/cm, 128.20 +/- 17.64 SD cells/cm and 121 +/- 17.91 SD cells/cm respectively in males and 35 +/- 4.62 SD pg/ml, 176 +/- 13.80 SD cells/cm, 108.40 +/- 6.90 SD cells/cm and 106.8 +/- 6.50 SD cells/cm respectively in females. The differences in serum gastrin levels, antral G-cell population and antral D-cell population between the two sexes were statistically significant (P less than 0.05, P less than 0.001, P less than 0.01). It is possible that endogenous androgens induce a relative hyperplasia and endogenous oestrogens a relative hypoplasia of G-cells. Antral D-cell differences may reflect an adaptive hormonal mechanism to the possible different states of gastric secretory functions.