gastrins and Necrosis

The NHE4 Na+/H+ exchanger is abundantly expressed on the basolateral membrane of gastric parietal cells. To test the hypothesis that it is required for normal acid secretion, NHE4-null mutant (NHE4-/-) mice were prepared by targeted disruption of the NHE4 (Slc9a4) gene. NHE4-/- mice survived and appeared outwardly normal. Analysis of stomach contents revealed that NHE4-/- mice were hypochlorhydric. The reduction in acid secretion was similar in 18-day-old, 9-week-old, and 6-month-old mice, indicating that the hypochlorhydria phenotype did not progress over time, as was observed in mice lacking the NHE2 Na+/H+ exchanger. Histological abnormalities were observed in the gastric mucosa of 9-week-old NHE4-/- mice, including sharply reduced numbers of parietal cells, a loss of mature chief cells, increased numbers of mucous and undifferentiated cells, and an increase in the number of necrotic and apoptotic cells. NHE4-/- parietal cells exhibited limited development of canalicular membranes and a virtual absence of tubulovesicles, and some of the microvilli had centrally bundled actin. We conclude that NHE4, which may normally be coupled with the AE2 Cl-/HCO3- exchanger, is important for normal levels of gastric acid secretion, gastric epithelial cell differentiation, and development of secretory canalicular and tubulovesicular membranes.

Topics: Achlorhydria; Alleles; Alternative Splicing; Animals; Apoptosis; Blotting, Northern; Blotting, Western; Cell Differentiation; DNA, Complementary; Dose-Response Relationship, Drug; Exons; Gastric Acid; Gastrins; Hydrogen-Ion Concentration; Immunoblotting; In Situ Nick-End Labeling; Mice; Mice, Transgenic; Microscopy, Electron; Models, Biological; Models, Genetic; Mutation; Necrosis; Parietal Cells, Gastric; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sodium-Hydrogen Exchangers; Time Factors

Oxyntic atrophy is the hallmark of chronic gastritis. Many studies have sought to develop animal models for oxyntic atrophy, but none of them are reversible. We now report that rats administered high doses of DMP 777 demonstrate reversible oxyntic atrophy.. DMP 777 was administered to CD-1 rats by oral gavage (200 mg. kg(-1). day(-1)). Serum gastrin level, in vivo acid secretion, and gastric histological changes were evaluated in DMP 777-dosed animals. Direct effects of DMP 777 on parietal cells were evaluated by assessment of aminopyrine accumulation into isolated rabbit parietal cells, as well as by assessment of DMP 777 effects on acridine orange fluorescence and H(+),K(+)-adenosine triphosphatase (ATPase) activity in isolated tubulovesicles.. Oral dosing with DMP 777 caused a rapid increase in serum gastrin levels and severe hypochlorhydria. DMP 777 inhibited aminopyrine accumulation into rabbit parietal cells stimulated with either histamine or forskolin. DMP 777 reversed a stimulated proton gradient in isolated parietal cell tubulovesicles. Oral dosing with DMP 777 led to rapid loss of parietal cells from the gastric mucosa. In response to the acute loss of parietal cells, there was an increase in the activity of the progenitor zone along with rapid expansion of the foveolar cell compartment. DMP 777 treatment also led to the emergence of bromodeoxyuridine-labeled cells and cells positive for periodic acid-Schiff in the basal region of fundic glands. With extended dosing over 3-6 months, foveolar hyperplasia and oxyntic atrophy were sustained while chief cell, enterochromaffin-like cell, and somatostatin cell populations were decreased. No histological evidence of neoplastic transformation was observed with dosing up to 6 months. Withdrawal of the drug after 3 or 6 months of dosing led to complete restitution of the normal mucosal lineages within 3 months.. DMP 777 acts as a protonophore with specificity for parietal cell acid-secretory membranes. DMP 777 in high doses leads to the specific loss of parietal cells. Foveolar hyperplasia, loss of normal gland lineages, and the emergence of basal mucous cells appear as sequelae of the absence of parietal cells. The results suggest that parietal cells are critical for the maintenance of the normal mucosal lineage repertoire.

Topics: Acridine Orange; Aminopyrine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Atrophy; Azetidines; Carbon Radioisotopes; Disease Models, Animal; Enzyme Inhibitors; Fluorescent Dyes; Gastric Acid; Gastrins; Gastritis; H(+)-K(+)-Exchanging ATPase; Ionophores; Leukocyte Elastase; Male; Necrosis; Nigericin; Parietal Cells, Gastric; Piperazines; Rabbits; Rats; Rats, Sprague-Dawley; Regeneration; Stomach

Topics: Animals; Dog Diseases; Dogs; Duodenum; Gastric Mucosa; Gastrinoma; Gastrins; Intestinal Mucosa; Male; Necrosis; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

An ulcer was induced in the anterior wall of the antrum of cats by local injection of acetic acid solution. Carbonized microspheres, 15 +/- 5 microns in diameter, labelled with 141Ce, were used to measure blood flow in different regions and layers of the stomach wall. The radioactivity of a blod reference sample and of tissue samples was determined, and the blood flow was calculated for each tissue sample. The gastric tissue samples were examined microscopically, and the level of gastrin in serum was determined. Two groups of anaesthetized animals were used: in one group of animals blood flow was determined 24 h after ulcer induction and in a group of control animals 24 h after laparotomy. In the ulcer animals the gastric blood flow as increased both in the mucosa and in the muscularis in a zone around the ulcer. Microscopic examination revealed tissue necrosis corresponding to the floor of the ulcer and acute inflammatory changes in the gastric wall around the necrotic area. The serum gastrin concentration tended to increase after ulcer induction.

Topics: Acute Disease; Animals; Cardiac Output; Cats; Female; Gastric Mucosa; Gastrins; Laparotomy; Male; Necrosis; Pyloric Antrum; Regional Blood Flow; Stomach; Stomach Ulcer

A patient in whom Cushing syndrome had been diagnosed at the age of 23 was found 14 years later to have subclinical diabetes mellitus, subcutaneous calcified fat tissue necroses, and hypergastrinemia suggesting Zollinger-Ellison syndrome. Histopathologic investigation revealed pancreatic adenomatosis of the glucagon producing A2-cells with accompanying B-cell hyperplasia, and hyperplasia of the adrenal cortex. The origin of the increased serum gastrin concentration in this patient is not yet known. The significance of A2-cell proliferation in Zollinger-Ellison syndrome and and in multiple endocrine adenomatosis is discussed.

Topics: Adipose Tissue; Adrenal Cortex; Adrenal Glands; Adult; Calcinosis; Cholecystectomy; Cushing Syndrome; Diabetes Complications; Gastrins; Glucagon; Humans; Hyperplasia; Islets of Langerhans; Male; Multiple Endocrine Neoplasia; Necrosis; Obesity; Pancreas; Zollinger-Ellison Syndrome