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Reversible drug-induced oxyntic atrophy in rats
- Source :
- Gastroenterology. 118(6)
- Publication Year :
- 2000
-
Abstract
- Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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. GASTROENTEROLOGY 2000;118:1080-1093
- Subjects :
- Male
medicine.medical_specialty
Biology
Piperazines
Gastric Acid
Rats, Sprague-Dawley
chemistry.chemical_compound
H(+)-K(+)-Exchanging ATPase
Necrosis
Atrophy
Parietal Cells, Gastric
Internal medicine
Gastrins
medicine
Gastric mucosa
Chief cell
Animals
Regeneration
Neoplastic transformation
Carbon Radioisotopes
Enzyme Inhibitors
Aminopyrine
Parietal cell
Fluorescent Dyes
Hepatology
Ionophores
Anti-Inflammatory Agents, Non-Steroidal
Stomach
Gastroenterology
medicine.disease
Acridine Orange
Rats
Foveolar cell
Disease Models, Animal
medicine.anatomical_structure
Endocrinology
Somatostatin
chemistry
Nigericin
Gastritis
Azetidines
Rabbits
Leukocyte Elastase
Histamine
Subjects
Details
- ISSN :
- 00165085
- Volume :
- 118
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Gastroenterology
- Accession number :
- edsair.doi.dedup.....5c17a5eb608f4d33a85f5d5caa4a3eb2