Reversible drug-induced oxyntic atrophy in rats.
OBJECTIVE
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.
Goldenring
J R
JR
Augusta Veterans Affairs Medical Center, Institute of Molecular Medicine, Department of Medicine, Medical College of Georgia, Augusta, Georgia, USA. jgolden@mail.mcg.edu
Ray
G S
GS
Coffey
R J
RJ
Meunier
P C
PC
Haley
P J
PJ
Barnes
T B
TB
Car
B D
BD
D000165:Acridine Orange; D000632:Aminopyrine / Q000493:pharmacokinetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D001284:Atrophy; D001384:Azetidines; D002250:Carbon Radioisotopes; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D005744:Gastric Acid / Q000378:metabolism; D005755:Gastrins / Q000097:blood; D005756:Gastritis / Q000139:chemically induced / Q000473:pathology*; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009336:Necrosis; D009550:Nigericin / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D013270:Stomach / Q000473:pathology* / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001384:Azetidines; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D005755:Gastrins; D007476:Ionophores; D010879:Piperazines; D000632:Aminopyrine; C105999:DMP 777; D019272:Leukocyte Elastase; D017506:H(+)-K(+)-Exchanging ATPase; D000165:Acridine Orange; D009550:Nigericin