Reversible drug-induced oxyntic atrophy in rats

Background & Aims: Oxyntic atrophy is the hallmark of chronic gastritis, Ma ny studies have sought to develop animal models for oxyntic atrophy, but no ne of them are reversible, We now report that rats administered high doses of DMP 777 demonstrate reversible oxyntic atrophy, Methods: DMP 777 was adm inistered to CD-1 rats by oral gavage (200 mg . kg(-1) . day(-1)). Serum ga strin level, in vivo acid secretion, and gastric histological changes were evaluated in DMP 777-dosed animals. Direct effects of DMP 777 on parietal c ells were evaluated by assessment of aminopyrine accumulation into isolated rabbit parietal cells, as well as by assessment of DMP 777 effects on acri dine orange fluorescence and H+,K+-adenosine triphosphatase (ATPase) activi ty in isolated tubulovesicles, Results: Oral dosing with DMP 777 caused a r apid increase in serum gastrin levels and severe hypochlorhydria. DMP 777 i nhibited aminopyrine accumulation into rabbit parietal cells stimulated wit h either histamine or forskolin, DMP 777 reversed a stimulated proton gradi ent 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 compartmen t. DMP 777 treatment also led to the emergence of bromodeoxyuridine-labeled cells and cells positive for periodic acid-Schiff in the basal region of f undic glands. With extended dosing over 3-6 months, foveolar hyperplasia an d oxyntic atrophy were sustained while chief cell, enterochromaffin-like ce ll, and somatostatin cell populations were decreased. No histological evide nce of neoplastic transformation was observed with dosing up to 6 months. W ithdrawal of the drug after 3 or 6 months of dosing led to complete restitu tion of the normal mucosal lineages within 3 months. Conclusions: DMP 777 a cts as a protonophore with specificity for parietal cell acid-secretory mem branes, 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 th e normal mucosal lineage repertoire.