Gastroenterology

Gastroenterology

Volume 118, Issue 6, June 2000, Pages 1080-1093
Gastroenterology

Alimentary Tract
Reversible drug–induced oxyntic atrophy in rats,☆☆

https://doi.org/10.1016/S0016-5085(00)70361-1Get rights and content

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

Section snippets

Materials

CD-1 rats were obtained from Charles River Breeding Laboratories (Wilmington, MA). [14C]Aminopyrine was purchased form DuPont/NEN (Boston, MA). Polyclonal antibodies against H+,K+-adenosine triphosphatase (ATPase) were a gift from Dr. Adam Smolka (Medical University of South Carolina, Charleston, SC). Polyclonal antibodies against rat intrinsic factor were a gift of Dr. David Alpers (Washington University, St. Louis, MO). Murine monoclonal immunoglobulin M (IgM) antibody against human

DMP 777 causes a rapid increase in serum gastrin levels

DMP 777 is a cell-permeant inhibitor of neutrophil elastase that can be administered orally (Figure 1).

. Chemical structure of DMP 777.

Short-term administration of DMP 777 orally at doses of either 50 or 200 mg/kg caused a rapid increase in serum gastrin levels that was statistically significant after 60 minutes (Table 1) and was sustained at even higher levels after 4 hours.

. Mean serum gastrin levels after DMP 777 administration

DMP 777 dosageControl (n = 5)15 mg/kg (n = 6)30 mg/kg (n = 6)50

Discussion

The results of this study represent the first demonstration of reversible oxyntic atrophy. Rats treated with DMP 777 demonstrate a rapid loss of parietal cells through the ability of the drug to act directly as a protonophore with selectivity for parietal cell secretory membranes. Loss of parietal cells is accompanied by rapid expansion of foveolar surface mucous cells. With continued dosing, further changes in fundic lineages occur with decreases in ECL, somatostatin, and chief cells. All of

Acknowledgements

The authors thank Ms. Jenetta Smith for technical assistance and Raymond Meade for electron microscopy.

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    Address requests for reprints to: James R. Goldenring, M.D., Ph.D., Institute for Molecular Medicine and Genetics, CB-2803, Medical College of Georgia, 1120 Fifteenth Street, Augusta, Georgia 30912-3175. e-mail: [email protected]; fax: (706) 721-7915.

    ☆☆

    Supported by the DuPont Pharmaceutical Corp.; by Department of Veterans Affairs Merit Award and National Institutes of Health (NIH) grants NIDDK DK48370 and DK43405 (to J.R.G.); and by NIH grant CA46413 (to R.J.C.).

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