Alimentary TractReversible drug–induced oxyntic atrophy in rats☆,☆☆
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).
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.
DMP 777 dosage Control (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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Regulation of Parietal Cell Homeostasis by Bone Morphogenetic Protein Signaling
2023, Gastro Hep AdvancesUp-regulation of Aquaporin 5 Defines Spasmolytic Polypeptide-Expressing Metaplasia and Progression to Incomplete Intestinal Metaplasia
2022, Cellular and Molecular Gastroenterology and HepatologyCitation Excerpt :Furthermore, the proportion of the AQP5-positive gland was increased over 3-fold, and AQP5- and GSII-co-positive glands were increased about 5-fold compared with the gastric mucosa after 2 doses of L635 (Figure 2B). We have also described a second model of acute oxyntic atrophy with the drug DMP-777, which induces SPEM over a longer time course and is associated with little detectable immune cell infiltrate.25,26 In accordance with the L635-induced SPEM model, DMP-777 treatment caused acute parietal cell loss, resulting in SPEM development, although over a longer time course.
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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.
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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.).