CHRONIC USE OF PROTON PUMP INHIBITORS AND THE QUANTITY OF G, D, AND ECL CELLS IN THE STOMACH

ABSTRACT Background: Acid inhibition from chronic proton pump inhibitor use and a possible increase in gastrin can lead to changes in the regulation of hydrochloric acid production. However, it has not known whether such chronic use changes the presence of gastrin, delta, and enterochromaffin-like cells in the stomach or the relationship between gastrin and delta cells. Aim: To analyze the number of gastrin-producing gastrin cells, somatostatin-producing cells, and histamine-producing cells in patients who were chronic users of proton pump inhibitor, with or without related Helicobacter pylori infection. Methods: Biopsies from 105 patients, including 81 chronic proton pump inhibitor users (experimental group) and 24 controls, were processed immunohistochemically and subjected to counting of gastrin, delta, and enterochromaffin-like cells in high-magnification microscopic fields and in 10 glands. Results: Gastrin cell, delta cell, and enterochromaffin-like cells counts were similar across the groups and appeared to be unaffected by Helicobacter pylori infection. The ratio between gastrin cells and delta cells was higher in the chronic users of proton pump inhibitor group than in controls. Conclusion: Chronic users of proton pump inhibitor does not affect gastrin cell, delta cell, and enterochromaffin-like cell counts significantly, but may alter the ratio between gastrin cells and delta cells.

Control of Gastric Acid Secretion in Somatostatin Receptor 2 Deficient Mice: Shift from Endocrine/Paracrine to Neurocrine Pathways

The gastrin-enterochromaffin-like (ECL) cell-parietal cell axis is known to play an important role in the regulation of gastric acid secretion. Somatostatin, acting on somatostatin receptor type 2 (SSTR2), interferes with this axis by suppressing the activity of the gastrin cells, ECL cells, and parietal cells. Surprisingly, however, freely fed SSTR2 knockout mice seem to display normal circulating gastrin concentration and unchanged acid output. In the present study, we compared the control of acid secretion in these mutant mice with that in wild-type mice. In SSTR2 knockout mice, the number of gastrin cells was unchanged; whereas the numbers of somatostatin cells were reduced in the antrum (−55%) and increased in the oxyntic mucosa (35%). The ECL cells displayed a reduced expression of histidine decarboxylase and vesicle monoamine transport type 2 (determined by immunohistochemistry), and an impaired transformation of the granules to secretory vesicles (determined by electron microscopic analysis), suggesting low activity of the ECL cells. These changes were accompanied by an increased expression of galanin receptor type 1 in the oxyntic mucosa. The parietal cells were found to respond to pentagastrin or to vagal stimulation (evoked by pylorus ligation) with increased acid production. In conclusion, the inhibitory galanin-galanin receptor type 1 pathway is up-regulated in the ECL cells, and the direct stimulatory action of gastrin and vagal excitation is enhanced on the parietal cells in SSTR2 knockout mice. We suggest that there is a remodeling of the neuroendocrine mechanisms that regulate acid secretion in these mutant mice.

Peptide Products of the Neurotrophin-Inducible Gene vgf Are Produced in Human Neuroendocrine Cells from Early Development and Increase in Hyperplasia and Neoplasia

Background: Although the neurotrophin-inducible gene vgf is expressed in mammalian neurons and endocrine cells, limited data is available in man. Aim: The objective of the study was to map proVGF peptides in human endocrine cells during development, adulthood, hyperplasia, and tumors. Methods: Antisera were generated against peptides related to internal cleavage or cleavage-amidation sites (rat proVGF422–430 and human proVGF298–306-NH2) and the proVGF C-terminal ending (human proVGF607–615). Developing and normal adult endocrine cells, hyperplastic endocrine lesions (thyroid, parathyroid, lung, and stomach), and 120 tumors (102 endocrine) were studied. Immunogold electron microscopy was performed on normal adult pancreas and gut, and Western blotting was performed on extracts of control tissues and endocrine tumors. Results: proVGF fragments were revealed in developing pituitary, gut, pancreas, and adrenal medulla from 10 gestational weeks, in normal adult pituitary and adrenal medulla, pancreatic glucagon, and insulin cells and gut serotonin cells, in hyperplastic thyroid calcitonin cells, lung P cells, gastric enterochromaffin-like cells, and gastrin cells, and in 88 of 102 endocrine tumors. At electron microscopy proVGF immunoreactivity was restricted to electron-dense granules. Western blotting revealed large molecular weight forms and cleavage fragments in both control tissues and tumor extracts. Conclusions: proVGF-related peptides are present in endocrine cells early during development and adulthood and increase in hyperplasia and tumors, and proVGF fragments could be novel diagnostic tools for endocrine cells and related lesions, including tumors.