Evidence for a Regulatory Role for Histamine in Gastric Enterochromaffin-Like Cell Proliferation Induced by Hypergastrinemia

Abstract

Background/Aims: Hypergastrinemia, induced by sustained suppression of gastric acid secretion, is associated with gastric enterochromaffin-like (ECL) cell hyperplasia and carcinoid tumor formation. We examined the effect of a selective Hi-histamine antagonist, terfenadine, on gastric mucosal cell proliferation to determine whether histamine might modulate ECL cell generation. Methods: The rodent mastomys received the H₂-antagonist loxtidine (2 g/l drinking water) alone or in combination with terfenadine (0.5 g/l or 35 mg/l drinking water) for 120 days. Controls received water or terfenadine alone. Serum gastrin levels and tissue histamine content were assayed by radioimmu-noassays, and tissue chromogranin levels determined (Western blot analysis). In vivo cell proliferation was measured by bromodeoxyuridine (BrdU, 200 mg/kg/day, 3 days) incorporation. Gastric mucosal thickness was determined, ECL cell number was assessed, and the percentage of proliferating ECL cells quantitated. To evaluate the direct action on ECL cells we then studied the effect of terfenadine on histamine secretion and DNA synthesis (BrdU uptake) in an isolated preparation (∼ 90% pure) of ECL cells. Results: Loxtidine increased serum gastrin levels, mucosal thickness, tissue chromogranin levels, tissue histamine content, BrdU incorporation, ECL cell number, and proliferating ECL cells (all parameters p < 0.05). Terfenadine alone, irrespective of dosage, had no significant effect. The high dose in combination with loxtidine significantly inhibited the increase in tissue chromogranin levels, tissue histamine content, ECL cell number and proliferating ECL cells (p < 0.05), but did not alter other parameters, compared to loxtidine alone. The low dose did not alter the loxtidine-induced changes. In pure isolated ECL cells, terfenadine did not alter histamine secretion either alone or in combination with gastrin (10 nM). DNA synthesis was significantly inhibited by terfenadine (IC₅₀ 10^-10M). Conclusions: Terfenadine specifically inhibited the effect of loxtidine-induced ECL cell proliferation in vivo and significantly inhibited ECL cell DNA synthesis in vitro. We postulate that histamine, through an H₁ receptor, positively modulates gastric ECL cell proliferation.

Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development

“…This resulted in the identification of alterations in the activator protein (AP)-1 pathway as well as the H 1 receptor in mediating Mastomys ECL cell proliferation and transformation (15), with the latter effect confirming our earlier in vivo studies (27). We have, however, identified that more Mastomys transcripts can be identified on mouse chips than on rat chips (22% vs. 16.5% of probe sets positive, P Ͻ 0.005).…”

Altered gastric chief cell lineage differentiation in histamine-deficient mice

“…Previous investigations have suggested that histamine can regulate the proliferation of ECL cells (14). Pharmacological inhibition of the H 2 -receptor leads to inhibition of acid secretion and elevated levels of gastrin but is not associated with alteration in chief cell lineages.…”

Intracellular Localization of the 74- and 53-kDa Forms ofl-Histidine Decarboxylase in a Rat Basophilic/Mast Cell Line, RBL-2H3

“…It is the only enzyme that forms histamine in mammals. Histamine is well known to act as an important physiological modulator (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). HDCs have been purified from the soluble fraction of various tissues and found to be a dimer consisting of two identical 53-kDa subunits (13)(14)(15)(16), while the size of cDNA-deduced HDC is around 74 kDa (17)(18)(19).…”