Elevation of parietal cell cAMP in cholera toxin transgenic mice results in mucous gland metaplasia

Abstract

BACKGROUND & AIMS: Histamine is a potent stimulator of acid secretion from parietal calls Histamine signals through increases in intracellular cAMP as well as Ca 2+. To more fully understand the independent effects of cAMP signaling, we engineered transgenic mice with hyperstimulation of the cAMP pathway in parietal cells. METHODS: The mouse parietal cell-specific H+/K+-ATPase [3 promoter was used to drive expression of the cholera toxin A1 subuint (Ctox), an irreversible stimulator of adenylyl cyclase. Founder transgeinc mice were identified by PCR genotyping, and transgene expression was analyzed by RT-PCR and western blot. Phospho-CREB protein levels were also measured by western blot as an indicator of elevated cAMP. Basal acid content was measured by titration, and plasma gastrin levels were measured by radioimmunoassay. Gastric morphology was analyzed in paraffin sections stained with HE however, preliminary analysis revealed that plasma gastrin levels were reduced in these mice. Line 7 transgenics exhibited the highest Ctox protein expression and accordingly showed elevations of CREB phosphorylation over controls Significant alterations were observed in the gastric morphology of line 7 mice as they aged. By 15 months of age there was a major transformation of the gastric mucosa w~th a marked expansion of neck mucous cells, a reduction of chief cells and the complete loss of parietal cells. Signs of mucous gland metaplasia were observed as early as 2 months in line 7 mice. Some intestinal markers were also elevated in these mice, including intestinal mucous production and increased expression of villin. CONCLUSIONS: The reduction in plasma gastrin levels suggests that elevated cAMP levels may result in enhanced acid secretion from parietal cells leading to compensatory alterations in gastrin secretion to maintain homeostasis. These studies also suggest that overproduction of cAMP leads to substantial morphologic changes in the gastric mucosa consistent with mucous gland metaplasia.