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Publication Detail

Title: Gastric achlorhydria in H/K-ATPase-deficient (Atp4a(-/-)) mice causes severe hyperplasia, mucocystic metaplasia and upregulation of growth factors.

Authors: Judd, Louise M; Andringa, Anastasia; Rubio, Carlos A; Spicer, Zachary; Shull, Gary E; Miller, Marian L

Published In J Gastroenterol Hepatol, (2005 Aug)

Abstract: BACKGROUND: Gastric neoplasia is common in humans, yet controversy remains over contributions of chronic achlorhydria, gastrinemia and hyperplasia, to cancer risk. To study this, mice lacking the gastric H/K-ATPase (Atp4a(-/-) mice) were used to determine whether chronic loss of acid secretion, with attendant hypergastrinemia, predisposes to cancer phenotype. METHODS: Atp4a(-/-) and Atp4a(+/+) mice, paired for age and gender, were examined at 3, 8, 12 and 20 months for histopathology, and for expression of the trefoil factor family (TFF)1-3, Reg IIIbeta, gamma and delta, osteopontin, CD44, chromogranin A, Crp-ductin, and galectin, all of which are important in cell growth. RESULTS: By 8 months, the glandular stomach of the Atp4a(-/-) mice doubled in weight and thickness, and several modulators of growth were increased. Female Atp4a(-/-) mice were more hyperplastic than Atp4a(-/-) males at 12 and 20 months. By 1 year, severe mucocystic hyperplasia, incomplete intestinal metaplasia, ciliated metaplasia, a shift in mucins from neutral to acidic, and inflammation were widespread. Cells in the mucus pit zone developed a pyloric-type appearance, containing large hyaline-like, periodic acid-Schiff (PAS)-negative/alcian blue-negative inclusions. But critical characteristics of gastric neoplasia, such as nuclear atypia, invasion into the muscularis mucosa, and metastases were absent. In Atp4a(-/-) mice, chromogranin A and histidine decarboxylase, RegIIIgamma and delta, TFF3, osteopontin and CD44 were upregulated while Reg IIIbeta, and TFF1 were reduced. CONCLUSIONS: Chronic achlorhydria and hypergastrinemia in aged Atp4a(-/-) mice produced progressive hyperplasia, mucocystic and incomplete intestinal metaplasia, and the upregulation of growth factors without histological evidence of neoplasia.

PubMed ID: 16048577 Exiting the NIEHS site

MeSH Terms: Achlorhydria/metabolism*; Achlorhydria/pathology; Age Factors; Animals; Disease Models, Animal; Endometrial Hyperplasia/pathology; Female; Gastric Mucosa/metabolism*; Gastric Mucosa/pathology; H(+)-K(+)-Exchanging ATPase/deficiency*; H(+)-K(+)-Exchanging ATPase/genetics; Hyperplasia; Male; Metaplasia; Mice; Mice, Knockout; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.; Sex Factors; Stomach/metabolism*; Stomach/pathology

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Last Reviewed: October 07, 2024