JOURNAL ARTICLE

Potentiation of oxyntic atrophy-induced gastric metaplasia in amphiregulin-deficient mice

Ki Taek Nam, Andrea Varro, Robert J Coffey, James R Goldenring
Gastroenterology 2007, 132 (5): 1804-19
17484876

BACKGROUND & AIMS: The loss of parietal cells from the gastric mucosa (oxyntic atrophy) is a critical step in the pathogenesis of chronic gastritis and gastric adenocarcinoma. Parietal cells are known to secrete epidermal growth factor receptor (EGFR) ligands, which are critical regulators of differentiation in the gastric mucosa. Although all of the actions of EGFR ligands are mediated through a common EGFR protein, individual ligands may produce different physiologic responses. Previous investigations have suggested that a deficit in EGFR signaling in waved-2 mice accelerates the emergence of metaplasia after induction of acute oxyntic atrophy. We sought to determine whether specific EGFR ligands regulate the metaplastic response to oxyntic atrophy.

METHODS: To induce spasmolytic polypeptide-expressing metaplasia (SPEM), amphiregulin (AR) and transforming growth factor-alpha-deficient mice and their wild-type littermates were treated with DMP-777 for 0-14 days and for 14 days followed by 14 days of recovery off drug. We evaluated the gastric mucosal response to oxyntic atrophy using cell lineage-specific markers.

RESULTS: Although loss of transforming growth factor-alpha did not influence the induction of SPEM, loss of AR caused an acceleration and amplification in the induction of SPEM after acute oxyntic atrophy. Trefoil factor family 2/spasmolytic polypeptide and intrinsic factor dual-immunostaining cells significantly increased in the SPEM of AR-deficient mice. At the bases of glands, intrinsic factor immunoreactive cells also were costained for 5-bromo-2'-deoxyuridine, suggesting their re-entry into the cell cycle.

CONCLUSIONS: The absence of AR promoted the rapid emergence of SPEM in response to oxyntic atrophy.

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