Nam Ki Taek, Varro Andrea, Coffey Robert J, Goldenring James R
Nashville Department of Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2733, USA.
Gastroenterology. 2007 May;132(5):1804-19. doi: 10.1053/j.gastro.2007.03.040. Epub 2007 Mar 24.
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.
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.
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.
The absence of AR promoted the rapid emergence of SPEM in response to oxyntic atrophy.
胃黏膜壁细胞的丧失（胃体萎缩）是慢性胃炎和胃腺癌发病机制中的关键步骤。已知壁细胞分泌表皮生长因子受体（EGFR）配体，其是胃黏膜分化的关键调节因子。尽管EGFR配体的所有作用均通过共同的EGFR蛋白介导，但个别配体可能产生不同的生理反应。先前的研究表明，waved-2小鼠中EGFR信号传导缺陷会加速急性胃体萎缩诱导后化生的出现。我们试图确定特定的EGFR配体是否调节对胃体萎缩的化生反应。
为诱导表达解痉多肽的化生（SPEM），用DMP-777处理双调蛋白（AR）和转化生长因子-α缺陷小鼠及其野生型同窝仔鼠0至14天，然后用药14天，随后停药恢复14天。我们使用细胞谱系特异性标志物评估胃黏膜对胃体萎缩的反应。
尽管转化生长因子-α的缺失不影响SPEM的诱导，但AR的缺失导致急性胃体萎缩后SPEM诱导的加速和放大。三叶因子家族2/解痉多肽和内因子双重免疫染色细胞在AR缺陷小鼠的SPEM中显著增加。在腺底部，内因子免疫反应性细胞也被5-溴-2'-脱氧尿苷共染色，表明它们重新进入细胞周期。
AR的缺失促进了对胃体萎缩反应中SPEM的快速出现。
