Gastric achlorhydria in H/K-ATPase-deficient (Atp4a(-/-)) mice causes severe hyperplasia, mucocystic metaplasia and upregulation of growth factors
Gastric achlorhydria in H/K-ATPase-deficient (Atp4a(-/-)) mice causes severe hyperplasia, mucocystic metaplasia and upregulation of growth factors
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DOI：
10.1111/j.1440-1746.2005.03867.x
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发表时间：
2005-08-01
影响因子：
4.1
通讯作者：
Miller, ML
中科院分区：
文献类型：
--
作者：
Judd, LM;Andringa, A;Miller, ML
背景资料：胃肿瘤在人类中很常见，但关于慢性无氯血症、胃泌素血症和增生对癌症风险的贡献仍存在争议。为了研究这一点，缺乏胃H/K-ATP酶的小鼠使用（Atp 4a（-/-）小鼠）来确定慢性酸分泌丧失以及伴随的高胃泌素血症是否容易导致癌症表型。方法：在第3、8、12和20个月时，对按年龄和性别配对的Atp 4a（-/-）和Atp 4a（+/+）小鼠进行组织病理学检查，以及三叶因子家族（TFF）1-3、Reg III β、γ和δ、骨桥蛋白、CD 44、嗜铬粒蛋白A、Crp-导管蛋白和半乳糖凝集素的表达，所有这些在细胞生长中都是重要的。到8个月时，Atp 4a（-/-）小鼠的腺胃重量和厚度增加了一倍，几种生长调节剂也增加了。在12和20个月时，雌性Atp 4a（-/-）小鼠比Atp 4a（-/-）雄性小鼠更增生。到1年时，严重的粘液囊性增生、不完全肠化生、纤毛化生、粘蛋白从中性到酸性的转变和炎症广泛存在。粘液陷窝区的细胞出现幽门型外观，含有大的透明样、高碘酸希夫（PAS）阴性/阿辛蓝阴性包涵体。但没有胃肿瘤的关键特征，如核浸润、浸润粘膜肌层和转移。在Atp 4a（-/-）小鼠中，嗜铬粒蛋白A和组氨酸脱羧酶，RegIII γ和δ，TFF 3，骨桥蛋白和CD 44上调，而Reg III β，和TFF 1 were reduced.Conclusions：慢性无氯血症和高胃泌素血症在老年Atp 4a（-/-）小鼠产生进行性增生，粘液囊性和不完全肠化生，和肿瘤的组织学证据的生长因子的上调。(C)2005年Blackwell Publishing Asia Pty Ltd.
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 III beta, 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, RegIII gamma and delta, TFF3, osteopontin and CD44 were upregulated while Reg III beta, 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. (C) 2005 Blackwell Publishing Asia Pty Ltd.