Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient mice
Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient mice
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DOI：
10.1152/ajpgi.00160.2004
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发表时间：
2005-02-01
影响因子：
4.5
通讯作者：
Goldenring, JR
中科院分区：
文献类型：
--
作者：
Nomura, S;Yamaguchi, H;Goldenring, JR
除了在胃酸分泌中的作用外，壁细胞还分泌许多生长因子，这些生长因子可能影响其他胃系的分化。事实上，氧合性萎缩被认为是与胃腺癌风险增加最显著相关的因素。我们研究了用壁细胞原细胞[S-(R*,S*)]- n-[1-（1,3-苯并二氧基-5-基）丁基]-3,3-二乙基-2[4-[（4-甲基-1-哌嗪基）羰基]-4-氧-1-氮杂啶羧酰胺（DMP-777）治疗C57BL/6和胃泌素缺乏小鼠引起急性氧合性萎缩引起的胃粘膜谱系的改变。在野生型和胃泌素敲除小鼠中，DMP-777在治疗2天内引起了壁细胞的快速损失。在野生型小鼠中，氧合性萎缩伴随着5-溴-2'-脱氧尿苷标记的增殖细胞的迅速增加和随之而来的表面细胞数量的增加。然而，胃泌素敲除小鼠没有表现出明显的小凹增生，并表现出迟钝的增殖反应。在野生型小鼠治疗7天后，随着表达TFF2/spasmolytic polypeptide （SPEM）的粘液细胞化生的发展，在基底腺基部出现第二增殖群体。然而，在胃泌素敲除小鼠中，同时表达TFF2 mRNA和蛋白的SPEM在DMP-777处理后仅1天就出现了。在野生型小鼠中，DMP-777诱导的所有变化在停止治疗14天后被逆转。在胃泌素缺乏的小鼠中，停止治疗后14天仍存在显著的SPEM。结果表明，foveolar增生需要胃泌素的影响，而SPEM的发展是对氧合萎缩的反应，不依赖于胃泌素，可能是通过主细胞的转分化。
In addition to their role in gastric acid secretion, parietal cells secrete a number of growth factors that may influence the differentiation of other gastric lineages. Indeed, oxyntic atrophy is considered the most significant correlate with increased risk for gastric adenocarcinoma. We studied the alterations in gastric mucosal lineages elicited by acute oxyntic atrophy induced by treatment of C57BL/6 and gastrin-deficient mice with the parietal cell protonophore [S-(R*,S*)]-N-[1-(1,3-benzodioxol-5-yl)butyl]-3,3-diethyl-2[4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy]-4-oxo-1-azetidine carboxamide (DMP-777). In both wild-type and gastrin knockout mice, DMP-777 elicited the rapid loss of parietal cells within 2 days of treatment. In wild-type mice, oxyntic atrophy was accompanied by a rapid increase in 5-bromo-2'-deoxyuridine-labeled proliferative cells and attendant increase in surface cell numbers. However, gastrin knockout mice did not demonstrate significant foveolar hyperplasia and showed a blunted proliferative response. After 7 days of treatment in wild-type mice, a second proliferative population emerged at the base of fundic glands along with the development of a mucous cell metaplasia expressing TFF2/spasmolytic polypeptide (SPEM). However, in gastrin knockout mice, SPEM expressing both TFF2 mRNA and protein developed after only 1 day of DMP-777 treatment. In wild-type mice, all changes induced by DMP-777 were reversed 14 days after cessation of treatment. In gastrin-deficient mice, significant SPEM was still present 14 days after the cessation of treatment. The results indicate that foveolar hyperplasia requires the influence of gastrin, whereas SPEM develops in response to oxyntic atrophy independent of gastrin, likely through transdifferentiation of chief cells.