Minegishi Y, Suzuki H, Arakawa M, Fukushima Y, Masaoka T, Ishikawa T, Wright N A, Hibi T
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
J Pathol. 2007 Oct;213(2):161-9. doi: 10.1002/path.2221.
Expression of sonic hedgehog (Shh), a morphogen for the gastric fundic glands, is reduced in the atrophic mucosa that develops in association with Helicobacter pylori infection, resulting in impaired differentiation of the fundic gland cells, increased expression of trefoil factor family 2 (TFF2) and the formation of spasmolytic polypeptide (SP)-expressing metaplasia (SPEM), a preneoplastic lesion. However, it is still unresolved whether H. pylori-induced inflammation and the resultant reduction in parietal cell number or reduced parietal cell function per se reduces Shh expression. The present study was designed to clarify the expression of Shh and TFF2 in the context of parietal cell dysfunction in the absence of inflammation, using histamine H(2) receptor-knockout (H(2)R-null) mice and an acid exposure model. Age-matched H(2)R-null mice and wild-type (WT) mice were used. The expression of Shh and TFF2 mRNA was quantified by quantitative RT-PCR. Immunohistochemistry was also performed to detect the expression of Shh, TFF2 and cell markers. To study the effects of acid exposure, HCl solution was administered to the animals. The H(2)R-null mice exhibited higher gastric pH, increased TFF2 expression and reduced Shh expression. Impaired mucous neck-to-zymogenic cell differentiation was observed in the H(2)R-null mice. Furthermore, Shh expression increased in the presence of gastric acid and showed a significant correlation with gastric surface pH. In conclusion, our results suggest that persistent parietal cell dysfunction alone (suppressed gastric acid secretion), in the absence of inflammation or parietal cell loss caused by H. pylori infection, may be sufficient to down-regulate Shh expression in TFF2-overexpressing preneoplastic lesions of the gastric fundus. Since exposure to acid restored fundic Shh expression, appropriate gastric acid secretion may play an important role in the morphogen dynamics involved in the maintenance of gastric fundic gland homeostasis.
胃底腺形态发生素音猬因子（Shh）在与幽门螺杆菌感染相关的萎缩性黏膜中表达降低，导致胃底腺细胞分化受损、三叶因子家族2（TFF2）表达增加以及解痉多肽（SP）表达化生（一种癌前病变）的形成。然而，幽门螺杆菌诱导的炎症以及由此导致的壁细胞数量减少或壁细胞功能本身降低是否会降低Shh表达仍未明确。本研究旨在利用组胺H₂受体基因敲除（H₂R基因敲除）小鼠和酸暴露模型，阐明在无炎症情况下壁细胞功能障碍背景下Shh和TFF2的表达情况。使用年龄匹配的H₂R基因敲除小鼠和野生型（WT）小鼠。通过定量逆转录聚合酶链反应（qRT-PCR）对Shh和TFF2 mRNA的表达进行定量。还进行了免疫组织化学检测Shh、TFF2和细胞标志物的表达。为了研究酸暴露的影响，给动物施用盐酸溶液。H₂R基因敲除小鼠表现出较高的胃pH值、TFF2表达增加和Shh表达降低。在H₂R基因敲除小鼠中观察到黏液颈细胞向酶原细胞分化受损。此外，胃酸存在时Shh表达增加，且与胃表面pH值呈显著相关。总之，我们的结果表明，在无幽门螺杆菌感染引起的炎症或壁细胞丢失的情况下，仅持续的壁细胞功能障碍（胃酸分泌受抑制）可能足以下调胃底TFF2过表达癌前病变中Shh的表达。由于酸暴露可恢复胃底Shh表达，适当的胃酸分泌可能在维持胃底腺稳态所涉及的形态发生素动态变化中起重要作用。
