Reduced Shh expression in TFF2-overexpressing lesions of the gastric fundus under hypochlorhydric conditions

• Published in: The Journal of pathology Vol. 213; no. 2; pp. 161 - 169
• Main Authors: Minegishi, Y, Suzuki, H, Arakawa, M, Fukushima, Y, Masaoka, T, Ishikawa, T, Wright, NA, Hibi, T
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-10-2007; Wiley
• Subjects: Achlorhydria - metabolism; Achlorhydria - pathology; Animals; Biological and medical sciences; Cell Differentiation; Down-Regulation; gastric acid; Gastric Acid - physiology; Gastric Acid - secretion; Gastric Fundus - metabolism; Gene Expression Regulation - drug effects; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hydrochloric Acid - pharmacology; Hydrogen-Ion Concentration - drug effects; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Mice; Mice, Knockout; morphogen; Mucins - genetics; Mucins - metabolism; Muscle Proteins - genetics; Muscle Proteins - metabolism; parietal cell; Parietal Cells, Gastric - pathology; Parietal Cells, Gastric - physiology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Peptides - genetics; Peptides - metabolism; Receptors, Histamine H2 - deficiency; Receptors, Histamine H2 - genetics; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - genetics; sonic hedgehog; Trefoil Factor-2; zymogenic cell; Stomach; morphogen; Anatomic pathology; zymogenic cell; Digestive system; Hedgehog protein; Gene overexpression; sonic hedgehog; Oxyntic cell; gastric acid; parietal cell; Lesion
• ISSN: 0022-3417; 1096-9896
• 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 H₂ receptor-knockout (H₂R-null) mice and an acid exposure model. Age-matched H₂R-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 H₂R-null mice exhibited higher gastric pH, increased TFF2 expression and reduced Shh expression. Impaired mucous neck-to-zymogenic cell differentiation was observed in the H₂R-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. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.