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This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/G460    most recent 00204.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Ueda, K. Articles by Ichinose, M. Search for Related Content PubMed PubMed Citation Articles by Ueda, K. Articles by Ichinose, M.

MUCOSAL BIOLOGY

Adaptive HNE-Nrf2-HO-1 pathway against oxidative stress is associated with acute gastric mucosal lesions

¹Second Department of Internal Medicine; ²Department of Anatomy and Cell Biology, Wakayama Medical University, Wakayama; ³Department of Legal Medicine, Graduate School of Medicine, University of Tokyo; and ⁴Department of Forensic Medicine, Juntendo University School of Medicine, Tokyo, Japan

Submitted 6 May 2007 ; accepted in final form 8 July 2008

Disturbance of the microcirculation and generation of reactive oxygen species are crucial in producing acute gastric mucosal lesions (AGML). To understand the protective mechanism against mucosal injury and oxidative stress in the stomach, we investigated sequential expression and localization of a product of lipid peroxidation and a chemical mediator of the oxidative response array, 4-hydroxynonenal (HNE), transcriptional factor, NF-E2-related factor (Nrf2), and the inducible heme oxygenase (HO-1) in the injured stomach. AGML was produced by intragastric administration of 0.6 N HCl in male rats. Expression and localization of HNE, Nrf2, and HO-1 were investigated by Western blotting, immunohistochemistry, real-time RT-PCR, and in situ hybridization histochemistry. Mucosal lesions and expression of HNE and HO-1 were assessed by prior treatment with the PGI₂ analog beraprast or after sensory denervation by pretreatment with capsaicin. Mucosal lesions were assessed by prior treatment with a HO-1 inhibitor, zinc protoporphyrin (ZnPP). After AGML, increased generation of HNE was observed in the injured mucosa and the surrounding submucosa, followed by nuclear translocation of Nrf2 and upregulation of HO-1 in the macrophages located in the margin of the injured mucosa and in the submucosa. Pretreatment with beraprost attenuated AGML and downregulated the expression of HNE and HO-1, while sensory denervation aggravated AGML and upregulated the expression of HNE and HO-1. Pretreatment with ZnPP also aggravated AGML. The sequential HNE-Nrf2-HO-1 pathway in the gastric mucosal cells and the macrophages is involved in an adaptive mechanism against oxidative stress after AGML.

heat shock protein 32; reactive oxygen species; microcirculation; macrophages; 4-hydroxynonenal; heme oxygenase