Submitted on May 6, 2007
Accepted on July 8, 2008
Adaptive HNE-Nrf2-HO1 pathway against oxidative stress is associated with acute gastric mucosal lesions
Kazuki Ueda1, Takashi Ueyama2*, Ken-ichi Yoshida3, Hiroko Kimura4, Takao Ito2, Yasuhito Shimizu1, Masashi Oka5, Yoshihiro Tsuruo6, and Masao Ichinose5
1 2nd Department of Internal Medicine, Wakayama Medical University School of Medicine, Wakayama, Japan
2 Department of Anatomy and Cell Biology, Wakayama Medical University School of Medicine, Wakayama, Japan
3 Department of Legal Medicine, Graduate School of Medicine, University of Tokyo, Japan
4 Department of Forensic Medicine, Juntendo University Scholl of Medicine, Japan
5 Wakayama, Japan; 2nd Department of Internal Medicine, Wakayama Medical University School of Medicine, Wakayama, Japan
6 Wakayama, Japan; Department of Anatomy and Cell Biology, Wakayama Medical University School of Medicine, Wakayama, Japan
* To whom correspondence should be addressed. E-mail: tueyama{at}wakayama-med.ac.jp.
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 intra-gastric administration of 0.6N 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 a PGI2 analog, beraprast or following sensory denervation by pretreatment with capsaicin. Mucosal lesions were assessed by prior treatment with a HO-1 inhibitor, zinc protoporphyrin (ZnPP). Following AGML, increased generation of HNE was observed in the injured mucosa and the surrounding submucosa, followed by nuclear translocation of Nrf2 and up-regulation of HO-1 in the macrophages located in the margin of the injured mucosa and in the submucosa. Pretreatment with beraprost attenuated AGML and down-regulated the expression of HNE and HO-1, while sensory denervation aggravated AGML and up-regulated the expression of HNE and HO-1. Pretreatment with ZnPP also aggravated AGML. Sequential HNE-Nrf2-HO-1 pathway in the gastric mucosal cells and the macrophages is involved in an adaptive mechanism against oxidative stress following AGML.
