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Published ahead of print on May 16, 2007, doi:10.1165/rcmb.2006-0423OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 37, pp. 322-329, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2006-0423OC

Glutathione Redox Regulates Airway Hyperresponsiveness and Airway Inflammation in Mice

Yoko Koike, Takeshi Hisada, Mitsuyoshi Utsugi, Tamotsu Ishizuka, Yasuo Shimizu, Akihiro Ono, Yukie Murata, Junji Hamuro, Masatomo Mori and Kunio Dobashi

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma; Pharmaceutical Research Laboratory, Ajinomoto Co. Inc., Kawasaki, Kanagawa; Department of Microbiology and Immunology, Keio University Medical School, Shinjuku, Tokyo; and Gunma University School of Health Sciences, Maebashi, Gunma, Japan

Correspondence and requests for reprints should be addressed to Kunio Dobashi, Gunma University School of Health Sciences, 3-39-15 Showamachi, Maebashi, Gunma, 371-8514, Japan. E-mail address: dobashi{at}health.gunma-u.ac.jp

Glutathione is the major intracellular redox buffer. We have shown that glutathione redox status, which is the balance between intracellular reduced (GSH) and oxidized (GSSG) glutathione, in antigen-presenting cells (APC) regulates the helper T cell type 1 (Th1)/Th2 balance due to the production of IL-12. Bronchial asthma is a typical Th2 disease. Th2 cells and Th2 cytokines are characteristic of asthma and trigger off an inflammation. Accordingly, we studied the effects of the intracellular glutathione redox status on airway hyperresponsiveness (AHR) and allergen-induced airway inflammation in a mouse model of asthma. We used {gamma}-Glutamylcysteinylethyl ester ({gamma}-GCE), which is a membrane-permeating GSH precursor, to elevate the intracellular GSH level and GSH/GSSG ratio of mice. In vitro, {gamma}-GCE pretreatment of human monocytic THP-1 cells elevated the GSH/GSSG ratio and enhanced IL-12(p70) production induced by LPS. In the mouse asthma model, intraperitoneal injection of {gamma}-GCE elevated the GSH/GSSG ratio of lung tissue and reduced AHR. {gamma}-GCE reduced levels of IL-4, IL-5, IL-10, and the chemokines eotaxin and RANTES (regulated on activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid, whereas it enhanced the production of IL-12 and IFN-{gamma}. Histologically, {gamma}-GCE suppressed eosinophils infiltration. Interestingly, we also found that {gamma}-GCE directly inhibited chemokine-induced eosinophil chemotaxis without affecting eotaxin receptor chemokine receptor 3 (CCR3) expressions. Taken together, these findings suggest that changing glutathione redox balance, increase in GSH level, and the GSH/GSSG ratio by {gamma}-GCE, ameliorate bronchial asthma by altering the Th1/Th2 imbalance through IL-12 production from APC and suppressing chemokine production and eosinophil migration itself.

Key Words: glutathione redox • mouse • bronchial asthma • Th1/Th2 balance • eosinophils


CLINICAL RELEVANCE

We demonstrated that changing glutathione redox by {gamma}-GCE ameliorates bronchial asthma by three mechanisms. This study provides in vivo evidence that regulation glutathione redox can be a novel approach for the treatment of allergic diseases.

 



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