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Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease¹

Isao Nakao^*, Sachiko Kanaji^*, Shoichiro Ohta^*, Hidetomo Matsushita^*, Kazuhiko Arima^*, Noriko Yuyama, Mutsuo Yamaya^¶, Katsutoshi Nakayama^¶, Hiroshi Kubo^¶, Mika Watanabe^||, Hironori Sagara^#, Kumiya Sugiyama^#, Hiroyuki Tanaka^**, Shuji Toda, Hiroaki Hayashi^*, Hiromasa Inoue, Tomoaki Hoshino^*, Aya Shiraki^*, Makoto Inoue^*, Koichi Suzuki^*, Hisamichi Aizawa^*, Satoshi Okinami, Hiroichi Nagai^**, Mamoru Hasegawa^*, Takeshi Fukuda^#, Eric D. Green^* and Kenji Izuhara^2,*

^* Department of Biomolecular Sciences, Department of Pathology and Biodefense, and Department of Ophthalmology, Saga Medical School, Saga; Genox Research Inc., Tokyo; ^¶ Department of Geriatrics and Gerontology and ^|| Department of Pathology, Tohoku University Hospital, Sendai; ^# Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Mibu; ^** Department of Pharmacology, Gifu Pharmaceutical University, Gifu; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences Kyushu University, Fukuoka; ^* Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume; ^* DNAVEC Corp., Tsukuba; ^* Department of Bioregulation, Leprosy Research Center, National Institute of Infectious Diseases, Higashimurayama, Japan; and ^* Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892

Excessive production of airway mucus is a cardinal feature of bronchial asthma and chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality in these diseases. IL-13, a Th2-type cytokine, is a central mediator in the pathogenesis of bronchial asthma, including mucus overproduction. Using a genome-wide search for genes induced in airway epithelial cells in response to IL-13, we identified pendrin encoded by the SLC26A4 (PDS) gene as a molecule responsible for airway mucus production. In both asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells in association with mucus overproduction. Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPD, in airway epithelial cells. Finally, the enforced expression of pendrin in airway epithelial cells in vivo, using a Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with neutrophilic infiltration in mice. These findings collectively suggest that pendrin can induce mucus production in airway epithelial cells and may be a therapeutic target candidate for bronchial asthma and COPD.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by a Research Grant for a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science and was carried out in part in the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Kenji Izuhara, Department of Biomolecular Sciences, Saga Medical School, Saga, 849-8501, Japan. E-mail address: kizuhara{at}cc.saga-u.ac.jp

³ Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; BEC, bronchial epithelial cell; BAL, bronchoalveolar lavage; EGFP, enhanced GFP; PAS, periodic acid-Schiff; Penh, enhanced pause.