Published ahead of print on March 9, 2006, doi:10.1164/rccm.200410-1420OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200410-1420OC
Niflumic Acid Suppresses Interleukin-13–induced Asthma PhenotypesResearch Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University; and First Department of Internal Medicine, Kurume University, Fukuoka, Japan Correspondence and requests for reprints should be addressed to Hiromasa Inoue, M.D., Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: inoue{at}kokyu.med.kyushu-u.ac.jp Rationale: Chloride channels have been implicated in the regulation of mucus production in epithelial cells. Expression of hCLCA1, a calcium-activated chloride channel, has been reported to be increased in the airway epithelium of patients with asthma. Interleukin (IL)-13 induces the cardinal features of bronchial asthma, and glucocorticoids are not sufficient to suppress IL-13–induced airway hyperresponsiveness or goblet cell hyperplasia. Objectives: We studied the effects of chloride channel inhibitors in IL-13–induced asthma. Methods: The effects of niflumic acid (NA), a relatively specific blocker of calcium-activated chloride channel (CLCA), on goblet cell hyperplasia, eosinophil accumulation, and airway hyperresponsiveness were evaluated after IL-13 instillation into the airways. Because IL-13–dependent features rely on JAK/STAT6 signaling, the effect of NA on phosphorylation of JAK2 and STAT6 after IL-13 stimulation was examined in airway epithelial cells in vitro. The expression of the mCLCA family in mouse lung after IL-13 local administration in vivo was analyzed using reverse transcription–polymerase chain reaction. Measurements and Main Results: Treatment with NA inhibited not only IL-13–induced goblet cell hyperplasia but also airway hyperresponsiveness and eosinophilic infiltration. NA suppressed the eotaxin levels in bronchoalveolar lavage fluids and overexpression of the MUC5AC gene, a marker of goblet cell hyperplasia, in the lung after IL-13 instillation. NA suppressed JAK2 activation, STAT6 activation, and eotaxin expression in epithelial cells. The expression of mCLCA3 (mouse homolog hCLCA1), but not that of other CLCA family members, was up-regulated by IL-13. Conclusions: These findings suggest that a chloride channel inhibitor can control IL-13–mediated airway features at least by suppressing JAK/STAT6 activation.
Key Words: airway hyperreactivity • calcium-activated chloride channel • goblet cell metaplasia • STAT6 This article has been cited by other articles:
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