Published ahead of print on March 9, 2006, doi:10.1164/rccm.200410-1420OC Am. J. Respir. Crit. Care Med., Volume 173, Number 11, June 2006, 1216-1221 A more recent version of this article appeared on June 1, 2006
Submitted on October 28, 2004 Niflumic Acid Suppresses Interleukin-13-Induced Asthma PhenotypesTakako Nakano1,1 Graduate School of Medical Sciences, Research Institute for Diseases of the Chest, Kyushu University, Fukuoka, Japan, 2 First Department of Internal Medicine, Kurume University, Kurume, Japan * To whom correspondence should be addressed. 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 asthmatics. 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, a relatively specific blocker of 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 niflumic acid 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-PCR. Measurements and Main Results: Treatment with niflumic acid inhibited not only IL-13-induced goblet cell hyperplasia but also airway hyperresponsiveness and eosinophilic infiltration. Niflumic acid suppressed the eotaxin levels in BAL fluids and overexpression of the MUC5AC gene, a marker of goblet cell hyperplasia, in the lung after IL-13. Niflumic acid suppressed JAK2 activation, STAT6 activation, and eotaxin expression in epithelial cells. The expression of mCLCA3 (mouse homologue hCLCA1), but not that of other CLCA family members, was upregulated 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
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