title: Niflumic acid suppresses interleukin-13-induced asthma phenotypes.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Nakano
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Inoue
authors.forename: Satoru
authors.initials: S
authors.lastname: Fukuyama
authors.forename: Koichiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Mikiko
authors.initials: M
authors.lastname: Matsumura
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tsuda
authors.forename: Takafumi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Hisamichi
authors.initials: H
authors.lastname: Aizawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology; D006965:Hyperplasia; D018793:Interleukin-13 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D055271:Mucin 5AC; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D009088:Mucoproteins / Q000235:genetics / Q000378:metabolism*; D009093:Mucus / Q000378:metabolism; D009544:Niflumic Acid / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D018793:Interleukin-13; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009077:Mucins; D009088:Mucoproteins; D011518:Proto-Oncogene Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D009544:Niflumic Acid; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2