Niflumic acid suppresses interleukin-13-induced asthma phenotypes

Am J Respir Crit Care Med. 2006 Jun 1;173(11):1216-21. doi: 10.1164/rccm.200410-1420OC. Epub 2006 Mar 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / chemically induced
  • Asthma / metabolism
  • Asthma / physiopathology*
  • Bronchoalveolar Lavage Fluid / cytology
  • Chloride Channels / antagonists & inhibitors*
  • Chloride Channels / genetics
  • Chloride Channels / metabolism
  • Eosinophils / drug effects
  • Goblet Cells / drug effects
  • Goblet Cells / pathology
  • Hyperplasia
  • Interleukin-13 / antagonists & inhibitors*
  • Janus Kinase 2
  • Male
  • Mice
  • Mice, Inbred A
  • Mucin 5AC
  • Mucins / genetics
  • Mucins / metabolism
  • Mucoproteins / genetics
  • Mucoproteins / metabolism*
  • Mucus / metabolism
  • Niflumic Acid / pharmacology*
  • Protein-Tyrosine Kinases / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • STAT6 Transcription Factor / drug effects
  • STAT6 Transcription Factor / metabolism
  • Up-Regulation


  • Chloride Channels
  • Clca3a1 protein, mouse
  • Interleukin-13
  • Muc5ac protein, mouse
  • Mucin 5AC
  • Mucins
  • Mucoproteins
  • Proto-Oncogene Proteins
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Niflumic Acid
  • Protein-Tyrosine Kinases
  • Jak2 protein, mouse
  • Janus Kinase 2