Niflumic acid suppresses interleukin-13-induced asthma phenotypes

Takako Nakano, Hiromasa Inoue, Satoru Fukuyama, Koichiro Matsumoto, Mikiko Matsumura, Miyuki Tsuda, Takafumi Matsumoto, Hisamichi Aizawa, Yoichi Nakanishi

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1216-1221
Number of pages6
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume173
Issue number11
DOIs
Publication statusPublished - Jun 1 2006

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Niflumic Acid
Interleukin-13
Asthma
Chloride Channels
Phenotype
Goblet Cells
Hyperplasia
Epithelial Cells
Lung
Bronchoalveolar Lavage Fluid
Mucus
Eosinophils
Glucocorticoids
Reverse Transcription

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Niflumic acid suppresses interleukin-13-induced asthma phenotypes. / Nakano, Takako; Inoue, Hiromasa; Fukuyama, Satoru; Matsumoto, Koichiro; Matsumura, Mikiko; Tsuda, Miyuki; Matsumoto, Takafumi; Aizawa, Hisamichi; Nakanishi, Yoichi.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 173, No. 11, 01.06.2006, p. 1216-1221.

Research output: Contribution to journalArticle

Nakano, T, Inoue, H, Fukuyama, S, Matsumoto, K, Matsumura, M, Tsuda, M, Matsumoto, T, Aizawa, H & Nakanishi, Y 2006, 'Niflumic acid suppresses interleukin-13-induced asthma phenotypes', American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 11, pp. 1216-1221. https://doi.org/10.1164/rccm.200410-1420OC
Nakano, Takako ; Inoue, Hiromasa ; Fukuyama, Satoru ; Matsumoto, Koichiro ; Matsumura, Mikiko ; Tsuda, Miyuki ; Matsumoto, Takafumi ; Aizawa, Hisamichi ; Nakanishi, Yoichi. / Niflumic acid suppresses interleukin-13-induced asthma phenotypes. In: American Journal of Respiratory and Critical Care Medicine. 2006 ; Vol. 173, No. 11. pp. 1216-1221.
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abstract = "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.",
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AU - Nakano, Takako

AU - Inoue, Hiromasa

AU - Fukuyama, Satoru

AU - Matsumoto, Koichiro

AU - Matsumura, Mikiko

AU - Tsuda, Miyuki

AU - Matsumoto, Takafumi

AU - Aizawa, Hisamichi

AU - Nakanishi, Yoichi

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N2 - 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.

AB - 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.

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