Nakano Takako, Inoue Hiromasa, Fukuyama Satoru, Matsumoto Koichiro, Matsumura Mikiko, Tsuda Miyuki, Matsumoto Takafumi, Aizawa Hisamichi, Nakanishi Yoichi
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Am J Respir Crit Care Med. 2006 Jun 1;173(11):1216-21. doi: 10.1164/rccm.200410-1420OC. Epub 2006 Mar 9.
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.
We studied the effects of chloride channel inhibitors in IL-13-induced asthma.
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.
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.
These findings suggest that a chloride channel inhibitor can control IL-13-mediated airway features at least by suppressing JAK/STAT6 activation.
氯离子通道与上皮细胞黏液分泌的调节有关。据报道，钙激活氯离子通道hCLCA1在哮喘患者的气道上皮中表达增加。白细胞介素（IL）-13诱导支气管哮喘的主要特征，而糖皮质激素不足以抑制IL-13诱导的气道高反应性或杯状细胞增生。
我们研究了氯离子通道抑制剂在IL-13诱导的哮喘中的作用。
在气道内注入IL-13后，评估钙激活氯离子通道（CLCA）的相对特异性阻滞剂尼氟灭酸（NA）对杯状细胞增生、嗜酸性粒细胞积聚和气道高反应性的影响。由于IL-13依赖的特征依赖于JAK/STAT6信号传导，因此在体外气道上皮细胞中检测了NA对IL-13刺激后JAK2和STAT6磷酸化的影响。使用逆转录-聚合酶链反应分析体内局部给予IL-13后小鼠肺中mCLCA家族的表达。
NA治疗不仅抑制了IL-13诱导的杯状细胞增生，还抑制了气道高反应性和嗜酸性粒细胞浸润。NA抑制了支气管肺泡灌洗液中的嗜酸性粒细胞趋化因子水平以及IL-13注入后肺中杯状细胞增生标志物MUC5AC基因的过表达。NA抑制上皮细胞中的JAK2激活、STAT6激活和嗜酸性粒细胞趋化因子表达。IL-13上调了mCLCA3（小鼠同源物hCLCA1）的表达，而其他CLCA家族成员的表达未上调。
这些发现表明，氯离子通道抑制剂至少可以通过抑制JAK/STAT6激活来控制IL-13介导的气道特征。
