A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma
A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma
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DOI：
10.1073/pnas.0900591106
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发表时间：
2009-06-02
影响因子：
11.1
通讯作者：
Jordt, Seven-Eric
中科院分区：
文献类型：
--
作者：
Caceres, Ana I.;Brackmann, Marian;Jordt, Seven-Eric
哮喘是一种由气道暴露于过敏原和化学刺激物引起的炎症性疾病。针对免疫、平滑肌和气道上皮功能的研究揭示了哮喘发病机制的多个方面。然而，免疫导向疗法的有限疗效表明哮喘气道炎症中还涉及其他机制。TRPA 1是一种在气道化学感受神经中表达的刺激感受离子通道。TRPA 1激活刺激，如香烟烟雾，氯，醛和气味是哮喘最常见的触发因素。内源性TRPA 1激动剂，包括活性氧和脂质过氧化产物，是哮喘中过敏原诱导的气道炎症的有力驱动因素。在这里，我们研究了TRPA 1在小鼠卵清蛋白模型过敏性哮喘中的作用。引人注目的是，TRPA 1基因消融抑制了气道中变应原诱导的白细胞浸润，减少了细胞因子和粘液的产生，几乎完全消除了气道对收缩刺激的高反应性。用HC-030031（TRPA 1拮抗剂）处理野生型小鼠可重现该表型。HC-030031在气道过敏原激发期间给药时，可抑制嗜酸性粒细胞浸润并防止气道高反应性的发生。trpa 1（-/-）小鼠在气道中化学和变应原诱导的神经肽释放方面表现出缺陷，这为炎症反应受损提供了一个潜在的解释。我们的数据表明，TRPA 1是气道中免疫和神经系统之间相互作用的关键整合剂，在吸入过敏原激发后驱动哮喘气道炎症。TRPA 1可能是治疗哮喘和其他过敏性炎症的一个有前途的药理学靶点。
Asthma is an inflammatory disorder caused by airway exposures to allergens and chemical irritants. Studies focusing on immune, smooth muscle, and airway epithelial function revealed many aspects of the disease mechanism of asthma. However, the limited efficacies of immune-directed therapies suggest the involvement of additional mechanisms in asthmatic airway inflammation. TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma. Here, we examined the role of TRPA1 in allergic asthma in the murine ovalbumin model. Strikingly, genetic ablation of TRPA1 inhibited allergen-induced leukocyte infiltration in the airways, reduced cytokine and mucus production, and almost completely abolished airway hyperreactivity to contractile stimuli. This phenotype is recapitulated by treatment of wild-type mice with HC-030031, a TRPA1 antagonist. HC-030031, when administered during airway allergen challenge, inhibited eosinophil infiltration and prevented the development of airway hyperreactivity. Trpa1(-/-) mice displayed deficiencies in chemically and allergen-induced neuropeptide release in the airways, providing a potential explanation for the impaired inflammatory response. Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge. TRPA1 may represent a promising pharmacological target for the treatment of asthma and other allergic inflammatory conditions.