TRPA1 Agonists Evoke Coughing in Guinea Pig and Human Volunteers
TRPA1 Agonists Evoke Coughing in Guinea Pig and Human Volunteers
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DOI：
10.1164/rccm.200905-0665oc
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发表时间：
2009-12-01
影响因子：
24.7
通讯作者：
Morice, Alyn H.
中科院分区：
文献类型：
--
作者：
Birrell, Mark A.;Belvisi, Maria G.;Morice, Alyn H.
理由：咳嗽是向家庭医生、普通科医生或呼吸科医生咨询的最常见原因。治疗选择有限，一项荟萃分析得出结论，非处方药无效。人们也越来越担心它们在儿童中的使用。人们认为，空气污染和香烟烟雾等环境刺激物会刺激气道感觉神经，从而引发咳嗽。然而，这种现象是如何发生的尚不完全清楚。 目的：我们假设 TRPA1（瞬时受体电位阳离子通道，亚科 A，成员 1）受体可能具有作为咳嗽药物的新靶点的作用，因为许多潜在的刺激物已被证明可以激活该通道。方法：我们在体外、豚鼠和人类中研究了 TRPA1 配体对迷走神经感觉神经活动的影响 测量和主要结果：我们证明 TRPA1 激动剂（例如丙烯醛）可激活 HEK293 细胞中克隆的人类 TRPA1 通道以及小鼠、豚鼠和人体组织中的迷走感觉神经。使用特定抑制剂和来自 Trpa1(-/-) 基因缺失动物的组织证实了 TRPA1 的作用。最后，TRPA1 配体在豚鼠模型和正常志愿者中均引起可重复的咳嗽反应。结论：这项研究确定 TRPA1 受体是一种混杂受体，可被多种刺激激活，使其成为引发咳嗽的完美靶点，因此是目前确定的镇咳药物开发最有希望的靶点之一。
Rationale: Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. Treatment options are limited and one meta-analysis concluded that over-the-counter remedies are ineffective. There is also increasing concern about their use in children. Environmental irritants such as air pollution and cigarette smoke are thought to evoke cough by stimulating airway sensory nerves; however, how this occurs is not fully understood.Objectives: We hypothesized that the TRPA1 (transient receptor potential cation channel, subfamily A, member 1) receptor may have a role as a novel target for tussive agents given that many potential irritants have been shown to activate this channel.Methods: We investigated the effect of TRPA1 ligands on vagal sensory nerve activity in vitro and in guinea pig and human tussive challenge models.Measurements and Main Results: We demonstrated that TRPA1 agonists such as acrolein activate cloned human TRPA1 channels in HEK293 cells and also vagal sensory nerves in murine, guinea pig, and human tissues. A role for TRPA1 was confirmed, using specific inhibitors and tissue from Trpa1(-/-) gene-deleted animals. Finally, TRPA1 ligands evoked reproducible tussive responses in both a guinea pig model and normal volunteers.Conclusions: This study identifies the TRPA1 receptor as a promiscuous receptor, activated by a wide range of stimuli, making it a perfect target for triggering cough and as such one of the most promising targets currently identified for the development of antitussive drugs.