Respiratory Pharmacology, Pharmacology and Toxicology Section, Imperial College London, Faculty of Medicine, National Heart and Lung Institute, Sir Alexander Fleming Building, London SW7 2AZ, UK.
Pulm Pharmacol Ther. 2011 Jun;24(3):286-8. doi: 10.1016/j.pupt.2010.11.002. Epub 2010 Nov 11.
In the early 1990's ion channels of the Transient Receptor Potential (TRP) class were implicated in the afferent sensory loop of the cough reflex and in the heightened cough sensitivity seen in disease. Agonists of the TRPV1 capsaicin receptor such as vanilloids and protons were demonstrated to be amongst the most potent chemical stimuli which cause cough. However, more recently, the TRPA1 receptor (not activated by capsaicin) has become of interest in the cough field because it is known to be activated by ligands such as acrolein which is present in air pollution and the acrid smoke from organic material. TRPA1 is a Ca(2+)-permeant non-selective cation channel with 14 ankyrin repeats in its amino terminus which belongs to the larger TRP family. TRPA1 has been characterised as a thermoreceptor which is activated by cold temperature, environmental irritants and reactive electrophilic molecules which can be generated by oxidant stress and inflammation. TRPA1 is primarily expressed in small diameter, nociceptive neurons where its activation probably contributes to the perception of noxious stimuli and the phenomena known as inflammatory hyperalgesia and neurogenic inflammation. The respiratory tract is innervated by primary sensory afferent nerves which are activated by mechanical and chemical stimuli. Activation of these vagal sensory afferents leads to central reflexes including dyspnoea, changes in breathing pattern and cough. Recently, it has been demonstrated that stimulating TRPA1 channels activates vagal bronchopulmonary C-fibres in the guinea pig and rodent lung, and recent data have shown that TRPA1 ligands cause cough in both animal models and normal volunteers. In summary, due to their activation by a wide range of irritant and chemical substances, either by exogenous agents, endogenously produced mediators during inflammation or by oxidant stress, we suggest TRPA1 channels should be considered as one of the most promising targets currently identified for the development of novel anti-tussive drugs.
在 20 世纪 90 年代早期，瞬时受体电位 (TRP) 通道家族的离子通道被牵涉到咳嗽反射的传入感觉回路中，以及疾病中所见的咳嗽敏感性增加。TRPV1 辣椒素受体的激动剂，如香草醛和质子，被证明是引起咳嗽的最有效化学刺激物之一。然而，最近，TRPA1 受体（不被辣椒素激活）在咳嗽领域引起了关注，因为已知它被丙烯醛等配体激活，丙烯醛存在于空气污染和有机物质的刺鼻烟雾中。TRPA1 是一种 Ca(2+)-通透的非选择性阳离子通道，其氨基末端有 14 个锚蛋白重复序列，属于较大的 TRP 家族。TRPA1 已被表征为一种热敏受体，可被冷温度、环境刺激物和反应性亲电分子激活，这些分子可由氧化应激和炎症产生。TRPA1 主要在小直径、伤害性神经元中表达，其激活可能有助于对有害刺激的感知，以及称为炎症性痛觉过敏和神经源性炎症的现象。呼吸道由初级感觉传入神经支配，这些神经受机械和化学刺激的激活。这些迷走感觉传入纤维的激活导致包括呼吸困难、呼吸模式改变和咳嗽在内的中枢反射。最近，已经证明刺激 TRPA1 通道会激活豚鼠和啮齿动物肺部的迷走支气管肺 C 纤维，最近的数据表明，TRPA1 配体在动物模型和正常志愿者中都会引起咳嗽。总之，由于它们可被广泛的刺激物和化学物质激活，无论是外源性物质、炎症期间内源性产生的介质还是氧化应激，我们认为 TRPA1 通道应该被视为目前为开发新型镇咳药物而确定的最有希望的靶点之一。
