Bessac Bret F, Sivula Michael, von Hehn Christian A, Caceres Ana I, Escalera Jasmine, Jordt Sven-Eric
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
FASEB J. 2009 Apr;23(4):1102-14. doi: 10.1096/fj.08-117812. Epub 2008 Nov 26.
The release of methyl isocyanate in Bhopal, India, caused the worst industrial accident in history. Exposures to industrial isocyanates induce lacrimation, pain, airway irritation, and edema. Similar responses are elicited by chemicals used as tear gases. Despite frequent exposures, the biological targets of isocyanates and tear gases in vivo have not been identified, precluding the development of effective countermeasures. We use Ca(2+) imaging and electrophysiology to show that the noxious effects of isocyanates and those of all major tear gas agents are caused by activation of Ca(2+) influx and membrane currents in mustard oil-sensitive sensory neurons. These responses are mediated by transient receptor potential ankyrin 1 (TRPA1), an ion channel serving as a detector for reactive chemicals. In mice, genetic ablation or pharmacological inhibition of TRPA1 dramatically reduces isocyanate- and tear gas-induced nocifensive behavior after both ocular and cutaneous exposures. We conclude that isocyanates and tear gas agents target the same neuronal receptor, TRPA1. Treatment with TRPA1 antagonists may prevent and alleviate chemical irritation of the eyes, skin, and airways and reduce the adverse health effects of exposures to a wide range of toxic noxious chemicals.
印度博帕尔市甲基异氰酸酯的泄漏引发了历史上最严重的工业事故。接触工业异氰酸酯会导致流泪、疼痛、气道刺激和水肿。用作催泪瓦斯的化学物质也会引发类似反应。尽管经常接触，但异氰酸酯和催泪瓦斯在体内的生物学靶点尚未确定，这使得无法开发有效的应对措施。我们利用钙离子成像和电生理学方法表明，异氰酸酯和所有主要催泪瓦斯制剂的有害作用是由芥子油敏感感觉神经元中钙离子内流和膜电流的激活所引起的。这些反应由瞬时受体电位锚蛋白1（TRPA1）介导，TRPA1是一种作为反应性化学物质探测器的离子通道。在小鼠中，对TRPA1进行基因敲除或药物抑制可显著降低眼部和皮肤接触异氰酸酯和催泪瓦斯后诱发的伤害防御行为。我们得出结论，异氰酸酯和催泪瓦斯制剂作用于相同的神经元受体TRPA1。用TRPA1拮抗剂进行治疗可能预防和减轻眼睛、皮肤和气道的化学刺激，并减少接触多种有毒有害化学物质所产生的不良健康影响。
