title: Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases.
abstract: 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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Bret F
authors.initials: BF
authors.lastname: Bessac
authors.forename: Michael
authors.initials: M
authors.lastname: Sivula
authors.forename: Christian A
authors.initials: CA
authors.lastname: von Hehn
authors.forename: Ana I
authors.initials: AI
authors.lastname: Caceres
authors.forename: Jasmine
authors.initials: J
authors.lastname: Escalera
authors.forename: Sven-Eric
authors.initials: SE
authors.lastname: Jordt
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006997:Hypochlorous Acid / Q000494:pharmacology; D017953:Isocyanates / Q000633:toxicity*; D007668:Kidney / Q000166:cytology / Q000196:embryology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D000074025:TRPA1 Cation Channel; D013665:Tear Gases / Q000633:toxicity*; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D017953:Isocyanates; D016877:Oxidants; D000074025:TRPA1 Cation Channel; D013665:Tear Gases; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D006997:Hypochlorous Acid