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.

A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

“…TRPA1-antagonists showed efficacy in animal models of acute and inflammatory pain and diminished the noxious effects of TRPA1 agonists known to cause asthma-related conditions (17,19,20,28,29). We asked whether a TRPA1 antagonist would prevent or diminish airway inflammation when administered to OVAsensitized Balb/C mice during the airway challenge phase of the OVA protocol.…”

“…TRPA1 may be a critical trigger for neuropeptide release crucial for leukocyte infiltration and inflammatory progression in asthmatic airways. To investigate this possibility, we compared neuropeptide release in airways of wild-type and and Trpa1 Ϫ/Ϫ mice in response to 2-chloroacetophenone (CN), a potent inflammatory TRPA1 agonist (20). We performed a 30-s BAL in mice with CN (4 mM) contained in the BAL buffer (PBS) and measured the resultant release of CGRP, substance P (SP) and neurokinin A (NKA) using EIA (Fig.…”

“…Agonists of TRPV1 and TRPA1, such as capsaicin, acrolein, or chlorine, are potent tussive agents and have been associated with allergic and occupational asthma and reactive airway dysfunction syndrome (RADS) (12,(17)(18)(19)(20)(21)(22)(23). Potential endogenous TRPA1 agonists include reactive oxygen species, hypochlorite, and lipid peroxidation products (18,(24)(25)(26).…”

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…The N terminus contains key regulatory regions in the linker region between the ankyrin repeats and first transmembrane domain, including conserved N-terminal cysteine residues (Doerner et al, 2007). These sites are essential for TRPA1 to "sense" and covalently bind painful molecules that possess electrophilic chemical groups, such as noxious irritants in airways (cigarette smoke, tear gas), pungent chemicals in the digestive system (allicin from garlic, allyl isothiocyanate from mustard oil, cinnamaldehyde from cinnamon) and reactive oxygen species released by damaged tissue (Tables 1 and 2) Macpherson et al, 2007;Andre et al, 2008;Brone et al, 2008;Bessac et al, 2009;Taylor-Clark et al, 2009;Cordero-Morales et al, 2011). TRPA1 is highly sensitive to inflammatory fatty acids and highly reactive thiol-reactive species, such as 4-hydroxynonenol (4-HNE), prostaglandin metabolites [15-dPGJ(2), PGA(2), and PGA (1)], and hydrogen peroxide Andersson et al, 2008;Materazzi et al, 2008).…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…In fact, TRPA1 is activated by a wide range of pungent and irritant compounds [125], including ingredients of various spicy foods, such as allyl isothiocyanate (mustard oil, wasabi and horseradish) [73], allicin and diallyldisulfide (garlic derivatives) [126], cinnamaldehyde (cinnamon), and environmental irritants and industry pollutants, such as acetaldehyde [127], formalin [128], hypochlorite, isocyanates [129], ozone [130], carbon dioxide [131], and acrolein [117], a highly reactive , -unsaturated aldehyde present in tear gas, and cigarette smoke [132]. Moreover, isofluorane [133], nicotine [134], NO donors [135], and cyclophosphamide [117] have been reported to activate TRPA1.…”