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Transient Receptor Potential Ankyrin 1 Mediates Toluene Diisocyanate–Evoked Respiratory Irritation

¹ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland; ² Discovery Biology, Respiratory Center for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania; and ³ Department of Pharmacology, King's College London, London, United Kingdom

Correspondence and requests for reprints should be addressed to M. Allen McAlexander, Ph.D., Discovery Biology, Respiratory Center for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406. E-mail: michael.a.mcalexander{at}gsk.com

Toluene diisocyanate (TDI), a reactive, hazardous irritant, causes respiratory symptoms such as cough, rhinitis, dyspnea, and chest tightness in exposed workers. Although previous animal studies have shown that TDI causes respiratory reflexes that are abolished by desensitization of capsaicin-sensitive sensory nerves, the specific molecular identity of the transducer(s) responsible for sensing this noxious stimulus has, to date, remained elusive. Recent studies have demonstrated that transient receptor potential ankyrin 1 (TRPA1), an ion channel largely restricted to a subset of capsaicin-sensitive sensory nerves, functions as a transducer capable of initiating reflex responses to many reactive chemical stimuli. We therefore hypothesized that TRPA1 is the primary molecular transducer through which TDI causes sensory nerve activation and respiratory reflexes. Consistent with this hypothesis, TDI activated TRPA1, but not the capsaicin-sensitive transient receptor potential vanilloid 1 channel, in heterologous expression systems. TDI also activated a subset of dissociated trigeminal sensory neurons from wild-type but not TRPA1-deficient mice. In vivo, TDI mimicked known TRPA1 agonists by causing a pronounced decrease in breathing rate, indicative of respiratory sensory irritation, and this reflex was abolished in TRPA1-deficient mice. Together, our data suggest that TDI causes sensory nerve activation and airway sensory irritation via the activation of the ion channel, TRPA1.

Key Words: toluene diisocyanate • formaldehyde • sensory irritation • transient receptor potential ankyrin-1

CLINICAL RELEVANCE Toluene diisocyanate (TDI) causes respiratory symptoms in exposed workers. We demonstrate that TDI activates sensory nerves in vitro and reflexes in vivo in a manner dependent on the expression of the ion channel TRPA1. TRPA1 represents a valid target for treatment of TDI exposures.

 

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