TRPA1 Antagonists as Potential Therapeutics for Respiratory Diseases

Exaggerated responses to inhaled irritant chemicals are a hallmark of human airway diseases such as asthma. While the inflammatory processes and structural remodeling caused by respiratory irritants have received considerable attention, the mechanisms responsible for triggering acute episodes of ­irritant-induced airflow obstruction remain poorly understood. The non-selective cation channel Transient Receptor Potential Ankyrin 1 (TRPA1) has emerged as a promising target for therapeutic intervention in respiratory disorders as result of its unique biology that allows it to serve as the primary neuronal sensor not only for many of the hazardous irritants that cause chronic respiratory disease, but also for multiple inflammatory and oxidant mediators triggered by irritant exposure. Herein, we survey current evidence regarding TRPA1’s role as a sensor of an exceptionally wide array of oxidants, inflammatory mediators and hazardous air pollutants. Further, we review studies demonstrating that pharmacological inhibition or genetic disruption of TRPA1 protects laboratory animals from irritant-­triggered expulsion/dilution reflexes. Lastly, we conclude with a comprehensive overview of patented TRPA1 antagonists and highlight recent progress made toward the goal of developing TRPA1-targeted therapeutics.