Abstract
Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel is expressed abundantly on the C fibers that innervate almost entire respiratory tract starting from oral cavity and oropharynx, conducting airways in the trachea, bronchi, terminal bronchioles, respiratory bronchioles and upto alveolar ducts and alveoli. Functional presence of TRPA1 on non-neuronal cells got recognized recently. TRPA1 plays a well-recognized role of “chemosensor”, detecting presence of exogenous irritants and endogenous pro-inflammatory mediators that are implicated in airway inflammation and sensory symptoms like chronic cough, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cystic fibrosis. TRPA1 can remain activated chronically due to elevated levels and continued presence of such endogenous ligands and pro-inflammatory mediators. Several selective TRPA1 antagonists have been tested in animal models of respiratory disease and their performance is very promising. Although there is no TRPA1 antagonist in advanced clinical trials or approved on market yet to treat respiratory diseases, however, limited but promising evidences available so far indicate likelihood that targeting TRPA1 may present a new therapy in treatment of respiratory diseases in near future. This review will focus on in vitro, animal and human evidences that strengthen the proposed role of TRPA1 in modulation of specific airway sensory responses and also on preclinical and clinical progress of selected TRPA1 antagonists.
Highlights
Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel and its biology is known for more than a decade
Evidence for potential role of TRPA1 in pain signaling based on TRPA1 knockout (TRPA1 KO) mice and siRNA studies emerged much earlier compared to its involvement in airway diseases—which is relatively recent and still emerging
It is well known that unlike traditional chemoreceptors, TRPA1 is activated by a wide variety of structurally different molecules with high chemical reactivity spanning from exogenous irritants to endogenously produced reactive reagents [4,5,6,7,8,9,10,11]
Summary
TRPA1 ion channel and its biology is known for more than a decade now. It has attracted academic scientists due to its interesting tissue distribution and functions. TRPA1 is abundantly expressed in peripheral nervous system and has demonstrated a chemosensory function. It has been assigned a role of “warning system” against external as well as internal assaults. Industrial researchers are interested in TRPA1 as a target for therapeutic intervention due to its implicated role in miscellaneous diseases. TRPA1 is highly expressed on pulmonary innervation—an anatomically relevant region for respiratory diseases, and could be one of the major players in orchestration of airway inflammatory response. A large number of recent studies have implicated TRPA1 in the pathogenesis of several respiratory diseases including chronic cough, asthma, COPD, allergic rhinitis and cystic fibrosis. Blockade of TRPA1 is perceived as a novel strategy for its therapeutic intervention
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