Blocking TRPA1 in Respiratory Disorders: Does It Hold a Promise?

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.

Roles of Transient Receptor Potential Ankyrin 1 in Oxaliplatin-Induced Peripheral Neuropathy

“…22,23) TRPA1 is activated by noxious cold (<17°C) in rodents (but see the discussion below) and by a large number of irritant chemicals, including allyl isothiocyanate (AITC), cinnamaldehyde, allicin, and aldehydes, as well as by oxidative stimuli, such as ROS and hyperoxia, and by hypoxia. [24][25][26][27][28] TRPA1 is focused as a novel target for treating pathological pain and respiratory disorders, because it is expressed abundantly on the nociceptive C fibers that innervate skin and respiratory tract from oral cavity and oropharynx. 29) Recent evidence suggests that these TRP channels play a crucial role in CIPN.…”

“…The TRPA1 channel can be opened by a variety of irritants 26,59,60) and oxidative stimuli, such as ROS 27) and hyperoxia. 28) Activation of TRPA1 is caused by reversible covalent or oxidative modifications of the cysteine residues at the N-terminus of TRPA1. [59][60][61][62] However, another mechanism for TRPA1 activation has been reported in which a decrease in oxygen concentration inhibits the activity of prolyl hydroxylases (PHDs).…”

“…[59][60][61][62] However, another mechanism for TRPA1 activation has been reported in which a decrease in oxygen concentration inhibits the activity of prolyl hydroxylases (PHDs). 28) This inhibition relieves TRPA1 from the PHD-dependent hydroxylation of a proline residue located within the N-terminal ankyrin repeat domain (Pro 394 in human TRPA1 [hTRPA1]), leading to hypoxia-induced opening of TRPA1. The 1-carboxylate and 2-oxo functional groups of oxalate are also common to a PHD cosubstrate, α-ketoglutarate, and the artificial PHD inhibitor dimethyloxalylglycine (DMOG).…”

TRPA1: A potential target for cold‐induced airway disease?

“…TRPA1 is a cation channel located on lung fibroblasts and C‐fibres, which innervate most of the tissues of the respiratory tract, including the trachea, bronchi, terminal bronchioles, respiratory bronchioles, alveolar ducts and alveoli . Given the location of C‐fibres in the airways, it is unsurprising that blockade of TRPA1 has been extensively studied in chronic cough, in both animal models and humans .…”

“…TRPA1 is a cation channel located on lung fibroblasts and C-fibres, which innervate most of the tissues of the respiratory tract, including the trachea, bronchi, terminal bronchioles, respiratory bronchioles, alveolar ducts and alveoli. 6 Given the location of C-fibres in the airways, it is unsurprising that blockade of TRPA1 has been extensively studied in chronic cough, in both animal models and humans. 7,8 Nevertheless, a function of the TRPA1 channel is to sense cold temperature, 9 This study shows that increased severity of allergic airways disease features are, at least partially, dependent on TRPA1 responses, which demonstrates a potential new mechanism of cold-induced allergic airways disease through TRPA1.…”