TRPA1 ion channels: a gateway to airway irritation and reflex responses induced by inhaled oxidants.

The adverse effects of ozone, an oxidant and one of the major environmental air pollutants, in the respiratory tract were first reported more than 30 years ago (Lee et al. 1979). These pulmonary effects, such as airway mucosa inflammation and bronchial hyper-reactivity, have been extensively studied and documented by numerous investigators in various species, including humans. For example, acute exposure to ozone at concentrations higher than common ambient levels induced airway hyper-responsiveness to histamine and acetylcholine inhalation challenges in healthy human volunteers, and the exaggerated bronchoconstrictive response was mediated primarily through the cholinergic pathway (see references in Holtzman et al. 1983). In the majority of these individuals, the airway hyper-responsiveness was also accompanied by sub-sternal pain, bronchial irritation and coughs upon taking a deep inspiration, suggesting an involvement of airway sensory nerves. Indeed, the possibility that an activation of bronchopulmonary C-fibres (non-myelinated afferents) contributed to these sensations was supported by the observations that acute exposure to ozone increased baseline activity of these sensory fibres and their sensitivity to chemical stimulations and lung inflation (Ho & Lee 1998). However, the mechanisms underlying the activation of these sensory terminals by ozone were not fully understood. TRPA1, a member of the transient receptor potential (TRP) family of ion channels, is known to be expressed in a subset of vagal bronchopulmonary C-fibres. In a recent issue of The Journal of Physiology, Taylor-Clark & Undem (2010) have clearly demonstrated that solubilized ozone activates HEK cells transfected with human TRPA1 and vagal sensory neurons isolated from wild-type mice, but not those from TRPA1-null mice. These results, combined with earlier studies by the same authors and other investigators (Bessac & Jordt, 2008; Taylor-Clark & Undem, 2010), have offered convincing evidence that reactive oxygen species can activate TRPA1 channels and are responsible for the stimulatory effect of ozone on these lung afferents. This is an interesting finding. More importantly, increasing evidence suggests that activation of these sensory fibres contributes to the manifestation of various airway dysfunctions and symptoms (e.g. bronchospasm, hypersecretion of mucous, cough, etc.) associated with airway inflammatory diseases. Together, these findings revealed a distinct possibility of TRPA1 as a transducer in sensing the oxidative stress and generating these adverse airway responses. Thus, this study has added ozone to a long list of inhaled chemical irritants that have been recently discovered as activators of TRPA1 (Bautista et al. 2006; Bessac & Jordt, 2008). It seems plausible that ozone may activate TRPA1 via indirect effects. In addition to the stimulatory and sensitizing effects on sensory nerves in the airways, acute exposure to ozone is also known to activate certain cell signalling pathways, produce pro-inflammatory cytokines, and trigger airway inflammation (Ciencewicki et al. 2008). Certain endogenous inflammatory mediators (e.g. bradykinin) are known to activate TRPA1 (Bautista et al. 2006). The relatively long latency in the response of the C-fibre sensory nerves to ozone (Taylor-Clark & Undem, 2010) seems to suggest a possible secondary action involving production and release of intermediate molecules (e.g. products of lipid peroxidation), cytokines (e.g. tumour necrosis factor α, etc.) or mediators. To further evaluate the role of TRPA1 in mediating the adverse effects of ozone on breathing, several interesting and important issues should be addressed. Although administering solubilized ozone was a novel and probably the only viable approach to study its effect on the TRPA1 channel expressed in cultured cells (Taylor-Clark & Undem, 2010), the actual physiological function of the TRPA1 channel in ‘sensing’ ozone in the respiratory tract can only be evaluated when ozone is inhaled in its natural state as a gas component in the environmental air. Therefore, it would be interesting to know to what extent that the reflex-mediated cardio-respiratory effects (e.g. rapid shallow breathing) caused by acute exposure to ozone are reduced or eliminated in TRPA1-null mice. Although vagal bronchopulmonary C-fibres are usually quiescent during eupnoeic breathing, their sensitivity to change in lung volume was markedly elevated after acute exposure to ozone (Ho & Lee, 1998). The increased mechanical sensitivity in these afferents was most probably responsible for the ozone-induced rapid shallow breathing as well as coughing while taking a deep inspiration; both of these responses are believed to be mediated through a vagal reflex mechanism. Interestingly, TRPA1 was initially recognized for its function as the mechanosensors in the vertebrate hair cells (Corey et al. 2004). Taken together, ozone-induced activation or sensitization of TRPA1 may be a major contributing factor to the increased mechanical sensitivity of these afferents and hence the adverse effects on breathing. It is well documented that these bronchopulmonary C-fibre afferents play an important role in protecting the airways against inhaled irritants. However, prolonged and/or intense stimulation is known to evoke the release of tachykinins and calcitonin gene-related peptide from these nerve terminals, which can then lead to the development of neurogenic inflammation and disease exacerbation. In view of the evidence described in this study (Taylor-Clark & Undem, 2010) of TRPA1 as a primary candidate mediating the stimulatory effect of ozone on C-fibre sensory nerves, a better understanding of the mechanism involved in the oxidant activation of the TRPA1 should provide important information for the future development of effective interventions in protecting the lung against inhaled oxidants in the atmosphere.