Zuzana Biringerova

Modulation of cough response by sensory inputs from the nose - role of trigeminal TRPA1 versus TRPM8 channels.

BackgroundCough, the most important airways defensive mechanism is modulated by many afferent inputs either from respiratory tussigenic areas, but also by afferent drive from other organs. In animal models, modulation of cough by nasal afferent inputs can either facilitate or inhibit the cough response, depending on the type of trigeminal afferents stimulated.MethodsIn this study we addressed the question of possible bidirectional modulation of cough response in human healthy volunteers by nasal challenges with TRPA1 and TRPM8 agonists respectively. After nasal challenges with isocyanate (AITC), cinnamaldehyde, (−) menthol and (+) menthol (all 10-3 M) nasal symptom score, cough threshold (C2), urge to cough (Cu) and cumulative cough response were measured).ResultsNasal challenges with TRPA1 relevant agonists induced considerable nasal symptoms, significantly enhanced urge to cough (p<0.05) but no statistically significant modulation of the C2 and cumulative cough response. In contrast, both TRPM8 agonists administered to the nose significantly modulated all parameters including C2 (p<0.05), Cu (p<0.01) and cumulative cough response (p <0.01) documenting strong anti irritating potential of menthol isomers.ConclusionsIn addition to trigeminal afferents expressing TRP channels, olfactory nerve endings, trigemino – olfactoric relationships, the smell perception process and other supramedullar influences should be considered as potential modulators of the cough response in humans.

Antitussive effects of nasal thymol challenges in healthy volunteers.

Eighteen healthy volunteers with normal lung function were tested for cough. Before and after nasal administration of thymol (0.025 ml, 10(-3) M) into both nostrils, urge-to-cough, cough threshold, cumulative and total count of coughs per provocation were estimated during standardized and validated capsaicin cough challenge. Nasal thymol challenges induced pleasant olfactory sensation and in 6 out of the 18 subjects also mild cooling sensation. Cough threshold was not influenced when compared with intranasal saline and vehicle challenges (12.5 vs. 13.2 vs. 10.2 μM of capsaicin to induce two or more coughs (C2), respectively), but the total count of coughs after nasal thymol challenge was significantly lower than that obtained after saline or vehicle (19 vs. 20 vs. 14 coughs/provocation, respectively; p<0.05). Importantly, subjects did not report the urge to cough, which appeared to correspond to C2. We conclude that the modulation of cough by thymol is mostly of olfactory origin.

The effects of nasal irritant induced responses on breathing and cough in anaesthetized and conscious animal models

There is little evidence to support the down-regulation of coughing from the nose. The cough response to citric acid (CA) was studied in anesthetized and conscious guinea pigs after nasal pretreatment with saline, 1% DMSO, allylisothiocyanate (TRPA1 agonist) and allylisothiocyanate +AP-18 (TRPA1 antagonist). Cough was induced by adding citric acid (CA) to the tracheal perfusion in anaesthetized animals, or by inhaling 0.4M CA in conscious animals. The cough response was counted from the dose response curves, airflow traces and cough sound analysis. In conscious animals, nasal allylisothiocyanate induced reproducible, dose dependent nasal symptoms and a significant drop in respiratory rate. Cough induced by CA was suppressed after nasal allylisothiocyanate (p<0.05), and this effect was prevented by AP-18 (1mM). In anaesthetized animals, nasal allylisothiocyanate induced a significant drop in respiratory rate. Cough induced subsequently by CA was suppressed when compared to baseline and vehicle responses (p<0.05). The reasons for the suppression of CA induced cough by TRPA1 agonist applied to the nose are not clear and remain to be elucidated.

The role of nasal trigeminal nerves expressing TRP channels in modulation of cough threshold and urge to cough – possible clinical application

Cough is a phenomenon frequently associated with upper airway diseases and as a reflex is modulated by many afferent inputs either from respiratory tussigenic areas, but also by afferent drive from other organs. Modulation of cough by nasal afferent inputs could either facilitate cough response or inhibit it in animal models, depending on the type of trigeminal afferents which are stimulated. In recent study we focused on afferents expressing TRPA1, TRPM8 & TRPV3 channels -- channels known as relevant for airway irritants (TRPA1), menthol and other cooling substances (TRPM8) and thymol (TRPV3). Particularly menthol and thymol are substances which are frequently used in over-the-counter medication for cough and common cold based on empirical approach. Objective evidence regarding the modulation of cough in humans has never been reported. 60 human healthy volunteers participated in the study, and they have been challenged by intranasal drops containing agonists of selected ion channels: isocyanate (AITC) & cinnamaldehyde for TRPA1, (-) menthol and (+) menthol for TRPM8 and thymol for TRPV3 ion channels in randomized order (all 10-3 M). Nasal symptom score, cough threshold (C2), urge to cough (Cu) and cumulative cough response had been assessed using capsaicin cough challenge tests. Nasal challenges of TRPA1 relevant agonists induced considerable nasal symptoms, significantly enhanced urge to cough (p < 0.05) but modulation of C2 and cumulative cough response did not reach significance level. Both TRPM8 agonists and TRPV3 agonist thymol administered to the nose significantly modulated all parameters including C2 (p<0.05), Cu (p <0.01) and cumulative cough response (p < 0.01) documenting strong anti irritating and antitussive potential of menthol isomers and thyme. Nasal afferent drive modulates cough reflex in human healthy volunteers and this knowledge could have clinical application involved in relieving lower airway symptoms in subjects with upper airway diseases. The role of trigeminal afferents, olfactory nerve endings, smell perception process and other supramedullar influences have to be taken into consideration as relevant enough to modulate cough response in humans.

The Nose as a Target of Air Pollution, Physiological Aspects and Clinical Relevance of Nasal Trpa1 (Transient Receptor Potential A1) Receptors

The Nose as a Target of Air Pollution, Physiological Aspects and Clinical Relevance of Nasal Trpa1 (Transient Receptor Potential A1) Receptors Worldwide more than several hundred million humans are exposed to severe air pollution, and a significant part of them also smoke. The effect of air pollution on human health has been recognized for many years. The nose, as the first portal of entry to the respiratory system is constantly exposed to a large volumes of air, which is composed of a mixture of gases, particulate matter and infectious agent, and any material other than physiological amount of oxygen, nitrogen, carbon dioxide and water is considered as pollutant. Being exposed to critical amount of air pollutants, nasal cavity shares sophisticated system of protective and defensive mechanisms regarding the lower airways and lungs, however the highest risk of direct exposure to relevant air pollutants is just within the nose. Air pollution is considered to be responsible for some of the pathological processes affecting airways prone to allergic reactions in predisposed subjects, onset of nasal sensorineural hyperresponsiveness, non-specific inflammation, sinonasal cancer and definitely, the risk is not limited just to the nasal mucosa, but can proceed toward the lower airways. The broad spectrum of irritants probably shares very similar molecular background of action. They are capable to activate the cation channenl tranisient receptor potential A1-TRPA1 by covalent modification of the channel protein, because many of them are highly reactive and nonstable molecules with possibilities for various chemical reactions. Activation of this channel is responsible for nociceptive reactions mediated by stimulation of afferent trigeminal nerves, retrograde release of tachykinins, activation of parasympathetic afferent drive leading to increase of mucus output and decrease of nasal patency, with subsequent alteration of nasal functions. Based on the recently described neuro-immune bidirectional relationships, air pollutants may be responsible for recruitment of immune cells with infiltration of the nasal mucosa possibly leading to the inflammatory processes and allergies. Our paper is discussing the nose as the target for air pollution, and focuses on the relevance of TRPA1 channel on trigeminal afferents in pollution mediated responses.