Tomas Buday

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.

Histamine, histamine intoxication and intolerance.

Excessive accumulation of histamine in the body leads to miscellaneous symptoms mediated by its bond to corresponding receptors (H1-H4). Increased concentration of histamine in blood can occur in healthy individuals after ingestion of foods with high contents of histamine, leading to histamine intoxication. In individuals with histamine intolerance (HIT) ingestion of food with normal contents of histamine causes histamine-mediated symptoms. HIT is a pathological process, in which the enzymatic activity of histamine-degrading enzymes is decreased or inhibited and they are insufficient to inactivate histamine from food and to prevent its passage to blood-stream. Diagnosis of HIT is difficult. Multi-faced, non-specific clinical symptoms provoked by certain kinds of foods, beverages and drugs are often attributed to different diseases, such as allergy and food intolerance, mastocytosis, psychosomatic diseases, anorexia nervosa or adverse drug reactions. Correct diagnosis of HIT followed by therapy based on histamine-free diet and supplementation of diamine oxidase can improve patients quality of life.

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 effect of selective antagonist of H4 receptor JNJ7777120 on nasal symptoms, cough, airway reactivity and inflammation in guinea pigs.

The efficacy of H4R antagonist JNJ7777120 on nasal symptoms, cough, airway resistance (Raw), inflammatory cell count in bronchoalveolar lavage (BAL) and blood in ovalbumin (OVA) induced allergic rhinitis (AR) was studied in guinea pigs. Animals (n=8) were sensitized by i.p. OVA and were repeatedly challenged with nasal OVA to induce rhinitis, seven animals were not sensitized. Animals were pre-treated with JNJ7777120 2.5 and 5mg/kg i.p. 30 min prior OVA. Cough was induced by inhalation of citric acid, Raw was measured in vivo by Pennocks method as baseline, during AR and after JNJ7777120 treatment. Leucocyte count in BAL and blood was analyzed. JNJ7777120 (5mg/kg) significantly suppressed nasal symptoms and the number of coughs. This compound significantly inhibited airway reactivity to histamine, but not methacholine. Pre-treatment with JNJ7777120 5mg/kg did not influence significantly the leucocyte count in BAL and blood except for a significant decrease in monocyte count in blood compared to the control group (p<0.05). We conclude that the antitussive action of JNJ7777120 is peripheral. The primary effect of the compound is anti-inflammatory, and the suppression of cough is a consequence of reduced airway inflammation.

Role of gender in basic cough research

Cough hypersensitivity affects mainly postmenopausal women. Pathogenesis remains unknown in their case; therefore, an optimal treatment is unavailable. Only male guinea pigs are used in basic cough research and exclusion of females leads to gender bias. Nowadays, the efforts of grant agencies aim to support projects which take gender into account and involve both sexes to reduce gender bias. The aim of our pilot study is to assess the suitability of female guinea pig model in cough research. Cough response to citric acid (0.4M) was obtained in female and male guinea pigs (n=12 each). Reproducibility of cough response was tested four times a week apart. The cough was detected from the airflow traces and cough sound analysis. Our initial results show that cough response of female guinea pigs is higher than in males. Variability of females is also higher than in males. Further investigations are necessary to validate this model in different conditions to achieve gender equality in cough studies.

Cough in sarcoidosis patients

Sarcoidosis is a multi-system disease of unknown aetiology characterized by presence of non-caseating granulomatous inflammation. Cough is a common and significant symptom in sarcoidosis, reducing quality of life. Objective 24 h cough monitoring proved that sarcoidosis patients have significantly higher cough frequency compared to controls and their cough has diurnal variation, it is gender-specific and shows racial differences. It correlates with the presence of inflammation in the airways, but is not influenced by the X-ray staging of the disease, nor the degree of airway obstruction. Subjects with sarcoidosis have heightened cough reflex sensitivity, which is a result of interaction between the airway cough sensors and consequences of pathological process, detailed pathogenesis of cough in this demographic is unclear. The airway hyperresponsiveness, sarcoidosis of the upper airways and sensitivity to biomechanical forces play a role. More studies should be performed to understand pathogenesis of cough in sarcoidosis patients to improve the management of this troublesome symptom.

Sensitivity of airway cough-related afferents is influenced by female sex hormones

Chronic hypersensitivity cough syndrome affects mainly postmenopausal women; however, the pathogenesis of cough hypersensitivity in this demographic is not entirely understood. The role of sex hormones in cough has never been studied in detail; however, sex hormones seem to play an important role in the lung health of women. Our study was aimed to analyse the effect of female sex hormones (oestrogen - E2 and progesterone - Pg) on cough sensitivity measured by inhalation of capsaicin in follicular and luteal phases of menstrual cycle, characterized by significantly different concentrations of sex hormones. These data were compared with a matched group of women taking oral contraceptives. Cough sensitivity to capsaicin increased in luteal phase in subjects with normal menstrual cycle, and this functional change was not present in group with contraceptive pills. The cough sensitivity correlates with the Pg/E2 ratio, and relative lack of oestrogen in luteal phase is associated with higher cough sensitivity to capsaicin.

TRPV4 antagonist GSK2193874 does not modulate cough response to osmotic stimuli

Osmolarity changes of airway superficial fluid are associated with cough and are used in research. TRPV4 is calcium channel initially described as osmosensor. In the airways, it can play role in increasing cough reflex sensitivity. The aim of our study was to test whether cough to osmotic stimuli is mediated via TRPV4 channel. Cough response was measured in 12 male guinea pigs by inhalation of saline, distilled water, hypertonic solution and citric acid for 10min in whole-body plethysmograph. Data were obtained in naïve animals and after pre-treatment with selective TRPV4 antagonist GSK2193874 in doses 300μg/kg (GSK300) and 900μg/kg (GSK900). Cough response to all tested aerosols was significantly higher than to saline. Pre-treatment with GSK300 did not influence response to osmotic stimuli - only reduced cough to citric acid. GSK900 reduced cough response to hypotonic stimuli and citric acid. TRPV4 mediated activation of airway afferents does not seem to be the exclusive mechanism responsible for cough to osmotic stimuli.

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.