Jana Plevkova

Modulation of experimentally-induced cough by stimulation of nasal mucosa in cats and guinea pigs

Stimulation of afferent nerves in upper airways may contribute to the pathogenesis of chronic cough in chronic disorders of nose and/or sinuses. We tested the hypothesis that stimulation of the nasal afferent nerves enhances experimentally-induced cough. Intranasal administration of capsaicin (50 microM, 25 microl) did not evoke cough in anaesthetized cats, but enhanced cough induced by mechanical stimulation of the tracheobronchial mucosa (number of coughs, median [IQR]) (6.5 [5.5-8.5] versus 10 [7-14]; P = 0.028, n = 13). In contrast, intranasal histamine (16 mM, 25 microl) had no effect. Intranasal capsaicin (50 microM, 15 microl) did not evoke cough, but enhanced cough evoked by mechanical stimulation of the tracheobronchial mucosa (1 [1-3] versus 3 [2-4]; P = 0.0037, n = 15) in anaesthetized guinea pigs and cough induced by inhalation of citric acid (0.3M, 2 min) in awake guinea pigs (3 [2-5] versus 5 [3-7], P ? 0.0026, n = 23). We conclude that stimulation of nasal afferent nerves with capsaicin enhances experimentally-induced cough. Our results suggest that afferent inputs from the nose interact with the cough reflex pathways in a manner that enhances cough.

Mechanisms of the cough associated with rhinosinusitis

The diseases of the nose and paranasal sinuses (rhinosinusitis) often in combination with asthma and gastroesophageal reflux are common causes of chronic cough in patients with normal chest radiograph. The relationships between rhinosinusitis and cough are incompletely understood. We investigated modulation of the cough reflex by the inputs from the nose. We demonstrate that the cough reflex is sensitized by the intranasal administration of sensory nerve activators in animal models and in humans. Cough reflex is also sensitized in the guinea pig model of allergic nasal inflammation and in patients with allergic rhinitis. In patients with allergic rhinitis the cough sensitization is augmented during the allergen season. We conclude that the cough reflex can be sensitized from the nose. Our data indicate that this sensitization is mediated by nasal sensory nerves. We speculate that by inducing the cough reflex sensitization rhinosinusitis contributes to chronic cough. If combined with environmental or endogenous cough triggers, the cough reflex sensitization is predicted to cause excessive coughing. The potential endogenous cough triggers may be associated with rhinosinusitis (postnasal drip, aspiration of nasal secrets) or secondary to a coexistent disease such as asthma or gastroesophageal reflux.

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.

The global epidemiology of chronic cough in adults: a systematic review and meta-analysis

Cough is an essential defence mechanism [1]. However, chronic cough is a significant cause of morbidity, seriously impairing quality of life [2]. Previously, chronic cough was considered a consequence of various diseases, such as asthma/eosinophilic bronchitis, rhinitis and gastro-oesophageal acid reflux disease [3, 4]. Recent evidence, however, suggests that chronic cough is a clinical syndrome with distinct intrinsic pathophysiology characterised by neuronal hypersensitivity [5–7]. Here, we estimated the worldwide epidemiological burden of chronic cough irrespective of putative diagnosis in general adult populations using a comprehensive systematic literature review. Chronic cough has a high global epidemiological burden. A standard definition would facilitate further studies. http://ow.ly/HPCnw

The role of trigeminal nasal TRPM8-expressing afferent neurons in the antitussive effects of menthol

The cold-sensitive cation channel TRPM8 is a target for menthol, which is used routinely as a cough suppressant and as an additive to tobacco and food products. Given that cold temperatures and menthol activate neurons through gating of TRPM8, it is unclear how menthol actively suppresses cough. In this study we describe the antitussive effects of (-)-menthol in conscious and anesthetized guinea pigs. In anesthetized guinea pigs, cough evoked by citric acid applied topically to the tracheal mucosa was suppressed by menthol only when it was selectively administered as vapors to the upper airways. Menthol applied topically to the tracheal mucosa prior to and during citric acid application or administered continuously as vapors or as an aerosol to the lower airways was without effect on cough. These actions of upper airway menthol treatment were mimicked by cold air delivered to the upper airways but not by (+)-menthol, the inactive isomer of menthol, or by the TRPM8/TRPA1 agonist icilin administered directly to the trachea. Subsequent molecular analyses confirmed the expression of TRPM8 in a subset of nasal trigeminal afferent neurons that do not coincidently express TRPA1 or TRPV1. We conclude that menthol suppresses cough evoked in the lower airways primarily through a reflex initiated from the nose.

Chronic cough in subjects with upper airway diseases - analysis of mechanisms and clinical applications

Cough is the commonest respiratory symptom leading to a medical consultation. Although acute cough which is usually associated with respiratory viral infection is not a problem to manage, chronic cough is frequently a diagnostic and therapeutic challenge as it does not respond to usual treatments. Specific group of chronic coughers are considered to have upper airway diseases, lately categorized as having upper airway cough syndrome. There is an increasing pool of evidence that upper airway diseases have significant involvements in the regulation of cough reflex, indicating that they must be taken into considerations as major triggers of coughing in the patients. Here we summarize current literature and experiences on the pathogenesis of upper airway cough syndrome, and discuss further clinical applications.

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.

Intranasal TRPV1 agonist capsaicin challenge and its effect on c-fos expression in the guinea pig brainstem.

Central neuronal interaction seems to play a role in pathogenesis of upper airway cough syndrome. In the guinea pig model we used the method c-fos expression to identify neurons involved in processing of nociceptive nasal stimuli and their contribution to enhancement of cough. 21 spontaneously breathing, urethane anaesthetized animals were used. The controls received intranasal saline, stimulation group received capsaicin (15 microl, 50 microM), and not-treated group was free of nasal challenge. After 2 h animals were deeply anaesthetized, exsanguinated and transcardially perfused with saline and paraformaldehyde. The brainstems were removed, post-fixed, and slices were processed immunohistochemically for c-fos. In capsaicin group the FLI was detected in the nTs 0.5 mm caudal, 1.5 mm lateral to the obex, the area postrema, LRN and VRG. Intensive FLI was identified in trigeminal nuclear complex. Mean number of FOS positive neurons per section was significantly higher in capsaicin group than that in no-treatment controls or saline controls at the level of obex (p<0.01). Neurons of nTs and VRG clearly activated after nasal provocation may participate in enhancement of cough.

Impact of Air Pollution on Age and Gender Related Increase in Cough Reflex Sensitivity of Healthy Children in Slovakia

Background: Numerous studies show higher cough reflex sensitivity (CRS) and cough outcomes in children compared to adults and in females compared to males. Despite close link that exists between cough and environment the potential influence of environmental air pollution on age- and gender -related differences in cough has not been studied yet. Purpose: The purpose of our study was to analyse whether the effects of exposure to environmental tobacco smoke (ETS) from parental smoking and PM10 from living in urban area are implied in age- and gender-related differences in cough outcomes of healthy, non-asthmatic children. Assessment of CRS using capsaicin and incidence of dry and wet cough was performed in 290 children (mean age 13.3 ± 2.6 years (138 females/152 males). Results: CRS was significantly higher in girls exposed to ETS [22.3 μmol/l (9.8–50.2 μmol/l)] compared to not exposed girls [79.9 μmol/l (56.4–112.2 μmol/l), p = 0.02] as well as compared to exposed boys [121.4 μmol/l (58.2–253.1 μmol/l), p = 0.01]. Incidence of dry cough lasting more than 3 weeks was significantly higher in exposed compared to not exposed girls. CRS was significantly higher in school-aged girls living in urban area [22.0 μmol/l (10.6–45.6 μmol/l)] compared to school-aged girls living in rural area [215.9 μmol/l (87.3–533.4 μmol/l); p = 0.003], as well as compared to teenage girls living in urban area [108.8 μmol/l (68.7–172.9 μmol/l); p = 0.007]. No CRS differences were found between urban and rural boys when controlled for age group. No CRS differences were found between school-aged and teenage boys when controlled for living area. Conclusions: Our results have shown that the effect of ETS on CRS was gender specific, linked to female gender and the effect of PM10 on CRS was both gender and age specific, related to female gender and school-age. We suggest that age and gender related differences in incidence of cough and CRS might be, at least partially, ascribed to the effect of environmental pollutants. The role of age and gender in the effect of air pollution on cough strongly suggest some interplay of development with biological and behavioral factors.