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Background: Allergic rhinitis (AR) is a common cause of chronic cough, linked to dysregulated airway C- and Aδ-fibres through inflammatory mediators. Despite the limited efficacy of current antitussive therapies, recent studies show that the Na V 1.7 inhibitor can block cough in naïve guinea pigs. This study aimed to analyse the effect of the Na V 1.7 blocker PF-05089771 on cough in guinea pigs with AR., Methods: Dunkin Hartley guinea pigs were sensitised and challenged with ovalbumin (OVA). Cough was induced using citric acid aerosol (0.4 M) before nasal challenge (NCH), and then one hour after the 1st, 3rd, and 6th NCH. The OVA-inhibitor group was pre-treated with inhaled Na V 1.7 blocker (PF-05089771, 100 μM) before tussigen inhalation., Results: Chronic AR increased cough response to citric acid in both males and females. Pre-treatment with Na V 1.7 blocker significantly inhibited cough reflex by ≈ 75 % in males and ≈ 80 % in females without affecting respiratory rate., Conclusion: Na V 1.7 blocker inhalation effectively inhibits cough in guinea pigs with AR., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Effects of sequential increase in airway resistance: no, low (5 kPa.s/l), high (24 kPa.s/l), and complete block in the inspiratory or expiratory phase of mechanically induced cough on the cough motor pattern were studied in 16 anesthetized (pentobarbital) spontaneously breathing cats (3.70±0.15 kg, 11♂, 5♀). Esophageal pressure and electromyographic activities of the diaphragm during inspiration and abdominal muscles during expiration were analyzed. No significant changes in the number of coughs occurred. Inspiratory occlusion caused a prolongation of cough inspiratory phase, cough inspiratory diaphragm activity, and all cough-related activity. Inspiratory occlusion along with high resistance increased inspiratory esophageal pressure amplitude, total cough cycle duration and the time between maximum activity of the diaphragm and abdominal muscles. High expiratory resistance and occlusion resulted in increased cough expiratory esophageal pressure amplitude, a longer active portion of cough expiration, and cough abdominal activity. Expiratory occlusion also prolonged cough expiratory phase, all cough activity, and total cough cycle. Significantly increased airway resistance and occlusion induce secondary, in addition to mechanical, changes in cough by significantly modulating the generated cough motor pattern. A certain level of resistance appears to be successfully compensated, resulting in minimal changes in coughing characteristics, including expiratory airflow and the rising time of the airflow. Afferent feedback from the respiratory tract, particularly volume feedback, represents a significant factor in modulating cough, mainly under various pathological conditions in the respiratory system., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: This study compares two methods of citric acid-induced cough in guinea pigs in whole-body plethysmography (WBP) and double chamber plethysmography (DCP) to evaluate their efficacy., Methods: Sixteen specific pathogen-free (SPF) and sixteen conventionally-bred (CON) animals were exposed to 0.4 M citric acid aerosol. They underwent cough provocation using both DCP and WBP methods. The number of coughs and latency to the first cough were recorded and analysed using statistical methods to determine significant differences between the two techniques., Results: WBP resulted in significantly higher cough counts (WBP vs. DCP: 13±9 vs 2±3 for SPF; 14±8 vs 5±5 for CON; p<0.0001) and shorter latency (WBP vs. DCP: 59±6 s vs 159±14 s for SPF; 77±4 s vs 112±12 s for CON; p<0.0001) compared to DCP in both groups., Conclusion: Methodological differences substantially impact cough responses. WBP provides a more reliable and physiologically relevant methodology for cough assessment, suggesting the need for standardized protocols in cough research to enhance translational relevance., Competing Interests: Declaration of Competing Interest Authors have no conflict of interest to declare, financial or otherwise., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Laboratory animal science associations recommend the usage of specific pathogen-free (SPF) animals in experiments to achieve appropriate results. However, their non-natural microbiome might represent an obstacle in the successful translation of obtained results into clinical practice, since the microbiome contributes to the regulation of the host's physiology. Inconsistent results, even in repeated experiments in separate animal groups, irrespective of the season or sex led us to assess the cough response of SPF animal variables and compare it to wild-type animals. The dose-response curves in citric acid and capsaicin cough challenge construction shows significantly increased cough threshold in SPF animals compared to wild-type animals of both sexes. The cause of cough response alteration in SPF animals is not presently known and thus their usage in basic cough research remains questionable. The relationship between airway reflexes and the airway microbiome has never been studied hence we propose that it might be microbiome-related., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

To clarify the role of oestrogen signalling and the role of oestrogen receptor alpha (ERα) in the cough pathways we performed a study in which coughing was observed in both sexes animal models after the treatment by selective ERα degrader fulvestrant (ICI 182-780) and inhibitor of oestrogen synthesis danazol. Degradation of ERα with the normal plasma oestrogen levels induced by fulvestrant, significantly augments the cough response of female but not male guinea pigs. These changes were observed in citric acid-induced cough. Female guinea pigs responded with an increased count of cough expulsions per challenge time and we also detected shorter cough latency. The capsaicin-induced cough did not change. A similar response was observed after danazol treatment, which decreased the plasma oestrogen level. Our results indicate that the transient receptor potential vanilloid-1 (TRPV1) channel-mediated cough is resistant to the hypoestrous state, while the citric acid-mediated cough is oestrogen-dependent and hypersensitive during the hypoestrous state., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cough, the main airway defensive process, is modulated by multiple sensory inputs from the respiratory system and outside of it. This modulation is one of the mechanisms that contributes to the sensitization of cough pathways at the peripheral and/or central level via neuroplasticity and it manifests most often as augmented coughing. Cardiorespiratory coupling is an important mechanism responsible for a match between oxygenation and cardiac output and bidirectional relationships exist between respiration and cardiovascular function. While the impact of cough with the robust swings of the intrathoracic pressure on haemodynamic parameters and heart electrophysiology are well characterized, little is known about the modulation of cough by haemodynamic parameters - mainly the blood pressure. Some circumstantial findings from older animal studies and more recent sophisticated analysis confirm that baroreceptor stimulation and unloading alters coughing evoked in experiments. Clinical relevance of such findings is not presently known., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cough is a vital airway reflex that keeps the respiratory tract wisely protected. It is also a sign of many diseases of the respiratory system and it may become a disease in its own right. Even though the efficacy of antitussive compounds is extensively studied in animal models with promising results, the treatment of pathological cough in humans is insufficient at the moment. The limited translational potential of animal models used to study cough causes, mechanisms and possible therapeutic targets stems from multiple sources. First of all, cough induced in the laboratory by mechanical or chemical stimuli is far from natural cough present in human disease. The main objective of this review is to provide a comprehensive summary of animal models currently used in cough research and to address their advantages and disadvantages. We also want to encourage cough researchers to call for precision is research by addressing the sex bias which has existed in basic cough research for decades and discuss the role of specific pathogen-free (SPF) animals., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The study investigates the effects of 6 occlusion conditions on the mechanically induced cough reflex in 15 anesthetized (pentobarbital) spontaneously breathing cats (14♂, 1♀). Esophageal pressure and integrated EMG activities of inspiratory (I) diaphragm and expiratory (E) abdominal muscles were recorded and analyzed. Occlusions: inspiratory (Io), continual I (cIo), during I and active E (I+Eo) cough phase, during I and then E phase with short releasing of airflow before each phase (I-Eo), and E occlusion (Eo) had little influence on cough number. Only continual E occlusion (cEo) reduced the number of coughs by 19 % (to 81 %, p < 0.05). Cough I esophageal pressure reached higher amplitudes under all conditions, but only Eo caused increased I diaphragm motor drive (p < 0.05). Cough E efforts (abdominal motor drive and E amplitudes of esophageal pressure) increased during Eo, decreased during I+Eo (p  < 0.05), and did not change significantly under other conditions (p > 0.05). All I blocks resulted in prolonged I cough characteristics (p < 0.05) mainly cough I phase (incrementing part of the diaphragm activity). Shorter I phase occurred with cEo (p < 0.05). Cough cycle time and active E phase (from the I maximum to the end of cough E motor drive) prolonged (p < 0.05) during all occlusions (E phase duration statistically non-significantly for I+Eo). Airflow block during cough (occlusions) results in secondary changes in the cough response due to markedly altered function of cough central pattern generator and cough motor pattern produced. Cough compensatory effects during airflow resistances are more favorable compared to occlusions. Volume feedback represents significant factor of cough modulation under various pathological obstruction and/or restriction conditions of the respiratory system., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The cough reflex is an airway defensive process that can be modulated by afferent inputs from organs located also out of the respiratory system. A bidirectional relationship between cough and heart dysfunctions are presented in the article, with the special insights into an arrhythmia-triggered cough. Albeit rare, cough induced by cardiac pathologies (mainly arrhythmias) seems to be an interesting and underestimated phenomenon. This condition is usually associated with the presence of abnormal heart rhythms and ceases with successful treatment of arrhythmia either by pharmacotherapy or by radiofrequency ablation of arrhythmogenic substrate. The two main hypotheses on cough-heart relationships - reflex and hemodynamic - are discussed in the review, including the authors' perspective based on the experiences with an arrhythmia-triggered cough.

Laboratory research of cough reflex utilizes almost exclusively male guinea pigs - a practice that represents a significant obstacle in the successful translation of results into clinical practice. Chronic hypersensitivity cough syndrome affects mostly postmenopausal women and it represents significant decrease in patient's quality of life. No cause for such exaggerated cough can be found, therefore this condition cannot be treated appropriately. One of the reasons leading to the lack of relevant data about mechanisms responsible for hypersensitivity of cough related pathways is nowadays widely discussed gender bias, which is present in nearly all branches of biomedical research. Since gender differences in cough reflex physiology do exist in humans, it would be reasonable to study cough-related phenomena on both sexes of laboratory animals. In this study, we focused on detailed characterization of cough response of female guinea pigs to aerosols of commonly used tussive agents (capsaicin, distilled water, allyl isothiocyanate, cinnamaldehyde, citric acid). In pooled data from multiple challenges we found no statistical difference in number of cough and cough latency between sexes. Based on our results we conclude that the utilization of female guinea pigs model does not lead to messy data and can be used in basic cough research.

Introduction: Sarcoidosis is a multisystem granulomatous disease of unknown aetiology, commonly involving the lungs.  Cough is a frequent and troublesome symptom of sarcoidosis that reduces patients' quality of life., Aim: Retrospective analysis of different factors-smoking history, Scadding stage, results of lung function testing, calcium metabolism, endobronchial finding, CD4+/CD8+ T-cell ratio in bronchoalveolar lavage fluid (BALF), and other sarcoidosis symptoms in relationship to presence/absence of cough in sarcoidosis patients., Methods: We retrospectively studied sarcoidosis patients diagnosed at the Clinic of Pneumology and Phthisiology of Martin University Hospital between 1998 and 2018. Patients with a history of cough-relevant comorbidities were excluded from the study. GraphPad Prism 7.0 software was used to perform statistical analysis., Results: 101 sarcoidosis patients were included to the study: 65 patients reporting from cough and 36 without cough. The cough was slightly more frequent in nonsmokers ( p =0.166) and in women ( p =0.688). Cough was associated with dyspnoea ( p =0.0007), fever ( p =0.0324), and chest pain ( p =0.0206) and did not associate with arthralgia ( p =0.317) and erythema nodosum ( p =0.505). Patients with cough had significantly a lower average value of calciuria ( p =0.0014) and lower MEF25 ( p =0.0304), MEF50 ( p =0.0061), FEV1 ( p =0.0025), and FVC ( p =0.0025) in % of predicted values, and more often positive endobronchial finding ( p =0.0206), compared to patients without cough. Calcemia, FEV1/FVC, DLCO, and CD4+/CD8+ T-cell ratio in BALF and occurrence of cough did not differ between different stages of the disease., Conclusions: We found significant differences between sarcoidosis patients with/without cough regarding symptoms, results of lung function tests, endobronchial finding, and calcium metabolism. Further research is needed to understand the etiopathogenesis of cough in sarcoidosis patients.

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Majority of patients visiting cough clinics are postmenopausal women, who are affected by intractable cough for years. Why the cough reflex becomes exaggerated in women is not known. Basic research excludes females from the studies contributing to the sex bias which may be responsible for lack of understanding of "hypersensitive" cough in women. Biological and behavioural differences between women and men are the factors affecting cough physiology. Gender also shapes the patterns of behaviour and determines the character of environmental exposures which differs between sexes. The article offers an insight into the physiology of the cough, differences in the maturation of it and biological, social and behavioural factors contributing to the sex differences in cough., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The effect of volume-related feedback and output airflow resistance on the cough motor pattern was studied in 17 pentobarbital anesthetized spontaneously-breathing cats. Lung inflation during tracheobronchial cough was ventilator controlled and triggered by the diaphragm electromyographic (EMG) signal. Altered lung inflations during cough resulted in modified cough motor drive and temporal features of coughing. When tidal volume was delivered (via the ventilator) there was a significant increase in the inspiratory and expiratory cough drive (esophageal pressures and EMG amplitudes), inspiratory phase duration (CTI), total cough cycle duration, and the duration of all cough related EMGs (Tactive). When the cough volume was delivered (via the ventilator) during the first half of inspiratory period (at CTI/2-early over inflation), there was a significant reduction in the inspiratory and expiratory EMG amplitude, peak inspiratory esophageal pressure, CTI, and the overlap between inspiratory and expiratory EMG activity. Additionally, there was significant increase in the interval between the maximum inspiratory and expiratory EMG activity and the active portion of the expiratory phase (CTE1). Control inflations coughs and control coughs with additional expiratory resistance had increased maximum expiratory esophageal pressure and prolonged CTE1, the duration of cough abdominal activity, and Tactive. There was no significant difference in control coughing and/or control coughing when sham ventilation was employed. In conclusion, modified lung inflations during coughing and/or additional expiratory airflow resistance altered the spatio-temporal features of cough motor pattern via the volume related feedback mechanism similar to that in breathing., (Copyright © 2016. Published by Elsevier B.V.)

Cough accompanying acute respiratory tract disorders is a self-limiting phenomenon, and it usually does not require sophisticated management. Chronic cough, in contrast, is a bothersome problem, considerably influencing the quality of life of affected individuals. Specialized cough clinics report that substantial proportion of their patients are middle aged-to-postmenopausal females who cough for years in response to otherwise non-tussigenic stimuli, without a clear underlying disease reason. A newly established entity - 'cough hypersensitivity syndrome' explains pathogenesis of this problem. However, the syndrome has not been generally accepted, and the guidelines regarding the diagnostic protocols and treatment are not yet available. The reason why females cough more than males do is unclear, but the analysis of literature and experience with the chronic cough patients allows selecting three main targets of hormonal background which can contribute to the enhanced coughing in females. They are as follows: increased activity of transient receptor potential (TRP) channels expressed on vagal C-fibers mediating cough, laryngeal hypersensitivity and laryngeal dysfunction with paradoxical vocal cord movement, and mast cells which are known to express receptors for female sexual hormones and are frequently found in the bronchoalveolar lavage in chronic cough patients. In this review we analyze the potential contribution of the factors above outlined to excessive cough in female subjects.

The guinea pig sensitized by ovalbumin is the most widely used model to study cough experimentally, as the neurophysiology of the vagus nerve in the guinea pig is closest to humans. Nonetheless, the choice of the antigen remains questionable, which influences the translation of results into clinical medicine. The present study seeks to develop an alternative model of cough study using house dust mite sensitization (HDM). Thirty guinea pigs were divided into the HDM group, ovalbumin (OVA) group, and control group based on their cough response to 0.4 M citric acid. In the HDM group animals were sensitized by 0.25 %HDM aerosol, which they inhaled for 5 min over 5 days, followed by inhalation of 0.5 %HDM in the same protocol. Sensitization was confirmed by a skin test. Symptoms of allergic rhinitis were induced by intranasal application of 15 μl 0.5 %HDM and cough challenges with citric acid were performed. Airway resistance was measured in vivo by Pennock's method. We found that both HDM and OVA-sensitized groups showed a significantly enhanced nasal reactivity and cough response compared with controls. The airway resistance data did not show significant differences. We conclude that the HDM cough model replicates functional aspects of the OVA model, which may make it an alternative to the latter. However, the superiority of the HDM model for experimental cough studies remains to be further explored.

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 Pennock's 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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Mutual interactions of cough and sneeze were studied in 12 spontaneously breathing pentobarbitone anesthetized cats. Reflexes were induced by mechanical stimulation of the tracheobronchial and nasal airways, respectively. The amplitude of the styloglossus muscle EMG moving average during the sneeze expulsion was 16-fold higher than that during cough (p<0.01). Larger inspiratory efforts occurred during coughing (p<0.01) vs. those in sneeze. The number of reflexes during simultaneous mechanical stimulation of the nasal and tracheal airways was not altered significantly compared to controls (p>0.05) and there was no modulation in temporal characteristics of the behaviors. When both reflexes occurred during simultaneous stimuli the responses were classified as either sneeze or cough (no hybrid responses occurred). During simultaneous stimulation of both airway sites, peak diaphragm EMG and inspiratory esophageal pressures during sneezes were significantly increased. The expiratory maxima of esophageal pressure and amplitudes of abdominal EMGs were increased in coughs and sneezes during simultaneous mechanical stimulation trials compared to control reflexes., (Copyright © 2014. Published by Elsevier B.V.)

The medullary raphé nuclei participate in the regulation of breathing and airway defensive reflexes. Our focus was to analyze the effects of codeine and kainic acid within the medullary raphé on coughing, sneezing, solitary expulsions, and concomitant breathing changes using models of anesthetized cats (n=12) and rabbits (n=15) and microinjection techniques. Our findings are consistent with (1) involvement of neurons within the medullary raphé in the generation of the cough motor pattern by a codeine-sensitive and -insensitive mechanisms, (2) a contribution of raphé nuclei to the control of expiratory efforts, (3) limited contribution of the medullary raphé to the cough-gating mechanism, (4) minor contribution of respiration/coughing neuronal network, including the portion within raphé nuclei and the respiratory/cough central pattern generator, to the production of the sneeze reflex motor pattern., (© 2014 Elsevier B.V. All rights reserved.)

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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In the present study we investigated the possibility of central convergence of neural pathways coming from distant anatomical regions in modulating the cough response. We addressed this issue by inducing cough from the tracheo-bronchial region on the background of capsaicin-stimulated and mesocain-blocked nasal mucosa in 14 anesthetized guinea pigs. The control group consisted of 6 guinea pigs in which the active agents, capsaicin and mesocain, were substituted for by inert physiological saline. All animals were tracheostomized, and the larynx was disconnected from the proximal part of the trachea with preserved innervations, and all were subjected to the same protocol. Cough, induced by mechanical irritation of the tracheo-bronchial mucosa, was elicited three times: in the control condition, after intranasal capsaicin challenge, and after another capsaicin challenge preceded by intranasal instillation of a local anesthetic, mesocain. The main finding of the study was that the number of cough efforts per bout, assessed from positive deflections on the intrapleural pressure recordings, was significantly enhanced by intranasal capsaicin challenge and this effect was reversed by intranasal pretreatment with the anesthetic mesocain [2.1 +/-0.2 (control) vs. 3.5 +/-0.4 (capsaicin) vs. 2.2 +/-0.2 (capsaicin after mesocain) (P<0.01)], with no appreciable changes in the magnitude of cough efforts. The cough response in the control group remained unchanged. We conclude that tracheo-bronchial cough may be modified by neural sensory input to the brain coming from nasal mucosa. Therefore, cough reflex is subject to central convergence of peripheral neural pathways originating at distant anatomical locations.

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.

Studies in healthy adult volunteers and patients with chronic cough have shown that women have increased cough sensitivity to inhaled tussigenic stimuli, including capsaicin. The explanation for this phenomenon remains unknown, although the influence of pubertal changes (dimensional, hormonal) may play a role. In the present study we set out to examine the effect of the pubertal status on cough reflex sensitivity in a population of male and female children and adolescents. The study consisted of cough reflex sensitivity (CRS) testing, spirometry, and a children-completed pubertal status questionnaire. The inclusion criteria were no current symptoms of respiratory disease, no respiratory infection in the preceding 2 weeks, no allergic disease, and no other disease that could modulate CRS. All children were non-smokers. For assessing the CRS we used a compressed air-driven nebuliser controlled by a dosimeter with an inspiratory flow regulator valve. Each subject inhaled up to 12 capsaicin aerosol concentrations (0.61-1250 micromol/l) during 400 ms at 1 min intervals. CRS was defined as the lowest capsaicin concentration that evoked minimally 2 coughs. 225 children (median age 13 yr, 103 girls/122 boys) were divided according to the pubertal status (prepubertal, early pubertal, and late pubertal) and gender. We found that CRS [geometric mean (95%CI)] was similar in prepubertal and early pubertal girls and boys. However, CRS was significantly higher in late pubertal girls (n=56) than in boys (n=26) [53.57 (35.62-80.64) micromol/l vs. 119.7 (70.74-208.55) micromol/l; respectively; P=0.017]. We conclude that puberty and gender have a significant influence on the cough threshold to capsaicin. It seems, however, hard to determine what factors are responsible for the observed gender differences in cough reactivity adolescents.

Increased cough reflex sensitivity is found in patients with allergic rhinitis and may contribute to cough caused by rhinitis. We have reported that cough to citric acid is enhanced in the guinea pig model of allergic rhinitis. Here we address the hypothesis that the cough reflex sensitivity is increased in this model. The data from our previous studies were analyzed for the cough reflex sensitivity. The allergic inflammation in the nose was induced by repeated intranasal instillations of ovalbumin in the ovalbumin-sensitized guinea pigs. Cough was induced by inhalation of doubling concentrations of citric acid (0.05-1.6 M). Cough threshold was defined as the lowest concentration of citric acid causing two coughs (C2, expressed as geometric mean [95% confidence interval]). We found that the cough threshold was reduced in animals with allergic rhinitis. C2 was 0.5 M [0.36-0.71 M] and 0.15 M [0.1-0.23 M] prior and after repeated intranasal instillations of ovalbumin, respectively, P<0.01, n=36). C2 was not affected in control animals (n=29). We have reported that the selective leukotriene cys-LT1 receptor antagonist montelukast inhibited cough enhancement in this model. We found that this was accompanied by inhibition of the changes in cough reflex sensitivity. C2 was reduced in animals with allergic rhinitis treated orally with vehicle (0.57 M [0.28-1.1] vs. 0.09 M [0.04-0.2 M], P<0.05, n=8), but not in animals treated with montelukast (0.57 M [0.22-1.4 M] vs. 0.52 M [0.17-1.6 M], NS, n=8). We conclude that the cough reflex sensitivity is increased in the guinea pig model of allergic rhinitis. Our results suggest that guinea pig is a suitable model for mechanistic studies of increased cough reflex sensitivity in rhinitis.

Hyperoxia-induced lung injury is well known in animal and human studies. We have previously shown that hyperoxic exposure of guinea pigs is associated with suppression of cough reflex. The goal of this study was to determine the effects of oral N-acetylcysteine (NAC) on hyperoxia-induced oxidative stress in lung tissue directed on cough reflex. The experimental group was pretreated with NAC daily for 7 days and subsequently exposed to 100% O2 for 60 h. Hyperoxic group inhaled 100% O2 only. The control group was exposed to normoxia. Cough was induced by inhalation of citric acid aerosol before and after exposure to oxygen. Cough was also induced by mechanical stimulation of airways in anesthetized animals just after the end of oxygen exposure. Our results showed a significant decrease (P=0.002) in citric acid-induced cough in hyperoxic animals and reversal of that effect in animals pretreated with NAC. In addition, there was a significant interaction between antioxidant therapy and hyperoxia (P=0.005). NAC also reversed the hyperoxia-induced inhibition of mechanically-induced cough. In conclusion, our results indicate that NAC attenuated hyperoxia-induced down-regulation of chemically and mechanically-induced cough.

There is many evidence that inhalation of high oxygen concentration has a toxic influence on pulmonary function and structures. Hyperoxia-induced oxidative stress is well characterized in rodents and has been used as a valuable model of human respiratory distress syndrome. We have previously shown that hyperoxic exposure of guinea pigs is associated with suppression of cough reflex. The goal of this study was to determine the effects of dietary intake of antioxidant flavonoids (Flavin7, Vita Crystal Slovakia Ltd., 2 ml/kg b.w.) on hyperoxia-induced oxidative stress in lung tissue directed on cough reflex. The experimental group (n = 8) was pretreated with Flavin7 as a single daily dose for 14 days and subsequently exposed to 100% 02 for 60 h. Hyperoxic group (n = 8) inhaled 100% Oz only. Control group (n = 8) was exposed to normoxia. Cough was induced by inhalation of citric acid aerosol at time before and after exposure to hyperoxia. Cough was also induced by mechanical stimulation of airways in anaesthetized animals just after the end of oxygen exposition. When to compare animal groups before and after hyperoxia, our results have shown a significant decrease 2 (1-6) vs 6 (4-6) p = 0.041 in citric acid-induced cough in hyperoxic animals and no significant changes 8 (5.5-8.5) vs 5 (4-6.5) p = 0.055 in animals with antioxidant therapy. Mechanically-induced cough after hyperoxia was not influenced by substitution with flavonoids. In conclusion, our results indicate that flavonoids attenuated hyperoxia-induced down-regulation especially of chemically-induced cough (Tab. 2, Fig. 2, Ref. 30). Full Text (Free, PDF) www.bmj.sk.

Testing cough reflex sensitivity (CRS) in children requires suitable methodology. A CRS test performed under control of inspiratory flow rate (IFR) shows excellent reliability in children, but it is difficult to perform, especially in younger children. The aim of the present study was to find whether the capsaicin CRS test performed without direct control of constant IFR in healthy children is reliable enough for practical use. The CRS test was performed in 27 healthy children, aged 7-17 yr three times within 8 days. Cough was induced by inhalation of capsaicin aerosol in doubling concentrations (0.61-1250 micromol/l) for 400 ms each. CRS was defined as the lowest capsaicin concentration that evoked 2 or more coughs (C2). Although the intraclass correlation coefficient values showed good to excellent reliability of this test, the within-subject standard deviation values revealed lower reliability of this method compared to the CRS test performed under control of IFR. From the results obtained it is reasonable to conclude that the method using uncontrolled IFR in CRS testing provides acceptable precision only when a bigger sample size is used or more tests are performed. Good to excellent reliability of this method was found in children with higher values of C2 and in those aged 13-17 yr.

Inhalation of high concentration of oxygen produces oxidative stress in men and experimental animals. Our previous experiments showed that the cough reflex is suppressed in guinea pigs after exposure to 100% O(2) for 60 hours. The aim of this study was to determine the effects of dietary antioxidant supplementation with vitamins C and E on hyperoxia-induced oxidative stress in airway and lung tissues directed on cough reflex. The experimental group (T-H, n=8) was pretreated with vitamins C (500 mg/kg) and E (300 mg/kg) for 4 weeks and subsequently exposed to 100% O(2) for 60 hours. Hyperoxic group (H, n=8) received saline instead of antioxidants and then inhaled 100% O(2) for 60 hours. Cough was induced by inhalation of citric acid aerosol in gradually increased concentration (0.05-1.6 M) at the end of antioxidant therapy and then at the end of exposure to 100% O(2). Cough was also induced by mechanical stimulation of laryngopharyngeal (LPh) and tracheobronchial (TBr) region in anaesthetized animals just 1 hour after the end of oxygen exposure. Our results showed a tendency to a decrease in citric acid-induced cough in hyperoxic animals and an increase in animals with antioxidant therapy after hyperoxia. Antioxidant therapy significantly unblocked hyperoxia-induced down-regulation of cough (P=0.004). Significant changes also were obtained from mechanically-induced TBr cough [2.5(1-4) vs. 1.0(1-2); P<0.01] between the experimental and hyperoxic (control) animals. In conclusion, our results indicate a protective effect of antioxidant supplementation on oxidant-mediated cough depression.

Cough associated with upper respiratory tract disorders is a common and troublesome problem in children and little is known about the etiology of this type of cough. This study examined the capsaicin cough sensitivity (CS) in children suffering from allergic rhinitis (AR) and upper respiratory tract infection (URI), comparing it with that in healthy children taken as controls (C). CS to capsaicin, spirometry, skin prick tests, and nose-throat examination were performed in 61 children grouped by the diagnosis of AR, URI, and C. The results, in order of C vs. AR vs. URI, expressed as a geometric mean (+/-95% CI) log(10) muM of capsaicin for C2 (the lowest concentration of capsaicin in mumol/l required to induce >or=2 coughs) were: 1.8 (1.6-1.9) vs. 1.0 (0.8-1.2) vs. 0.48 (0.2-0.8), P<0.001 and for C5 (the lowest concentration of capsaicin in mumol/l required to induce >or=5 coughs) 2.9 (2.8-2.9) vs. 2.6 (2.5-2.6) vs. 2.1 (2.0-2.3), P<0.05. We found that CS in children with AR, even when tested out of pollen season, was significantly heightened compared with controls. CS in children with URI was extremely high compared with both C and AR groups. We conclude that pathological processes in the nose of any etiology could cause a sensitization of the cough reflex with decreased cough threshold during asymptomatic period of AR. Cough also is enhanced by acute inflammation in the upper airways in nonatopic children.

Unlabelled: The aim of the study was to investigate the effects of nasal histamine on the intensity of cough reflex and the effects of intensified nasal breathing following the nasal histamine challenge on cough sensitivity (CS) in humans. 20 volunteers (mean age 23, nonsmokers, no history of nasal or respiratory system diseases and atopy) were recruited to the study. Baseline CS was determined in all subjects. 2 days later the subjects (n = 20) were challenged with nasal histamine (8 mg/ml, 0.1 ml) and the number of coughs was determined after four consecutive single-breath inhalations of capsaicin C2 concentration during the period of the most intensive nasal symptoms (sneezing, itching of the nose). The same capsaicin C2 challenge was performed after nasal saline challenge two days later. One week later CS was determined after nasal histamine challenge with subsequent 10 min of intensified breathing (5-6 sniff-like aspirations to total lung capacity per minute) through the nose and mouth in randomized order in ten volunteers, and with a two-day interval between the challenges. The same manoeuvres after intranasal saline challenge were performed in volunteers of the control group (n = 10). The number of coughs after nasal histamine was significantly higher than that after intranasal saline challenge (8(6-10) vs 5(3-7); p = 0.038(. CS was not significantly different between the baseline challenge and challenges after nasal histamine followed by the intensified nasal and mouth breathing ((2.21 (1.8-2.62) vs 2.04 (1.57-2.51) vs 2.05 (1.6-2.5) log(10) of capsaicin concentration in mumol.l(-1); p = 0.09)., Conclusions: During the period of maximum nasal symptoms after nasal histamine challenge the cough response to inhaled capsaicin was enhanced. Capsaicin cough sensitivity measured after a 10-min. intensified nasal breathing after nasal histamine challenge, compared to a previous measurement of CS, remain unchanged.

Experimental allergic rhinitis produces enhanced cough response in awake guinea pigs. Leukotriene receptor antagonists, as anti-inflammatory agents, have been effective in treatment of asthma and allergic rhinitis to inhibit the early and late allergic response. In the present study, we evaluated the effect of montelukast (Singulair, Merck, USA) on the cough reflex in an experimental model of allergen-induced rhinitis in guinea pigs. Guinea pigs (n=16) were sensitized with intraperitoneal ovalbumin (OVA). The animals were then used to develop a model of allergic rhinitis by repeated intranasal instillation of 0.5% OVA at weekly intervals for 8 weeks. Allergic rhinitis was evaluated from the occurrence of typical clinical symptoms including sneezing, conjunctival and nasal secretion, or nasal acoustic phenomenon. Between the 6(th) and 8(th) nasal challenge (NCh) the animals (n=8) were treated daily for 14 days with oral montelukast (10mg/kg). Cough was induced by citric acid aerosol inhalation in gradually increasing concentration (0.05-1.6 M) and was evaluated before sensitization and then after the 1(st), 6(th), and 8(th) nasal challenge when rhinitis symptoms were most conspicuous. The intensity of cough was significantly increased after the first and repeated nasal OVA challenges, and reduced after the 8(th) NCh that was preceded with montelukast treatment [9(6-14) vs. 16.5(14-22) vs. 25.5(23-42) vs. 8.5(8-13); P=0.0003]. We conclude that antileukotriene therapy suppresses the stimulating effect of experimental allergic rhinitis on the chemically-induced cough in awake guinea pigs.

In the present study we investigated the effects of nasal histamine on the intensity of coughing and the effects of intensified nasal breathing following nasal histamine on cough sensitivity (CS) in 14 subjects with seasonal allergic rhinitis. The study consisted of two parts performed one week apart. First, baseline CS to capsaicin was determined, followed by intranasal histamine challenge (4 mg/ml, 0.1 ml) and the count of the number of coughs to inhaled capsaicin on the background of most intensive nasal symptoms (sneezing, itching, rhinorrhea, and nasal blockage) evoked by histamine. In the second part, CS was determined after intranasal histamine followed by 10 min of intensified nasal breathing through the nose or mouth in a randomized order at 2-day intervals. The number of coughs induced after intranasal histamine was significantly higher, compared with intranasal saline, [9 (7-12) vs. 4.5 (4-6), P<0.001]. CS also was significantly increased after nasal histamine, but nasal intensified breathing failed to cause any changes in CS. We conclude that stimulation of nasal mucosa with histamine enhanced the cough response in subjects with allergic rhinitis.

Background: Gastroesophageal reflux disease is one of the most common causes of chronic cough. The mechanism of the cough initiation in these patients remains unresolved., Objectives: This study was designed to investigate the effect of intraesophageal (IE) administration of capsaicin on cough and specific airway resistance (Saw) in guinea pigs., Methods: Male TRIK strain guinea pigs were used. In the first experiment 12 controls received IE saline, 9 animals (group 1) received IE capsaicin (400 microM, 0.2 ml) and 12 guinea pigs (group 2) received IE capsaicin (400 microM, 0.2 ml) 24 hours after IE administration of hydrochloric acid (3 M, 0.2 ml). Cough induced by inhalation of citric acid (CA) and Saw was determined after IE administration of saline in controls and capsaicin in groups 1 a 2. In the second experiment, CA induced cough was determined in guinea pigs (n=13) in the beginning of the study (control response), after NaOH (1 M, 0.2 ml) was administered IE. One week later in conditions of corrosive esophagitis CA induced cough was determined after IE administration of capsaicin (cough during esophageal stimulation)., Results: There was no difference in CA induced cough between controls, group 1 and 2 (p=0.98). Saw was hot affected by IE capsaicin stimulation and CA inhalation in group 1 and group 2. There was no difference found between control cough response and those induced after IE capsaicin in animals with corrosive esophagitis (p=0.75)., Conclusion: Esophageal stimulation with capsaicin did not trigger and/or modulate CA induced cough and Saw in guinea pigs models. (Fig. 5, Ref. 22.)

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.

Rhinosinusitis is the most common cause of chronic cough. There is clinical experience that cough can be elicited from lower airways including the larynx. However, there is no experimental evidence, that afferent nerve endings localized in the nose or sinuses can directly mediate the cough reflex. Stimulation of nasal afferents affects breathing pattern (apnea) and bronchial smooth muscles (nasobronchial reflex). The question arises of whether stimulation of nasal afferents could also interfere with the cough reflex. Intranasal capsaicin enhances the cough response in cats and guinea pigs. In the present study we address the problem of modulation of the cough response by intranasal capsaicin challenge in humans. Twelve healthy volunteers were recruited for the study. The effect of intranasal capsaicin (25 microl, 750 microM) and the airway cough threshold were determined at the start of the experiment. After that, cough response was provoked by inhalation of a tussigen during stimulation of nasal afferents with capsaicin and in control conditions in a randomized order. The cough response provoked during intranasal capsaicin was significantly enhanced compared with that during control conditions. Thus, the result was similar to that obtained in previous animal studies. The enhancement of the cough response could be explained by a facilitating interaction between the afferent information of nasal origin and the central neuronal network responsible for creation of cough pattern.

Allergic rhinitis is a common cause of chronic cough. Topical corticosteroids are regarded as the most effective first-time treatment in allergic rhinitis. In this study we evaluated the cough sensitivity during the early and late allergic responses in guinea pigs with experimental allergic rhinitis. Another aim of the study was to follow up the effect of inhaled beclomethasone dipropionate on the cough in guinea pigs with allergic rhinitis. 31 guinea pigs were sensitized with ovalbumin (OA). Animals were intranasally challenged with OA (experiment) or saline (control) in 7-day intervals for 9 weeks. Cough was induced by inhalation of citric acid aerosols in gradually increasing concentrations for 30 s and was evaluated 1 h after the 8(th) nasal challenge (NCH) and 17 h after the 9(th) NCH. Cough was significantly increased only during an early allergic response, 1 h after repeated NCH [18 (14-23) vs. 8 (3-10); P<0.001]. Five experimental animals were inhaling aerosol of beclomethasone dipropionate seven days between the 8(th) and the 9(th) NCH and cough was evaluated 1 h after the 9(th) NCH. Inhaled corticosteroids significantly inhibited the enhanced allergic rhinitis related cough [4 (1-9) vs.19 (9-37) vs. 6 (3-9); P<0.05].

Inhalation of aromatic vapours suppressed coughing induced by citric acid (CA) in naive animals. No data are available about their effects in an animal model with primarily up-regulated cough reflex. New data indicate that aromatic vapours suppress cough via effect on nasal sensory nerves.

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. [ABSTRACT FROM AUTHOR]