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Hyperoxia-induced lung injury is well known in animal and human studies. The respiratory epithelium including sensory nerve endings is a major target for oxidative injury that manifested in lung function changes including cough. On the basis of available information we supposed that hyperoxia alone or in combination with primary lung tissue injury should have a damaging effect on lungs, including the airway nerve endings with the changes in the sensitivity of the central and peripheral neuronal pathways regulating cough. We have previously demonstrated that long-term exposure to 100% oxygen inhibits the cough reflex in cat. This review article summarizes the effect of hyperoxia on the cough reflex in guinea pig model using different concentrations of oxygen and different time of exposure. We also present information on the potential role of antioxidants in reversal of the detrimental effects of hyperoxia on coughing and additional analysis of experiments from previously published studies were obtained and analysed for the cough reflex sensitivity., (Copyright © 2018 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.)

Asthma is a chronic inflammatory disease characterized by bronchospasms accompanied with frequent coughing, the pathogenesis of which is not clear. In healthy adults deep inspirations (DIs) provide a protective effect against bronchoconstriction triggered by methacholine inhalation, which correlates with the number of accompanying cough efforts. The aim was to study the effect of deep nasal inspirations representing the voluntary equivalent of the sniff-like aspiration reflex on the capsaicin-induced cough in children with mild asthma. The cough reflex sensitivity to capsaicin was determined using a compressed air-driven nebulizer in 21 children (8 girls and 13 boys of median age 13.3 year) suffering from mild asthma (FEV(1)∼80%). The effect of five previous DIs through the nose was examined on the elicitability of two and five or more cough efforts (C2, C5). Under control conditions, the concentration of 20.86 (14.58-29.8) μmol/l of capsaicin provoked two cough efforts (C2). After five DIs similar reaction required significantly higher concentrations of capsaicin: 29.02 (18.88-44.6) μmol/l; P=0.016. Five or more cough efforts (C5) were not significantly changed after previous DIs 161.49 (77.31-337.33) μmol/l and without DIs 141.52 (68.77-291); P=0.54. A series of five deep inspirations decreases the cough reflex sensitivity to evoke two efforts (C2) in children with mild asthma. The inhibitory effect of similar DIs disappeared after repeated applications of increasing doses of capsaicin, aiming to evoke five or more cough efforts, suggesting a reflex character of protective effect of DIs.

The Workshop considered the mechanisms whereby the 'cough center' could be tuned by various afferent inputs. There were particular presentations on the effects of inputs from the nose, mouth, respiratory tract and lungs, cerebral cortex, somatic tissues and the pharynx. From all these sites cough induced from the lungs could be increased or decreased in its strength or modified in its pattern. Thus 'tuning' of cough could be due to the interaction of afferent inputs, or to the sensitization or desensitization of brainstem neural pathways. The pattern of response depended on the 'type' of cough being studied and, in some instances, on the timing of the sensory input into the brainstem. Cough inputs could also affect various 'non-cough' motor outputs from the brain, although this was not the main theme of the Workshop. The main conclusion was that cough is not a stereotyped output from the medullary 'cough center', but that its pattern and strength depend on many afferent inputs acting on the 'cough center'., (Copyright © 2011. Published by Elsevier Ltd.)

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.

The expiration reflex (ER) is a forced expiratory effort against a closed glottis that subsequently opens to eject laryngeal debris and prevent aspiration of material. It is distinct from the cough reflex. Its source is usually assumed to be restricted to the larynx and vocal folds, and its possible origin from the tracheobronchial (TB) tree has been suggested but never studied. The current authors re-analysed previous records with mechanical or chemical stimulation of the TB tree to see if an ER can consistently be elicited, and to see whether it has properties similar to that from the larynx and vocal folds. A random review was made of some of the extensive literature on TB "cough" to see if it confirmed the authors' conclusions. The TBER was consistently seen in cats and rabbits, either alone or followed by cough. These results are consistent with many studies in other species, including humans. It was enhanced, relative to cough, by inflation of the lungs and by general anaesthesia. Tracheobronchial expiration reflex occurs frequently with mechanical stimulation of the tracheobronchial tree. It differs fundamentally from many of the properties of "true" cough. Its features similar to the laryngeal expiration reflex suggest that both should be labelled "expiration reflexes" and not cough. Its existence should be taken into account in experimental, and possibly clinical, studies on tracheobronchial cough.

Experimental and clinical studies performed in adults revealed that gastresophageal reflux disease (GORD) is associated with an appreciable increase in cough reflex sensitivity (CRS). The association between respiratory diseases and GORD is also present in children, but there is little evidence that GORD without aspiration of refluxate (proximal reflux) is a frequent cause of cough in children. The aim of this study was to find out whether CRS in children with GORD will be changed compared with healthy children, and if so, to determine the role of proximal vs. distal reflux in these changes. CRS and 24-h esophageal pH monitoring were performed in 20 children of whom 13 had confirmed GORD and 7 were suspected to have GORD. The control group consisted of 27 healthy children. For assessing the CRS, each subject inhaled 12 capsaicin aerosol concentrations (0.61-1250 micromol/l) at 1 min intervals. CRS was defined as the lowest capsaicin concentration that evoked minimally 2 coughs (C2). CRS in the group of children with suspected GORD [C2: 17.0 micromol/l (6.4-45.6 micromol/l)] and with confirmed GORD [C2: 13.4 micromol/l (3.6-50.9 micromol/l)] were significantly elevated (P<0.05) compared with healthy children [C2: 72.1 micromol/l (25.5-203.9 micromol/l)]. According to the parameters of 24-h pH monitoring, a significantly higher exposure to acid was present in the distal compared with proximal oesophagus. CRS changes correlated negatively with the distal, but not proximal, esophageal acid exposure. In conclusion, CRS changes in children suffering from GORD are similar to those described in adult patients with GORD. It is plausible that the main role in increased CRS in children with GORD play episodes of distal acid refluxes.

Radiotherapy of tumors in the chest and neck regions may have serious pulmonary side effects. It is well known that inflammation is an essential manifestation of radiation-induced injury. This can heal spontaneously, by specific treatment, or it may progress to more intensive inflammation up to irreversible pulmonary fibrosis. To prevent such complications, it would be useful to have a simple non-invasive and sensitive method for monitoring the course of airway and lung post-irradiation inflammation. This study is devoted to search for such a method. We supposed that cough response intensity (CRI) could be one of the methods, which we are looking for. Guinea pigs (Trik strain, n=32) were used in the study. Animals were divided into two subgroups. Animals of a non-untreated (NT) group (n=14; M=7, F=7) were submitted to sham chest irradiation. The animals of a treated (XRT) group (n=18; M=9, F=9) were exposed to a single dose of gamma rays. Cough was provoked by exposure of animals to citric acid aerosol (CA) in gradually increasing concentrations (0.05-1.6M). CRI testing was performed two days before sham/real chest irradiation, than on 1st, 3rd, 10th, 15th, 21st, and 28th days following the day of irradiation. CRI was quantified in each animal by counting the number of coughs induced by all used concentration of CA. We found a significant increase of CRI in the animals of XRT group on 10th and 21st day compared with the NT animals. An increase of CRI also was found inside the XRT group on the 10th day after irradiation compared with the pre-irradiation value of CRI.

Diabetic autonomic neuropathy (DAN) is manifested by dysfunction of one or more organ systems. Its subclinical form (sDAN) can be recognized with the use of noninvasive cardiovascular reflex tests. As the cough reflex is mediated via autonomic nervous system, there is a reason to suppose that it can also be changed due to presence of sDAN. The aim of the present study was to assess cough reflex sensitivity (CRS) in diabetic children with and without sDAN. A CRS test was performed in 35 children suffering from diabetes mellitus type 1 and the results were compared with those from age-matched 27 healthy children. 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 parameter) and 5 or more coughs (C5 parameter). We found that CRS in the whole group of diabetic children was not significantly different from that in healthy children [diabetic children--C2: 75.1 micromol/l (95% CI: 42.0-134.2 micromol/l)] vs. healthy children--C2: 72.4 micromol/l (95% CI: 75.7-644.8 micromol/l)]. However, a significant decrease (P=0.005) in CRS was found in diabetic children with sDAN [n=12; C2: 221.0 micromol/l (95% CI: 75.7-644.8 micromol/l)] compared with diabetic children without sDAN [(n=23; C2: 42.7 micromol/l (95% CI: 23.1-79.0 micromol/l)]. We conclude that testing cough reflex sensitivity might be a way to establish the presence of diabetic neuropathy.

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.

It is reasonable to suppose that airway mucosa can be damaged by irradiation applied to chest and neck regions. The inflammatory process is a consequence of an injury. Airway inflammation is one mechanism responsible for cough induction. So, one can suppose that radiotherapy (RT) focused on the patients' chest or neck may injure airway mucosa, which might change sensitivity of the nerve-endings mediating the cough reflex. The purpose of this study was to examine cough reflex sensitivity (CRS) in patients who underwent RT in the chest and neck regions. CRS test using capsaicin was performed in patients with breast cancer (Group A, n=19), and with lung or neck cancer in (Group B, n=14) who underwent RT. Capsaicin aerosol in doubled concentrations (0.49-1000 microM) was inhaled by a single breath. CRS was defined as the lowest capsaicin concentration that evoked 2 or more coughs (C2). Radiation doses ranged from 40 to 70 Gy. Capsaicin cough challenge was performed before and then in the 2(nd) and 5(th) week of RT. We observed a significantly reduced value of C2, i.e., increased cough reflex sensitivity, in Group B in the 2(nd) week of RT (P= 0.04). We conclude that CRS in the lung or neck cancer patients undergoing RT is significantly enhanced, which could result from injury to the nerve endings in airway mucosa.

Thoracic irradiation may cause an acute lymphocytic alveolitis or hypersensitivity pneumonitis. It is well known that cough reflex is sensitized by a number of inflammatory mediators. The purpose of the present study was to investigate the effect of the thoracic irradiation on the cough response in awake guinea pigs. Guinea pigs (Trik strain) were exposed to sham irradiation (n=16), a single irradiation dose of 10 Gy (n=12), and a fractionated irradiation dose (in five fractions) of 15 Gy (n=12) delivered to the thorax. Cough was induced by citric acid aerosol inhalation in gradually increasing concentrations (0.05-1.6 M) during the first week after thoracic irradiation. The cough response was expressed as a total number of coughs induced during all citric acid challenges. Irradiated animals with single dose of 10 Gy exhibited a time- dependent significant increase of citric acid-induced cough in the 6th day after irradiation compared with control animals (P=0.005), whereas cough was not altered significantly in irradiated animals with fractionated dose of 15 Gy. This study demonstrates that the increased cough response may be a determinant of the functional changes of airway nerve-endings mediating cough in the early phase after thoracic irradiation.

We have reviewed the role of afferent inputs and blood chemical changes to the central nervous system, and the way in which they modify the cough and expiration reflexes (CR and ER). Slowly adapting pulmonary stretch receptors (SARs) augment the CR, insofar as when their activity is abolished the CRs from the tracheobronchial (TB) tree and larynx are abolished or weakened. However, stimulation of SARs by lung inflation has an inconsistent effect on the CR. Activation of SARs strongly potentiates the ER from the vocal folds, by a reflex mechanism, and inhibition of SARs weakens the ER. Bronchopulmonary C-fibre receptors inhibit the CR, as do capsaicin-sensitive afferents from the heart and splanchnic bed, cutaneous cold receptors and those that respond to chest wall vibration. Nasal receptors responsive to the irritant agent capsaicin potentiate the reflex. Acute hypoxia also augments the CR, and the reflex is down-regulated by carotid body resection. On the other hand, the CR is inhibited by prolonged hypoxia and hyperoxia, and by hypercapnia. Thus different inputs to the cough-controlling mechanism in the brainstem have very varied effects on the CR. We conclude that the sensitivities of the CR and ER can be modified in a large variety of physiological and clinical conditions, and that there is no clear relationship between the reflexes and changes in breathing caused by the interventions.

Inhalation of high concentration of oxygen produces a lung injury in men and experimental animals. In our previous experiment we have found suppression of cough reflex in healthy guinea pigs after an exposure to 100% O2 for 60 hours. This study was designed to find the effect of hyperoxia on cough reflex in guinea pigs with lungs damaged by bleomycin. We used 48 animals (300-400 g) in two separated experiments. 32 of them were intratracheally injected with 1.5 mg bleomycin (Bleocin, Nippon Kayaku Co., Ltd., Tokyo, Japan) for induction of lung damage according to the method described by Parizada et al (20). 16 animals were given saline, only (control). Animals of experimental group were divided into two subgroups according to the lapse of time from bleomycin application. 13 days after bleomycin application animals of the 1st subgroup (16) were exposed to 100% O2 (8) or to room air (8) for 48 h. Similarly, 20 days after bleomycin application guinea pigs of the 2nd subgroup (16) were exposed to 100% O2 (8) or air (8), respectively. Cough was provoked in conscious animals placed in bodyplethysmograph box by inhalation of citric acid aerosol (0.3 mol/L) before, then 13 or 20 days after bleomycin application, and finally at the end of 48-h exposition to 100% O2 (air). The number of coughs was counted from airflow trace recorded by pneumotachograph. Cough was also induced by mechanical stimulation of laryngopharyngeal (LPh) and tracheobronchial (TBr) region in anaesthetized animals (Urethane, 1.1 g/kg, i.p.) just after the end of oxygen exposition and was evaluated from the interpleural pressure record. The results have shown a tendency to inhibition of citric acid cough reflex in animals 13 days treated with bleomycin and exposed to 100% O2, and significant decrease in citric acid induced cough in animals 20 days treated with bleomycin and exposed to 100% O2. Significant changes were present in cough intensity induced by mechanical stimulation of TBr region of the guinea pigs airway treated with bleomycin and exposed to oxygen, too. (Tab. 1, Fig. 3, Ref: 29.)

The cough reflex elicitability (CRE), cough reflex strength (CRS) and Hering-Breuer inflation reflex (HBIR) were studied in 51 anaesthetized (Pentobarbital Spofa, 30 mg/kg, i.v.) female rabbits 24-h and 48-h after SO2 breathing. To provoke cough, the interior of the trachea and carina were stroked with a polyethylene catheter. To elicit the HBIR, the lungs were inflated to 1.0 kPa intratracheal pressure. Intrapleural and systemic blood pressures were recorded. The CRE, CRS and HBIR obtained 24-h and 48-h after SO2 breathing were compared with correspondent values of control animals. It was found, that CRE and HBIR were fully recovered 24-h after SO2 breathing, but the CRS was still decreased, however, there were no significant differences in CRE, CRS and HBIR between animals 48-h after SO2 breathing and control animals. It can be concluded, that decrease of the CRS 24-h after SO2 breathing is not due to slowly adapting stretch receptors block of airways.