Chronic Cough as a Female Gender Issue.

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 House Dust Mite: A Model of Experimental Cough Studies.

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.

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 patient's quality of life.

The effect of stimulation and unloading of baroreceptors on cough in experimental conditions.

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.

Legacy of Prof. Juraj Korpás: International Impact of Slovak School of Experimental Respirology.

Human health is the main role of medical research. Scientists were always intrigued by disease prevention, their diagnostics and proper treatment. In fact, research in medicine is always directed towards the improvement of the health care and improvement of the quality of life of the target population. Nowadays, physiological research, which is the base stone for clinical research, progresses fast forward, providing new information about body functions in health and diseases. This obvious progress is associated with modern methods, such as neuronal tracing, patch-clamp methods, electrophysiology, molecular biology and many more, which supported by comprehensive information technology guarantees high quality and complex data. Our younger colleagues, young scientists, post-docs or PhD students are well-trained and qualified in utilizing these new methods.

Female Guinea Pig Model for Cough Studies and Its Response to Most Common Tussive Substances.

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.

Various aspects of sex and gender bias in biomedical research.

The main role of research in medicine is to provide relevant knowledge which, after successful translation to clinical practice, improves the quality of healthcare. The sex bias which is still present in the majority of research disciplines prefers male subjects despite legislation changes in the US grant agencies and European research programme Horizon 2020. Male subjects (cells, animals) still dominate in preclinical research and it has detrimental consequences for women's health and the quality of science. Opposite bias exists for data obtained mainly in animal models utilizing female subjects (e.g. research in multiple sclerosis, osteoporosis) with skewed outcomes for men affected by these diseases. Either way, scientists are producing results which compromise half of the population. Assumptions that females as cohorts are more variable and another assumption that the oestrous cycle should be tracked in case the females are enrolled in preclinical studies were proven wrong. Variability of male versus female cohorts are comparable and do not only stem from hormonal levels. The widespread prevalence of sex differences in human diseases ultimately requires detailed experiments performed on both sexes, unless the studies are specifically addressing reproduction or sex-related behaviors.

Cough as a Cause and Consequence of Heart Dysfunction - Current State of Art.

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.

Exhaled and Nasal Nitric Oxide - Impact for Allergic Rhinitis.

FeNO measurement is a validated non-invasive technique, which is used for diagnosis and monitoring of asthma. It would be desirable to find a reliable method to monitor allergic rhinitis (AR) via measurement of FeNO, and/or nasal nitric oxide (nNO). The aim of our study was the assessment of the efficacy of FeNO and nNO as markers in AR treatment. FeNO and nNO were measured with the portable NO analyser (NIOX MINO®) in healthy participants and in patients with AR. The patients were examined during the pollen season and out of it. The effect of local corticosteroids and antihistamine therapy was observed in patients with AR during pollen season after three weeks of therapy. There are significant differences between FeNO and nNO in patients with AR compared to healthy controls at all set points of measurements. While FeNO responded well to the treatment with both antihistamines and combined therapy, nNO decreased only after combined therapy with antihistamines and nasal corticosteroids. nNO monitoring alone is not a suitable method to monitor inflammation of the upper airways in AR and its suppression by anti-allergic treatment and should be correlated with other markers as FeNO or symptom scores.

Oral N-acetylcysteine reverses hyperoxia-related cough suppression in guinea pigs.

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.

Dietary intake of flavonoids and hyperoxia-induced oxidative stress related cough in guinea pigs.

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.

Sex differences in cough reflex.

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.

Physiology of nitric oxide in the respiratory system.

Nitric oxide (NO) is an important endogenous neurotransmitter and mediator. It participates in regulation of physiological processes in different organ systems including airways. Therefore, it is important to clarify its role in the regulation of both airway and vascular smooth muscle, neurotransmission and neurotoxicity, mucus transport, lung development and in the. surfactant production. The bioactivity of NO is highly variable and depends on many factors: the presence and activity of NO-producing enzymes, activity of competitive enzymes (e.g. arginase), the amount of substrate for the NO production, the presence of reactive oxygen species and others. All of these can change NO primary physiological role into potentially harmful. The borderline between them is very fragile and in many cases not entirely clear. For this reason, the research focuses on a comprehensive understanding of NO synthesis and its metabolic pathways, genetic polymorphisms of NO synthesizing enzymes and related effects. Research is also motivated by frequent use of exhaled NO monitoring in the clinical manifestations of respiratory diseases. The review focuses on the latest knowledge about the production and function of this mediator and understanding the basic physiological processes in the airways.

Nasal nitric oxide in healthy adults - reference values and affecting factors.

Nitric oxide (NO) is an important endogenous mediator with significant role in the respiratory system. Many endogenous and exogenous factors influence the synthesis of NO and its level is significantly changed during the inflammation. Analysis of nasal nitric oxide (nNO) is not validated so far as the diagnostic method. There is a lack of reference values with possible identification of factors modulating the nNO levels. In healthy adult volunteers (n=141) we studied nasal NO values by NIOX MINO® (Aerocrine, Sweden) according to the recommendations of the ATS & ERS. Gender, age, height, body weight, waist-to-hip ratio, FEV1/FVC, PEF and numbers of leukocytes, eosinophils, basophils and monocytes were studied as potential variables influencing the levels of nNO. The complexity of the results allowed us to create a homogenous group for nasal NO monitoring and these data can be used further as the reference data for given variables. Because of significant correlation between nNO and exhaled NO, our results support the "one airway - one disease" concept. Reference values of nasal NO and emphasis of the individual parameters of tested young healthy population may serve as a starting point in the non-invasive monitoring of the upper airway inflammation.

Early and late allergic phase related cough response in sensitized guinea pigs with experimental allergic rhinitis.

Cough is a common and important symptom of asthma and allergic rhinitis. Previous experimental evidence has shown enhanced cough sensitivity during early phase of experimental allergic rhinitis in guinea pigs. We hypothesized that airway inflammation during the late phase response after repeated nasal antigen challenge may affect the afferent sensory nerve endings in the larynx and tracheobronchial tree and may also modulate cough response. In the present study we evaluated the cough sensitivity during a period of early and late allergic response in sensitized guinea pigs after repeated nasal antigen challenges. Forty-five guinea pigs were sensitized with ovalbumin (OVA). Four weeks later 0.015 ml of 0.5 % OVA was intranasally instilled to develop a model of allergic rhinitis that was evaluated from the occurrence of typical clinical symptoms. Animals were repeatedly intranasally challenged either by OVA (experimental group) or by saline (controls) in 7-day intervals for nine weeks. Cough was elicited by inhalation of citric acid aerosols. Cough was evaluated at 1 or 3 h after the 6th nasal challenge and 17 or 24 h after the 9th nasal challenge. The cough reflex was significantly increased at 1 and 3 h after repeated nasal challenge in contrast to cough responses evoked at 17 and 24 h after repeated nasal challenge. In conclusion, enhanced cough sensitivity only corresponds to an early allergic response after repeated nasal challenges.

The effect of chemical stimulation of esophageal mucosa on citric acid induced cough and specific airway resistance in guinea pig.

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.)

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

The efficacy of H4R antagonist JNJ7777120 on nasal symptoms, cough, airway resistance (Raw), inflammatory cell count in bronchoalveolar lavage (BAL) and blood in ovalbumin (OVA) induced allergic rhinitis (AR) was studied in guinea pigs. Animals (n=8) were sensitized by i.p. OVA and were repeatedly challenged with nasal OVA to induce rhinitis, seven animals were not sensitized. Animals were pre-treated with JNJ7777120 2.5 and 5mg/kg i.p. 30 min prior OVA. Cough was induced by inhalation of citric acid, Raw was measured in vivo by 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.

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.

[Histamine intolerance]. / Histamínová intolerancia.

Histamine intolerance (HIT) is a pathological process that results from a disbalance between levels of released histamine and the ability of the body to metabolize it. Accumulated histamine leads to the onset of "histamine mediated" reactions which are usually excessive and decrease quality of life. Although we have a lot of knowledge about histamine intolerance, HIT is still vastly underestimated, because it manifests via the diversity of clinical symptoms, that are often misinterpreted by the patient and sometimes even by a physician. Clinical symptoms and their provocation by certain kinds of food, beverages and drugs are often attributed to the different diseases, such as food allergy and intolerance of sulfites, or other biogenic amines (eg. tyramine), mastocytosis, psychosomatic diseases or adverse drug reactions in general. Proper diagnosis of HIT followed by therapy based on histamine--free diet and supplementation of diaminooxidase can considerably improve patient's quality of life.

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

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