Increased Cough Sensitivity Research Articles

Establishment of a Mouse Model with Cough Hypersensitivity via Inhalation of Citric Acid.

Cough is one of the most common symptoms of many respiratory diseases. Chronic cough significantly impacts quality of life and imposes a considerable economic burden. Increased cough sensitivity is a pathophysiological hallmark of chronic cough. It has been observed that cough hypersensitivity is related to airway inflammation, remodeling of airway sensory nerves, and alterations in the central nervous system. However, the precise molecular mechanisms remain unclear and require further elucidation using suitable animal models. Previous studies have utilized guinea pigs as models for studying cough, but these models present several experimental limitations, including high costs, a lack of transgenic tools, and a scarcity of commercial reagents. In addition, guinea pigs typically exhibit poor environmental tolerance and high mortality when exposed to stimuli. In contrast, mice are smaller, easier to maintain, more cost-effective, and amenable to genetic manipulation, making them more suitable for mechanistic investigations. In this study, we established a mouse model with cough hypersensitivityviacontinuous inhalation of citric acid (CA). This model is straightforward to operate and yields reproducible results, making it a valuable tool for further studies on the mechanisms and potential novel treatments for chronic cough.

Investigation into actions of Xiebai and Zengye decoction on cough sensitivity, airway inflammation and gut microbiota in the rat model of post-infectious cough

This work was undertaken to observe therapeutic effect of Xiebai and Zengye (XBZY) decoction on post-infectious cough (PIC) in rats, as well as its effect on gut microbiota and the exploration of the intestinal microecological mechanisms of XBZY decoction in the treatment of PIC. Using a random number table, the rats that were successfully modelled were assigned to the PIC, XBZY group (14.8 g/kg/d), and montelukast sodium treatment (MAS) group (1 mg/kg/d). The cough sensitivity of rats and changes in fecal water content were assessed, and serum interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) levels were determined by ELISA. The histopathological changes in the bronchus and colon tissues were observed under the microscope after hematoxylin-eosin staining. Short-chain fatty acids (SCFAs) in fecal samples were measured by gas chromatography, and changes in gut microbiota were observed using 16S rRNA sequencing. The PIC rats showed decreased fecal water content, increased cough sensitivity, elevated serum TNF-α and IL-8 levels, and higher bronchitis scores comparing to normal control group. The PIC rats showed reductions in SCFAs and significant changes in the structure of gut microbiota. XBZY decoction intervention led to increased fecal water content in rats, reduced cough sensitivity, decreased serum IL-8 and TNF-α levels, decreased bronchitis scores, and alleviated inflammatory cell infiltration was observed in the colonic mucosa. Additionally, elevated SCFAs levels were observed in the PIC rats. XBZY decoction intervention improved alpha-/beta-diversity, and corrected microbiota imbalance in PIC rats. SCFAs, TNF-α and IL-8, acetic acid was revealed to be positively associated with Allobaculum but inversely correlated with unclassified_f_Oscillospiraceae; propanoic acid was positively associated with Lactobacilli but negatively associated with Romboutsia; butanoic acid exhibited positive correlations with Akkermansia and Lactobacilli, but negative correlations with unclassified_f_Oscillospiraceae, Eubacterium_xylanophilum_group, and Lachnospiraceae_NK4A136_group; Additionally, TNF-α was inversely linked to Allobaculum, while IL-8 was positively related to Romboutsia and Turicibacter. In conclusion, XBZY decoction significantly reduced cough sensitivity and airway inflammation in PIC rats while ameliorating stool dryness and colonic inflammation. The protective effects of XBZY decoction could be linked to modulat gut microbiota in PIC rats, and regulat SCFAs contents in PIC rats, while the regulator mechanisms of XBZY decoction in gut microbiota still requires further in-depth investigation.

Evaluation methods and influencing factors of cough sensitivity

Increased cough sensitivity is an important mechanism of chronic cough, and the evaluation of cough sensitivity helps understand the mechanism of cough and explore better methods to reduce cough. Evaluation methods may be direct or indirect. Direct methods include mechanical stimulation and chemical stimulation, and indirect methods include laryngeal reflex test, questionnaires, and brain functional magnetic resonance imaging (fMRI). Chemical stimulation is the most common method, while the capsaicin cough challenge test is proven and widely used. In this article, we will compare evaluation methods and explore influencing factors of cough sensitivity.

Sinomenine Attenuated Capsaicin-Induced Increase in Cough Sensitivity in Guinea Pigs by Inhibiting SOX5/TRPV1 Axis and Inflammatory Response.

BackgroundChronic cough is a common complaint which affects a large number of patients worldwide. Increased cough sensitivity is a very important cause of chronic persistent cough. However, there are limited clinical diagnosis and treatment for increased cough sensitivity. Transient receptor potential vanilloid-1 (TRPVl) is a member of the transient receptor potential (TRP) family of channels which is very closely associated with respiratory diseases. However, the mechanism through which TRPV1 that influences downstream events is still poorly understood.ResultsCapsaicin induced increase in cough sensitivity by upregulating the protein level of TRPV1, leading to the secretions of Substance P and neurokinin A which stimulated neurogenic inflammation. However, sinomenine, a component of traditional Chinese medicine, significantly attenuated the capsaicin-induced cough by inhibiting the expression of TRPV1 in guinea pigs. In addition, capsaicin increased the expression of SOX5 which mediated the transcriptional upregulation of TRPV1. However, pretreatment with sinomenine reduced the expression of SOX5.ConclusionThese results indicate that capsaicin induced increase in cough sensitivity by activating neurogenic inflammation, while sinomenine attenuated the increase in cough sensitivity by inhibiting the expressions of SOX5 and TRPV1 in guinea pigs. This finding may provide a novel target for the treatment of aggravated cough sensitivity.

Gender Difference in Chronic Cough: Are Women More Likely to Cough?

Chronic cough is a common complaint for patients to seek medical cares all over the world. Worldwide, about two thirds of chronic cough patients are females. However, in some regions of China the prevalence of chronic cough between sexes is roughly the same. Estrogen and progesterone can not only have an effect on transient receptor potential vanilloid 1 channel, eosinophils and mast cells, but also influence laryngeal dysfunction, gastroesophageal reflux disease and obstructive sleep apnea hypopnea syndrome, which may lead to increased cough sensitivity in women. On the other hand, the quality of life was adversely affected more in female patients with chronic cough. Both hormones possibly cause gender difference in chronic cough.

A Sensory Stimulation Protocol to Modulate Cough Sensitivity: A Randomized Controlled Trial Safety Study.

Purpose This study evaluated the safety and efficacy of a sensory stimulation protocol that was designed to modulate citric acid cough thresholds as a potential treatment for silent aspiration. Method Healthy adults (n = 24) were randomly assigned to one of three sensory stimulation groups: (a) high-intensity ultrasonically nebulized distilled water (UNDW) inhalations (1.6 ml/min); (b) low-intensity UNDW inhalations (0.5 ml/min); and (3) control, 0.9% saline inhalations (1.6 ml/min). Sensory stimulation was delivered once a day, for 4 consecutive days. Citric acid cough thresholds were determined at baseline, Day 3, and Day 5 to evaluate changes in cough sensitivity. Spirometry was undertaken before, during, and after each sensory stimulation session to monitor for bronchoconstriction. Results No participant showed evidence of bronchoconstriction during the sensory stimulation protocol. There was an interaction effect between day and group on suppressed cough thresholds, χ2(4) = 11.32, p = .02. When compared to the control group, there was a decrease in citric acid cough thresholds across Days 1-5 in the high-intensity (-1.8 doubling concentrations, 95% confidence interval [-2.88, -0.72], p = .01) and low-intensity (-1.3 doubling concentrations, 95% confidence interval [-2.4, -0.2], p = .03) UNDW inhalation groups, representing a sensitization effect of UNDW inhalations on cough sensitivity. Conclusions The UNDW sensory stimulation protocol was safe in healthy adults. The findings provide preliminary evidence that UNDW inhalations sensitize laryngeal afferents related to citric acid-induced cough induction. The therapeutic potential of the UNDW sensory stimulation protocol will be explored in patients with reduced cough sensitivity who are at risk of silent aspiration and aspiration pneumonia. Plain Language Summary This study explored the safety and efficacy of a sensory stimulation protocol that was designed to modulate cough sensitivity as a potential treatment for silent aspiration. The study revealed that inhalations of nebulized distilled water were safe and increased cough sensitivity, when compared to control saline inhalations.

Arnold Nerve Reflex: Vagal Hypersensitivity in Chronic Cough With Various Causes

A higher incidence of Arnold nerve reflex (ANR) has been observed in patients with chronic cough. However, the different ANR response in various causes of chronic cough remains unclear. Furthermore, it is unknown whether ANR will change after effective treatment. Patients with chronic cough were enrolled in the Guangzhou Institute of Respiratory Health. The causes of chronic cough were diagnosed via a validated management algorithm. Patients underwent an assessment of ANR response before and after 1month of etiologic treatment. A total of 127 patients with chronic cough and 55 healthy control subjects were enrolled. The positive response, defined as cough-only ANR or urge-to-cough (UTC), was present in 14.8%of patients with cough variant asthma (CVA), 11.1%of patients with upper airway cough syndrome, 15.4%of patients with gastroesophageal reflex related cough (GERC), 4.8%of patients with eosinophilic bronchitis, and 26.9%of patients with unexplained cough (UC). No ANR or UTC was found in the healthy control subjects. The incidence of the positive response was higher in subjects with CVA, GERC, and UC compared with healthy control subjects (all P< .05). No difference was observed among the different causes of chronic cough (all P > .05). After 1month of treatment, 87.5%of patients identified with a positive response changed to a negative response. In a subgroup analysis, an increased cough sensitivity to capsaicin was found in the patients with a positive response compared with the patients with a negative response (P< .05). A positive ANR appears to be a sign of vagal hypersensitivity and can be reversed after effective treatment of chronic cough. However, although various causes of chronic cough share a similar feature of an elevated ANR response in a minority of patients, there appears to be limited usefulness in assessing ANR because it does not appear to be a valid predictor of etiology of chronic cough or outcome of treatment.

The duration of cough in patients with H1N1 influenza.

BackgroundCough is one of common symptoms of influenza, the cough duration and prevalence of postinfectious cough (PIC) after viral upper respiratory tract infection has not been well described.ObjectivesWe aim to investigate the duration of cough and prevalence of PIC and its relation with acute symptoms, airway inflammation and cough sensitivity in patients with H1N1 influenza.MethodsPatients with acute symptoms of H1N1 influenza were enrolled and followed up until cough relived. Spirometry, induced sputum test, capsaicin challenge test were conducted in patients with PIC. Cough sensitivity was presented as logarithm of provocative concentration inducing five or more coughs (logC5).ResultsA total of 141 cases with H1N1 influenza were enrolled. In patients with H1N1 influenza, 97.2% of them complained cough. The duration of cough was as following: <1 week (73.0%); 1–2 weeks (7.8%); 2–3 weeks (7.8%); ≥3 weeks (8.5%). Twelve (8.5%) patients had cough lasting more than 3 weeks (PIC), 4 (2.8%) patients developed chronic cough (>8 weeks). Acute symptoms, spirometry, bronchial responsiveness and sputum differential cell count were similar between patients with PIC and those without PIC, however, there was a higher prevalence of previous PIC (58.3% vs 14.7%, P < 0.05) and elevated cough sensitivity (lgC5: 1.18 ± 0.58 vs 2.73 ± 0.33, P < 0.01) in patients with PIC as compared with the patients without PIC.ConclusionsAcute cough is common in patients with H1N1 PIC, only a few of patients develop chronic cough. Acute symptoms cannot predict PIC which is related with previous PIC and increased cough sensitivity.

Nerves, Cough, and Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. It has a poor prognosis with a median survival of approximately 3 years, and whilst new therapies are finally beginning to offer hope of improved survival, most patients will require palliation of symptoms as their disease progresses. Whilst all patients with IPF complain of breathlessness, up to 80% develop a distressing cough, which is detrimental to their quality of life and difficult to treat. This article examines the possible causes of cough in the wider context of current theories of the pathogenesis of IPF and its associated comorbidities, which may also cause or exacerbate cough. We examine the evidence for increased cough sensitivity in patients with IPF and neuroplasticity in animal models of lung pathology. Finally, we discuss new therapies that are becoming available to treat cough in IPF and their possible mechanisms of action, and which highlight the need for further, appropriately powered studies that include objective measures of cough as an outcome.

Parainfluenza 3 virus induces increased cough sensitivity, tracheal BDNF expression, and vagal sensory TRPV1 expression

Parainfluenza virus type 3 (PIV3) infection causes excessive coughing and croup in children, and is associated with exacerbation of asthma. We infected guinea pigs intranasally with PIV3 and quantified the cough response in conscious animals. The guinea pigs infected with PIV3 (day 4) coughed nearly three times more than those treated with the viral growth medium (control) in response to either capsaicin or bradykinin (P<0.05). In an ex vivo perfused guinea pig tracheal preparation, we found that within 8 hr of infusion PIV3 resulted in a ~10-fold increase in brain-derived neurotrophic factor (BDNF) mRNA (qPCR) in the tissue. We have previously reported that tracheal BDNF is an effective inducer of transient receptor potential cation channel, subfamily V, member 1 (TRPV1) in nodose Aδ tracheal cough neurons that normally do not express this channel (Am J Physiol; 302:L941-8). Consistent with this, PIV3 infection (day 4) increased TRPV1 expression in tracheal-specific nodose Aδ neurons. In vehicle treated animals only 20±10% of the tracheal-specific nodose neurons expressed TRPV1 (single neuron rt-PCR), whereas 4 days after PIV3 infection 60±2% of the neurons expressed TRPV1 (n=6 ganglia ~60 neurons; P<0.05). In summary, PIV3 infection in guinea pigs evokes BDNF expression in the trachea and this increased de novo TRPV1 expression in tracheal specific cough nodose neurons, and a heightened cough response to capsaicin and bradykinin. Supported by NIH.

Is your cough getting better?

Is your cough getting better?

Now is the Right Time to Establish a New Strategy for Managing Chronic Cough as a Neuropathic Disorder.

Now is the Right Time to Establish a New Strategy for Managing Chronic Cough as a Neuropathic Disorder.

Year in review 2012: Asthma and chronic obstructive pulmonary disease

Year in review 2012: Asthma and chronic obstructive pulmonary disease

Respiratory movement and pain thresholds in airway environmental sensitivity, asthma and COPD

Patients with "sensory hyperreactivity" (SHR) have airway environmental sensitivity, chronic cough and dyspnoea. Cough, chest discomfort and sense of difficulties getting air are some of the symptoms these patients seek medical attendance for. The patients have increased cough sensitivity to inhaled capsaicin, mediated by ion channel receptors on sensory nerves also known to react to pain stimuli. Whether a link exists between capsaicin airway sensitivity and pain sensitivity has not yet been evaluated. The aim was to investigate chest mobility, respiratory movement and pain sensitivity in SHR patients compared with patients with asthma, chronic obstructive pulmonary disease (COPD) and alleged healthy control subjects. Thirty-five patients diagnosed with SHR, 19 with COPD, 32 with asthma and 28 control subjects were included. Chest expansion was measured with a measuring tape and thoracic and abdominal movement with light sensors. Pain sensitivity was assessed using a pressure algometer. Groups differed significantly in lung function, respiratory rate and pain sensitivity but also in chest expansion and abdominal breathing movement. In comparison with the control and asthma groups but not the COPD patients, SHR patients had an increased respiratory rate and reduced abdominal movement during deep breathing. All patient groups showed lower pain thresholds than the controls. Patients with SHR have evident signs of dysfunctional breathing and appeared to be most similar to the COPD group except for lung function. Lower pain thresholds among the patients indicate a general up-regulation of the sensory nerve system.

The airway sensory hyperreactivity syndrome

After exclusion of diverse pulmonary illnesses, the remaining explanations for chronic cough include medication with angiotensin-converting enzyme (ACE) inhibitor, gastroesophageal reflux disease (GERD), and post-nasal drip. Different clinics report shifting frequencies for both the causes of chronic cough and the success of treatment. However, after all evaluations, differential diagnosis still leaves a group of patients with unexplained cough. This unexplained cough is also known as chronic idiopathic cough (CIC), though there are widely varying opinions as to its existence. Among patients previously diagnosed with CIC, a subgroup has been identified with both upper and lower airway symptoms, including cough induced by odours and chemicals, and with increased cough sensitivity to inhaled capsaicin, which is known to stimulate the airway sensory nerves. A suggested explanation for this condition is a hyperreactivity of the sensory nerves of the entire airways, and hence the condition is known as sensory hyperreactivity (SHR). SHR affects more than 6% of the adult population in Sweden. It is a longstanding condition, and is clearly associated with significant social and psychological impacts.

The Role of Nitrosative Stress in the Pathogenesis of Chronic Dry Cough With Increased Cough Sensitivity

The Role of Nitrosative Stress in the Pathogenesis of Chronic Dry Cough With Increased Cough Sensitivity

Effect of Smoking on Cough Reflex Sensitivity: Basic and Preclinical Studies

In healthy nonsmokers, inhalation of one single puff of cigarette smoke immediately evoked airway irritation and cough, which were either prevented or markedly diminished after premedication with hexamethonium. Single-fiber recording experiments performed in anesthetized animals showed that both C fibers and rapidly adapting receptors in the lungs and airways were stimulated by inhalation of one breath of cigarette smoke. Application of nicotine evoked an inward current and triggered depolarization and action potentials in a concentration-dependent manner in a subset of isolated vagal pulmonary sensory neurons. Taken together, these studies showed that activation of the nicotinic acetylcholine receptors expressed on airway sensory nerves is mainly responsible for the acute airway irritation and cough reflex elicited by inhaled cigarette smoke. Chronic exposure to cigarette smoke consistently induces enhanced cough responses to various inhaled tussive agents in guinea pigs. The increased cough sensitivity involves primarily an elevated sensitivity of cough sensors and also an enhanced synaptic transmission of their afferent signals at the nucleus tractus solitaries. In contrast to the observations in animal studies, both enhanced and diminished cough sensitivities to tussive agents have been reported in chronic smokers. This discrepancy is probably related to the history of chronic smoking of the individual smokers and the severity of existing airway inflammation and dysfunction. Furthermore, several other factors possibly contributing to the regulation of cough receptor sensitivity in chronic smokers should also be considered.

Down-regulation of cough sensitivity after eucapnic dry air provocation in chronic idiopathic cough

Down-regulation of cough sensitivity in humans is rarely discussed in terms other than pharmacological treatment of cough or hypersensitive cough reflex. Chronic cough and increased cough sensitivity could be due to a number of airway and other diseases. When such conditions are excluded, there still remains a group of patients with no evident medical explanation for persistent coughing; such patients are often described as having “chronic idiopathic cough”. The aim of this study was to use a standardized eucapnic dry air provocation among patients with chronic idiopathic cough in order to study physiological parameters and measure their possible influence on capsaicin cough sensitivity. Fourteen female patients with chronic idiopathic cough and ten healthy controls underwent a capsaicin inhalation provocation on two occasions. In all patients, irritating environmental factors were known to induce cough and airway symptoms. One of the two capsaicin provocations was preceded by a eucapnic dry air provocation. Number of coughs, spirometry, respiratory rate, pulse rate, end-tidal CO 2, and oxygen saturation by pulse oximetry (PSaO 2) were registered and compared. The patients showed increased capsaicin sensitivity compared with the control subjects. This sensitivity was decreased when the capsaicin test was preceded by a eucapnic dry air provocation. Before the dry air provocation and after the capsaicin provocations, end-tidal CO 2 was decreased among the patients in comparison with the controls. After dry air provocation, spirometry values remained unchanged. The results suggest that in patients with chronic idiopathic cough, physiological down-regulation of the cough sensitivity is possible with a eucapnic dry air provocation.

Inhaled ethanol potentiates the cough response to capsaicin in patients with airway sensory hyperreactivity

A suggested explanation for airway symptoms induced by chemicals and scents is sensory hyperreactivity (SHR) of airway mucosal nerves. Patients with SHR have increased cough sensitivity to inhaled capsaicin, mediated by transient receptor potential (TRP) ion channels. In animal experiments, some TRP receptors are potentiated by ethanol, which is why in this study, the aim was to evaluate whether a pre-inhalation of ethanol could influence the capsaicin cough response in patients with SHR. Fifteen patients with SHR and 15 healthy controls were provoked on three occasions with two concentrations of inhaled capsaicin. Before each capsaicin provocation, a pre-inhalation of saline or one of two concentrations of ethanol was given in a double-blind, randomized fashion. The participants reacted in a dose-dependent way with cough on the capsaicin inhalations. Among the patients, but not in the control group, pre-inhalation of ethanol increased the cough response dose-dependently. The results suggest that the pathophysiology of SHR is related to airway mucosal TRP receptors in the sensory nerves. In scented products, the combination of ethanol as a solvent and perfume may augment an airway reaction in sensitive individuals.

Quality of Life and Capsaicin Sensitivity in Patients with Airway Symptoms Induced by Chemicals and Scents: A Longitudinal Study

ObjectiveIt is common in asthma and allergy clinics to see patients presenting with upper and lower airway symptoms that are induced by chemicals and scents and not explained by allergic or asthmatic reactions. Previous studies have shown that these patients often have increased cough sensitivity to inhaled capsaicin; such sensitivity is known to reflect the airway sensory reactivity. The aim of this study was to evaluate the duration of symptoms induced by chemicals and scents and to measure health-related quality of life (HRQL) in patients with chemically induced airway symptoms. We also wished to determine and compare repeatability of the cough response to capsaicin inhalation, and to evaluate the patients’ airway sensory reactivity in a long-term perspective.ParticipantsSeventeen patients with a history of at least 12 months of airway symptoms induced by chemicals and scents were followed over 5 years with repeated questionnaires, measurements of HRQL, and capsaicin inhalation tests.ResultsThe symptoms persisted and did not change significantly over time, and the patients had a reduced HRQL that did not change during the 5-year period. The capsaicin sensitivity was increased at the start of the study, the cough sensitivity was long-lasting, and the repeatability of the capsaicin inhalation test was considered to be good in a long-term perspective.ConclusionsUpper and lower airway symptoms induced by chemicals and scents represent an entity of chronic diseases, different from asthma or chronic obstructive pulmonary disease, with persistent symptoms, a reduced HRQL, and unchanged sensory hyperreactivity.