Enhanced cough response to hyperpnea with cold air challenge in chronic cough patients showing increased cough sensitivity to inhaled capsaicin

BACKGROUND: Although many chronic cough patients have complained of an induced cough by cold air contact, the clinical relevance of cold air to inducing a cough and the diagnostic value of a hyperpnea with cold air (HCA) challenge to detect a hyperreactive cough reflex have not yet been investigated. METHODS: Recordings of cough counts after a 2-min HCA challenge were performed in 49 chronic cough patients and 15 healthy controls. Capsaicin cough provocation tests, which determine the threshold concentration of capsaicin that induces five or more consecutive coughs (C5), were also administered. RESULTS: After comparing the results from the capsaicin cough provocation tests of the patients and the controls, the chronic cough patients were divided into two groups: an increased cough sensitivity (ICS) group (n = 28) (C5 < 32 micromol/l) and a normal cough sensitivity (NCS) group (n = 21) (C5 >or= 32 micromol/l). The median value of induced cough counts after a HCA challenge was 11 coughs in patients with ICS and was a significantly enhanced cough response compared to that of the patients with NCS and healthy controls (four coughs, respectively). CONCLUSIONS: A simple cough provocation test using a HCA challenge may be useful for detecting ICS. It also suggests that hyperreactive cough reflexes may be one of the mechanisms of inducing chronic cough.     

Sensitivity to methacholine and capsaicin in patients with unclear respiratory symptoms

BACKGROUND: Capsaicin, the pungent ingredient in red pepper, is known to stimulate coughing via the sensory nervous system. Earlier studies showed that patients with airway symptoms induced by chemicals and strong scents cough more after inhalation of capsaicin than healthy control subjects and this has been interpreted as a hyperreactivity of airway sensory nerves. Our aim was to study airway sensitivity to inhaled capsaicin and the occurrence of airway symptoms induced by strong scents in patients who underwent a bronchial methacholine test, primarily because of suspected asthma. METHODS: Fifty-two consecutive patients referred for testing with methacholine were also provoked with inhaled capsaicin in increasing concentrations. Cough sensitivity to capsaicin was compared with that in 40 healthy control subjects. RESULTS: The patients coughed significantly more compared with the healthy control subjects with each dose of capsaicin (P < 0.0001). Twelve patients (23%) had a positive methacholine test, and of these, nine were diagnosed with asthma. There was no difference in capsaicin sensitivity between patients sensitive or insensitive to methacholine. CONCLUSIONS: The majority of the patients had no increased sensitivity to methacholine but did demonstrate sensory hyperreactivity (SHR). SHR appears to be a common diagnosis in investigations of patients with obscure airway symptoms.     

Quality of life and capsaicin sensitivity in patients with sensory airway hyperreactivity

BACKGROUND: A group of patients with asthma-like symptoms and sensitivity to chemical irritants has shown an increased cough sensitivity to inhaled capsaicin compared to patients with asthma and to healthy controls. The condition is called sensory hyperreactivity (SHR), and the patients often feel that they are socially handicapped because of the risk of exposure to chemical irritants in daily life. METHODS: Twenty-six patients with asthma-like symptoms after exposure to nonspecific irritating stimuli, but without IgE-mediated allergy or demonstrable bronchial obstruction, were selected for a study of the response to a capsaicin test and measurement of quality of life by a general health profile (the Nottingham Health Profile [NHP]). We also investigated whether there was a correlation between quality of life and sensitivity to capsaicin. RESULTS: The patients demonstrated a dose-dependent response to the capsaicin provocation, with coughing and respiratory and other symptoms, that significantly differed from 12 healthy controls. The health profile showed that patients with SHR had a significantly reduced quality of life compared to reference values, and there was a significant correlation between the health profile and sensitivity to capsaicin. CONCLUSIONS: Patients with asthma-like symptoms verified by the capsaicin inhalation test for sensory hyperreactivity have a poor quality of life. The correlation between quality of life and sensitivity to capsaicin objectively demonstrates the validity of this general health profile study.     

Sensory hyperreactivity – a possible mechanism underlying cough and asthma-like symptoms

Background Investigations of patients referred for suspected asthma have revealed a little-known group with symptoms suggesting hyperreactive airways in whom provocation with methacholine does not lead to bronchial obstruction. The underlying mechanisms are not known, and no objective diagnostic method has been available.
Methods Provocations by inhalation of capsaicin solutions in stepwise increasing concentrations were used. Ten patients with asthma-like symptoms after exposure to nonspecific irritating stimuli, but without IgE-mediated allergy or demonstrable bronchial obstruction, were compared to 10 patients with verified bronchial asthma and 28 healthy controls. Results The patients with asthma-like symptoms reacted with cough in a dose-dependent way. The number of coughs was significantly greater than in asthmatic patients and healthy controls. The latter two groups did not differ significantly.
Conclusions The capsaicin provocation test may be a valuable method for showing not only a greater cough sensitivity, but also asthma-like symptoms. The pathophysiology underlying the symptoms may be related to increased sensitivity of free, overactive nerve endings in the respiratory mucosa. Therefore, we suggest that this overreaction in the lower airways be called "sensory hyperreactivity".     

Cough provocation with capsaicin is an objective way to test sensory hyperreactivity in patients with asthma-like symptoms

BACKGROUND: A group of patients with asthma-like symptoms and sensitivity to chemical irritants, but without bronchial obstruction, has been found among subjects referred for suspected asthma. They have no well-defined diagnosis, and no objective diagnostic method has previously been available. These patients are more sensitive to inhaled capsaicin than are patients with asthma or healthy controls. The aim was to study cough and other capsaicin-induced symptoms and to test the effect of a drug (lidocaine) that inhibits nerve transmission in sensory nerves. METHODS: Twelve patients were provoked with three different concentrations of inhaled capsaicin solutions in a randomized, double-blind order. They all had asthma-like symptoms and were sensitive to chemical irritants, but had no IgE-mediated allergy or demonstrable bronchial obstruction. Before the provocations, the patients inhaled lidocaine or placebo (saline), also in a double-blind, randomized order. The results were expressed as the number of coughs and scores of various symptoms. RESULTS: The patients reacted in a dose-dependent way with cough, airway, and eye symptoms, which were significantly reduced after preinhalation of lidocaine. CONCLUSIONS: A drug that inhibits transmission in sensory nerves successfully blocked the number of coughs and other symptoms provoked by inhalation of capsaicin. This indicates that the mechanisms underlying chemical sensitivity in these patients may originate in the sensory nervous system, and we call this condition "sensory hyperreactivity".     

Exhaled monoxides in asymptomatic atopic subjects

BACKGROUND: Atopy is a genetically determined condition and some atopic people develop airway hyperresponsiveness and sometimes asthma later in life. Since airway inflammation may be present before the onset of clinical symptoms of asthma, early and noninvasive detection of inflammation would be useful in atopic subjects. Mediators produced by activated inflammatory cells may lead to induction of inducible nitric oxide synthase producing nitric oxide (NO) and inducible heme oxygenase releasing carbon monoxide (CO) in the airways. Both monoxides are present in exhaled air and their levels are elevated in asthma reflecting airway inflammation. OBJECTIVE: We have measured exhaled NO and CO levels in atopic and nonatopic healthy non-smoking subjects to determine whether inflammation is present in the airways. METHODS: Exhaled NO was measured by a chemiluminescence analyser and exhaled CO electrochemically and NO in asymptomatic atopic and age-matched nonatopic normal subjects. RESULTS: Exhaled NO and CO levels were both significantly elevated in 15 atopic subjects compared with 40 nonatopic individuals (means +/- SEM: 18.3+/-3.0 p.p.b. vs. 6.3+/-0.3 p.p.b., P< 0.0001 and 4.7+/-0.3 p.p.m. vs 2.8+/-0.2 p.p.m., P = 0.0005, respectively). CONCLUSION: Increase in exhaled monoxide levels may be an early and noninvasive marker of airway inflammation in asymptomatic atopic subjects.     

Characterization of increased cough sensitivity after antigen challenge in guinea pigs

Increased sensitivity of cough reflex is a fundamental feature of bronchodilator resistant non-productive cough associated with eosinophilic tracheobronchitis. Our hypothesis is that cough sensitivity is increased by airway allergic reaction characterized by airway eosinophilic inflammation. The aim of this study was to elucidate the hypothesis and clarify the characteristics of the increased cough sensitivity. Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an aerosolized antigen or saline in actively sensitized or non-sensitized (naive) conscious guinea pigs and then bronchoalveolar lavage was performed. The cough response was also measured 1 day before and 1, 2, 3, 5 and 7 days after an aerosolized antigen challenge in sensitized or naive animals. In addition, effect of procaterol (0.1 mg/kg), atropine (1 or 10 mg/kg), phosphoramidon (2.5 mg/kg) given intraperitoneally 30 min before the capsaicin challenge or capsaicin desensitization on the cough response was examined. Furthermore, the thromboxane A2 (TXA2) receptor antagonist S-1452 in a dose of 0.01 or 0.1 mg/kg or vehicle (saline) was given intraperitoneally at 24 and 1 h before the measurement of cough response. Number of coughs caused by capsaicin was extremely increased 24 h after an antigen challenge in sensitized guinea pigs compared with a saline or an antigen challenge in naive animals or a saline challenge in sensitized animals. The increased cough response disappeared at 3-7 days after the antigen challenge. Eosinophils in bronchoalveolar lavage fluid obtained after the measurement of capsaicin-induced coughs, which was performed 24 h after the antigen challenge, were significantly increased in sensitized guinea pigs. The eosinophil count was significantly correlated to the number of capsaicin-induced coughs. Procaterol or atropine did not alter the antigen-induced increase of cough sensitivity, whereas atropine did reduce the cough response in naive animals. Phosphoramidon increased the number of capsaicin-induced coughs in naive guinea pigs but not in sensitized and antigen-challenged animals. Capsaicin desensitization decreased the cough response in both antigen-challenged sensitized guinea pigs and naive animals. S-1452 reduced the antigen-induced increase of cough response in sensitized guinea pigs, but not in naive animals. Airway allergy accompanied with airway eosinophilia induces transient increase in cough sensitivity, which is not mediated by bronchoconstriction. The increased cough sensitivity may result in part from inactivation of neutral endopeptidase and TXA2, one of the inflammatory mediators.     

Methacholine vs adenosine on intra and extrathoracic airway hyperresponsiveness in patients with cough variant asthma

Background: Airway hyperresponsiveness (AHR) can be studied by bronchoprovocation test (BPT) using direct (methacholine – MCh) or indirect (adenosine 5′‐monophosphate – AMP) stimuli. These two substances have not been compared in cough variant asthma (CVA). Objective: We designed a randomized, single‐blind, cross‐over study to compare AMP and MCh in the detection of CVA. Additionally, we examined whether assessment of extrathoracic airway hyperresponsiveness (EAHR) during MCh and AMP helped in the evaluation of CVA. Methods: Patients with CVA with previous positive MCh BPT performed challenges with AMP and MCh. The variables were: (i) a provocative dose producing a 20% fall in forced expiratory volume in 1 s (FEV₁) value (PD₂₀MCh); (ii) a provocative dose producing a 25% fall in the maximal mid‐inspiratory flow (FIF₅₀) from baseline (PD₂₅MCh) for MCh; (iii) a provocative concentration producing a 20% fall in FEV₁ value (PC₂₀AMP) and (iv) a provocative concentration producing a 25% fall in the FIF₅₀ from baseline (PC₂₅AMP) for AMP. Results: All 113 patients with CVA responded to PD₂₀MCh and 96% and 69% responded to PC₂₀AMP, if we used PC₂₀ ≤ 200 mg/ml or PC₂₀ ≤ 100 mg/ml, respectively, with an excellent correlation between these two tests (r = 0.87 and 0.76, respectively). Extrathoracic AHR associated with AHR was found in 10% in MCh challenge and in 11% with AMP challenge and no patients had EAHR alone. Conclusion: Adenosine challenges correlate well with MCh in patients with CVA. A minority (c. 10%) of CVA patients have EAHR as measured by these tests, while most had AHR as assessed with each of the challenge agents.     

Attenuating effect of H+K+ATPase inhibitors on airway cough hypersensitivity induced by allergic airway inflammation in guinea-pigs

BACKGROUND: Gastrooesophageal reflux (GER) is a frequent cause of chronic cough. Several investigators have indicated that inhibitors of H(+)K(+)ATPase (proton pump inhibitors; PPIs) could relieve coughing via inhibition of acid reflux. However, we considered that PPIs might directly inhibit increased cough reflex sensitivity. OBJECTIVE: The present study was designed to examine whether PPIs directly inhibit antigen-induced increase in cough reflex sensitivity and to elucidate the mechanism. METHODS: Actively sensitized guinea-pigs were challenged with aerosol antigen (ovalbumin, OVA) and cough reflex sensitivity to inhaled capsaicin was measured 24 h later. The PPIs (omeprazole and rabeprazole) or the histamine H(2) blocker cimetidine were administered intraperitoneally 1 h before OVA challenge and before measuring cough reflex sensitivity, then bronchoalveolar lavage fluid (BALF) was immediately collected. The pH of the fluid obtained by bronchial washing was determined after examining the effect of rabeprazole on the cough response to capsaicin. RESULTS: The number of coughs elicited by capsaicin was significantly increased 24 h after challenge with OVA compared with saline, indicating antigen-induced increase in cough reflex sensitivity. Both PPIs dose dependently and significantly inhibited antigen-induced cough hypersensitivity. Omeprazole did not influence the antigen-induced increase in the total number of cells or ratio (%) of eosinophils in BALF. Cimetidine did not affect the antigen-induced cough hypersensitivity or cellular components of BALF. The pH of the bronchial washing fluid was significantly decreased in antigen-challenged animals. Rabeprazole did not affect the antigen-induced decrease in the pH of bronchial washing fluid. CONCLUSION: These findings show that PPIs, but not histamine H(2) blockers, can directly decrease antigen-induced cough reflex hypersensitivity, while the mechanism remains unclear.     

Effects of ketotifen on symptoms and on bronchial mucosa in patients with atopic asthma

Ketotifen is marketed throughout the world as an antiallergy drug, but whether it affects infiltration of inflammatory cells into airway mucosa is not known. We studied the effects of ketotifen on symptoms, pulmonary function, and airway inflammation in 25 patients with atopic asthma. Patients took ketotifen (1 mg twice daily) or a matching placebo for 8 weeks in a double-blind, parallel-group study. Data recorded on diary cards were used for 2 weeks before treatment began, and they were used for the last 2 weeks of treatment to study asthma symptoms, use of β2–agonists, and peak expiratory flow (PEF). Pulmonary function tests, bronchial responsiveness to methacholine, and fiberoptic bronchoscopy were performed before and after treatment. Biopsy specimens were obtained by bronchoscopy. Specimens were stained immunohistochemically with monoclonal antibodies against stored eosinophil cationic protein (EG1), the secreted form of eosinophil cationic protein (EG2), mast-cell tryptase (AA1), neutrophil elastase (NP57), CD3, CD4, CD8, and CD25. The numbers of positively stained cells in the lamina propria were counted. Compared with the placebo, the ketotifen-treated group exhibited significant improvement of asthma symptoms ( P <0.05) and bronchial responsiveness (P<0.05). This was accompanied by a reduction of EG2+ eosinophils ( P <0.05), CD3+ T cells ( P <0.001), CD4+ T cells (P<0.01), and CD25+ activated T cells ( P <0.01) in the bronchial mucosa. These results suggested that the beneficial effects of ketotifen in bronchial asthma may result from consequent inhibition of activated eosinophils and T-cell recruitment into the airway. Moreover, ketotifen may relieve allergic inflammation in bronchial asthma.     

Atopy may be related to exercise-induced bronchospasm in asthma

BACKGROUND: Recent studies suggest that atopy may be associated with exercise-induced bronchospasm (EIB) in asthma. However, it is not clear whether atopy is related to EIB, regardless of airway hyper-responsiveness (AHR) to methacholine, because asthmatic subjects often show AHR to exercise and methacholine simultaneously. OBJECTIVE: To investigate whether atopy is related to EIB in asthmatic subjects, independently of AHR to methacholine. METHODS: Fifty-eight male asthmatic subjects were studied. Initial spirometry was performed. Skin prick test was carried out, using 53 common allergens including mites dust antigen. Atopy score was defined as a sum of mean weal diameters to all allergens tested. Methacholine bronchial provocation testing was performed. Twenty-four hours later, free running test was performed. Positive EIB was defined as a 15% reduction or more in FEV1 from baseline after exercise. RESULTS: All subjects had AHR to methacholine. The degree of AHR to methacholine in asthmatics with EIB was similar to that in asthmatics without EIB. However, atopy score and skin reaction to Dermatophagoides pteronyssinus significantly increased in asthmatics with EIB compared with those without EIB (P < 0.05, respectively). Furthermore, the degree of EIB significantly correlated with atopy score in all subjects (r = 0.35, P < 0.01). This relationship was maintained even after the exclusion of EIB-negative asthmatic subjects. CONCLUSION: Atopy defined as skin test reactivity may contribute to the development of EIB in asthma, independently of AHR to methacholine.     

Mannitol challenge for assessment of airway responsiveness,airway inflammation and inflammatory phenotype in asthma

Background Assessment of airway inflammation in asthma is becoming increasingly important, as the inflammatory phenotype underpins the treatment response. Objective This study aimed to evaluate mannitol as a tool for assessing airway responsiveness and airway inflammation in asthma, compared with hypertonic saline. Methods Fifty‐five subjects with stable asthma completed a hypertonic (4.5%) saline challenge and a mannitol challenge at two separate visits, performed 48–72 h apart, in random order. Results Induced sputum was obtained from 49 (89%) subjects during the saline challenge and 42 (76%) subjects during the mannitol challenge (P>0.05). There was a significant correlation between the greatest percentage fall in forced expiratory volume in 1 s (FEV₁) (r=0.6, P<0.0001), the dose–response slope (r=0.73), cumulative dose (r=0.55) and PD15 (r=0.46) for mannitol and hypertonic saline. The greatest percentage fall in FEV₁ to mannitol was less in non‐eosinophilic asthma. There was a lower total cell count in mannitol vs. hypertonic‐saline‐induced sputum. However, sputum eosinophils and neutrophils were not significantly different. Using mannitol, a higher proportion of subjects were classified as having eosinophilic asthma. There were no differences in IL‐8, neutrophil elastase or matrix‐metalloproteinase 9 concentrations in sputum samples induced with mannitol or hypertonic saline. Conclusion We conclude that mannitol can be used to induce good‐quality sputum, useful for analysis of inflammatory mediators and for predicting the inflammatory phenotype in asthma. Cite this as: L. G. Wood, H. Powell and P. G. Gibson, Clinical & Experimental Allergy, 2010 (40) 232–241.     

Effects of suplatast tosilate, a new type of anti-allergic agent, on airway cough hypersensitivity induced by airway allergy in guinea-pigs

BACKGROUND: Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non-productive cough. Suplatast tosilate, an anti-allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)-4, IL-5, immunoglobulin (Ig)E production, and local eosinophil accumulation. OBJECTIVE: The purpose of this study was to investigate the effect of suplatast on antigen-induced airway cough hypersensitivity and eosinophil infiltration into the airway. METHODS: Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an antigen challenge in conscious guinea-pigs and then bronchoalveolar lavage was performed. We investigated the effect of single (before antigen challenge or capsaicin provocation) or repetitive treatment with intraperitoneal suplatast at a dose of 10 or 30 mg/kg on antigen-induced cough hypersensitivity. RESULTS: Twenty-four hours after antigen challenge, guinea-pigs developed an increase in cough receptor sensitivity to inhaled capsaicin and eosinophil infiltration in the airways. After a 2-week treatment with suplatast, but not after only a single treatment before antigen challenge or capsaicin provocation, the antigen-induced early phase bronchoconstriction, cough hypersensitivity, and airway eosinophilia were inhibited in a dose-dependent manner. CONCLUSION: These results indicate that suplatast inhibits airway cough hypersensitivity underlying allergic eosinophilic inflammation.     

Blood markers of early and late airway responses to allergen in asthmatic subjects. Relationship with functional findings

We evaluated the relationship between blood markers of mast-cell (plasma histamine and serum level of heat-stable neutrophil chemotactic activity [NCA]) and eosinophil (serum eosinophil cationic protein [ECP]) activation during early airway response (EAR) and late airway response (LAR) to allergen inhalation in 24 asthmatic subjects. After EAR, 14 subjects showed significant LAR (FEV₁ fall: 25%), while 10 subjects showed equivocal LAR (FEV₁ fall: 15–20%). A significant increase from baseline value was observed in plasma histamine and in serum NCA during both EAR and LAR, while serum ECP significantly increased only during LAR. The sensitivity of different markers to detect significant FEV₁ fall during EAR and LAR was low, except for NCA. Changes in blood mediators were similar in both groups with significant and equivocal LAR. There was a significant relationship between the increase in NCA during EAR and the severity of LAR. Stepwise regression between changes in different blood markers showed a significant relationship between histamine increase during EAR and ECP increase during LAR. Thus, serum NCA is a more sensitive marker of EAR and LAR than plasma histamine and serum ECP, and its increase during EAR seems predictive of the severity of the subsequent LAR.     

Bronchial hyperresponsiveness to mannitol,airway inflammation and Asthma Control Test in atopic asthmatic children

Introduction

The aim of this study was to evaluate the relationship between airway hyperresponsiveness (AHR) to mannitol and bronchial inflammation measured as exhaled nitric oxide (FeNO) and to assess whether asthma control correlates with AHR to mannitol and FeNO in atopic asthmatic children.

Material and methods

Allergy evaluation, the mannitol challenge test, FeNO levels and the Asthma Control Test (ACT) questionnaire were assessed in 40 children with intermittent and mild persistent allergic asthma.

Results

All the subjects showed positive AHR to mannitol. Pearson''s correlation test revealed a significant inverse correlation between AHR (mannitol PD₁₅) and FeNO (p = 0.020). There was also a significant positive correlation between ACT and PD₁₅ (p = 0.020) and a significant negative correlation between ACT and FeNO levels (p = 0.003). The study population was divided into two groups according to FeNO levels (group A ≥ 16 ppb vs. group B < 16 ppb). In group A mannitol PD₁₅ was significantly lower (p = 0.040) and ACT score values were significantly lower (p = 0.001) compared to group B. In group A, the ACT showed that 13.3% of subjects had well-controlled asthma, 80% had partially controlled asthma and 6.7% had uncontrolled asthma. In group B, the ACT showed that 72% of subjects had well-controlled asthma and 28% had partially controlled asthma.

Conclusions

Our findings indicate that the degree of AHR to mannitol correlates with the degree of airway inflammation in asthmatic atopic children; moreover, better control of asthma correlates with a lower degree of AHR to both mannitol and FeNO.     

Validated safety predictions of airway responses to house dust mite in asthma

BACKGROUND: House dust mite (HDM) is the most common aeroallergen causing sensitization in many Western countries and is often used in allergen inhalation challenges. The concentration of inhaled allergen causing an early asthmatic reaction [provocative concentration of inhaled allergen causing a 20% fall of forced expiratory volume in 1 s (FEV(1))(PC(20) allergen)] needs to be predicted for safety reasons to estimate accurately the severity of allergen-induced airway responsiveness. This can be accomplished by using the degree of non-specific airway responsiveness and skin sensitivity to allergen. OBJECTIVE: We derived prediction equations for HDM challenges using PC(20) histamine or PC(20) methacholine and skin sensitivity data obtained from patients with mild to moderate persistent asthma and validated these equations in an independent asthma population. METHODS: PC(20) histamine or PC(20) methacholine, skin sensitivity, and PC(20) allergen were collected retrospectively from 159 asthmatic patients participating in allergen challenge trials. Both the histamine and methacholine groups (n=75 and n=84, respectively), were divided randomly into a reference group to derive new equations to predict PC(20) allergen, and a validation group to test the new equations. RESULTS: Multiple linear regression analysis revealed that PC(20) allergen could be predicted either from PC(20) methacholine only ((10)log PC(20) allergen=-0.902+0.741.(10)log PC(20) methacholine) or from PC(20) histamine and skin sensitivity (SS) ((10)log PC(20) allergen=-0.494+0.231.(10)log SS+0.546.(10)log PC(20) histamine). In the validation study, these new equations accurately predicted PC(20) allergen following inhalation of HDM allergen allowing a safe starting concentration of allergen of three doubling concentrations below predicted PC(20) allergen in all cases. CONCLUSION: The early asthmatic response to inhaled HDM extract is predominantly determined by non-specific airway responsiveness to methacholine or histamine, whereas the influence of the cutaneous sensitivity to HDM appears to be rather limited. Our new equations accurately predict PC(20) allergen and hence are suitable for implementation in HDM inhalation studies.     

Sensory neuropeptides induce histamine release from bronchoalveolar lavage cells in both nonasthmatic coughers and cough variant asthmatics

BACKGROUND: Sensory neuropeptides have been suggested to play a role in the pathogenesis of a number of respiratory diseases including asthma and chronic non-productive cough. OBJECTIVES: To investigate the action of sensory neuropeptides on airway mast cells obtained by bronchoalveolar lavage (BAL). METHODS: BAL was performed on 23 nonasthmatic patients with cough (NAC), 11 patients with cough variant asthma (CVA) and 10 nonatopic controls. Washed lavage cells were stimulated (20 min, 37 degrees C) with calcitonin gene-related peptide (CGRP), neurokinin A (NKA) and substance P (25 and 50 micromol/L). RESULTS: The neuropeptides tested induced histamine release in all groups studied. Only CGRP (50 micromol/L) induced significantly more histamine release from both NAC and CVA patients compared with control subjects (P = 0.038 and 0.045, respectively). CONCLUSION: Regardless of aetiology, mast cells from patients with chronic cough appear to have an increased responsiveness to CGRP compared with controls. The results of the present study suggest that the role of CGRP in chronic cough should be further investigated.     

Natural killer T cells are dispensable in the development of allergen-induced airway hyperresponsiveness, inflammation and remodelling in a mouse model of chronic asthma

Natural killer T (NK T) cells have been shown to play an essential role in the development of allergen-induced airway hyperresponsiveness (AHR) and/or airway inflammation in mouse models of acute asthma. Recently, NK T cells have been reported to be required for the development of AHR in a virus induced chronic asthma model. We investigated whether NK T cells were required for the development of allergen-induced AHR, airway inflammation and airway remodelling in a mouse model of chronic asthma. CD1d^−/− mice that lack NK T cells were used for the experiments. In the chronic model, AHR, eosinophilic inflammation, remodelling characteristics including mucus metaplasia, subepithelial fibrosis and increased mass of the airway smooth muscle, T helper type 2 (Th2) immune response and immunoglobulin (Ig)E production were equally increased in both CD1d^−/− mice and wild-type mice. However, in the acute model, AHR, eosinophilic inflammation, Th2 immune response and IgE production were significantly decreased in the CD1d^−/− mice compared to wild-type. CD1d-dependent NK T cells may not be required for the development of allergen-induced AHR, eosinophilic airway inflammation and airway remodelling in chronic asthma model, although they play a role in the development of AHR and eosinophilic inflammation in acute asthma model.     

Progesterone increases airway eosinophilia and hyper-responsiveness in a murine model of allergic asthma

BACKGROUND: Sex hormones might affect the severity and evolution of bronchial asthma. From existing literature, there exists, however, no convincing evidence for either exacerbation or improvement of allergic symptoms by progesterone. OBJECTIVE: This study was aimed to explore the effect of exogenously administered progesterone in a mouse model of allergic asthma. METHODS: BALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal injections with OVA followed by chronic inhalation of nebulized OVA or physiologic saline (Sal). Medroxyprogesterone acetate or placebo was instilled daily into the oesophagus before and during the inhalatory OVA challenge phase. RESULTS: Progesterone worsened allergic airway inflammation in OVA-challenged mice, as evidenced by enhanced bronchial responsiveness to inhaled metacholine and increased bronchial eosinophilia. Elevated airway eosinophilia corresponded with higher bronchial and systemic IL-5 levels in the progesterone group. The ratio of IL-4/IFN-gamma levels in bronchoalveolar lavage fluid and numbers of eosinophil colony-forming units in the bone marrow were also elevated in the latter group. Progesterone, however, did not influence allergen-specific IgE production, nor did it affect bronchial responses in Sal-challenged mice. CONCLUSION: Our data show that exogenously administered progesterone aggravates the phenotype of eosinophilic airway inflammation in mice by enhancing systemic IL-5 production. Progesterone also increases bronchial hyper-reactivity.