Airway Responsiveness In Asthma Research Articles

Cholinergic synapse pathway gene polymorphisms associated with allergen-induced late asthmatic responses.

Cholinergic synapse pathway gene polymorphisms may play a role in regulating a type of asthmatic airway response triggered upon allergen challenge http://bit.ly/2lJx1VG

Triclosan‐induced alteration of gut microbiome and aggravation of asthmatic airway response in aeroallergen‐sensitized mice

Triclosan‐induced alteration of gut microbiome and aggravation of asthmatic airway response in aeroallergen‐sensitized mice

Effects of interleukin-6 receptor blockade on allergen-induced airway responses in mild asthmatics.

BackgroundInterleukin (IL)‐6 signalling has been implicated in allergic asthma by animal, genetic association and clinical studies. In this study, we tested the hypothesis that tocilizumab (TCZ), a human monoclonal antibody that blocks IL‐6 signalling, can prevent the development of allergen‐induced bronchoconstriction in humans.MethodsWe performed a randomised, double‐blind, placebo‐controlled study, with eligible participants completing two allergen inhalation challenge tests, conducted before and after treatment with a single dose of TCZ or placebo. The primary efficacy endpoint was the magnitude of the late asthmatic response recorded between 3 and 7 after allergen challenge. The secondary efficacy endpoint was the early asthmatic response, measured 20 min to 2 h after allergen challenge.ResultsA total of 66 patients enrolled between September 2014 and August 2017, when the trial was stopped for futility based on results from an interim analysis. Eleven patients fulfilled all eligibility criteria assessed at baseline and were subsequently randomised to the TCZ (n = 6) or placebo (n = 5) groups. Both the primary and secondary efficacy endpoints were not significantly different between the two groups. Five patients reported adverse events (AEs), three in the TCZ group (11 AEs) and two in the placebo group (four AEs). Only one AE was TCZ‐related (mild neutropenia), and there were no serious AEs. Significant treatment effects were observed for serum levels of C‐reactive protein, IL‐6 and soluble IL‐6R levels.ConclusionIn a small proof‐of‐concept clinical trial, we found no evidence that a single dose of tocilizumab was able to prevent allergen‐induced bronchoconstriction. (Trial registered in the Australian New Zealand Clinical Trials Registry, number ACTRN12614000123640).

Chitotriosidase inhibits allergic asthmatic airways via regulation of TGF-β expression and Foxp3+ Treg cells.

Chitotriosidase (chitinase 1, Chit1), a major true chitinase in humans, is induced in childhood asthma and has been implicated in the pathogenesis of a variety of inflammatory and tissue remodeling responses. However, the role and the mechanisms that underlie these contributions to the diseases have not been defined. We hypothesized that Chit1 plays a significant role in the pathogenesis of allergic asthma. Wild-type and Chit1-deficient mice and cells in culture were used to define the roles of Chit1 in models of allergic adaptive Th2 inflammation. In addition, the levels of sputum Chit1 were evaluated in pediatric asthma patients and compared to control. The levels of sputum Chit1 were significantly increased in the patients with childhood asthma. Mice with Chit1 null mutation demonstrated enhanced allergic Th2 inflammatory and cytokine and IgE responses to OVA or house dust mite allergen sensitization and challenge. However, the expression levels of TGF-β1 were significantly decreased with a diminished number of Foxp3+ regulatory T cells (Treg) in the lungs of Chit1-/- mice compared to WT controls. In vitro, the absence of Chit1 significantly reduced TGF-β-stimulated conversion of CD4+ CD25- naïve T cells to CD4+ Foxp3+ Treg cells, suggesting Chit1 is required for optimal effect of TGF-β1 in Treg cell differentiation. Chit1 plays a protective role in the pathogenesis of allergic inflammation and asthmatic airway responses via regulation of TGF-β expression and Foxp3+ Treg cells.

A Common Pattern of Peripheral Airway Responsiveness in Asthma and Allergic Rhinitis

A Common Pattern of Peripheral Airway Responsiveness in Asthma and Allergic Rhinitis

'The Microbiome and the Pathophysiology of Asthma'.

Asthma is a chronic respiratory disease whose prevalence is increasing in the western world. Recently research has begun to focus on the role the microbiome plays in asthma pathogenesis in the hope of further understanding this respiratory disorder. Considered sterile until recently, the lungs have revealed themselves to contain a unique microbiota. A shift towards molecular methods for the quantification and sequencing of microbial DNA has revealed that the airways harbour a unique microbiota with apparent, reproducible differences present between healthy and diseased lungs. There is a hope that in classifying the microbial load of the asthmatic airway an insight may be afforded as to the possible role pulmonary microbes may have in propagating an asthmatic airway response. This could potentially pave the way for new therapeutic strategies for the treatment of chronic lung conditions such as asthma.

The extracellular matrix of the lung and airway responsiveness in asthma

The extracellular matrix is the main determinant of the structure and of mechanical behaviour of the lung. The extracellular matrix is also responsible for the mechanical interdependence between airway and parenchyma due to the alveolar attachments to the airways. Asthma is characterized by bronchial hyperresponsiveness, airway remodelling and inflammation, and an altered extracellular matrix may play a role in all these functional and structural abnormalities. The excessive airway narrowing observed in asthma may be related to the altered viscoelastic properties of lung parenchyma and airway wall, determining a decrease in the mechanical load opposing the airways' smooth muscle contraction. Indeed, an altered extracellular matrix deposition in asthma in humans, has been demonstrated. In addition, in the asthmatic lung, the matrix seems to contribute to airway inflammation, airway remodelling, and to those alterations of the smooth muscle function of the airway and morphology typical of asthma.

Randomized trial of allergen-induced asthmatic response in smokers andnon-smokers: effects of inhaled corticosteroids.

It is thought that asthmatics who smoke cigarettes respond less well to inhaled corticosteroid (ICS) therapy than asthmatics who do not smoke. To evaluate the effects of smoking on allergen-induced airway responses in asthmatics treated with ICS. Randomized, double-blind, crossover study evaluating twice daily fluticasone propionate (FP) 100μg, FP 500μg and placebo, for 7days, on allergen-induced asthmatic responses in 18 non-smoking and 17 smoking atopic asthmatics (NCT01400906). At 1h post-morning dose on Day 6, forced expiratory volume in 1 sec (FEV1 ) was measured up to 10h post-challenge. Exhaled nitric oxide (eNO), induced sputum cell counts, and responsiveness to methacholine were assessed the following day. The late asthmatic response (LAR) was suppressed by FP in smokers and non-smokers; with placebo, the LAR was also attenuated in smokers versus non-smokers (adjusted mean minimum change in FEV1 (L) over 4-10h [95% CI] in non-smokers: placebo -1.01 [1.31, 0.70], FP 100μg -0.38 [0.54, 0.22], FP 500μg -0.35 [0.54-0.22]; and in smokers: placebo -0.63 [0.84, 0.43]; FP 100μg -0.44 [0.65, 0.23]; FP 500μg -0.46 [0.59-0.32]). The Early AR was suppressed by FP treatment in non-smokers, but was not impacted in smokers. The reduction in methacholine hyperresponsiveness after FP was greater in non-smokers (1.5- and twofold doubling dose difference from placebo after FP 100μg and FP 500μg) than smokers (1.0 and 1.3 difference, respectively). Allergen-induced increases in eNO and sputum eosinophils were lower in smokers than non-smokers and were suppressed in both groups by FP. Allergen-induced LARs were of a similar amplitude in both smoking and non-smoking atopic asthmatics at the end of ICS treatment, but attenuation of the LAR in smokers was only partly associated with ICS treatment. The marked attenuation of the LAR observed in smokers in the absence of ICS treatment is a novel observation.

Spirometry in children with asthma and/or allergic rhinitis: comparison of FEF25-75% with the standard measures

Forced expiratory flow between 25% and 75% of vital capacity (FEF25-75%), a spirometric measure of small airways, may predict the presence of airway responsiveness both in asthmatics and in allergic rhinitis (AR). We aimed to search the correlation between FEF25-75% and standard measures of spirometry (forced expiratory volume in the first second [FEV1%] and FEV1/FVC [forced vital capacity]) in different clinical conditions, that is in children with asthma, in children with asthma and AR, in children with AR and in healthy children. Children with asthma (N.=116), asthma plus AR (N.=25), AR (N.=75) and healthy controls (N.=52) were evaluated. Clinical examinations, spirometry and bronchodilation tests were performed. In asthmatics there was a strong correlation between FEF25-75% and FEV1% (r=0.596, P<0.001); and between FEF25-75% and FEV1/FVC (r=0.740, P<0.001). In AR patients correlation between FEF25-75% and FEV1% (r=0.367, P=0.001); and between FEF25-75% and FEV1/FVC (r=0.534, P<0.001) were less prominent compared to asthmatics but they were still significant and strong. In children with both AR and asthma correlation between FEF25-75% and FEV1% (r=0.633, P=0.001) and between FEF25-75% and FEV1/FVC (r=0.539, P=0.005) were again significant. Pre-test FEV1% and FEF25-75% in AR patients were lower than that of the control subjects. After the bronchodilation, percentage change in the FEV1 in AR patients were significantly higher than the control subjects (P=0.010). AR patients showed significant increases in FEV1%, (P<0.001), FEF25-75%, (P<0.001) and (P=0.001) after the bronchodilation test. Within the AR patients, only 12/75 (16.0%) showed bronchodilation with salbutamol. Among the ones with a FEF25-75% <65%, FEV1% was normal in 6/43 (14%) patients in asthmatics, and FEV1% was normal in 3/9 (33%) patients in asthma +AR patients. Besides the FEV1% and FEV1/FVC, the FEF25-75% may be a useful and early spirometric parameter to evaluate the children with asthma and or AR.

Plasma arginine metabolites reflect airway dysfunction in a murine model of allergic airway inflammation.

L-arginine metabolism is important in the maintenance of airway tone. Shift of metabolism from the nitric oxide synthase to arginase pathways contributes to the increased airway responsiveness in asthma. We tested the hypothesis that systemic levels of L-arginine metabolites are biomarkers reflective of airway dysfunction. We used a mouse model of acute allergic airway inflammation to OVA that manifests with significant airway hyperresponsiveness to methacholine. To determine tissue arginase activity in vivo, the isotopic enrichment of an infused L-arginine stable isotope and its product amino acid L-ornithine were measured in lung and airway homogenates using liquid chromatography-tandem mass spectrometry. Tissue and plasma concentrations of other L-arginine metabolites, including L-citrulline and symmetric and asymmetric dimethylarginine, were measured and correlated with lung arginase activity and methacholine responsiveness of the airways. The effectiveness of intratracheal instillation of an arginase inhibitor (boronoethylcysteine) on pulmonary arginase activity and circulating concentrations of L-arginine metabolites was also studied. We demonstrate that 1) plasma indexes of L-arginine bioavailability and impairment of nitric oxide synthase function correlate with airway responsiveness to methacholine; 2) plasma levels of L-ornithine predict in vivo pulmonary arginase activity and airway function; and 3) acute arginase inhibition reduces in vivo pulmonary arginase activity to control levels and normalizes plasma L-ornithine, but not L-arginine, bioavailability in this model. We conclude that plasma L-ornithine may be useful as a systemic biomarker to predict responses to therapeutic interventions targeting airway arginase in asthma.

Editorial introductions

Editorial introductions

Science Translational Medicine Podcast: 2 July 2014

Jeffrey M. Harris and Lawren C. Wu describe how the drug quilizumab reduced allergen-induced asthmatic airway responses in mild asthmatics.

Anti-oxidant N-acetylcysteine diminishes diesel exhaust-induced increased airway responsiveness in person with airway hyper-reactivity.

Inhalation of diesel exhaust (DE) at moderate concentrations causes increased airway responsiveness in asthmatics and increased airway resistance in both healthy and asthmatic subjects, but the effect of baseline airway responsiveness and anti-oxidant supplementation on this dynamic is unknown. We aimed to determine if changes in airway responsiveness due to DE are attenuated by thiol anti-oxidant supplementation, particularly in those with underlying airway hyper-responsiveness. Participants took N-acetylcysteine (600 mg) or placebo capsules three times daily for 6 days. On the last of these 6 days, participants were exposed for 2 h to either filtered air (FA) or DE (300 μg/m(3) of particulate matter smaller than 2.5 microns). Twenty-six non-smokers were studied under each of three experimental conditions (filtered air with placebo, diesel exhaust with placebo, and diesel exhaust with N-acetylcysteine) using a randomized, double-blind, crossover design, with a 2-week washout between conditions. Methacholine challenge was performed pre-exposure (baseline airway responsiveness) and post-exposure (effect of exposure). Anti-oxidant supplementation reduced baseline airway responsiveness in hyper-responsive individuals by 20% (p = 0.001). In hyper-responsive individuals, airway responsiveness increased 42% following DE compared with FA (p = 0.03) and this increase was abrogated with anti-oxidant supplementation (diesel exhaust with N-acetylcysteine vs. filtered air with placebo, p = 0.85). Anti-oxidant (N-acetylcysteine) supplementation protects against increased airway responsiveness associated with DE inhalation and reduces need for supplement bronchodilators in those with baseline airway hyper-responsiveness. Individuals with variants in genes of oxidative stress metabolism when exposed to DE are protected from increases in airway responsiveness if taking anti-oxidant supplementation.

Aeroallergen and food IgE sensitization and local and systemic inflammation in asthma

We recently reported an independent association between IgE sensitization to food allergens and increased airway inflammation, assessed by fraction of exhaled nitric oxide (FeNO), in a population-based study (J Allergy Clin Immunol, 130, 2012, 397). Similar studies have not been performed in populations with asthma. The aim of the present study was to investigate the allergic sensitization profile in asthmatics and examine FeNO, airway responsiveness and blood eosinophilia in relation to type and degree of IgE sensitization. FeNO, airway responsiveness, blood eosinophil count (B-Eos) and IgE sensitization to food allergens and aeroallergens were determined in 408 subjects with asthma, aged 10-34 years. Asthmatics had higher prevalence of IgE sensitization against all allergens than controls (P < 0.001). Mite, pollen, furry animal, mould and food sensitizations were each associated with increased FeNO, airway responsiveness and B-Eos in asthmatics. IgE sensitization to mould, furry animals and food allergens was independently related to FeNO (all P < 0.05) after adjustment for age, sex, height, smoking history and medication. IgE sensitization to mould (P < 0.001) and furry animals (P = 0.02) was related to airway responsiveness in a similar model. Finally, IgE sensitization to mould (P = 0.001), furry animals (P < 0.001) and food allergens (P < 0.001) was independently related to B-Eos. Independent effects of IgE sensitization to aeroallergens (furry animals and mould) and food allergens were found on both local and systemic markers of inflammation in asthma. The finding regarding food IgE sensitization is novel, and a clinical implication might be that even food sensitization must be assessed to fully understand inflammation patterns in asthma.

Editorial introductions

Editorial introductions

Immunomodulating approach to asthma using mycobacteria.

Immunomodulating approach to asthma using mycobacteria.

Interleukin-2 levels in exhaled breath condensates, asthma severity, and asthma control in nonallergic asthma

There was evidence that interleukin (IL)-2 and IL-10 in the airways play roles in regulating the asthmatic inflammatory response. The purpose of this study was to measure the levels of these cytokines in exhaled breath condensates (EBCs) from asthmatic airways and their correlation with a clinical assessment of asthma severity. The levels of IL-2 and IL-10 in EBC, Asthma Control Test (ACT) score, and the forced expiratory volume in 1 second (FEV1) were studied in 28 steroid-free asthmatic patients and 10 healthy volunteers. The results were analyzed according to their allergic status, asthma severity, and body weight. The correlations between IL-2 and IL-10 levels, percent predicted FEV1, ACT score, and body mass index were also determined. Both IL-2 and IL-10 levels in EBC significantly increased in asthmatic patients, especially in patients with moderate-to-severe persistent asthma, compared with those in normal controls. However, the signification correlations between IL-2 levels and ACT (r = -0.684; p = 0.007), as well as with percent predicted FEV1 (r = -0.671; p = 0.009), were established only in patients with nonallergic asthma. The elevation of IL-2 levels in EBC in obese subjects was observed but was probably related to asthma severity. The levels of IL-2 and IL-10 in EBC increase in asthmatic patients but only IL-2 levels significantly correlate with the ACT score and percent predicted FEV1 in nonallergic asthma. Additional studies should be explored to confirm the reliability of ACT score as a predictor of inflammatory response in asthmatic airways. Clinical trial NCT01246414, http://www.clinicaltrials.gov.

Ventilation heterogeneity is associated with airway responsiveness in asthma but not COPD

Airway hyperresponsiveness (AHR) occurs in both asthma and COPD. In older people with asthma, AHR is associated with increased acinar ventilation heterogeneity, but it is unknown if this association exists in COPD.Thirty one COPD and 19 age-matched asthmatic subjects had measures of spirometry, lung volumes, exhaled nitric oxide, ventilation heterogeneity, and methacholine challenge. Indices of acinar (Sacin) and conducting (Scond) airway ventilation heterogeneity were calculated from the multiple breath nitrogen washout. Predictors of AHR were then determined.In COPD, AHR was predicted by lower Sacin and lower FVC (model r2=0.35, p=0.001). In asthma, AHR was predicted by higher Sacin and higher residual volume (model r2=0.62, p<0.001).These findings suggest that airway responsiveness in COPD and asthma is determined by underlying disease-specific processes, rather than a common pattern of physiological abnormality.

Effects of exercise training on airway closure in asthmatics

We previously reported that responsiveness to methacholine (Mch) in the absence of deep inspiration (DI) decreased in healthy subjects after a short course of exercise training. We assessed whether a similar beneficial effect of exercise on airway responsiveness could occur in asthmatics. Nine patients (male/female: 3/6; mean age ± SD: 24 ± 2 yr) with mild untreated asthma [forced expiratory volume in 1 s (FEV(1)): 100 ± 7.4% pred; FEV(1)/vital capacity (VC): 90 ± 6.5%] underwent a series of single-dose Mch bronchoprovocations in the absence of DI in the course of a 10-wk training rowing program (6 h/wk of submaximal and maximal exercise), at baseline (week 0), and at week 5 and 10. The single-dose Mch was established as the dose able to induce ≥ 15% reduction in inspiratory vital capacity (IVC) and was administered to each subject at every challenge occasion. Five asthmatics (male/female: 1/4; mean age ± SD: 26 ± 3 yr) with similar baseline lung function (FEV(1): 102 ± 7.0% predicted; FEV(1)/VC: 83 ± 6.0%; P = 0.57 and P = 0.06, respectively) not participating in the exercise training program served as controls. In the trained group, the Mch-induced reduction in IVC from baseline was 22 ± 10% at week 0, 13 ± 11% at week 5 (P = 0.03), and 11 ± 8% at week 10 (P = 0.028). The Mch-induced reduction in FEV(1) did not change with exercise (P = 0.69). The reduction in responsiveness induced by exercise was of the same magnitude of that previously obtained in healthy subjects (50% with respect to pretraining). Conversely, Mch-induced reduction in IVC in controls remained unchanged after 10 wk (%reduction IVC at baseline: 21 ± 20%; after 10 wk: 29 ± 14%; P = 0.28). This study indicates that a short course of physical training is capable of reducing airway responsiveness in mild asthmatics.

Interferon-&amp;gamma; , Pulmonary Macrophages and Airway Responsiveness in Asthma

Asthma is increasingly being recognised as involving not only allergic inflammatory mechanisms but also a variety of other cell types and cytokines. While the role of interferon-γ(IFN-γ) in asthma remains controversial, it has been proposed to contribute to the pathogenesis of both chronic stable asthma and acute severe asthma. We have shown that in a model of chronic allergic asthma in mice, airway hyper-responsiveness (AHR) is independent of various Th2 cytokines and their signalling pathways, but is dependent on IFN-γ. In a model of an allergen-induced acute exacerbation of chronic asthma, we have demonstrated that activation of pulmonary macrophages may play a critical role in driving the inflammatory response. Furthermore, we have demonstrated that IFN-γ stimulation of macrophages can lead to steroidresistant airway inflammation and AHR via the production of interleukin-27. These findings strengthen the notion that the pathogenesis of the lesions of asthma, and especially of AHR, involves both Th2 and Th1 cytokines, as well as interaction between the allergic response and the innate host defence system. Targeting the effects of IFN-γ on pulmonary macrophages may be particularly relevant to the treatment of steroid-resistant acute exacerbations of asthma.