Airway Narrowing In Asthma Research Articles

Designing and validating an experimental protocol to induce airway narrowing in older adults with and without asthma

BackgroundPersons with asthma may experience excessive airway narrowing due to exercise or exposure to cold air, worsening their daily functionality. Exercise has several benefits for asthma control, but it may induce airway narrowing in some persons with asthma. When combined with cold temperatures, it introduces another layer of challenges. Therefore, managing this interaction is crucial to increase the quality of life in individuals with asthma. The purpose of this study was to develop a reliable experimental protocol to assess the effects of exercise and cold air on airway narrowing in adults with asthma in a controlled and safe environment.MethodsThis study was a randomized cross-over study in adults with and without asthma. Participants underwent a protocol involving a 10-min seated rest, followed by a 10-min cycling on a stationary bike in different temperatures of 0, 10, or 20 ∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document}C. The sequence of room temperatures was randomized, and there was a 30-min interval for recovery between each temperature transition. In each temperature, to measure lung function and respiratory symptoms, oscillometry and a questionnaire were used at 0 min (baseline), after 10 min of sitting and before starting biking (pre-exercise), and after 10 min of biking (post-exercise). At each room temperature, the changes in airway mechanics and asthma symptoms among baseline, pre-exercise, and post-exercise were compared with one-way repeated measures ANOVA or Friedman Rank Test. Within each arm, cardiac and thoraco-abdominal motion respiration signals were also measured continuously using electrodes and calibrated respiratory inductance plethysmographs, respectively.ResultsA total of 23 persons with asthma (11 females, age: 56.3 ± 10.9 years, BMI: 27.4 ± 5.7 kg/m2) and 6 healthy subjects (3 females, age: 61.8 ± 9.1 years, BMI: 28.5 ± 3.1 kg/m2) were enrolled in the study. Cold temperature of 0 ∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document}C induced airway narrowing in those with and without asthma after 10 and 20 min, respectively. Exercise intervention had significant changes in airway narrowing in participants with asthma in the range of 10–20 ∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document}C. Our results showed that in asthma, changes in subjective respiratory symptoms were due to both cold temperatures of 0 and 10 ∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document}C and exercise in the 0–20 ∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document}C range. Respiratory symptoms were not noticed among the healthy participants.ConclusionIn conclusion, our findings suggest that exposure to cold temperatures of 0 ∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document}C could serve as a reliable method in the experimental protocol for inducing airway narrowing in asthma. The impact of exercise on airway narrowing was more variable among participants. Understanding these triggers in the experimental protocol is essential for the successful management of asthma in future studies.

Allosteric modulator potentiates β2AR agonist-promoted bronchoprotection in asthma models.

Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with limited efficacy - bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a β2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on β2AR-mediated bronchoprotection. Consistent with our findings using human β2ARs, Cmpd-6 allosterically potentiated β2-agonist binding to guinea pig β2ARs and downstream signaling of β2ARs. In contrast, Cmpd-6 had no such effect on murine β2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced β2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but - in line with the binding studies - not in mice. Moreover, Cmpd-6 robustly potentiated β2 agonist-mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced β2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of β2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.

Bronchial thermoplasty in asthma: an exploratory histopathological evaluation in distinct asthma endotypes/phenotypes

BackgroundBronchial thermoplasty regulates structural abnormalities involved in airway narrowing in asthma. In the present study we aimed to investigate the effect of bronchial thermoplasty on histopathological bronchial structures in distinct asthma endotypes/phenotypes.MethodsEndobronchial biopsies (n = 450) were collected from 30 patients with severe uncontrolled asthma before bronchial thermoplasty and after 3 sequential bronchial thermoplasties. Patients were classified based on blood eosinophils, atopy, allergy and smoke exposure. Tissue sections were assessed for histopathological parameters and expression of heat-shock proteins and glucocorticoid receptor. Proliferating cells were determined by Ki67-staining.ResultsIn all patients, bronchial thermoplasty improved asthma control (p < 0.001), reduced airway smooth muscle (p = 0.014) and increased proliferative (Ki67 +) epithelial cells (p = 0.014). After bronchial thermoplasty, airway smooth muscle decreased predominantly in patients with T2 high asthma endotype. Epithelial cell proliferation was increased after bronchial thermoplasty in patients with low blood eosinophils (p = 0.016), patients with no allergy (p = 0.028) and patients without smoke exposure (p = 0.034).In all patients, bronchial thermoplasty increased the expression of glucocorticoid receptor in epithelial cells (p = 0.018) and subepithelial mesenchymal cells (p = 0.033) and the translocation of glucocorticoid receptor in the nucleus (p = 0.036). Furthermore, bronchial thermoplasty increased the expression of heat shock protein-70 (p = 0.002) and heat shock protein-90 (p = 0.001) in epithelial cells and decreased the expression of heat shock protein-70 (p = 0.009) and heat shock protein-90 (p = 0.002) in subepithelial mesenchymal cells. The effect of bronchial thermoplasty on the expression of heat shock proteins -70 and -90 was distinctive across different asthma endotypes/phenotypes.ConclusionsBronchial thermoplasty leads to a diminishment of airway smooth muscle, to epithelial cell regeneration, increased expression and activation of glucocorticoid receptor in the airways and increased expression of heat shock proteins in the epithelium. Histopathological effects appear to be distinct in different endotypes/phenotypes indicating that the beneficial effects of bronchial thermoplasty are achieved by diverse molecular targets associated with asthma endotypes/phenotypes.

Investigating whether bronchodilator medications can prevent effects of rostral fluid shift on airway narrowing in asthma - preliminary results

Investigating whether bronchodilator medications can prevent effects of rostral fluid shift on airway narrowing in asthma - preliminary results

Effects of preventing fluid retention in the legs on overnight airway narrowing in asthma

Effects of preventing fluid retention in the legs on overnight airway narrowing in asthma

Lung Computational Models and the Role of the Small Airways in Asthma.

Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique-derived resistance at 5 Hz (R5) - resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date.Objectives: To validate the use of forced oscillation R5 - R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma.Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 - R20 (n = 31). The computational models were coupled with regression models in an asthmatic cohort (n = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials (n = 137).Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 - R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 - R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%.Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 - R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.

Effect of airway narrowing in asthma: active learning through a simple and didactic model.

Effect of airway narrowing in asthma: active learning through a simple and didactic model.

Respiratory impedance is correlated with airway narrowing in asthma using three-dimensional computed tomography.

Respiratory impedance comprises the resistance and reactance of the respiratory system and can provide detailed information on respiratory function. However, details of the relationship between impedance and morphological airway changes in asthma are unknown. We aimed to evaluate the correlation between imaging-based airway changes and respiratory impedance in patients with asthma. Respiratory impedance and spirometric data were evaluated in 72 patients with asthma and 29 reference subjects. We measured the intraluminal area (Ai) and wall thickness (WT) of third- to sixth-generation bronchi using three-dimensional computed tomographic analyses, and values were adjusted by body surface area (BSA, Ai/BSA, and WT/the square root (√) of BSA). Asthma patients had significantly increased respiratory impedance, decreased Ai/BSA, and increased WT/√BSA, as was the case in those without airflow limitation as assessed by spirometry. Ai/BSA was inversely correlated with respiratory resistance at 5Hz (R5) and 20Hz (R20). R20 had a stronger correlation with Ai/BSA than did R5. Ai/BSA was positively correlated with forced expiratory volume in 1second/forced vital capacity ratio, percentage predicted forced expiratory volume in 1second, and percentage predicted mid-expiratory flow. WT/√BSA had no significant correlation with spirometry or respiratory impedance. Respiratory resistance is associated with airway narrowing.

TGF-β1 Evokes Human Airway Smooth Muscle Cell Shortening and Hyperresponsiveness via Smad3.

Transforming growth factor β1 (TGF-β1), a cytokine whose levels are elevated in the airways of patients with asthma, perpetuates airway inflammation and modulates airway structural cell remodeling. However, the role of TGF-β1 in excessive airway narrowing in asthma, or airway hyperresponsiveness (AHR), remains unclear. In this study, we set out to investigate the direct effects of TGF-β1 on human airway smooth muscle (HASM) cell shortening and hyperresponsiveness. The dynamics of AHR and single-cell excitation-contraction coupling were measured in human precision-cut lung slices and in isolated HASM cells using supravital microscopy and magnetic twisting cytometry, respectively. In human precision-cut lung slices, overnight treatment with TGF-β1 significantly augmented basal and carbachol-induced bronchoconstriction. In isolated HASM cells, TGF-β1 increased basal and methacholine-induced cytoskeletal stiffness in a dose- and time-dependent manner. TGF-β1-induced single-cell contraction was corroborated by concomitant increases in myosin light chain and myosin phosphatase target subunit 1 phosphorylation levels, which were attenuated by small interfering RNA-mediated knockdown of Smad3 and pharmacological inhibition of Rho kinase. Strikingly, these physiological effects of TGF-β1 occurred through a RhoA-independent mechanism, with little effect on HASM cell [Ca2+]i levels. Together, our data suggest that TGF-β1 enhances HASM excitation-contraction coupling pathways to induce HASM cell shortening and hyperresponsiveness. These findings reveal a potential link between airway injury-repair responses and bronchial hyperreactivity in asthma, and define TGF-β1 signaling as a potential target to reduce AHR in asthma.

Peripheral ventilation heterogeneity determines the extent of bronchoconstriction in asthma.

In asthma, bronchoconstriction causes topographically heterogeneous airway narrowing, as measured by three-dimensional ventilation imaging. Computation modeling suggests that peripheral airway dysfunction is a potential determinant of acute airway narrowing measured by imaging. We hypothesized that the development of low-ventilation regions measured topographically by three-dimensional imaging after bronchoconstriction is predicted by peripheral airway function. Fourteen asthmatic subjects underwent ventilation single-photon-emission computed tomography/computed tomography scan imaging before and after methacholine challenge. One-liter breaths of Technegas were inhaled from functional residual capacity in upright posture before supine scanning. The lung regions with the lowest ventilation (Ventlow) were calculated using a thresholding method and expressed as a percentage of total ventilation (Venttotal). Multiple-breath nitrogen washout was used to measure diffusion-dependent and convection-dependent ventilation heterogeneity (Sacin and Scond, respectively) and lung clearance index (LCI), before and after challenge. Forced expiratory volume in 1 s (FEV1) was 87.6 ± 15.8% predicted, and seven subjects had airway hyperresponsiveness. Ventlow at baseline was unrelated to spirometry or multiple-breath nitrogen washout indices. Methacholine challenge decreased FEV1 by 23 ± 5% of baseline while Ventlow increased from 21.5 ± 2.3%Venttotal to 26.3 ± 6.7%Venttotal (P = 0.03). The change in Ventlow was predicted by baseline Sacin (rs = 0.60, P = 0.03) and by LCI (rs = 0.70, P = 0.006) but not by Scond (rs = 0.30, P = 0.30). The development of low-ventilation lung units in three-dimensional ventilation imaging is predicted by ventilation heterogeneity in diffusion-dependent airways. This relationship suggests that acinar ventilation heterogeneity in asthma may be of mechanistic importance in terms of bronchoconstriction and airway narrowing.NEW & NOTEWORTHY Using ventilation SPECT/CT imaging in asthmatics, we show induced bronchoconstriction leads to the development of areas of low ventilation. Furthermore, the relative volume of the low-ventilation regions was predicted by ventilation heterogeneity in diffusion-dependent acinar airways. This suggests that the pattern of regional airway narrowing in asthma is determined by acinar airway function.

Contribution of rostral fluid shift to intrathoracic airway narrowing in asthma.

In asthma, supine posture and sleep increase intrathoracic airway narrowing. When humans are supine, because of gravity fluid moves out of the legs and accumulates in the thorax. We hypothesized that fluid shifting out of the legs into the thorax contributes to the intrathoracic airway narrowing in asthma. Healthy and asthmatic subjects sat for 30 min and then lay supine for 30 min. To simulate overnight fluid shift, supine subjects were randomized to receive increased fluid shift out of the legs with lower body positive pressure (LBPP, 10-30 min) or none (control) and crossed over. With forced oscillation at 5 Hz, respiratory resistance (R5) and reactance (X5, reflecting respiratory stiffness) and with bioelectrical impedance, leg and thoracic fluid volumes (LFV, TFV) were measured while subjects were seated and supine (0 min, 30 min). In 17 healthy subjects (age: 51.8 ± 10.9 yr, FEV1/FVC z score: -0.4 ± 1.1), changes in R5 and X5 were similar in both study arms (P > 0.05). In 15 asthmatic subjects (58.5 ± 9.8 yr, -2.1 ± 1.3), R5 and X5 increased in both arms (ΔR5: 0.6 ± 0.9 vs. 1.4 ± 0.8 cmH2O·l-1·s-1, ΔX5: 0.3 ± 0.7 vs. 1.1 ± 0.9 cmH2O·l-1·s-1). The increases in R5 and X5 were 2.3 and 3.7 times larger with LBPP than control, however (P = 0.008, P = 0.006). The main predictor of increases in R5 with LBPP was increases in TFV (r = 0.73, P = 0.002). In asthmatic subjects, the magnitude of increases in X5 with LBPP was comparable to that with posture change from sitting to supine (1.1 ± 0.9 vs. 1.4 ± 0.9 cmH2O·l-1·s-1, P = 0.32). We conclude that in asthmatic subjects fluid shifting from the legs to the thorax while supine contributed to increases in the respiratory resistance and stiffness.NEW & NOTEWORTHY In supine asthmatic subjects, application of positive pressure to the lower body caused appreciable increases in respiratory system resistance and stiffness. Moreover, these changes in respiratory mechanics correlated positively with increase in thoracic fluid volume. These findings suggest that fluid shifts from the lower body to the thorax may contribute to overnight intrathoracic airway narrowing and worsening of asthma symptoms.

Non-linear parameters of specific resistance loops to characterise obstructive airways diseases

BackgroundSpecific resistance loops appear in different shapes influenced by different resistive properties of the airways, yet their descriptive ability is compressed to a single parameter - its slope. We aimed to develop new parameters reflecting the various shapes of the loop and to explore their potential in the characterisation of obstructive airways diseases.MethodsOur study included 134 subjects: Healthy controls (N = 22), Asthma with non-obstructive lung function (N = 22) and COPD of all disease stages (N = 90). Different shapes were described by geometrical and second-order transfer function parameters.ResultsOur parameters demonstrated no difference between asthma and healthy controls groups, but were significantly different (p < 0.0001) from the patients with COPD. Grouping mild COPD subjects by an open or not-open shape of the resistance loop revealed significant differences of loop parameters and classical lung function parameters. Multiple logistic regression indicated RV/TLC as the only predictor of loop opening with OR = 1.157, 95% CI (1.064–1.267), p-value = 0.0006 and R2 = 0.35. Inducing airway narrowing in asthma gave equal shape measures as in COPD non-openers, but with a decreased slope (p < 0.0001).ConclusionThis study introduces new parameters calculated from the resistance loops which may correlate with different phenotypes of obstructive airways diseases.

Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma?

Despite current guidelines and the range of available treatments, over a half of patients with asthma continue to suffer from poor symptomatic control and remain at risk of future worsening. Although a number of non-pharmacological measures are crucial for good clinical management of asthma, new therapeutic controller medications will have a role in the future management of the disease. Several long-acting anticholinergic bronchodilators are under investigation or are available for the treatment of respiratory diseases, including tiotropium bromide, aclidinium bromide, glycopyrronium bromide, glycopyrrolate and umeclidinium bromide, although none is yet licensed for the treatment of asthma. A recent Phase III investigation demonstrated that the once-daily long-acting anticholinergic bronchodilator tiotropium bromide improves lung function and reduces the risk of exacerbation in patients with symptomatic asthma, despite the use of inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs). This has prompted the question of what the rationale is for long-acting anticholinergic bronchodilators in asthma. Bronchial smooth muscle contraction is the primary cause of reversible airway narrowing in asthma, and the baseline level of contraction is predominantly set by the level of ‘cholinergic tone’. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce. Further, anticholinergic compounds may also have anti-inflammatory properties. Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations.

H2S relaxes isolated human airway smooth muscle cells via the sarcolemmal KATP channel

Here we explored the impact of hydrogen sulfide (H2S) on biophysical properties of the primary human airway smooth muscle (ASM)–the end effector of acute airway narrowing in asthma. Using magnetic twisting cytometry (MTC), we measured dynamic changes in the stiffness of isolated ASM, at the single-cell level, in response to varying doses of GYY4137 (1–10mM). GYY4137 slowly released appreciable levels of H2S in the range of 10–275μM, and H2S released was long lived. In isolated human ASM cells, GYY4137 acutely decreased stiffness (i.e. an indicator of the single-cell relaxation) in a dose-dependent fashion, and stiffness decreases were sustained in culture for 24h. Human ASM cells showed protein expressions of cystathionine-γ-lyase (CSE; a H2S synthesizing enzyme) and ATP-sensitive potassium (KATP) channels. The KATP channel opener pinacidil effectively relaxed isolated ASM cells. In addition, pinacidil-induced ASM relaxation was completely inhibited by the treatment of cells with the KATP channel blocker glibenclamide. Glibenclamide also markedly attenuated GYY4137-mediated relaxation of isolated human ASM cells. Taken together, our findings demonstrate that H2S causes the relaxation of human ASM and implicate as well the role for sarcolemmal KATP channels. Finally, given that ASM cells express intrinsic enzymatic machinery of generating H2S, we suggest thereby this class of gasotransmitter can be further exploited for potential therapy against obstructive lung disease.

Thoracic Oncology HERMES syllabus: setting the basis for thoracic oncology training in Europe

Background: The mechanism of exaggerated airway narrowing in asthma is unclear and there is little to no biological data on whether increased airway smooth muscle (ASM) increases narrowing capacity. Objective: Determine whether increased airway narrowing in asthma is related to increased ASM mass. Methods: Bronchial segments were acquired from subjects undergoing surgery, mostly to remove pulmonary neoplasms. Subjects reported doctor-diagnosed asthma (n=5) or had no history of asthma (n=8). In vitro airway narrowing in response to acetylcholine (3x10-6M to 3x10-3M) was assessed to determine maximal bronchoconstriction and sensitivity. Fixed airway segments were sectioned for measurement of airway wall dimensions, particularly the ASM layer. Results: Airways from the asthma group had increased ASM (P=0.014), greater maximal airway narrowing (P=0.003) but no change in sensitivity. Maximal airway narrowing was positively correlated with the area of the ASM layer (r=0.58, P=0.039) but was not related to any other morphological parameter including inner and outer wall dimensions. Conclusions: Results suggest that greater ASM mass in asthma contributes to increased maximal airway narrowing in vivo. In contrast, properties of the ASM may not determine increased airway sensitivity.

IMAGE-BASEDIN VIVOQUANTITATIVE ASSESSMENT OF HUMAN AIRWAY OPENING AND CONTRACTILITY BY FIBER OPTICAL NASOPHARYNGOSCOPY IN HEALTHY AND ASTHMATIC SUBJECTS

Assessment of human airway lumen opening is important in diagnosing and understanding the mechanisms of airway dysfunctions such as the excessive airway narrowing in asthma and chronic obstructive pulmonary disease (COPD). Although there are indirect methods to evaluate the airway calibre, direct in vivo measurement of the airway calibre has not been commonly available. With recent advent of the flexible fiber optical nasopharyngoscope with video recording it has become possible to directly visualize the passages of upper and lower airways. However, quantitative analysis of the recorded video images has been technically challenging. Here, we describe an automatic image processing and analysis method that allows for batch analysis of the images recorded during the endoscopic procedure, thus facilitates image-based quantification of the airway opening. Video images of the airway lumen of volunteer subject were acquired using a fiber optical nasopharyngoscope, and subsequently processed using Gaussian smoothing filter, threshold segmentation, differentiation, and Canny image edge detection, respectively. Thus the area of the open airway lumen was identified and computed using a predetermined converter of the image scale to true dimension of the imaged object. With this method we measured the opening/narrowing of the glottis during tidal breathing with or without making "Hee" sound or cough. We also used this method to measure the opening/narrowing of the primary bronchus of either healthy or asthmatic subjects in response to histamine and/or albuterol treatment, which also provided an indicator of the airway contractility. Our results demonstrate that the image-based method accurately quantified the area change waveform of either the glottis or the bronchus as observed by using the optical nasopharygoscope. Importantly, the opening/narrowing of the airway lumen generally correlated with the airflow and resistance of the airways, and could differentiate the level of airway contractility between the healthy and asthmatic subjects. Thus, this quantitative assessment of airway opening may provide a useful tool to assist clinical diagnosis of airway dysfunctions and understanding the mechanisms of associated pathophysiologies.

Glucocorticosteroids and β2-Adrenoceptor Agonists Synergize to Inhibit Airway Smooth Muscle Remodeling

Airway remodeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to increased airway narrowing in asthma. Increased ASM mass may be caused by exposure to mitogens, including platelet-derived growth factor (PDGF) and collagen type I, which induce a proliferative, hypocontractile ASM phenotype. In contrast, prolonged exposure to insulin induces a hypercontractile phenotype. Glucocorticosteroids and β₂-adrenoceptor agonists synergize to increase glucocorticosteroid receptor translocation in ASM cells; however, the impact of this synergism on phenotype modulation is unknown. Using bovine tracheal smooth muscle, we investigated the effects of the glucocorticosteroids fluticasone (10 nM), budesonide (30 nM), and dexamethasone (0.1-1 μM) and the combination of low concentrations of fluticasone (3-100 pM) and fenoterol (10 nM) on ASM phenotype switching in response to PDGF (10 ng/ml), collagen type I (50 μg/ml), and insulin (1 μM). All glucocorticosteroids inhibited PDGF- and collagen I-induced proliferation and hypocontractility, with the effects of collagen I being less susceptible to glucocorticosteroid action. At 100-fold lower concentrations, fluticasone (100 pM) synergized with fenoterol to prevent PDGF- and collagen I-induced phenotype switching. This inhibition of ASM phenotype switching was associated with a normalization of the PDGF-induced decrease in the cell cycle inhibitors p21(WAF1/CIP1) and p57(KIP2). At this concentration, fluticasone also prevented the insulin-induced hypercontractile phenotype. At even lower concentrations, fluticasone (3 pM) synergized with fenoterol to inhibit this phenotype switch. Collectively, these findings indicate that glucocorticosteroids and β₂-agonists synergistically inhibit ASM phenotype switching, which may contribute to the increased effectiveness of combined treatment with glucocorticosteroids and β₂-agonists in asthma.

Mechanical properties of asthmatic airway smooth muscle

Airway smooth muscle (ASM) is the major effector of excessive airway narrowing in asthma. Changes in some of the mechanical properties of ASM could contribute to excessive narrowing and have not been systematically studied in human ASM from nonasthmatic and asthmatic subjects. Human ASM strips (eight asthmatic and six nonasthmatic) were studied at in situ length and force was normalised to maximal force induced by electric field stimulation (EFS). Measurements included: passive and active force versus length before and after length adaptation, the force-velocity relationship, maximal shortening and force recovery after length oscillation. Force was converted to stress by dividing by cross-sectional area of muscle. The only functional differences were that the asthmatic tissue was stiffer at longer lengths (p<0.05) and oscillatory strain reduced isometric force in response to EFS by 19% as opposed to 36% in nonasthmatics (p<0.01). The mechanical properties of human ASM from asthmatic and nonasthmatic subjects are comparable except for increased passive stiffness and attenuated decline in force generation after an oscillatory perturbation. These data may relate to reduced bronchodilation induced by a deep inspiration in asthmatic subjects.

Contribution of the OBSCN Nonsynonymous Variants to Aspirin Exacerbated Respiratory Disease Susceptibility in Korean Population

Airway remodeling and exacerbated airway narrowing in asthma have been attributed to the regulation of intracellular Ca(2+) by sarcoplasmic reticulum (SR) of the airway smooth muscle cells. The protein encoded by obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF (OBSCN) is a crucial factor in determining the SR architecture in Obscn(-/-) mice. This study genotyped a total of 55 common single-nucleotide polymorphisms (SNPs) in 592 Korean asthmatics including 163 aspirin exacerbated respiratory disease (AERD) cases and 429 aspirin-tolerant asthma (ATA) controls. Eight SNPs, including two nonsynonymous polymorphisms rs1188722C>T (Leu2116Phe) and rs1188729G>C (Cys4642Ser), and one haplotype BL2_ht1 showed statistically significant associations with AERD development (p=0.003-0.03). Two variants, rs1188722C>T (Leu2116Phe) and rs369252C>A, also revealed nominal association with FEV1 decline by aspirin provocation in asthmatics (p=0.03-0.04). Intriguingly, rs1188722C>T (Leu2116Phe) is a highly conserved amino acid residue among species, suggesting its functional relevance to AERD. In addition, the A allele of rs369252C>A, which was more prevalent in AERD than in ATA, was predicted as a potential branch point (BP) site for alternative splicing (BP score=4.29). Although further functional evaluation is required, our findings suggest that OBSCN polymorphisms, in particular, highly conserved nonsynonymous Leu2116Phe variant, might contribute to aspirin hypersensitivity in asthmatics.

Neuronale Kontrolle bei chronisch entzündlichen und obstruktiven Lungenerkrankungen wie Asthma bronchiale und COPD

Airway nerves have the capacity to control airway functions via neuronal reflexes and through neuromediators and neuropeptides. Neuronal mechanisms are known to play a key role in the initiation and modulation of airway hyperresponsiveness and inflammation. Therefore, the nerve fibres may contribute to airway narrowing in asthma and COPD. In addition to the traditional transmitters such as norepinephrine in postganglionic sympathetic nerve fibres and acetylcholine in parasympathetic nerve fibres, a large number of neuropeptides have been identified to have different pharmacological effects on the muscle tone of the vessels and bronchi, mucus secretion and immune cells. Meanwhile, a broad range of stimuli including capsaicin, bradykinin, hyperosmolar saline, tobacco smoke, allergens, ozone, inflammatory mediators and even cold, dry air have been shown to activate sensory nerve fibres to release neuropeptides such as the tachykinins substance P (SP) and neurokinin A (NKA) to mediate neurogenic inflammation. Different aspects of the neurogenic inflammation have been well studied in animal models of chronic airway inflammation and anticholinergic agents such as ipratropium bromide (Atrovent (®)) and tiotropium bromide (Spiriva (®)) have been proved to be important when used as bronchodilators for the treatment of obstructive airway diseases such as COPD. However, little is known about the role of neurogenic airway inflammation in human diseases. In this review, we address the current knowledge of the airway sensory nerves in human asthma and COPD.