Methacholine Airway Hyperresponsiveness Research Articles

Increased Ratio of Matrix Metalloproteinase-9 (MMP-9)/Tissue Inhibitor Metalloproteinase-1 from Alveolar Macrophages in Chronic Asthma with a Fast Decline in FEV1 at 5-Year Follow-up.

Chronic asthma is associated with progressive airway remodeling, which may contribute to declining lung function. An increase in matrix metalloproteinases-9 (MMP-9)/tissue inhibitor metalloproteinase-1 (TIMP-1) may indicate airway inflammation and bronchial injury. Bronchial biopsy specimens and alveolar macrophages (AMs) were obtained from patients with asthma under regular treatment with inhaled corticosteroids or combination therapy and normal subjects (n = 10). Asthmatics included those with a slow forced expiratory volume in one second (FEV1) decline (<30 mL/year, n = 13) and those with a fast FEV1 decline (≥30 mL/year, n = 8) in 5-year follow-up. Immunostaining expression of MMP-9 and TIMP-1 was detected in airway tissues. MMP-9 and TIMP-1 was measured from AMs cultured for 24 h. After the 5-year treatment, the methacholine airway hyperresponsiveness of the slow FEV1 decline group was decreased, but that of the fast FEV1 decline group was increased (PC20, provocative concentration causing a 20% decrease in FEV1, 3.12 ± 1.10 to 1.14 ± 0.34 mg/dL, p < 0.05). AMs of asthma with a fast FEV1 decline released a higher level of MMP-9 (8.52 ± 3.53 pg/mL, p < 0.05) than those of a slow FEV1 decline (0.99 ± 0.20 pg/mL). The MMP-9/TIMP ratio in the fast FEV1 decline group (0.089 ± 0.032) was higher than that of the slow FEV1 decline group (0.007 ± 0.001, p < 0.01). The annual FEV1 decline in 5 years was proportional to the level of MMP-9 (r = 57, p < 0.01) and MMP-9/TIMP-1 ratio (r = 0.58, p < 0.01). The airways of asthma with greater yearly decline in FEV1 showed an increased thickness of submucosa and strong expression of MMP-9. An increase in MMP-9 and MMP-9/TIMP-1 in airways or AMs could be indicators of chronic airway inflammation and contribute to a greater decline in lung function of patients with chronic asthma.

Short-term effect of once-daily fluticasone furoate on methacholine-induced bronchoconstriction in mild asthmatics.

Inhaled corticosteroids (ICS) decrease airway inflammation and airway hyperresponsiveness (AHR). Previous studies have generally investigated the effect of ICS on methacholine-induced AHR following weeks or months of medium to high dose treatment. The short-term effects of once-daily fluticasone furoate (FF) 100 mcg on methacholine-induced AHR and airway inflammation were examined over the course of one week. Eleven mild asthmatics completed this randomized, double-blind crossover study. Once-daily FF (100 mcg) and identical appearing placebo Ellipta® inhalers were given for 7 days with a 2-week washout. Methacholine challenges were performed before and 24 h after the first, third and seventh doses. Fractional exhaled nitric oxide (FeNO) was measured initially and at 7 days. FF significantly (p = 0.0009-0.0078) increased methacholine PD20 (provocative dose causing 20% fall in forced expiratory volume in 1 s) at all times. Doubling dose shifts (95% CI) were 1.23 (0.60-1.86), 1.17 (0.68-1.67) and 1.44 (0.93-1.94) after the first, third and seventh dose respectively. FeNO (geometric mean, 95% CI) decreased significantly (p = 0.0049) following FF treatment from 37.9 ppb (23.7-60.5) initially to 22.9 ppb (14.8-35.5) at 7 days. Placebo did not affect methacholine PD20 or FeNO. Single-dose FF 100 mcg decreased methacholine AHR at 24 h without significant further improvement with continued daily use over 7 days. The inhibition in AHR after one week of daily dosing coincided with a significant decrease in FeNO at 7 days. Contrary to past assumptions, the ICS FF appears to rapidly reduce AHR to methacholine.

Obesity and airway hyper-responsiveness

RATIONALE: Data on the relationship between airway hyper-responsiveness (AHR) to methacholine and obesity are conflicting.OBJECTIVE: To assess the relationship between obesity, morbid obesity and objectively determined methacholine AHR in 1000 unselected methacholine challenge tests.METHODS: We reviewed data from 1000 unselected methacholine tests from a hospital-based pulmonary function laboratory; tests were performed in subjects with respiratory symptoms and non-diagnostic spirometry. We assessed the prevalence of obesity and morbid obesity, defined as BMI ≥30 and ≥40 kg/m2, respectively, in subjects with (PC20 ≤ 8 mg/mL) and without (PC20 > 8 mg/mL) AHR.RESULTS: Obesity was present in 34.6% of the 1000: this included 40.6% of the 315 subjects with AHR vs. 31.8% of those without AHR (p = 0.007). Morbid obesity was present in 5.8% including 9.5% vs. 4.1% of those with and without AHR respectively (p = 0.0006). Results were significant in females but not in males. Log PC20 (artificially extrapolated in the 685 subjects with PC20 > 8 mg/mL) correlated negatively with BMI (r = -0.105, p = 0.0009) and positively with FEV1% (r = 0.28, p < 0.0001). BMI correlated negatively with FEV1% (r = - 0.15, p < 0.0001); however, the correlation of log PC20 vs BMI remained significant when adjusted for FEV1%.CONCLUSIONS: Obesity was more prevalent among those with methacholine AHR than those without; the relationship was more evident in females and in morbidly obese vs. obese. Reduced FEV1 due to chest wall restriction may be a contributing factor.

Celastrol Alleviates Airway Hyperresponsiveness and Inhibits Th17 Responses in Obese Asthmatic Mice.

Severe airway hyperresponsiveness (AHR) is a clinical feature of asthma, which has been associated with obesity and has shown a poor response to standard asthma treatments such as glucocorticoids. Numerous studies have shown that Interleukin (IL)-17 producing CD4+T cells (Th17 cells), which could be inhibited by celastrol, is essential in mediating steroid-resistant AHR. The following study investigates the impact of celastrol and its mechanism on the regulation of AHR in murine model of obesity and asthma. C57BL/6 mice were sensitized by intraperitoneal injection of ovalbumin (OVA) on day 1 and 13 starting from 12th week, which was followed by aerosol OVA challenge that lasted for 30 min per daily for 7 consecutive days starting from 16th week. Diet-induced obesity (DIO) mice were fed a high fat diet (HFD) for 16 weeks. Celastrol was administrated orally for 7 consecutive days, 30 min before every challenge in DIO-OVA-induced mice. Lung functions were analyzed by measuring the airway resistance (Rn) and methacholine (MCh) AHR, while H&E staining was used to examine histological changes in the lungs. Immunohistochemistry was used to observe IL-17A protein in lung tissues; flow cytometry to detect the proportion of Th17 cells in CD4+T cells. The concentration of cytokines IL-17A in serum was assessed by standardized sandwich ELISA, while the expression of IL-17A mRNA in lung was examined by quantitative real-time RT-PCR. Briefly, our data indicated that celastrol reduced body mass in DIO-OVA-induced obesity and asthma. Both baseline Rn and MCh AHR were significantly lower in celastrol group. Moreover, celastrol treatment decreased the frequency of Th17 cell expansion and reduced the production of IL-17A in both lung and serum. To sum up, our findings indicated that Th17 and its cytokine measured in the spleen and lung were closely associated with AHR. In addition, celastrol has shown the ability to suppress AHR through Th17 inhibition in obese asthmatic mice.

Longitudinally Stable, Clinically Defined Clusters of Patients with Asthma Independently Identified in the ADEPT and U-BIOPRED Asthma Studies.

ADEPT (Airways Disease Endotyping for Personalized Therapeutics) and U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome Consortium) are independent asthma biomarker studies that aim to enable personalization of therapies. Patients in both studies were identified by similar criteria, and similar clinical parameters and biomarkers were assessed in blood, sputum, and airway samples. Fuzzy partition-around-medoid clustering was performed on the ADEPT dataset (n = 154) and independently on the U-BIOPRED asthma dataset (n = 82), filtered to match ADEPT inclusion criteria. For both studies, the same eight easily measurable clinical variables were used, and ADEPT also included methacholine airway hyperresponsiveness. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and the full U-BIOPRED adult asthma dataset (n = 397) as independent external validation. Four clusters were identified in the ADEPT-asthma study population with distinct clinical and biomarker profiles. In general, Cluster 1 consists of patients with mild asthma not treated with steroids and well controlled with preserved lung function and a low-inflammatory phenotype; Cluster 2 is partially controlled, with mild airflow obstruction but severe airway hyperresponsiveness and a Th2 phenotype (brittle phenotype); Cluster 3 is partially controlled with mild airflow obstruction but reduced vital capacity, less bronchodilator reversibility, and a non-Th2 phenotype with neutrophilic inflammation (chronic obstructive pulmonary disease-like); and Cluster 4 is poorly controlled, with marked airflow obstruction, marked bronchodilator reversibility, and a mixed inflammatory phenotype. Overall, the ADEPT clusters were stable over 12 months and reproduced by identifying four analogous clusters in the U-BIOPRED asthma dataset, with distributions for most clustering and nonclustering variables similar to ADEPT. We report four clinical clusters in ADEPT and confirmed these by external validation in U-BIOPRED. The ADEPT clusters have distinct clinical and molecular characteristics, are stable over 12 months, and present opportunities for the development of tailored therapeutics for asthma.

Pituitary Adenylate Cyclase Activating Peptide (1-38) and its analog (Acetyl-[Ala15, Ala20] PACAP 38-polyamide) reverse methacholine airway hyperresponsiveness in rats

The aim of this study was to investigate both functionally and structurally bronchodilator effects of Pituitary adenylate cyclase activating peptide (PACAP38) and acetyl-[Ala15, Ala20] PACAP38-polyamide, a potent PACAP38 analog, in rats challenged by methacholine (MeCh). Male Wistar rats were divided randomly into five groups. Groups 1 and 2 inhaled respectively aerosols of saline or increasing doses of MeCh (0.5, 1, 2.12, 4.25, 8.5, 17, 34 and 68mg/L). The other groups received terbutaline (Terb) (250 µg/rat) (10-6 M), PACAP38 (50 µg/rat) (0.1 mM) or PACAP38 analog (50 µg/rat) associated to MeCh from the dose of 4.25 mg/L. Total lung resistances (RL) were recorded before and 2 min after MeCh administration by pneumomultitest equipment. MeCh administration induced a significant and a dose-dependent increase (p&lt;0.05) of RL compared to control rats. Terb, PACAP38 and PACAP38 analog reversed significantly the MeCh-induced bronchial constriction, smooth muscle (SM) layer thickness and bronchial lumen mucus abundance. PACAP38 analog prevents effectively bronchial smooth muscle layer thickness, mucus hypersecretion and lumen decrease. Therefore, it may constitute a potent therapeutic bronchodilator.

Randomized placebo-controlled trial to evaluate chronic dosing effects of propranolol in asthma.

Unblinded studies have shown improvements in airway hyperresponsiveness with chronic nadolol in steroid-naive patients with asthma. To assess the effects of chronic nonselective β-blockade as add-on to inhaled corticosteroids (ICS) in patients with asthma. A double-blind randomized placebo-controlled crossover trial of propranolol in patients with mild-to-moderate asthma receiving ICS was performed. Participants underwent a 6- to 8-week dose titration of propranolol or placebo as tolerated to a maximum of 80 mg per day. Tiotropium was given for the first 4 to 6 weeks of each treatment period. Primary outcome was methacholine challenge. Secondary outcomes included histamine challenge, pulmonary function, mini-asthma quality of life questionnaire (mini-AQLQ), and asthma control questionnaire (ACQ). Eighteen patients completed (mean [SEM]): age, 36 (4) yr; FEV1%, 93 (2); ICS, 440 (66) μg/d. No significant difference was observed in methacholine or histamine challenge after exposure to propranolol versus placebo. For methacholine challenge, the doubling dilution difference was 0.04 (95% confidence interval [CI], -0.56 to 0.63), P = 0.89. Albuterol recovery at 20 minutes after histamine challenge was partially attenuated by propranolol versus placebo: FEV1% mean difference, 5.28 (95% CI, 2.54-8.01), P = 0.001. After chronic β-blockade there was a small worsening in FEV1 % predicted of 2.4% (95% CI, -0.1 to 4.8), P = 0.055. No difference was found for ACQ or mini-AQLQ. This is the first placebo-controlled study to assess the effects of chronic nonselective β-blockade in asthma, showing no significant effect of propranolol compared with placebo on either methacholine or histamine airway hyperresponsiveness and no change in ACQ or AQLQ. Clinical trial registered with www.clinicaltrials.gov (NCT01074853).

Safety of bronchial thermoplasty in patients with severe refractory asthma

BackgroundPatients with severe refractory asthma treated with bronchial thermoplasty (BT), a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle, were followed up for 5 years to evaluate long-term safety of this procedure. ObjectivesTo assess long-term safety of BT for 5 years. MethodsPatients with asthma aged 18 to 65 years requiring high-dose inhaled corticosteroids (ICSs) (>750 μg/d of fluticasone propionate or equivalent) and long-acting β2-agonists (LABAs) (at least 100 μg/d of salmeterol or equivalent), with or without oral prednisone (≤30 mg/d), leukotriene modifiers, theophylline, or other asthma controller medications were enrolled in the Research in Severe Asthma (RISA) Trial. Patients had a prebronchodilator forced expiratory volume in 1 second of 50% or more of predicted, demonstrated methacholine airway hyperresponsiveness, had uncontrolled symptoms despite taking maintenance medication, abstained from smoking for 1 year or greater, and had a smoking history of less than 10 pack-years. ResultsFourteen patients (of the 15 who received active treatment in the RISA Trial) participated in the long-term follow-up study for 5 years. The rate of respiratory adverse events (AEs per patient per year) was 1.4, 2.4, 1.7, and 2.4, respectively, in years 2 to 5 after BT. There was a decrease in hospitalizations and emergency department visits for respiratory symptoms in each of years 1, 2, 3, 4, and 5 compared with the year before BT treatment. Measures of lung function showed no deterioration for 5 years. ConclusionOur findings suggest that BT is safe for 5 years after BT in patients with severe refractory asthma. Trial Registrationclinicaltrials.gov Identifier: NCT00401986

S7 Influence of Beta-2 Adrenoceptor Genotype on Response to Regular Racemic or Levosalbutamol in Steroid Treated Asthmatics

Background Asthmatic patients receiving inhaled corticosteroids often take frequent add-on therapy with albuterol despite on-demand prescription. We wished to evaluate trough methacholine airway hyper-responsiveness (the primary outcome) following regular treatment with racemic salbutamol and levosalbutamol compared to placebo, in steroid treated asthmatics stratified according to beta-2 adrenoceptor 16 genotype. Methods We performed a randomised, double-blind, placebo-controlled, triple crossover trial comparing 2 weeks of regular therapy with inhaled racemic salbutamol (200µg qid); levosalbutamol (100µg qid); or placebo on methacholine PC20 6 hours post dose in 30 persistent asthmatics (15 homozygous Arg16 and Gly16) receiving inhaled corticosteroids. Results There was no rebound worsening of trough airway hyper-responsiveness to methacholine after chronic exposure to either racemic (p=0.53) or levosalbutamol (p=0.84) compared to placebo; nor between genotypes - as doubling dilution (dd) difference in methacholine PC20 from placebo (Figure 1): salbutamol/Arg16= 0.36dd (95% CI: –0.43, 1.15); salbutamol/Gly16=0.01dd (95% CI: –0.47, 0.49); levosalbutamol/Arg16=–0.01dd (95% CI: –0.89, 0.87); levosalbutamol/Gly16=0.28dd (95% CI: –0.22, 0.77). Both active treatments improved morning PEF in Gly16 (p=0.04) but not Arg16 patients (p=0.50); while evening PEF improved in both Gly16 (p Conclusions Chronic exposure to either racemic or levosalbutamol added to inhaled corticosteroids did not cause rebound worsening of airway hyper-responsiveness at trough compared to placebo; with no difference seen between beta-2 adrenoceptor 16 genotypes.

Local and systemic immunological parameters associated with remission of asthma symptoms in children.

The immunological and clinical parameters that are associated with asthma remission are poorly understood. The cytokine and local mediator changes associated with the resolution of asthma symptoms were examined in three groups of subjects 12–18 years of age (n = 15 in each group): (a) continuing asthma group (CA) who had persistent symptoms since early childhood, (b) an age, sex and atopic status-matched group who had persistent symptoms in early childhood but in whom these had resolved (RA), and (c) a non-atopic, non-asthmatic control group. Clinical parameters, sputum cell counts, peripheral blood mononuclear cell (PBMC) cytokine production and activation marker expression were determined. All of the CA had methacholine airway hyperresponsiveness compared with only half of the RA subjects. The CA showed elevated numbers of eosinophils and increased ECP and IL-5 in sputum, which were not observed in the RA. PBMC cytokine studies revealed increased production of the type 1 cytokines IL-12, IFN-γ and TNF-α in the CA group compared with the RA group, under a range of activation conditions, however, the production of IL-4 and IL-5 were unchanged. These findings suggest that decreased type 1 cytokine expression as well as decreased eosinophilic inflammation is associated with the resolution of asthma symptoms.

Association of Body Mass Index With the Development of Methacholine Airway Hyperresponsiveness in Adult: End the Controversy

Association of Body Mass Index With the Development of Methacholine Airway Hyperresponsiveness in Adult: End the Controversy

Plasma Substance P Levels in Patients with Persistent Cough

Background: Substance P (SP) is involved in the pathogenesis of cough in animal models. However, few studies in humans have been reported and the roles of SP in clinical cough remain obscure. Objectives: To clarify the relevance of plasma levels of SP in patients with persistent cough. Methods: We studied 82 patients with cough persisting for at least 3 weeks and 15 healthy controls. Patients were classified as having asthmatic cough (cough-variant asthma and cough-predominant asthma; n = 61) or nonasthmatic cough (n = 21; postinfectious cough, n = 6; gastroesophageal reflux disease, n = 5; idiopathic cough, n = 5, and others, n = 5). Correlations were evaluated between plasma SP levels as measured with ELISA and methacholine airway hyperresponsiveness (airway sensitivity and airway reactivity), capsaicin cough sensitivity, sputum eosinophil and neutrophil counts, and pulmonary function. Results: Plasma SP levels were significantly elevated in patients with both asthmatic and nonasthmatic cough compared with controls [31.1 pg/ml (range 18.0–52.2) and 30.0 pg/ml (range 15.1–50.3) vs. 15.4 pg/ml (range 11.3–23.7); p = 0.003 and p = 0.038, respectively] but did not differ between the two patient groups (p = 0.90). Plasma SP levels correlated with airway sensitivity (threshold dose of methacholine) in the patients with asthmatic cough (r = –0.37, p = 0.005) but not with airway reactivity, cough sensitivity, FEV₁ values, or sputum eosinophil and neutrophil counts in either group. Conclusions: Increased levels of SP in plasma are associated with persistent cough in humans and might be related to airway sensitivity in asthmatic cough.

Allergen inhalation challenge in smoking compared with non-smoking asthmatic subjects

Smoking asthmatics experience more severe symptoms, require more rescue medication and have more asthma-related hospitalizations than non-smoking asthmatics. However, studies in mice suggest that mainstream cigarette smoke may reduce airway inflammation and may attenuate airway hyperresponsiveness. A comparison of allergen-induced airway inflammatory responses of smoking and non-smoking atopic asthmatics has not been examined previously. To determine whether allergen-induced airway responses and inflammatory profiles are attenuated in smoking when compared with non-smoking mild allergic asthmatic subjects. Allergen inhalation challenges were performed in 13 smoking and 19 non-smoking mild allergic asthmatic subjects. The forced expired volume in 1 s (FEV(1) ) was measured up to 7 h after allergen inhalation. Methacholine airway responsiveness was measured before and at 24 h after allergen and sputum was induced before and at 7 and 24 h after allergen. Both the smoking and non-smoking groups developed similar allergen-induced falls in FEV(1) during the early and late asthmatic responses and similar increases in allergen-induced airway eosinophils. The mean maximum fall in FEV(1) during the late response was 16.3 ± 4.3% in non-smokers and 12.9 ± 7.2% in smokers. The smoking asthmatics, however, did not develop allergen-induced methacholine airway hyperresponsiveness, whereas the non-smoking controls developed a 1.18 doubling dose shift in methacholine PC(20) (P < 0.05). Mild allergic asthmatic subjects, who were current smokers with a mean 6-year pack history, develop allergen-induced eosinophilic airway inflammation and late responses, similar in magnitude to non-smoking asthmatics, but do not develop methacholine airway hyperresponsiveness associated with the allergen-induced airway eosinophilia.

Association between genetic variations of the transforming growth factor β receptor type III and asthma in a Korean population

Transforming growth factor-beta (TGF-ß) and its receptors have been suggested to play key roles in the pathogenesis of asthma. The aim of this study was to evaluate the effects of genetic variations in the TGF-ß receptor type III (TGFBR3) on asthma and on its related phenotypes in the general population. A cohort of 2,118 subjects aged from 10 to 18 years responded to a questionnaire concerning asthma symptoms and risk factors. Methacholine airway hyperresponsiveness (AHR), skin test responses to common aeroallergens, and serum total IgE levels were evaluated in the cohort. A total of 19 SNPs for TGFBR3 were found using direct re-sequencing in 24 healthy adults. Of these, informative SNPs [+44T>C (S15F) and +2753G>A at 3'UTR] were selected and scored using the high throughput single base extension method. Atopy was identified in subjects with 44T>C allele [P=0.04, OR (95% CI)=0.79 (0.62-0.99)] and in subjects with Ht1 (CG) more frequently than in subjects with other haplotypes [P=0.04, OR (95% CI)=1.27 (1.01-1.59)]. The A allele in 2753G>A was more common in subjects with non-atopic asthma [OR (95% CI)=1.76 (1.01-3.05)]. A significant association was found between non-atopic asthma and 44T_2753A [OR (95% CI) =2.16 (1.22-3.82)]. Genetic variations in TGFBR3 appear to be associated with a genetic predisposition to development of asthma and to phenotypes of asthma. Also, the minor allele 2753G and the haplotype TA in the TGFBR3 gene were associated with a pathogenesis of non-atopic asthma.

IL-12-STAT4-IFN-γ axis is a key downstream pathway in the development of IL-13-mediated asthma phenotypes in a Th2 type asthma model

IL-4 and IL-13 are closely related cytokines that are produced by Th2 cells. However, IL-4 and IL-13 have different effects on the development of asthma phenotypes. Here, we evaluated downstream molecular mechanisms involved in the development of Th2 type asthma phenotypes. A murine model of Th2 asthma was used that involved intraperitoneal sensitization with an allergen (ovalbumin) plus alum and then challenge with ovalbumin alone. Asthma phenotypes, including airway-hyperresponsiveness (AHR), lung inflammation, and immunologic parameters were evaluated after allergen challenge in mice deficient in candidate genes. The present study showed that methacholine AHR and lung inflammation developed in allergen-challenged IL-4-deficient mice but not in allergen-challenged IL-13-deficient mice. In addition, the production of OVA-specific IgG2a and IFN-gamma-inducible protein (IP)-10 was also impaired in the absence of IL-13, but not of IL-4. Lung-targeted IFN-gamma over-expression in the airways enhanced methacholine AHR and non-eosinophilic inflammation; in addition, these asthma phenotypes were impaired in allergen-challenged IFN-gamma-deficient mice. Moreover, AHR, non-eosinophilic inflammation, and IFN-gamma expression were impaired in allergen-challenged IL-12Rbeta2- and STAT4-deficient mice; however, AHR and non-eosinophilic inflammation were not impaired in allergen-challenged IL-4Ralpha-deficient mice, and these phenomena were accompanied by the enhanced expression of IL-12 and IFN-gamma. The present data suggest that IL-13-mediated asthma phenotypes, such as AHR and non-eosinophilic inflammation, in the Th2 type asthma are dependent on the IL-12-STAT4-IFN-gamma axis, and that these asthma phenotypes are independent of IL-4Ralpha-mediated signaling.

Airway Responsiveness to Inhaled Aspirin is Influenced by Airway Hyperresponsiveness in Asthmatic Patients

Background/AimsMany patients with aspirin-induced asthma have severe methacholine airway hyperresponsiveness (AHR), suggesting a relationship between aspirin and methacholine in airway response. This study was performed to determine whether methacholine AHR affects the response of asthmatics to inhaled aspirin.MethodsThe clinical records of 207 asthmatic patients who underwent inhalation challenges with both aspirin and methacholine were reviewed retrospectively. An oral aspirin challenge was performed in patients with a negative inhalation response. The bronchial reactivity index (BRindex) was calculated from the percent decrease in lung function divided by the last dose of the stimulus.ResultsForty-one (20.9%) and 14 (7.1%) patients showed a positive response to aspirin following an inhalation and oral challenge, respectively. Only 24.3 and 14.3% of the responders had a history of aspirin intolerance, respectively. The methacholine BRindex was significantly higher in the inhalation responders (1.46 ± 0.02) than in the oral responders (1.36 ± 0.03, p < 0.01) and in non-responders (n = 141, 1.37 ± 0.01, p < 0.001). The aspirin BRindex was significantly correlated with the methacholine BRindex (r = 0.270, p < 0.001). Three of four patients who received the oral challenge, despite a positive inhalation test, showed negative responses to the oral challenge. Two of these patients had severe AHR.ConclusionsA considerable number of asthmatic patients with no history of aspirin intolerance responded to the inhalation aspirin challenge. The airway response to aspirin was significantly correlated with methacholine-AHR, and a false-positive response to aspirin inhalation test seemed to occur primarily in patients with severe AHR.

Importin-13 genetic variation is associated with improved airway responsiveness in childhood asthma

BackgroundGlucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20).Methods10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association.ResultsAmong participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51–2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01–0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids.ConclusionIPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.

Relationship Between Serum Vascular Endothelial Growth Factor and Airway Hyperresponsiveness in Asthmatic Children

RATIONALE: Bronchial asthma is physiologically characterized by variable airflow obstruction and airway hyperresponsiveness (AHR). Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and enhancer of vascular permeability with subsequent edema and thereby contributes to the pathogenesis of asthma. The aim of the present study was to investigate a relationship between serum VEGF levels and methacholine AHR in asthmatic children.

Effects of dehydroepiandrosterone on Th2 cytokine production in peripheral blood mononuclear cells from asthmatics

Background/AimsThe androgen dehydroepiandrosterone (DHEA) attenuates allergic inflammatory airway reactions by down-regulating the Th2 response in mice. The purpose of this study was to investigate whether DHEA suppresses Th2 cytokine production in cultured peripheral blood mononuclear cells (PBMCs) from asthmatic patients.MethodsSixty-one consecutive suspected asthmatic or non-asthmatic men underwent tests for asthma. PBMCs from each subject were cultured with and without DHEA (0.01~10 µM) for 48 h. The concentrations of interferon (IFN)-γ, interleukin (IL)-5, and IL-10 in the culture supernatant were measured via an enzyme-linked immunosorbent assay.ResultsIn PBMCs from subjects exhibiting methacholine airway hyperresponsiveness (AHR), DHEA significantly suppressed IL-10, IL-5, and IFN-γ production in a dose-dependent manner (all p<0.001) and tended to increase the IFN-γ/IL-5 ratio (p=0.087). DHEA (10 µM) suppressed cytokine production to a greater degree in subjects with AHR compared with those without AHR (IL-5: 24.0±7.8% vs. 40.9±3.6%, p<0.01; IFN-γ: 29.7±7.0% vs. 54.5±5.1%, p<0.01). Cytokine suppression was significantly related to AHR, serum total IgE levels, and skin reactivity to house dust mites.ConclusionsDHEA suppressed both Th1 and Th2 responses, with a Th1 bias, and the degree of suppression was associated with the severity of AHR or atopy. Therefore, DHEA may be a useful therapy for asthma.

Complementary roles of capsaicin cough sensitivity test and induced sputum test to methacholine bronchial provocation test in predicting response to inhaled corticosteroids in patients with chronic nonproductive cough

The capsaicin cough sensitivity test (CCST), methacholine bronchial provocation test (MBPT), and induced sputum test (IST) are widely used in the clinical evaluation of chronic nonproductive cough. However, little is known about their roles in predicting response to inhaled corticosteroids (ICSs) in patients with chronic nonproductive cough. To test the hypothesis that the CCST and IST play complementary roles to the MBPT for predicting the response to ICS treatment in patients with chronic nonproductive cough. A total of 43 patients with chronic nonproductive cough who showed isolated capsaicin cough hypersensitivity (CCST group) and 55 patients with chronic nonproductive cough who had methacholine airway hyperresponsiveness (MBPT group) were enrolled. These patients underwent the IST followed by treatment with ICSs for 4 weeks. Measurement of symptom improvement was recorded by the visual analog scale. The response rates to ICS treatment in the CCST and MBPT groups were similar (74.5% vs 86.0%; P = .21). Only the neutrophil count in the IST group was significantly different in responders and nonresponders after the ICS treatments (P = .005 for the CCST group and P = .006 for the MBPT group). Interestingly, the absence of sputum neutrophilia used as a criterion for subgroup analysis increased response rates in the patients with either methacholine airway hyperresponsiveness or capsaicin cough hypersensitivity. In the present study, we demonstrate that CCST and IST play complementary roles to MBPT. By combining the results of these tests, we are able to identify more patients with chronic nonproductive cough and treat patients more successfully with ICSs by improving the response rate to ICS treatment.