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Respirology (Carlton, Vic.) May 2023
Topics: Humans; Respiratory Function Tests; Asthma; Bronchi; Bronchial Provocation Tests; Methacholine Chloride; Bronchial Hyperreactivity; Forced Expiratory Volume
PubMed: 36722470
DOI: 10.1111/resp.14463 -
Exercise Immunology Review 2019Aerobic training (AT) decreases airway inflammation in asthma, but the underlying cellular and molecular mechanisms are not completely understood. Thus, this study...
BACKGROUND
Aerobic training (AT) decreases airway inflammation in asthma, but the underlying cellular and molecular mechanisms are not completely understood. Thus, this study evaluated the participation of SOCS-JAK-STAT signaling in the effects of AT on airway inflammation, remodeling and hyperresponsiveness in a model of allergic airway inflammation.
METHODS
C57Bl/6 mice were divided into Control (Co), Exercise (Ex), HDM (HDM), and HDM+Exercise (HDM+ Ex). Dermatophagoides pteronyssinus (100ug/mouse) were administered oro-tracheally on days 0, 7, 14, 21, 28, 35, 42 and 49. AT was performed in a treadmill during 4 weeks in moderate intensity, from day 24 until day 52.
RESULTS
AT inhibited HDM-induced total cells (p<0.001), eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in BAL, and eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in peribronchial space. AT also reduced BAL levels of IL-4 (p<0.001), IL-5 (p<0.001), IL-13 (p<0.001), CXCL1 (p<0.01), IL-17 (p<0.01), IL-23 (p<0.05), IL-33 (p<0.05), while increased IL- 10 (p<0.05). Airway collagen fibers (p<0.01), elastic fibers p<0.01) and mucin (p<0.01) were also reduced by AT. AT also inhibited HDM-induced airway hyperresponsiveness (AHR) to methacholine 6,25mg/ml (p<0.01), 12,5mg/mL (p<0.01), 25mg/mL (p<0.01) and 50mg/mL (p<0.01). Mechanistically, AT reduced the expression of STAT6 (p<0.05), STAT3 (p<0.001), STAT5 (p<0.01) and JAK2 (p<0.001), similarly by peribronchial leukocytes and by airway epithelial cells. SOCS1 expression (p<0.001) was upregulated in leukocytes and in epithelial cells, SOCS2 (p<0.01) was upregulated in leukocytes and SOCS3 down-regulated in leukocytes (p<0.05) and in epithelial cells (p<0.001).
CONCLUSIONS
AT reduces asthma phenotype involving SOCSJAK- STAT signaling.
Topics: Animals; Asthma; Disease Models, Animal; Eosinophils; Interleukins; Janus Kinases; Lymphocytes; Methacholine Chloride; Mice; Mice, Inbred C57BL; Neutrophils; Physical Conditioning, Animal; Respiratory Hypersensitivity; STAT Transcription Factors; Signal Transduction; Suppressor of Cytokine Signaling Proteins
PubMed: 30785869
DOI: No ID Found -
Respirology (Carlton, Vic.) Jul 2019
Topics: Aged; Asthma; Humans; Methacholine Chloride; Obesity; Phenotype; Respiratory System
PubMed: 30901134
DOI: 10.1111/resp.13533 -
BMC Pulmonary Medicine May 2019Physical activity is an important part of life, and hence exercise-induced bronchoconstriction (EIB) can reduce the quality of life. A standardized test is needed to... (Clinical Trial)
Clinical Trial
BACKGROUND
Physical activity is an important part of life, and hence exercise-induced bronchoconstriction (EIB) can reduce the quality of life. A standardized test is needed to diagnose EIB. The American Thoracic Society (ATS) guidelines recommend an exercise challenge in combination with dry air. We investigated the feasibility of a new, ATS guidelines conform exercise challenge in a cold chamber (ECC) to detect EIB. The aim of this study was to investigate the surrogate marker reaction to methacholine, ECC and exercise challenge in ambient temperature for the prediction of a positive reaction and to re-evaluate the reproducibility of the response to an ECC.
METHODS
Seventy-eight subjects aged 6 to 40 years with suspected EIB were recruited for the study. The subjects performed one methacholine challenge, two ECCs, and one exercise challenge at an ambient temperature. To define the sensitivity and specificity of the predictor, a receiver-operating characteristic curve was plotted. The repeatability was evaluated using the method described by Bland and Altman (95% Limits of agreement).
RESULTS
The following cut-off values showed the best combination of sensitivity and specificity: the provocation dose causing a 20% decrease in the forced expiratory volume in 1 s (PDFEV) of methacholine: 1.36 mg (AUC 0.69, p < 0.05), the maximal decrease in FEV during the ECC: 8.5% (AUC 0.78, p < 0.001) and exercise challenges at ambient temperatures: FEV 5.2% (AUC 0.64, p = 0.13). The median decline in FEV was 14.5% (0.0-64.2) during the first ECC and 10.7% (0.0-52.5) during the second ECC. In the comparison of both ECCs, the Spearman rank correlation of the FEV decrease was r = 0.58 (p < 0.001). The 95% limits of agreement (95% LOAs) for the FEV decrease were - 17.7 to 26.4%.
CONCLUSIONS
The surrogate markers PDFEV of methacholine and maximal decrease in FEV during ECC can predict a positive reaction in another ECC, whereas the maximal FEV decrease in an exercise challenge at an ambient temperature was not predictive. Compared with previous studies, we can achieve a similar reproducibility with an ECC.
CLINICAL TRIAL REGISTRATION
NCT02026492 (retrospectively registered 03/Jan/2014).
Topics: Adolescent; Adult; Asthma, Exercise-Induced; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Child; Cross-Over Studies; Exercise Test; Female; Forced Expiratory Volume; Germany; Humans; Male; Methacholine Chloride; Quality of Life; ROC Curve; Reproducibility of Results; Sensitivity and Specificity; Young Adult
PubMed: 31097027
DOI: 10.1186/s12890-019-0845-3 -
American Journal of Physiology. Lung... Feb 2022There are renewed interests in using the parameter K of Salazar-Knowles' equation to assess lung tissue compliance. K either decreases or increases when the lung's...
There are renewed interests in using the parameter K of Salazar-Knowles' equation to assess lung tissue compliance. K either decreases or increases when the lung's parenchyma stiffens or loosens, respectively. However, whether K is affected by other common features of respiratory diseases, such as inflammation and airway smooth muscle (ASM) contraction, is unknown. Herein, male C57BL/6 mice were treated intranasally with either saline or lipopolysaccharide (LPS) at 1 mg/kg to induce pulmonary inflammation. They were then subjected to either a multiple or a single-dose challenge with methacholine to activate ASM to different degrees. A quasi-static pressure-driven partial pressure-volume (P-V) maneuver was performed before and after methacholine. The Salazar-Knowles' equation was then fitted to the deflation limb of the P-V loop to obtain K, as well as the parameter A, an estimate of lung volume (inspiratory capacity). The fitted curve was also used to derive the quasi-static elastance (E) at 5 cmHO. The results demonstrate that LPS and both methacholine challenges increased E. LPS also decreased A, but did not affect K. In contradistinction, methacholine decreased both A and K in the multiple-dose challenge, whereas it decreased K but not A in the single-dose challenge. These results suggest that LPS increases E by reducing the open lung volume (A) and without affecting tissue compliance (K), whereas methacholine increases E by decreasing tissue compliance with or without affecting lung volume. We conclude that lung tissue compliance, assessed using the parameter K of Salazar-Knowles' equation, is insensitive to inflammation but sensitive to ASM contraction.
Topics: Airway Resistance; Animals; Inflammation; Lipopolysaccharides; Lung; Lung Compliance; Male; Methacholine Chloride; Mice; Mice, Inbred C57BL; Muscle Contraction; Respiratory Mechanics
PubMed: 34936511
DOI: 10.1152/ajplung.00384.2021 -
Pediatrics and Neonatology Dec 2018Airway hyperresponsiveness (AHR) is a key feature of asthma and can be detected using various bronchoprovocation tests. In pediatric populations, the percentage of a...
BACKGROUND
Airway hyperresponsiveness (AHR) is a key feature of asthma and can be detected using various bronchoprovocation tests. In pediatric populations, the percentage of a positive methacholine challenge test (MCCTs) in children with asthma varies among studies, and some have reported seasonal variability. However, these studies have mostly been conducted in temperate regions. This study evaluated the prevalence of AHR to methacholine and its seasonal variation in asthmatic children in Taiwan, a subtropical country.
METHODS
A total of 276 children with asthma and their MCCT results were retrospectively reviewed. All were diagnosed with asthma and received asthma controllers regularly. They were assigned to four season groups depending in which season MCCTs were administered, with seasons categorized by the Central Weather Bureau of Taiwan. Subgroup analyses, including for sex, age, and atopy level, were compared for seasonal difference.
RESULTS
The prevalence of methacholine hyperresponsiveness was 70.7% (n = 195), and the children who were younger and had higher total serum IgE were more sensitive to methacholine (p = 0.019 and p < 0.005, respectively). No significant difference in AHR prevalence among seasons was observed (p = 0.480). The percentage of borderline, mild, and moderate severity of MCCT results was almost equally distributed among the seasons. In subgroup analysis, the children with a higher IgE level (≥75th percentile of all data) had a higher proportion of positive MCCTs in summer (88.6%, p = 0.016).
CONCLUSION
In total, 70% of the children with asthma in Taiwan had AHR to methacholine, which varied among seasons. Children with a higher total serum IgE level may be more seasonally dependent, particularly in summer.
Topics: Asthma; Bronchial Provocation Tests; Bronchoconstrictor Agents; Child; Female; Humans; Immunoglobulin E; Male; Methacholine Chloride; Prevalence; Retrospective Studies; Seasons; Taiwan
PubMed: 29398555
DOI: 10.1016/j.pedneo.2018.01.005 -
Respiratory Care Apr 2023Spirometry tests with a bronchodilator response (BDR) in FEV a methacholine concentration that produces a 20% drop in FEV (PC) ≤ 2 mg/mL, and a positive exercise test...
BACKGROUND
Spirometry tests with a bronchodilator response (BDR) in FEV a methacholine concentration that produces a 20% drop in FEV (PC) ≤ 2 mg/mL, and a positive exercise test have high specificity for the diagnosis of asthma in children. However, the value of forced expiratory flow during the middle half of the FVC maneuver (FEF) in spirometry has been questioned. The objective of this study was to relate the BDR in FEF of spirometry tests with normal FEV and FEV/FVC to airway hyper-responsiveness (AHR) to methacholine or exercise in children age 5-15 y with clinical suspicion of asthma.
METHODS
This was a cross-sectional study of spirometry tests performed between January 2017-December 2019 in children age 5-15 y with diagnostic suspicion of asthma who had a methacholine and/or exercise testing within a period not exceeding 60 d between exams.
RESULTS
The mean (± SD) age of the children was 9.04 ± 2.67 y, with a range of 5-15 y, and 56.17% were male. Of the 324 spirometry tests with normal FEV and FEV/FVC, 66 (20.4%) tests showed BDR in FEF. A total of 46.9% and 33.3% of the children with and without BDR in FEF, respectively, had a PC value ≤ 2 mg/mL and/or a positive exercise testing ( = .039).
CONCLUSIONS
Children with suspected asthma and normal spirometry, other than BDR in FEF, had greater AHR than those without BDR in FEF. BDR in FEF was not always accompanied by AHR to confirm the diagnosis of asthma, so this study suggests that assessment of FEF alone is not always reliable for ruling in or ruling out AHR in the setting of otherwise normal spirometry results in children with suspected asthma.
Topics: Humans; Male; Child; Child, Preschool; Adolescent; Female; Bronchodilator Agents; Methacholine Chloride; Cross-Sectional Studies; Asthma; Respiratory Function Tests; Spirometry; Forced Expiratory Volume
PubMed: 36963964
DOI: 10.4187/respcare.10177 -
The American Journal of the Medical... Dec 2017This study aimed to confirm the ameliorative effect of ghrelin on asthma and investigate its mechanism.
BACKGROUND
This study aimed to confirm the ameliorative effect of ghrelin on asthma and investigate its mechanism.
MATERIALS AND METHODS
The murine model of asthma was induced by ovalbumin (OVA) treatment and assessed by histological pathology and airway responsiveness to methacholine. The total and differential leukocytes were counted. Tumor necrosis factor α, interferon γ, interleukin-5 and interleukin-13 levels in bronchoalveolar lavage fluid were quantified by commercial kits. The protein levels in pulmonary tissues were measured by Western blot analysis.
RESULTS
Ghrelin ameliorated the histological pathology and airway hyperresponsiveness in the OVA-induced asthmatic mouse model. Consistently, OVA-increased total and differential leukocytes and levels of tumor necrosis factor α, interferon γ, interleukin-5 and interleukin-13 in bronchoalveolar lavage fluid were significantly attenuated by ghrelin. Ghrelin prevented the increased protein levels of the endoplasmic reticulum stress markers glucose regulated protein 78 and CCAAT/enhancer binding protein homologous protein and reversed the reduced levels of p-Akt in asthmatic mice.
CONCLUSIONS
Ghrelin might prevent endoplasmic reticulum stress activation by stimulating the Akt signaling pathway, which attenuated inflammation and ameliorated asthma in mice. Ghrelin might be a new target for asthma therapy.
Topics: Animals; Anti-Asthmatic Agents; Asthma; Blotting, Western; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endoplasmic Reticulum; Ghrelin; Keratins; Lung; Male; Methacholine Chloride; Mice; Mice, Inbred C57BL; Stress, Physiological
PubMed: 29208260
DOI: 10.1016/j.amjms.2017.08.022 -
Archivos de Bronconeumologia Feb 2023The role of bronchial provocation tests in the diagnosis of asthma remains to be fully explored. We aimed to evaluate methacholine and mannitol challenge testing, and... (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
INTRODUCTION
The role of bronchial provocation tests in the diagnosis of asthma remains to be fully explored. We aimed to evaluate methacholine and mannitol challenge testing, and explore the factors associated with this broncoprovocation response.
METHODS
Observational, cross-over, randomized trial evaluating adult cases with suspected asthma, naïve to treatment, with normal pre-bronchodilator spirometry, and negative bronchodilator test. Patients were randomized to start with methacholine or mannitol. The diagnosis of bronchial asthma was confirmed if there was a good functional and clinical response to one month with twice daily formoterol/budesonide 9/320. The diagnostic profile and the concordance were calculated. Factors associated with a positive provocation test were entered into a multivariate binomial logistic regression analysis, and classification trees were created for both tests.
RESULTS
The study included 108 cases (50.0% diagnosed with asthma and 51.9% cases starting with methacholine). The percentage of cases positive to methacholine and mannitol were 30.6% and 25.0% respectively. Kappa values were 0.40 (p<0.001). The diagnostic profile for methacholine was sensitivity 59.3% and specificity 98.1%, while for mannitol it was sensitivity 48.1% and specificity 98.1%. Variables associated with a positive methacholine response included sex, atopy, FEV, FEV/FVC and FENO, whereas they were FEV/FVC and FENO for mannitol. A FENO value>26ppb, FEV1≤103.3% and female sex correctly classified 78.7% of methacholine responders. FENO value>26ppb was enough to correctly classify 81.5% of mannitol responders.
CONCLUSIONS
Our study confirms the diagnostic profile of methacholine and mannitol challenge tests and describes the variable associated to their positivity with new proposed cutoff values.
Topics: Adult; Humans; Bronchial Provocation Tests; Methacholine Chloride; Bronchodilator Agents; Cross-Over Studies; Nitric Oxide; Asthma; Mannitol
PubMed: 36371327
DOI: 10.1016/j.arbres.2022.10.008 -
American Journal of Physiology. Lung... Apr 2021Obesity increases incidence and severity of asthma but the molecular mechanisms are not completely understood. Hyperinsulinemia potentiates vagally induced...
Obesity increases incidence and severity of asthma but the molecular mechanisms are not completely understood. Hyperinsulinemia potentiates vagally induced bronchoconstriction in obese rats. Since bronchoconstriction results from airway smooth muscle contraction, we tested whether insulin changed agonist-induced airway smooth muscle contraction. Obesity-prone and resistant rats were fed a low-fat diet for 5 wk and treated with insulin (Lantus, 3 units/rat sc) 16 h before vagally induced bronchoconstriction was measured. Ex vivo, contractile responses to methacholine were measured in isolated rat tracheal rings and human airway smooth muscle strips before and after incubation (0.5-2 h) with 100 nM insulin or 13.1 nM insulin like growth factor-1 (IGF-1). M and M muscarinic receptor mRNA expression was quantified by qRT-PCR and changes in intracellular calcium were measured in response to methacholine or serotonin in isolated rat tracheal smooth muscle cells treated with 1 µM insulin. Insulin, administered to animals 16 h prior, potentiated vagally induced bronchoconstriction in both obese-prone and resistant rats. Insulin, not IGF-1, significantly increased methacholine-induced contraction of rat and human isolated airway smooth muscle. In cultured rat tracheal smooth muscle cells, insulin significantly increased M, not M mRNA expression and enhanced methacholine- and serotonin-induced increase in intracellular calcium. Insulin alone did not cause an immediate increase in intracellular calcium. Thus, insulin acutely potentiated agonist-induced increase in intracellular calcium and airway smooth muscle contraction. These findings may explain why obese individuals with hyperinsulinemia are prone to airway hyperreactivity and give insights into future targets for asthma treatment.
Topics: Animals; Bronchial Hyperreactivity; Bronchoconstriction; Calcium; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Male; Methacholine Chloride; Muscarinic Agonists; Muscle Contraction; Muscle, Smooth; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Trachea; Vagus Nerve
PubMed: 33501891
DOI: 10.1152/ajplung.00232.2020