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Chest Apr 2023The purpose of this study was to investigate physiological phenotypes of asthma in obesity.
BACKGROUND
The purpose of this study was to investigate physiological phenotypes of asthma in obesity.
RESEARCH QUESTION
Do physiological responses during bronchoconstriction distinguish different groups of asthma in people with obesity, and also differentiate from responses simply related to obesity?
STUDY DESIGN AND METHODS
Cross-sectional study of people with obesity (31 with asthma and 22 without lung disease). Participants underwent methacholine challenge testing with measurement of spirometry and respiratory system impedance by oscillometry.
RESULTS
Participants had class III obesity (BMI, 46.7 ± 6.6 kg/m in control subjects and 47.2 ± 8.2 kg/m in people with asthma). Most participants had significant changes in peripheral airway impedance in response to methacholine: in control subjects, resistance at 5 Hz measured by oscillometry increased by 45% ± 27% and area under the reactance curve (AX) by 268% ± 236% in response to 16 mg/mL methacholine; in people with asthma, resistance at 5 Hz measured by oscillometry increased by 52% ± 38% and AX by 361% ± 295% in response to provocation concentration producing a 20% fall in FEV dose of methacholine. These responses suggest that obesity predisposes to peripheral airway reactivity. Two distinct groups of asthma emerged based on respiratory system impedance: one with lower reactance (baseline AX, 11.8; interquartile range, 9.9-23.4 cm HO/L) and more concordant bronchoconstriction in central and peripheral airways; the other with high reactance (baseline AX, 46.7; interquartile range, 23.2-53.7 cm HO/L) and discordant bronchoconstriction responses in central and peripheral airways. The high reactance asthma group included only women, and reported significantly more gastroesophageal reflux disease, worse chest tightness, more wheeze, and more asthma exacerbations than the low reactance group.
INTERPRETATION
Peripheral airway reactivity detected by oscillometry is common in obese control subjects and obese people with asthma. There is a subgroup of obese asthma characterized by significant peripheral airway dysfunction by oscillometry out of proportion to spirometric airway dysfunction. This peripheral dysfunction represents clinically significant respiratory disease not readily assessed by spirometry.
Topics: Female; Humans; Methacholine Chloride; Cross-Sectional Studies; Asthma; Respiratory System; Spirometry; Bronchial Provocation Tests; Obesity; Airway Resistance; Forced Expiratory Volume
PubMed: 36610669
DOI: 10.1016/j.chest.2022.12.030 -
Experimental Physiology Apr 2017What is the central question of this study? The parasternal intercostal electromyogram (EMGpara) is known to provide an accurate, non-invasive index of respiratory...
What is the central question of this study? The parasternal intercostal electromyogram (EMGpara) is known to provide an accurate, non-invasive index of respiratory load-capacity balance. Although relationships between EMGpara and both airflow obstruction and hyperinflation have been shown, the independent contribution of each factor has not been examined. What is the main finding and its importance? Reductions in airway calibre and inspiratory capacity along with increases in EMGpara were induced via methacholine challenge. A strong inverse relationship was observed between EMGpara and airway obstruction, with no influence of inspiratory capacity. These data suggest that EMGpara is more strongly influenced by airway calibre than by changes in end-expiratory lung volume during airway challenge testing. Neural respiratory drive, measured via the parasternal intercostal electromyogram (EMGpara), provides a non-invasive index of the load-capacity balance of the respiratory muscle pump. Previous studies in patients with obstructive lung disease have shown strong relationships between EMGpara and the extent of both airflow obstruction and hyperinflation. The relative influence of the two factors has not, however, been described. Airflow obstruction was induced via methacholine challenge testing in 25 adult humans. Forced expiratory volume in 1 s (FEV ) and surface EMGpara during tidal breathing were measured after each dose, with 20 of the participants also undergoing measurements of inspiratory capacity (IC) at each stage. Linear mixed model analysis was used to assess dose-wise changes in FEV and EMGpara, and thereafter to determine the influence of changes in FEV and IC on change in EMGpara. Median (interquartile range) FEV decreased significantly [from 96.00 (80.00-122.30) to 67.80 (37.98-92.27)% predicted, P < 0.0001] and EMGpara increased significantly [from 5.37 (2.25-8.92) to 6.27 (3.37-19.60) μV, P < 0.0001] from baseline to end of test. Linear mixed model analysis showed a significant interaction between methacholine dose and induced change in EMGpara, with an increase in EMGpara of 0.24 (95% confidence interval 0.11-0.37) μV per methacholine dose . Change in FEV further influenced this relationship [increase in slope of 0.002 (0.004-0.001) μV dose per % predicted fall in FEV , P = 0.011], but not with change in IC. These data suggest that bronchoconstriction exerts a more potent influence on levels of EMGpara than changes in end-expiratory lung volume during methacholine challenge.
Topics: Adult; Bronchial Provocation Tests; Bronchoconstriction; Female; Forced Expiratory Volume; Humans; Inspiratory Capacity; Intercostal Muscles; Lung; Lung Volume Measurements; Male; Methacholine Chloride; Respiratory Muscles; Tidal Volume; Young Adult
PubMed: 28194830
DOI: 10.1113/EP086120 -
American Journal of Physiology. Lung... Feb 2022Obese asthmatics tend to have severe, poorly controlled disease and exhibit methacholine hyperresponsiveness manifesting in proximal airway narrowing and distal lung...
Obese asthmatics tend to have severe, poorly controlled disease and exhibit methacholine hyperresponsiveness manifesting in proximal airway narrowing and distal lung tissue collapsibility. Substantial weight loss in obese asthmatics or in mouse models of the condition decreases methacholine hyperresponsiveness. Ketone bodies are rapidly elevated during weight loss, coinciding with or preceding relief from asthma-related comorbidities. As ketone bodies may exert numerous potentially therapeutic effects, augmenting their systemic concentrations is being targeted for the treatment of several conditions. Circulating ketone body levels can be increased by feeding a ketogenic diet or by providing a ketone ester dietary supplement, which we hypothesized would exert protective effects in mouse models of inherent obese asthma. Weight loss induced by feeding a low-fat diet to mice previously fed a high-fat diet was preceded by increased urine and blood levels of the ketone body β-hydroxybutyrate (BHB). Feeding a ketogenic diet for 3 wk to high-fat diet-fed obese mice or genetically obese mice increased BHB concentrations and decreased methacholine hyperresponsiveness without substantially decreasing body weight. Acute ketone ester administration decreased methacholine responsiveness of normal mice, and dietary ketone ester supplementation of high-fat diet-fed mice decreased methacholine hyperresponsiveness. Ketone ester supplementation also transiently induced an "antiobesogenic" gut microbiome with a decreased ratio. Dietary interventions to increase systemic BHB concentrations could provide symptom relief for obese asthmatics without the need for the substantial weight loss required of patients to elicit benefits to their asthma through bariatric surgery or other diet or lifestyle alterations.
Topics: 3-Hydroxybutyric Acid; Animals; Asthma; Bronchial Hyperreactivity; Diet, High-Fat; Diet, Ketogenic; Disease Models, Animal; Esters; Gastrointestinal Microbiome; Ketone Bodies; Ketosis; Male; Methacholine Chloride; Mice, Inbred C57BL; Obesity; Weight Loss; Mice
PubMed: 34936508
DOI: 10.1152/ajplung.00309.2021 -
International Journal of Medical... 2023Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER) breast cancer patients, a significant number of patients still develop metastasis or...
Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase () might play essential roles in the recurrence of tamoxifen-resistant ER patients. increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how regulates the tumor microenvironment for tamoxifen-resistant ER breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of in breast cancer cell lines decreased cell proliferation and influenced expressions of specific downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of , which provide new targets for the treatment of tamoxifen-resistant breast cancer patients.
Topics: Female; Humans; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Fulvestrant; Gene Expression Regulation, Neoplastic; Glutamate-Ammonia Ligase; MicroRNAs; Tamoxifen; Tumor Microenvironment
PubMed: 36619229
DOI: 10.7150/ijms.75625 -
Scientific Reports Aug 2022Asthma affects 340 million people worldwide and varies in time. Twenty years ago, in Canada, the Saguenay-Lac-Saint-Jean asthma family cohort was created to study the...
Asthma affects 340 million people worldwide and varies in time. Twenty years ago, in Canada, the Saguenay-Lac-Saint-Jean asthma family cohort was created to study the genetic and environmental components of asthma. This study is a follow-up of 125 participants of this cohort to explore the appearance, persistence, and progression of asthma over 10-20 years. Participants answered a clinical standardized questionnaire. Lung function was assessed (forced expiratory volume in 1 s, forced vital capacity, bronchial reversibility, and methacholine bronchoprovocation), skin allergy testing was performed, blood samples were obtained (immunoglobulin E, white blood cell counts) and phenotypes were compared between recruitment and follow-up. From the participants without asthma at recruitment, 12% developed a phenotype of adult-onset asthma with the presence of risk factors, such as atopy, high body mass index, and exposure to smoking. A decrease of PC values in this group was observed and a decrease in the FEV/FVC ratio in all groups. Also, 7% of individuals with asthma at recruitment developed chronic obstructive pulmonary disease, presenting risk factors at recruitment, such as moderate-to-severe bronchial hyperresponsiveness, exposure to smoking, and asthma. This study allowed a better interpretation of the evolution of asthma. Fine phenotypic characterization is the first step for meaningful genetic and epigenetic studies.
Topics: Asthma; Canada; Follow-Up Studies; Forced Expiratory Volume; Humans; Methacholine Chloride
PubMed: 35963877
DOI: 10.1038/s41598-022-17959-6 -
The Tokai Journal of Experimental and... Sep 2022The utility of an analysis of breath sounds as a non-invasive lung function test in children and adults has been studied. Analyzing specific breath sounds during...
OBJECTIVE
The utility of an analysis of breath sounds as a non-invasive lung function test in children and adults has been studied. Analyzing specific breath sounds during methacholine inhalation challenge is useful for evaluating airway constriction in asthmatic patients.
PATIENTS AND METHODS
The study population included 57 children with atopic asthma (male: female = 38: 19; median age, 10 years [range, 5-16 years]). The breath sound spectrum was measured before a methacholine inhalation test, just after the methacholine inhalation challenge and after β agonist inhalation. The values of breath sound parameters were analyzed and the direct changes of the sound spectrum during methacholine inhalation challenge were evaluated.
RESULTS
The values of breath sound parameters, RPF and RPF, were significantly decreased after methacholine inhalation (P < 0.001, p < 0.001, respectively), indicationg bronchoconstriction, and increased after β agonist inhalation (P < 0.001, p < 0.001, respectively), indicating bronchodilation. The high-pitch area of the sound spectrum curve around 1,500 Hz was significantly increased after methacholine inhalation (P < 0.001). The values returned to the baseline level after β agonist inhalation.
CONCLUSIONS
Bronchoconstriction by methacholine inhalation induced a reversible high-pitch sound. The assessment of changes in the high-pitch area of the breath sound spectrum may be useful for the detection of airway narrowing in asthmatic patients.
Topics: Asthma; Bronchial Provocation Tests; Bronchoconstriction; Child; Female; Humans; Male; Methacholine Chloride; Respiratory Sounds
PubMed: 36073283
DOI: No ID Found -
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 -
Respirology (Carlton, Vic.) Mar 2023
Topics: Humans; Methacholine Chloride; Asthma; Bronchial Provocation Tests
PubMed: 36411237
DOI: 10.1111/resp.14416 -
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 -
Respiratory Physiology & Neurobiology Oct 2021Balb/c mice respiratory mechanics was studied in two intravenous methacholine (MCh) protocols: bolus and continuous infusion. The Constant Phase Model (CPM) was used in...
Balb/c mice respiratory mechanics was studied in two intravenous methacholine (MCh) protocols: bolus and continuous infusion. The Constant Phase Model (CPM) was used in this study. The harmonic distortion index (k) was used to assess the respiratory system nonlinearity. The analysis of variance showed difference between groups (OVA vs control) and among doses for both protocols. Bolus protocol posttest: there was a difference between OVA and control at 0.3 and 1 mg/kg doses (p<0.0001 and p<0.001) for R. Infusion: there was a difference between OVA and control at 192 μg.kg.min dose for R, G and H, (p<0.01; p<0.001; p<0.001). An increment was found in k values near to the observed peak values in bolus protocol. The bolus protocol could better differentiate inflamed and non-inflamed airway resistance, whereas the differences between OVA and control in continuous infusion protocol were associated to airway- and, mainly, parenchyma-related parameters. Moreover, the bolus protocol presented a higher nonlinear degree compared to the infusion protocol.
Topics: Animals; Asthma; Bronchoconstrictor Agents; Disease Models, Animal; Male; Methacholine Chloride; Mice; Mice, Inbred BALB C; Models, Theoretical; Respiratory Mechanics
PubMed: 34062282
DOI: 10.1016/j.resp.2021.103705