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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 -
Experimental Lung Research 2020This study aimed to analyze the Constant Phase Model (CPM) Coefficient of Determination (COD) and an index of harmonic distortion ([Formula: see text]) behavior in...
This study aimed to analyze the Constant Phase Model (CPM) Coefficient of Determination (COD) and an index of harmonic distortion ([Formula: see text]) behavior in intravenous methacholine dose response curve. We studied the COD and [Formula: see text] behavior of Control and Lung Inflammation (OVA) groups of mice and we proposed an alternative for moments when the CPM should not be applied. 9-week female BALB/c mice were studied, 8 of the control group (23.11 ± 1.27 g) and 11 of the lung inflammation group (OVA) (21.45 ± 2.16 g). The COD values were obtained during the respiratory mechanics assessment via Forced Oscillation Technique (FOT) and the [Formula: see text] was estimated a posteriori. Both control and OVA groups were submitted to 4 doses of Methacholine (MCh) protocol. A strong correlation between COD and [Formula: see text] was present at the last two doses (0.3 mg/kg: = -0.75, = 0.0013 and 1 mg/kg: = -0.91; < 0.0001) in the OVA group. Differences were found in doses of 0.3 mg/kg between control and OVA for the maximum values of Rn (Newtonian Resistance) and G (tissue viscous); and between groups at PBS and doses of 0.03, 0.1 and 0.3 mg/kg for H (Elastance). A similar behavior was observed for the analysis of Area Under the Curve with the exclusion of the 3 first measurements of each dose. However, in this scenario, the comparison with the maximum value presented a higher discriminatory capacity of the parameters associated with the parenchyma. During severe bronchoconstriction there is a strong negative correlation between model goodness of fit and nonlinearities levels, reinforcing that COD is a robust acceptance criterion, whether still simple and easily obtained from the ventilator. We also pointed out the area under the CPM parameters dose response curve is a useful and can be used as a complementary analysis to peak comparison following bolus injections of methacholine.
Topics: Airway Resistance; Animals; Bronchoconstriction; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Lung; Methacholine Chloride; Mice; Mice, Inbred BALB C; Ovalbumin; Pneumonia; Respiratory Function Tests; Respiratory Mechanics
PubMed: 31931646
DOI: 10.1080/01902148.2020.1711831 -
Medicine and Science in Sports and... May 2015Elite athletes frequently experience asthma and airway hyperresponsiveness (AHR). We aimed to investigate predictors of airway pathophysiology in a group of unselected...
INTRODUCTION
Elite athletes frequently experience asthma and airway hyperresponsiveness (AHR). We aimed to investigate predictors of airway pathophysiology in a group of unselected elite summer-sport athletes, training for the summer 2008 Olympic Games, including markers of airway inflammation, systemic inflammation, and training intensity.
METHODS
Fifty-seven Danish elite summer-sport athletes with and without asthma symptoms all gave a blood sample for measurements of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α), completed a respiratory questionnaire, and underwent spirometry. Bronchial challenges with mannitol were performed in all 57 athletes, and 47 agreed to perform an additional methacholine provocation.
RESULTS
Based on a physician's diagnosis, 18 (32%) athletes were concluded to be asthmatic. Asthmatic subjects trained more hours per week than the 39 nonasthmatics (median (min-max): 25 h·wk (14-30) versus 20 h·wk (11-30), P = 0.001). AHR to both methacholine and mannitol (dose response slope) increased with the number of weekly training h (r = 0.43, P = 0.003, and r = 0.28, P = 0.034, respectively). Serum levels of IL-6, IL-8, TNF-α, and hs-CRP were similar between asthmatics and nonasthmatics. However, there was a positive association between the degree of AHR to methacholine and serum levels of TNF-α (r = 0.36, P = 0.04). Fifteen out of 18 asthmatic athletes were challenged with both agents. In these subjects, no association was found between the levels of AHR to mannitol and methacholine (r = 0.032, P = 0.91).
CONCLUSION
AHR in elite athletes is related to the amount of weekly training and the level of serum TNF-α. No association was found between the level of AHR to mannitol and methacholine in the asthmatic athletes.
Topics: Adult; Asthma; Biomarkers; Bronchial Hyperreactivity; Bronchial Provocation Tests; C-Reactive Protein; Cross-Sectional Studies; Female; Humans; Interleukin-6; Interleukin-8; Male; Mannitol; Methacholine Chloride; Physical Education and Training; Spirometry; Sports; Tumor Necrosis Factor-alpha; Young Adult
PubMed: 25202844
DOI: 10.1249/MSS.0000000000000496 -
Journal of Applied Physiology... Jun 2022Specific ventilation imaging (SVI) measures the spatial distribution of specific ventilation (SV) in the lung with MRI by using inhaled oxygen as a contrast agent....
Specific ventilation imaging (SVI) measures the spatial distribution of specific ventilation (SV) in the lung with MRI by using inhaled oxygen as a contrast agent. Because of the inherently low signal-to-noise ratio in the technique, multiple switches between inspiring air and O are utilized, and the high spatial resolution SV distribution is determined as an average over the entire imaging period (∼20 min). We hypothesized that a trade-off between spatial and temporal resolution could allow imaging at a higher temporal resolution, at the cost of a coarser, yet acceptable, spatial resolution. The appropriate window length and spatial resolution compromise were determined by generating synthetic data with signal- and contrast-to-noise characteristics reflective of that in previously published experimental data, with a known and unchanging distribution of SV, and showed that acceptable results could be obtained in an imaging period of ∼7 min (80 breaths), with a spatial resolution of ∼1 cm. Previously published data were then reanalyzed. The average heterogeneity of the temporally resolved maps of SV was not different from the previous overall analysis, however, the temporally resolved maps were less effective at detecting the amount of bronchoconstriction resulting from methacholine administration. The results further indicated that the initial response to inhaled methacholine and subsequent inhalation of albuterol were largely complete within ∼22 min and ∼9 min, respectively, although there was a tendency for an ongoing developing effect in both cases. These results suggest that it is feasible to use a shortened SVI protocol, with a modest sacrifice in spatial resolution, to measure temporally dynamic processes. Dynamic imaging providing maps of specific ventilation with a temporal resolution of ∼7 min with a spatial resolution of ∼1 cm using MRI was shown to be practical. The technique provides an ionizing radiation free means of temporally following the spatial pattern of specific ventilation. Reanalysis of previously published data showed that the effects of inhaled methacholine and albuterol were largely complete at ∼22 min and ∼9 min, respectively after administration.
Topics: Albuterol; Bronchoconstriction; Lung; Magnetic Resonance Imaging; Methacholine Chloride; Oxygen
PubMed: 35482322
DOI: 10.1152/japplphysiol.00652.2021 -
Revue Des Maladies Respiratoires Sep 2018Bronchial challenge with the direct bronchoconstrictor agent methacholine is commonly used for the diagnosis of asthma. The "Lung Function" thematic group of the French...
Bronchial challenge with the direct bronchoconstrictor agent methacholine is commonly used for the diagnosis of asthma. The "Lung Function" thematic group of the French Pulmonology Society (SPLF) elaborated a series of guidelines for the performance and the interpretation of methacholine challenge testing, based on French clinical guideline methodology. Specifically, guidelines are provided with regard to the choice of judgment criteria, the management of deep inspirations, and the role of methacholine bronchial challenge in the care of asthma, exercise-induced asthma, and professional asthma.
Topics: Asthma; Asthma, Exercise-Induced; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; France; Humans; Methacholine Chloride; Plethysmography; Respiratory Function Tests; Spirometry
PubMed: 30097294
DOI: 10.1016/j.rmr.2018.02.010 -
Respirology (Carlton, Vic.) Mar 2023
Topics: Humans; Methacholine Chloride; Asthma; Bronchial Provocation Tests
PubMed: 36411237
DOI: 10.1111/resp.14416 -
Chest Aug 2020
Topics: Asthma; Bronchial Provocation Tests; Bronchodilator Agents; Humans; Methacholine Chloride; Spirometry
PubMed: 32768054
DOI: 10.1016/j.chest.2020.04.034