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American Journal of Respiratory Cell... Nov 2020Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity (AHR). The objective was to investigate whether...
Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity (AHR). The objective was to investigate whether sphingolipid synthesis could be a target for asthma therapeutics. The effects of GlyH-101 and fenretinide via modulation of sphingolipid synthesis on AHR was evaluated in mice deficient in SPT (serine palmitoyl-CoA transferase), the rate-limiting enzyme of sphingolipid synthesis. The drugs were also used directly in human airway smooth-muscle and epithelial cells to evaluate changes in sphingolipid metabolites and calcium release. GlyH-101 and fenretinide increased sphinganine and dihydroceramides ( sphingolipid metabolites) in lung epithelial and airway smooth-muscle cells, decreased the intracellular calcium concentration in airway smooth-muscle cells, and decreased agonist-induced contraction in proximal and peripheral airways. GlyH-101 also decreased AHR in SPT-deficient mice . This study identifies the manipulation of sphingolipid synthesis as a novel metabolic therapeutic strategy to alleviate AHR.
Topics: Alveolar Epithelial Cells; Bradykinin; Bronchial Hyperreactivity; Calcium; Calcium Signaling; Fenretinide; Glycine; Humans; Hydrazines; Metabolome; Methacholine Chloride; Muscle Contraction; Serine C-Palmitoyltransferase; Sphingolipids
PubMed: 32706610
DOI: 10.1165/rcmb.2020-0194OC -
The cumulative effect of methacholine on large and small airways when deep inspirations are avoided.Respirology (Carlton, Vic.) Mar 2023The effect of serial incremental concentrations of methacholine is only slightly cumulative when assessed by spirometry. This limited cumulative effect may be attributed...
BACKGROUND AND OBJECTIVE
The effect of serial incremental concentrations of methacholine is only slightly cumulative when assessed by spirometry. This limited cumulative effect may be attributed to the bronchodilator effect of deep inspirations that are required between concentrations to measure lung function. Using oscillometry, the response to methacholine can be measured without deep inspirations. Conveniently, oscillometry can also dissociate the contribution of large versus small airways. Herein, oscillometry was used to assess the cumulative effect of methacholine in the absence of deep inspirations on large and small airways.
METHODS
Healthy and asthmatic volunteers underwent a multiple-concentration methacholine challenge on visit 1 and a single-concentration challenge on visit 2 using the highest concentration of visit 1. The maximal response was compared between visits to assess the cumulative effect of methacholine. The lung volume was also measured after the final concentration to assess hyperinflation.
RESULTS
In both healthy and asthmatic subjects, increases in resistance at 19 Hz (R ), reflecting large airway narrowing, did not differ between the multiple- and the single-concentration challenge. However, increases in resistance at 5 Hz (R ) minus R , reflecting small airway narrowing, were 117 and 270% greater in the multiple- than the single-concentration challenge in healthy (p = 0.006) and asthmatic (p < 0.0001) subjects, respectively. Hyperinflation occurred with both challenges and was greater in the multiple- than the single-concentration challenge in both groups.
CONCLUSION
Without deep inspirations, the effect of methacholine is cumulative on small airways but not on large airways. Lung hyperinflation and derecruitment may partially explain these different responses.
Topics: Humans; Methacholine Chloride; Asthma; Respiratory System; Bronchial Provocation Tests; Lung Volume Measurements; Airway Resistance; Forced Expiratory Volume
PubMed: 36210352
DOI: 10.1111/resp.14387 -
Respiratory Research Jul 2023Accumulating clinical evidence links Obstructive Sleep Apnea (OSA) with worse outcomes of asthma, but impact on airway function remains sparsely studied. We tested...
INTRODUCTION
Accumulating clinical evidence links Obstructive Sleep Apnea (OSA) with worse outcomes of asthma, but impact on airway function remains sparsely studied. We tested effects of Chronic Intermittent Hypoxia (CIH) - a hallmark of OSA - on airway hyperresponsiveness (AHR), in a rat model of chronic allergen-induced inflammation.
METHODS
Brown Norway rats were exposed to six weeks of CIH or normoxia (NORM) concurrent with weekly house dust mites (HDM) or saline (SAL) challenges. At endpoint, we assessed responses to seven Methacholine (Mch) doses (0, 4, 8, 16, 32, 64, 128 mg/mL) on a FlexiVent system (Scireq). Maximal (or plateau) responses (reactivity) for total respiratory system Resistance (R) and Elastance (E), Newtonian airway resistance (R a measure of central airways function) and tissue damping (G, a measure of distal airways function) were plotted.
RESULTS
HDM/CIH-treated animals demonstrated the highest reactivity to Mch in R and E compared to all other groups (HDM/NORM, SAL/CIH and SAL/NORM p < 0.05 for all comparisons, for doses 5-7 for R, and for doses 4-7 for E). The enhanced R response was due to an increase in G (doses 4-7, p < 0.05 for comparisons to all other groups), whereas R was not affected by CIH.
CONCLUSIONS
In rats chronically challenged with HDM, concurrent CIH exposure induces AHR primarily in the distal airways, which affects the respiratory system frequency-dependent elastic properties.
Topics: Rats; Animals; Pyroglyphidae; Allergens; Respiratory Hypersensitivity; Lung; Hypoxia; Methacholine Chloride; Inflammation; Sleep Apnea, Obstructive; Disease Models, Animal
PubMed: 37468919
DOI: 10.1186/s12931-023-02493-4 -
The Clinical Respiratory Journal Aug 2021The American Thoracic Society (ATS) guideline for methacholine challenge testing (MCT) recommended using the English Wright (EW) nebuliser. However, other brands of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The American Thoracic Society (ATS) guideline for methacholine challenge testing (MCT) recommended using the English Wright (EW) nebuliser. However, other brands of nebulisers are also indicated to be acceptable for this technique, but further validation of nebuliser performance is recommended.
OBJECTIVE
To compare the methacholine provocation concentration causing a 20% fall in forced expiratory volume in 1 second (PC -FEV ) measured by using EW nebuliser and DV 646 nebuliser.
METHODS
Subjects were randomly assigned to undergo 2-min tidal breathing methacholine challenge with either EW or DV 646 nebuliser on two separate days, which were at least 24 hours but not more than 7 days apart. The above procedure was repeated for each subject in 1 month, but the nebulisers were selected in a reverse order.
RESULTS
The study includes 15 mild and stable asthmatic patients. The geometric means (SD) of methacholine PC measured with using EW and DV 646 nebulisers were 1.82 (6.38) mg/mL versus 0.83 (1.82) mg/mL, respectively in the initial two visits and 2.56 (6.29) mg/mL versus 0.78 (1.40) mg/mL in the following two visits (both P < 0.05). There are well correlations between PC20-EW1 and PC20-EW2 (r = 0.99, P < 0.01), PC20-DV1 and PC20-DV2 (r = 0.88, P < 0.01), and between PC20-EW1 and PC20-DV1 (r = 0.91, P < 0.01), PC20-EW2 and PC20-DV2 (r = 0.78, P < 0.01).
CONCLUSIONS
PC -FEV measured by using the two conventional jet nebulisers was both repeatable and the results were highly correlated.
Topics: Asthma; Bronchial Provocation Tests; Forced Expiratory Volume; Humans; Methacholine Chloride; Nebulizers and Vaporizers
PubMed: 33840150
DOI: 10.1111/crj.13374 -
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 -
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 -
Allergy Mar 2023Obesity is known to diminish lung volumes and worsen asthma. However, mechanistic understanding is lacking, especially as concerns small-airway responsiveness. The...
BACKGROUND
Obesity is known to diminish lung volumes and worsen asthma. However, mechanistic understanding is lacking, especially as concerns small-airway responsiveness. The objective of this study was therefore to compare small-airway responsiveness, as represented by the change in expiratory:inspiratory mean lung density ratios (MLD , as determined by computed tomography [CT]) throughout methacholine testing in obese versus non-obese women with asthma.
METHODS
Thoracic CT was performed during methacholine bronchoconstriction challenges to produce standardized response curves (SRC: response parameter versus ln[1 + % PD20], where PD20 is the cumulative methacholine dose) for 31 asthma patients (n = 18 non-obese and n = 13 obese patients). Mixed models evaluated obesity effects and interactions on SRCs while adjusting for age and bronchial morphology. Small airway responsiveness as represented by SRC slope was calculated for each third of the MLD response and compared between groups.
RESULTS
Obesity-associated effects observed during experimental bronchoconstriction included: (i) a significant baseline effect for forced expiratory volume in 1 second with lower values for the obese (73.11 ± 13.44) versus non-obese (82.19 ± 8.78; p = 0.002) groups prior to methacholine testing and (ii) significantly higher responsiveness in small airways as estimated via differences in MLD slopes (group×ln(1 + % PD20 interaction; p = 0.023). The latter were pinpointed to higher slopes in the obese group at the beginning 2/3 of SRCs (p = 0.004 and p = 0.021). Significant obesity effects (p = 0.035 and p = 0.008) indicating lower forced vital capacity and greater % change in MLD (respectively) throughout methacholine testing, were also observed.
CONCLUSION
In addition to baseline differences, small-airway responsiveness (as represented by the change in MLD ) during methacholine challenge is greater in obese women with asthma as compared to the non-obese.
Topics: Humans; Female; Methacholine Chloride; Asthma; Bronchoconstriction; Bronchial Provocation Tests; Obesity; Forced Expiratory Volume
PubMed: 36070075
DOI: 10.1111/all.15509 -
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 -
The Journal of Asthma : Official... Jul 2021Bronchial hyperresponsiveness (BHR) is a representative feature of asthma. Although methacholine and mannitol are commonly used for bronchial challenge tests, the... (Meta-Analysis)
Meta-Analysis
Diagnostic comparison of methacholine and mannitol bronchial challenge tests for identifying bronchial hyperresponsiveness in asthma: a systematic review and meta-analysis.
OBJECTIVE
Bronchial hyperresponsiveness (BHR) is a representative feature of asthma. Although methacholine and mannitol are commonly used for bronchial challenge tests, the optimal roles of the two agents for assessing BHR remain unclear. We compared the diagnostic performance of methacholine and mannitol in bronchial challenge tests.
METHODS
A systematic literature search was performed using MEDLINE, EMBASE, and the Cochrane Central Register. The sensitivity, specificity, diagnostic odds ratio (DOR), and a hierarchical summary of the receiver-operating characteristic curve (HSROC) of the two agents for detecting BHR in asthma were pooled using meta-analysis. A meta-regression analysis was used to identify potential sources of heterogeneity within the selected studies.
RESULTS
We identified six studies comprising 565 patients. The pooled sensitivity, specificity, and DOR of methacholine were 0.61 (95%CI, 0.44-0.76), 0.93 (95%CI, 0.70-0.99), and 23.47 (95% CI, 2.51-219.89), respectively. The pooled sensitivity, specificity, and diagnostic odds ratio of mannitol were 0.50 (95%CI, 0.28-0.73), 0.97 (95% CI, 0.94-0.99), and 35.22 (95% CI, 8.82-140.62), respectively. The area under the HSROC for mannitol was higher than that for methacholine (0.97 vs. 0.81, < 0.01). Considerable between-study heterogeneity was present for sensitivity and specificity in studies of both index tests. Univariate meta-regression analysis revealed that age and sex of the study participants were probable sources of heterogeneity for specificity in studies of methacholine.
CONCLUSION
Although mannitol showed better diagnostic performance than methacholine for identifying BHR in asthma, substantial between-study heterogeneity necessitates caution when interpreting the data.
Topics: Age Factors; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Humans; Mannitol; Methacholine Chloride; ROC Curve; Sensitivity and Specificity; Sex Factors
PubMed: 32138564
DOI: 10.1080/02770903.2020.1739704 -
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