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International Journal of Occupational... Mar 2020Various indirect or direct airway challenge tests are used to measure nonspecific bronchial hyper-responsiveness (NSBHR). The evaluation of NSBHR in diagnosing...
OBJECTIVES
Various indirect or direct airway challenge tests are used to measure nonspecific bronchial hyper-responsiveness (NSBHR). The evaluation of NSBHR in diagnosing occupational asthma (OA) is performed, e.g., to monitor the specific inhalation challenge test (SICT). The aim of this study was to preliminarily compare the results of methacholine and mannitol inhalation challenge tests in SICT monitoring in bakers with work-related airway symptoms.
MATERIAL AND METHODS
Four bakery workers with a suspicion of OA underwent single-blind placebo-controlled SICTs involving workplace allergens, accompanied by the evaluation of NSBHR with mannitol and methacholine, both before and after SICTs. Clinical examinations, spirometry tests, skin prick tests (SPTs) to common aeroallergens and occupational allergens, as well as tests to determine serum specific IgE antibodies to occupational aeroallergens were also performed.
RESULTS
Positive SPTs results to occupational aeroallergens were found in all bakery workers, and specific IgE antibodies to flour were detected in 2 subjects. Three patients displayed positive SICT reactions. In all of these 3 patients, airway responsiveness to methacholine increased significantly. In 2 patients, airway reaction to mannitol was significant, whereas in 1 subject there was no increase in NSBHR after mannitol inhalation. The patient with a negative SICT result did not reveal any changes in NSBHR before and after the test, either to methacholine or mannitol.
CONCLUSIONS
The data obtained by the authors show that there is no clear correlation between the methacholine and mannitol inhalation challenge tests in SICT monitoring. Preliminary results indicate the need for further investigations to evaluate the usefulness of the mannitol challenge test in the diagnostics of OA. Int J Occup Med Environ Health. 2020;33(2):235-9.
Topics: Adult; Allergens; Asthma, Occupational; Bronchial Provocation Tests; Female; Humans; Male; Mannitol; Methacholine Chloride; Middle Aged; Single-Blind Method
PubMed: 32080681
DOI: 10.13075/ijomeh.1896.01459 -
American Journal of Physiology. Lung... Oct 2022The enzyme, nitric oxide-sensitive guanylyl cyclase (NO-GC), is activated by binding NO to its prosthetic heme group and catalyzes the formation of cGMP. The NO-GC is...
The enzyme, nitric oxide-sensitive guanylyl cyclase (NO-GC), is activated by binding NO to its prosthetic heme group and catalyzes the formation of cGMP. The NO-GC is primarily known to mediate vascular smooth muscle relaxation in the lung, and inhaled NO has been successfully used as a selective pulmonary vasodilator. In comparison, NO-GC's impact on the regulation of airway tone is less acknowledged and, most importantly, little is known about the issue that NO-GC signaling is accomplished by two isoforms: NO-GC1 and NO-GC2, implying the existence of distinct "cGMP pools." Herein, we investigated the functional role of the NO-GC isoforms in respiration by measuring lung function parameters of isoform-specific knockout (KO) mice using noninvasive and invasive techniques. Our data revealed the participation and ongoing influence of NO-GC1-derived cGMP in the regulation of airway tone by showing that respiratory resistance was enhanced in NO-GC1-KOs and increased more pronouncedly after the challenge with the bronchoconstrictor methacholine. The tissue resistance and stiffness of NO-GC1-KOs were also higher because of narrowed airways that cause tissue distortion. Contrariwise, NO-GC2-KOs displayed reduced tissue elasticity, elastic recoil, and airway reactivity to methacholine, which did not even increase in an ovalbumin model of asthma that induced hyperresponsiveness in NO-GC1-KOs. In addition, conscious NO-GC2-KOs showed a higher breathing rate with a shorter duration of inspiration and expiration time, which remained faster even in the presence of bronchoconstrictors that slow down breathing. Thus, we provide evidence of two distinct NO/cGMP pathways in airways, accomplished by either NO-GC1 or NO-GC2, adjusting differentially the airway reactivity.
Topics: Animals; Bronchoconstrictor Agents; Cyclic GMP; Guanylate Cyclase; Heme; Methacholine Chloride; Mice; Mice, Knockout; Nitric Oxide; Ovalbumin; Protein Isoforms; Soluble Guanylyl Cyclase; Vasodilator Agents
PubMed: 35972838
DOI: 10.1152/ajplung.00404.2021 -
Tuberkuloz Ve Toraks Mar 2021Airway hyper-responsiveness (AHR) is a characteristic feature of asthma. The aim of this study was to compare the impulse oscillometry (IOS) and spirometry to... (Comparative Study)
Comparative Study
INTRODUCTION
Airway hyper-responsiveness (AHR) is a characteristic feature of asthma. The aim of this study was to compare the impulse oscillometry (IOS) and spirometry to methacholine for AHR detection among individuals with clinically hyper-reactive airway disease suggestive of bronchial asthma and baseline spirometry were normal.
MATERIALS AND METHODS
Adults with symptoms suggestive of AHR and normal baseline spirometry test were selected. The short protocol of methacholine challenge test (MCT) was performed for all subjects using IOS and spirometry simultaneously. The primary endpoint was to compare the methacholine dosage causing a 20% drop in forced expiratory volume in one second (FEV1), with methacholine dosage that causing 40% increasing the baseline respiratory resistance at 5 hertz (R5), as measured by IOS.
RESULT
A total of 235 participants were analyzed, 184 (78.2%) had positive test results with R5, while 81 (34.4%) had positive MCT results with FEV1.The sensitivity and specificity of MCT with R5were 87.3%, 64.6%, and MCT with FEV1 were 39.1%, 85.4%, respectively. The area under the receiver operating characteristic (ROC) curve was greater at lower doses of MCT at R5, (AUROC: 0.653; p= 0.01).
CONCLUSIONS
The results showed higher sensitivity, negative predictive value, and earlier response of the short protocol of MCT with IOS, compared to MCT with spirometry. Our study suggested the utility of IOS in addition to conventional spirometry as a method of choice in MCT for detection of AHR.
Topics: Adult; Airway Obstruction; Airway Resistance; Asthma; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Oscillometry; ROC Curve; Respiratory Function Tests; Respiratory Hypersensitivity; Sensitivity and Specificity; Spirometry
PubMed: 33853300
DOI: 10.5578/tt.20219901 -
Biochemical Pharmacology Sep 2020Demonstration of bronchial hyperresponsiveness is a key feature in asthma diagnosis. Methacholine challenge has proved to be a highly sensitive test to diagnose asthma...
Demonstration of bronchial hyperresponsiveness is a key feature in asthma diagnosis. Methacholine challenge has proved to be a highly sensitive test to diagnose asthma in patients with chronic respiratory symptoms and preserved baseline lung function (FEV1 > 70% pred.) but is time consuming and may sometimes reveal unpleasant to the patient. We conducted a retrospective study on 270 patients recruited from the University Asthma Clinic of Liege. We have compared the values of several lung function indices and fractional exhaled nitric oxide (FeNO) in predicting a provocative methacholine concentration ≤16 mg/ml on a discovery cohort of 129 patients (57 already on ICS) and on a validation cohort of 141 patients (66 already on ICS). In the discovery study (n = 129), 85 patients (66%) had a positive methacholine challenge with PC20M ≤ 16 mg/ml. Those patients had lower baseline % predicted FEV1 (92% vs. 100%; p < 0.01), lower FEV1/FVC ratio (79% vs. 82%; p < 0.05), higher RV/TLC ratio (114% vs. 100%; p < 0,0001), lower SGaw (specific conductance) (0.76 vs. 0.95; p < 0,001) and higher FeNO (29 ppb vs. 19 ppb; p < 0,01). When performing ROC curve the RV/TLC ratio provided the greatest AUC (0.74, p < 0.001), sGAW had intermediate AUC of 0.69 (p < 0.001) while FeNO, FEV1 and FEV1/FVC ratio were modestly predictive (AUC of 0.65 (p < 0.05), 0,67 (p < 0.001) and 0,63 (p < 0.001). These results were confirmed in the validation study (n = 141). Based on a logistic regression analysis, significant variables associated with positive methacholine challenge were FeNO and RV/TLC (% Pred). A combined application of FeNO and RV/TLC (% Pred) for predicting the PC20M had a specificity of 85%, a sensitivity of 59% and an AUC of 0.79. In the validation study, three variables (RV/TLC, FeNO and FEV1) were independently associated with positive methacholine challenge and the combination of these three variables yielded a specificity of 77%, a sensitivity of 39% and an AUC of 0.77. The RV/TLC ratio combined to FeNO may be of interest to predict significant methacholine bronchial hyperresponsiveness.
Topics: Adrenal Cortex Hormones; Adult; Aged; Anti-Asthmatic Agents; Asthma; Breath Tests; Bronchi; Female; Humans; Male; Methacholine Chloride; Middle Aged; Nitric Oxide; Plethysmography, Whole Body; Reproducibility of Results; Respiratory Function Tests
PubMed: 32305435
DOI: 10.1016/j.bcp.2020.113981 -
Pediatric Research Jun 2020Supplemental oxygen exposure administered to premature infants is associated with chronic lung disease and abnormal pulmonary function. This study used mild (40%),...
BACKGROUND
Supplemental oxygen exposure administered to premature infants is associated with chronic lung disease and abnormal pulmonary function. This study used mild (40%), moderate (60%), and severe (80%) oxygen to determine how hyperoxia-induced changes in lung structure impact pulmonary mechanics in mice.
METHODS
C57BL/6J mice were exposed to room air or hyperoxia from birth through postnatal day 8. Baseline pulmonary function and methacholine challenge was assessed at 4 and 8 weeks of age, accompanied by immunohistochemical assessments of both airway (smooth muscle, tethering) and alveolar (simplification, elastin deposition) structure.
RESULTS
Mild/moderate hyperoxia increased baseline airway resistance (40% only) and airway hyperreactivity (40 and 60%) at 4 weeks accompanied by increased airway smooth muscle deposition, which resolved at 8 weeks. Severe hyperoxia increased baseline compliance, baseline resistance, and total elastin/surface area ratio without increasing airway hyperreactivity, and was accompanied by increased alveolar simplification, decreased airway tethering, and changes in elastin distribution at both time points.
CONCLUSIONS
Mild to moderate hyperoxia causes changes in airway function and airway hyperreactivity with minimal parenchymal response. Severe hyperoxia drives its functional changes through alveolar simplification, airway tethering, and elastin redistribution. These differential responses can be leveraged to further develop hyperoxia mouse models.
Topics: Animals; Animals, Newborn; Dose-Response Relationship, Drug; Female; Hyperoxia; Lung; Lung Compliance; Male; Methacholine Chloride; Mice; Mice, Inbred C57BL; Muscarinic Agonists; Muscle, Smooth; Pulmonary Alveoli; Respiratory Function Tests; Respiratory Mechanics; Sex Factors
PubMed: 31835269
DOI: 10.1038/s41390-019-0723-y -
Journal of Applied Physiology... Jun 2018It is suggested that the frequent strain the airways undergo in asthma because of repeated airway smooth muscle (ASM)-mediated constrictions contributes to airway wall...
It is suggested that the frequent strain the airways undergo in asthma because of repeated airway smooth muscle (ASM)-mediated constrictions contributes to airway wall remodeling. However, the effects of repeated constrictions on airway remodeling, as well as the ensuing impact of this presumptive remodeling on respiratory mechanics, have never been investigated in subjects without asthma. In this study, we set out to determine whether repeated constrictions lead to features that are reminiscent of asthma in mice without asthma. BALB/c mice were subjected to a 30-min constriction elicited by aerosolized methacholine every other day over 6 wk. Forty-eight hours after the last constriction, the mechanics of the respiratory system was evaluated at baseline and in response to incremental doses of nebulized methacholine with the flexiVent. The whole-lung lavages, the tracheas, and the lungs were also collected to evaluate inflammation, the contractile capacity of ASM, and the structural components of the airway wall, respectively. The resistance and the compliance of the respiratory system, as well as the Newtonian resistance and the resistive and elastic properties of the lung tissue, were not affected by repeated constrictions, both at baseline and in response to methacholine. All the other examined features also remained unaltered, except the number of goblet cells in the epithelium and the number of macrophages in the whole-lung lavages, which both increased with repeated constrictions. This study demonstrates that, despite causing goblet cell hyperplasia and a mild macrophagic inflammation, repeated constrictions with methacholine do not lead to structural changes that adversely impact the physiology. NEW & NOTEWORTHY Repeated airway constrictions led to signs of remodeling that are typically observed in asthma, which neither altered respiratory mechanics nor the contractile capacity of airway smooth muscle. These findings shed light on a debate between those claiming that constrictions induce remodeling and those convinced that methacholine challenges are harmless. Insofar as our results with mice relate to humans, the findings indicate that repeated challenges with methacholine can be performed safely.
Topics: Airway Remodeling; Animals; Bronchoconstriction; Female; Inflammation; Methacholine Chloride; Mice, Inbred BALB C; Muscle, Smooth
PubMed: 29470147
DOI: 10.1152/japplphysiol.01073.2017 -
Biosensors & Bioelectronics Oct 2021The methacholine challenge test is considered to be the gold standard bronchoprovocation test used to diagnose asthma, and this test is always performed in pulmonary...
The methacholine challenge test is considered to be the gold standard bronchoprovocation test used to diagnose asthma, and this test is always performed in pulmonary function labs or doctors' offices. Methacholine (MCH) acts by inducing airway tightening/bronchoconstriction, and more importantly, MCH is hydrolyzed by cholinesterase enzyme (ChE). Recently, the American Thoracic Society raised concerns about pulmonary function testing during the COVID-19 pandemic due to recently reported correlation between cholinesterase and COVID-19 pneumonia severity/mortality, and it was shown that cholinesterase levels are reduced in the acute phase of severe COVID-19 pneumonia. This work describes the microfabrication of potentiometric sensors using copper as the substrate and chemically polymerized graphene nanocomposites as the transducing layer for tracking the kinetics of MCH enzymatic degradation in real blood samples. The in-vitro estimation of the characteristic parameters of the MCH metabolism [Michaelis-Menten constant (K) and reaction velocity (V)] were found to be 241.041 μM and 56.8 μM/min, respectively. The proposed sensor is designed to be used as a companion diagnostic device that can (i) answer questions about patient eligibility to perform methacholine challenge tests, (ii) individualize/personalize medical dosing of methacholine, (iii) provide portable and inexpensive devices allowing automated readouts without the need for operator intervention (iv) recommend therapeutic interventions including intensive care during early stages and reflecting the disease state of COVID-19 pneumonia. We hope that this methacholine electrochemical sensor will help in assaying ChE activity in a "timely" manner and predict the severity and prognosis of COVID-19 to improve treatment outcomes and decrease mortality.
Topics: Biosensing Techniques; Bronchoconstrictor Agents; COVID-19; Humans; Methacholine Chloride; Pandemics; SARS-CoV-2
PubMed: 34166943
DOI: 10.1016/j.bios.2021.113439 -
Behavioural Brain Research May 2017Human and animal studies have shown that physical challenges and stressors during adolescence can have significant influences on behavioral and neurobiological...
Human and animal studies have shown that physical challenges and stressors during adolescence can have significant influences on behavioral and neurobiological development associated with internalizing disorders such as anxiety and depression. Given the prevalence of asthma during adolescence and increased rates of internalizing disorders in humans with asthma, we used a mouse model to test if and which symptoms of adolescent allergic asthma (airway inflammation or labored breathing) cause adult anxiety- and depression-related behavior and brain function. To mimic symptoms of allergic asthma in young BALB/cJ mice (postnatal days [P] 7-57; N=98), we induced lung inflammation with repeated intranasal administration of house dust mite extract (most common aeroallergen for humans) and bronchoconstriction with aerosolized methacholine (non-selective muscarinic receptor agonist). Three experimental groups, in addition to a control group, included: (1) "Airway inflammation only", allergen exposure 3 times/week, (2) "Labored breathing only", methacholine exposure once/week, and (3) "Airway inflammation+Labored breathing", allergen and methacholine exposure. Compared to controls, mice that experienced methacholine-induced labored breathing during adolescence displayed a ∼20% decrease in time on open arms of the elevated plus maze in early adulthood (P60), a ∼30% decrease in brainstem serotonin transporter (SERT) mRNA expression and a ∼50% increase in hippocampal serotonin receptor 1a (5Htr1a) and corticotropin releasing hormone receptor 1 (Crhr1) expression in adulthood (P75). This is the first evidence that experimentally-induced clinical symptoms of adolescent asthma alter adult anxiety-related behavior and brain function several weeks after completion of asthma manipulations.
Topics: Age Factors; Animals; Anxiety; Asthma; Behavior, Animal; Disease Models, Animal; Female; Gene Expression; Hippocampus; Male; Methacholine Chloride; Mice; Mice, Inbred BALB C; Muscarinic Agonists; Pyroglyphidae; Sex Factors
PubMed: 28284954
DOI: 10.1016/j.bbr.2017.02.046 -
The European Respiratory Journal Feb 2021Oxidised phosphatidylcholines (OxPCs) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in...
Oxidised phosphatidylcholines (OxPCs) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in allergic asthma is unexplored. The aim of this study was to characterise the OxPC profile in the airways after allergen challenge of people with airway hyperresponsiveness (AHR) or mild asthma. The capacity of OxPCs to contribute to pathobiology associated with asthma was also to be determined.Using bronchoalveolar lavage fluid from two human cohorts, OxPC species were quantified using ultra-high performance liquid chromatography-tandem mass spectrometry. Murine thin-cut lung slices were used to measure airway narrowing caused by OxPCs. Human airway smooth muscle (HASM) cells were exposed to OxPCs to assess concentration-associated changes in inflammatory phenotype and activation of signalling networks.OxPC profiles in the airways were different between people with and without AHR and correlated with methacholine responsiveness. Exposing patients with mild asthma to allergens produced unique OxPC signatures that associated with the severity of the late asthma response. OxPCs dose-dependently induced 15% airway narrowing in murine thin-cut lung slices. In HASM cells, OxPCs dose-dependently increased the biosynthesis of cyclooxygenase-2, interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor and the production of oxylipins protein kinase C-dependent pathways.Data from human cohorts and primary HASM cell culture show that OxPCs are present in the airways, increase after allergen challenge and correlate with metrics of airway dysfunction. Furthermore, OxPCs may contribute to asthma pathobiology by promoting airway narrowing and inducing a pro-inflammatory phenotype and contraction of airway smooth muscle. OxPCs represent a potential novel target for treating oxidative stress-associated pathobiology in asthma.
Topics: Administration, Inhalation; Allergens; Animals; Asthma; Humans; Methacholine Chloride; Mice; Phosphatidylcholines
PubMed: 32883680
DOI: 10.1183/13993003.00839-2020 -
Respiratory Care Dec 2021Methacholine bronchoprovocation or challenge testing (MCT) is commonly performed to assess airway hyper-responsiveness in the setting of suspected asthma. Nebulization...
BACKGROUND
Methacholine bronchoprovocation or challenge testing (MCT) is commonly performed to assess airway hyper-responsiveness in the setting of suspected asthma. Nebulization is an aerosol-generating procedure, but little is known about the risks of MCT in the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic. We aimed to quantify and characterize aerosol generation during MCT by using different delivery methods and to assess the impact of adding a viral filter.
METHODS
Seven healthy subjects performed simulated MCT in a near particle-free laboratory space with 4 different nebulizers and with a dosimeter. Two devices continuously sampled the ambient air during the procedure, which detected ultrafine particles, from 0.02-1 μm, and particles of sizes 0.3, 0.5, 1.0, 2.0, 5.0, and 10 µm, respectively. Particle generation was compared among all the devices, with and without viral filter placement.
RESULTS
Ultrafine-particle generation during simulated MCT was significant across all the devices. Ultrafine-particle (0.02-1 μm) concentrations decreased 77%-91% with the addition of a viral filter and varied significantly between unfiltered < .001) and filtered devices < .001). Ultrafine-particle generation was lowest when using the dosimeter with filtered Hudson nebulizer (1,258 ± 1,644 particle/mL). Ultrafine-particle concentrations with the filtered nebulizer devices using a compressor were higher than particle concentrations detected when using the dosimeter: Monaghan (3,472 ± 1,794 particles/mL), PARI (4,403 ± 2,948), Hudson (6,320 ± 1,787) and AirLife (9,523 ± 5,098).
CONCLUSIONS
The high particle concentrations generated during MCT pose significant infection control concerns during the COVID-19 pandemic. Particle generation during MCT was significantly reduced by using breath-actuated delivery and a viral filter, which offers an effective mitigation strategy.
Topics: Aerosols; COVID-19; Humans; Infection Control; Methacholine Chloride; Nebulizers and Vaporizers; Pandemics; Particle Size; SARS-CoV-2
PubMed: 34789516
DOI: 10.4187/respcare.09236