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Respirology (Carlton, Vic.) Jul 2019
Topics: Aged; Asthma; Humans; Methacholine Chloride; Obesity; Phenotype; Respiratory System
PubMed: 30901134
DOI: 10.1111/resp.13533 -
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 -
Respiratory Care Mar 2021A 20% reduction in the FEV is routinely used as an end point for methacholine challenge testing (MCT). Measurement of FEV is effort dependent, and some patients are not...
BACKGROUND
A 20% reduction in the FEV is routinely used as an end point for methacholine challenge testing (MCT). Measurement of FEV is effort dependent, and some patients are not able to perform acceptable and repeatable forced expiration maneuvers. The goal of the present study was to investigate the diagnostic value of airway resistance measurement by forced oscillation technique (FOT), body plethysmography, and interrupter technique compared with the traditionally accepted standard FEV measurement in evaluating the responsiveness to methacholine during MCT.
METHODS
We included in the study adult subjects referred for MCT because of asthma-like symptoms and with normal baseline spirometry. We modified routine MCT protocol by adding the assessment of airway resistance to the measurement of FEV at each step of MCT.
RESULTS
We observed, in the subjects with airway hyper-responsiveness versus those with normal airway responsiveness, a significantly greater percentage change in median (interquartile range) FOT resistance at 10 Hz (25.9% [13.7%-35.4%] vs 16% [15.7%-27.2%]), plethysmographic resistance (70.2% [39.5%-116.3%] vs 37.1% [23.9%-81.9%]), and mean ± SD conductance (-41.3 ± 15.4% vs -29.6 ± 15.9%); and a significantly greater change in mean ± SD FOT reactance at 10 Hz (-0.41 ± 0.48 cm HO/L/s vs -0.09 ± 0.32 cm HO/L/s) and at 15 Hz (-0.29 ± 0.2 cm HO/L/s vs -0.1 ± 0.19 cm HO/L/s). We also recorded significant differences in airway resistance parameters (FOT resistance at 10 Hz, FOT reactance at 15 Hz, plethysmographic airway resistance, and conductance indices as well as interrupter resistance) in FEV non-responders at the onset of respiratory symptoms during MCT compared with baseline.
CONCLUSIONS
Measurements of airway resistance could possibly be used as an alternative method to spirometry in airway challenge. Significant changes in airway mechanics during MCT are detectable by airway resistance measurement in FEV non-responders with methacholine-induced asthma-like symptoms. (ClinicalTrials.gov registration NCT02343419.).
Topics: Adult; Airway Resistance; Bronchial Provocation Tests; Forced Expiratory Volume; Humans; Methacholine Chloride; Spirometry
PubMed: 33203723
DOI: 10.4187/respcare.08331 -
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 -
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 -
Drug Design, Development and Therapy 2020Hesperetin-5,7,3'--trimethylether (HTME), a synthetic liposoluble hesperetin, has been reported to be a dual phosphodiesterase (PDE)3/4 inhibitor. We investigated its...
INTRODUCTION
Hesperetin-5,7,3'--trimethylether (HTME), a synthetic liposoluble hesperetin, has been reported to be a dual phosphodiesterase (PDE)3/4 inhibitor. We investigated its inhibitory effects on methacholine (MCh)-induced airway hyperresponsiveness (AHR) and its potential for treating atypical asthma and COPD.
METHODS
FlexiVent system was used to determine AHR in ovalbumin (OVA) sensitized and challenged mice. Determination of cytokines was performed by using mouse T helper (Th)1/Th2 cytokine CBA kits, and of total immunoglobulin (Ig)E and OVA-specific IgE using ELISA kits. The number of inflammatory cells was counted using a hemocytometer. Xylazine/ketamine-induced anesthesia was to assess nausea, vomiting, and gastric hypersecretion in these mice.
RESULTS
HTME dually and competitively inhibited PDE3/4 activities in the Lineweaver-Burk analysis. HTME (30 and 100 μmol/kg) dose-dependently and significantly decreased the airway resistance (R) and increased lung dynamic compliance (C) values induced by MCh. It significantly suppressed numbers of total inflammatory cells and neutrophils, and levels of cytokines in bronchoalveolar lavage fluid (BALF). HTME dose-dependently and significantly inhibited total and OVA-specific IgE levels in the BALF and serum. However, HTME did not influence xylazine/ketamine-induced anesthesia.
CONCLUSION
HTME exerted anti-inflammatory and bronchodilator effects and may be useful in treating chronic obstructive pulmonary disease and allergic atypical asthma with no gastrointestinal side effects.
Topics: Animals; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Female; Hesperidin; Methacholine Chloride; Mice; Mice, Inbred BALB C; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Respiratory Hypersensitivity
PubMed: 32099334
DOI: 10.2147/DDDT.S227432 -
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 -
Pulmonary Pharmacology & Therapeutics Feb 2015Mice with Plp1 gene duplication model the most common form of Pelizaeus-Merzbacher disease (PMD), a CNS disease in which patients may suffer respiratory complications....
Mice with Plp1 gene duplication model the most common form of Pelizaeus-Merzbacher disease (PMD), a CNS disease in which patients may suffer respiratory complications. We hypothesized that affected mice would lack airway responsiveness compared to wild-type and carrier mice during methacholine challenge. Wild-type (n = 10), carrier female (n = 6) and affected male (n = 8) mice were anesthetized-paralyzed, tracheostomized and ventilated. Respiratory mechanics were recorded at baseline and during escalating doses of nebulized methacholine followed by albuterol. Lung resistance (RL) was the primary endpoint. Lung tissues were assayed for inflammatory and histological differences. At baseline, phase angles were higher in carrier and affected mice than wild-type. Dose-response RL curves in affected and carrier mice indicated a lack of methacholine response. Albuterol reduced RL in wild-type and carrier, but not affected mice. Affected mice exhibited lower interleukin (IL)-6 tissue levels and alveolar inflammatory infiltrates. Affected and carrier mice, compared to wild-type, lacked airway reactivity during methacholine challenge, but only affected mice exhibited decreased lung tissue levels of IL-6 and inflammation.
Topics: Albuterol; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Duplication; Interleukin-6; Male; Methacholine Chloride; Mice; Myelin Proteolipid Protein; Pelizaeus-Merzbacher Disease; Pneumonia; Respiratory Mechanics
PubMed: 25445931
DOI: 10.1016/j.pupt.2014.10.004 -
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