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Journal of Applied Physiology... Dec 2021Late-onset nonallergic (LONA) asthma in obesity is characterized by increased peripheral airway closure secondary to abnormally collapsible airways. We hypothesized that...
Late-onset nonallergic (LONA) asthma in obesity is characterized by increased peripheral airway closure secondary to abnormally collapsible airways. We hypothesized that positive expiratory pressure (PEP) would mitigate the tendency to airway closure during bronchoconstriction, potentially serving as rescue therapy for LONA asthma of obesity. The PC [provocative concentration of methacholine causing 20% drop in forced expiratory volume in 1 s (FEV1)] dose of methacholine was determined in 18 obese participants with LONA asthma. At each of four subsequent visits, we used oscillometry to measure input respiratory impedance (Z) over 8 min; participants received their PC concentration of methacholine aerosol during the first 4.5 min. PEP combinations of either 0 or 10 cmHO either during and/or after the methacholine delivery were applied, randomized between visits. Parameters characterizing respiratory system mechanics were extracted from the Z spectra. In 18 patients with LONA asthma [14 females, body mass index (BMI): 39.6 ± 3.4 kg/m], 10 cmHO PEP during methacholine reduced elevations in the central airway resistance, peripheral airway resistance, and elastance, and breathing frequency was also reduced. During the 3.5 min following methacholine delivery, PEP of 10 cmHO reduced A and peripheral elastance compared with no PEP. PEP mitigates the onset of airway narrowing brought on by methacholine challenge and airway closure once it is established. PEP thus might serve as a nonpharmacological therapy to manage acute airway narrowing for obese LONA asthma. Standard pharmacological treatments are not effective in people with obesity and asthma. We assessed the efficacy of positive expiratory pressure (PEP) as a therapy to mitigate airway hyperresponsiveness in the asthma of obesity. Our results indicate that PEP might serve as a nonpharmacological therapy to manage acute airway narrowing in obese individuals with late-onset nonallergic asthma.
Topics: Asthma; Bronchial Provocation Tests; Bronchoconstriction; Female; Forced Expiratory Volume; Humans; Methacholine Chloride; Obesity
PubMed: 34647827
DOI: 10.1152/japplphysiol.00399.2021 -
Physiological Reports Sep 2019Ozone causes airway hyperresponsiveness, a defining feature of asthma, and is an asthma trigger. In mice, ozone-induced airway hyperresponsiveness is greater in males...
Ozone causes airway hyperresponsiveness, a defining feature of asthma, and is an asthma trigger. In mice, ozone-induced airway hyperresponsiveness is greater in males than in females, suggesting a role for sex hormones in the response to ozone. To examine the role of androgens in these sex differences, we castrated 4-week-old mice. Controls underwent sham surgery. At 8 weeks of age, mice were exposed to ozone (2ppm, 3 h) or room air. Twenty-four hours later, mice were anesthetized and measurements of airway responsiveness to inhaled aerosolized methacholine were made. Mice were then euthanized and bronchoalveolar lavage was performed. Castration attenuated ozone-induced airway hyperresponsiveness and reduced bronchoalveolar lavage cells. In intact males, flutamide, an androgen receptor inhibitor, had similar effects to castration. Bronchoalveolar lavage concentrations of several cytokines were reduced by either castration or flutamide treatment, but only IL-1α was reduced by both castration and flutamide. Furthermore, an anti-IL-1α antibody reduced bronchoalveolar lavage neutrophils in intact males, although it did not alter ozone-induced airway hyperresponsiveness. Our data indicate that androgens augment pulmonary responses to ozone and that IL-1α may contribute to the effects of androgens on ozone-induced cellular inflammation but not airway hyperresponsiveness.
Topics: Androgen Antagonists; Androgens; Animals; Bronchoalveolar Lavage Fluid; Corticosterone; Cytokines; Flutamide; Interleukin-1alpha; Interleukin-6; Lung; Male; Methacholine Chloride; Mice, Inbred C57BL; Neutrophil Infiltration; Orchiectomy; Oxidative Stress; Ozone; Pneumonia; Respiratory Hypersensitivity; Respiratory Mechanics; Sex Characteristics
PubMed: 31544355
DOI: 10.14814/phy2.14214 -
Respiratory Care Jun 2022There are several tests recommended by the American Thoracic Society (ATS) to evaluate for airway hyper-responsiveness (AHR), one of which is methacholine challenge...
BACKGROUND
There are several tests recommended by the American Thoracic Society (ATS) to evaluate for airway hyper-responsiveness (AHR), one of which is methacholine challenge testing (MCT). Few studies have examined the correlation of baseline spirometry to predict AHR in MCT, especially in the younger, relatively healthy military population under clinical evaluation for symptoms of exertional dyspnea. The study aim was to retrospectively correlate baseline spirometry values with MCT responsiveness.
METHODS
This study is a retrospective review of all MCT performed at Brooke Army Medical Center/Wilford Hall Medical Center over a 12-y period; all completed studies were obtained from electronic databases. The following parameters were analyzed from the studies: baseline FEV, FVC, FEV/FVC, mid-expiratory flow (FEV), FEV/FVC. Studies were categorized based on baseline obstruction, restriction, FEF lower limit of normal, and response to bronchodilator testing (if completed); these values were compared based on methacholine reactivity and severity.
RESULTS
Methacholine challenge studies ( 1,933) were reviewed and categorized into reactive ( 577) and nonreactive ( 1,356) as determined by ATS guidelines. The mean baseline FEV (% predicted) with MCT reactivity was 88.0 ± 13.0% versus no MCT reactivity was 92.7 ± 13.0% ( < .001). The mean baseline FVC (% predicted) was 93.1 ± 13.7% versus 95.3 ± 13.5% ( < .001). The mean baseline FEV (% predicted) was 80.0 ± 22.1% versus 89.0 ± 23.4% ( < .001). Based on partition analysis, methacholine reactivity was most prevalent with baseline obstruction, 115 (43%), and in the absence of obstruction, when the FEF (% predicted) was below 0.70, 111 (40%). The negative predictive value with normal spirometry was 73%.
CONCLUSIONS
The analysis of baseline spirometry prior to MCT proved useful in the evaluation of exertional dyspnea in a military population. The presence of airways obstruction (FEV/FVC < lower limit of the normal range) followed by a reduction in FEV < 70% predicted showed a positive correlation with underlying AHR. In patients with exertional dyspnea and normal baseline spirometry, the use of the FEF may be a useful surrogate measurement to predict reactivity during MCT and consideration for additional testing or treatment.
Topics: Bronchial Provocation Tests; Dyspnea; Forced Expiratory Volume; Humans; Methacholine Chloride; Retrospective Studies; Spirometry
PubMed: 35042746
DOI: 10.4187/respcare.09163 -
PloS One 2015Mechanisms driving alteration of lung function in response to inhalation of a methacholine aerosol are incompletely understood. To explore to what extent large and small... (Clinical Trial)
Clinical Trial
Mechanisms driving alteration of lung function in response to inhalation of a methacholine aerosol are incompletely understood. To explore to what extent large and small airways contribute to airflow limitation and airway closure in this context, volumetric capnography was performed before (n = 93) and after (n = 78) methacholine provocation in subjects with an intermediate clinical probability of asthma. Anatomical dead space (VDaw), reflecting large airway volume, and the slope of the alveolar capnogram (slope3), an index of ventilation heterogeneity linked to small airway dysfunction, were determined. At baseline, VDaw was positively correlated with lung volumes, FEV1 and peak expiratory flow, while slope3 was not correlated with any lung function index. Variations in VDaw and slope3 following methacholine stimulation were correlated to a small degree (R2 = -0.20). Multivariate regression analysis identified independent associations between variation in FEV1 and variations in both VDaw (Standardized Coefficient-SC = 0.66) and Slope3 (SC = 0.35). By contrast, variation in FVC was strongly associated with variations in VDaw (SC = 0.8) but not Slope3. Thus, alterations in the geometry and/or function of large and small airways were weakly correlated and contributed distinctly to airflow limitation. While both large and small airways contributed to airflow limitation as assessed by FEV1, airway closure as assessed by FVC reduction mostly involved the large airways.
Topics: Adult; Bronchial Provocation Tests; Bronchoconstrictor Agents; Female; Forced Expiratory Volume; Humans; Lung; Male; Methacholine Chloride; Middle Aged; Tidal Volume
PubMed: 26599006
DOI: 10.1371/journal.pone.0143550 -
Investigative Ophthalmology & Visual... Jun 2021Patients that medicate with antidepressants commonly report dryness of eyes. The cause is often attributed to the anticholinergic properties of the drugs. However,...
PURPOSE
Patients that medicate with antidepressants commonly report dryness of eyes. The cause is often attributed to the anticholinergic properties of the drugs. However, regulation of tear production includes a substantial reflex-evoked component and is regulated via distinct centers in the brain. Further, the anticholinergic component varies greatly among antidepressants with different mechanisms of action. In the current study it was wondered if acute administration of antidepressants can disturb production of tears by affecting the afferent and/or central pathway.
METHODS
Tear production was examined in vivo in anesthetized rats in the presence or absence of the tricyclic antidepressant (TCA) clomipramine or the selective serotonin reuptake inhibitor (SSRI) escitalopram. The reflex-evoked production of tears was measured by challenging the surface of the eye with menthol (0.1 mM) and cholinergic regulation was examined by intravenous injection with the nonselective muscarinic agonist methacholine (1-5 µg/kg).
RESULTS
Acute administration of clomipramine significantly attenuated both reflex-evoked and methacholine-induced tear production. However, escitalopram only attenuated reflex-evoked tear production, while methacholine-induced production of tears remained unaffected.
CONCLUSIONS
This study shows that antidepressants with different mechanisms of action can impair tear production by attenuating reflex-evoked signaling. Further, antimuscarinic actions are verified as a likely cause of lacrimal gland hyposecretion in regard to clomipramine but not escitalopram. Future studies on antidepressants with different selectivity profiles and mechanisms of action are required to further elucidate the mechanisms by which antidepressants affect tear production.
Topics: Animals; Antidepressive Agents; Cholinergic Antagonists; Citalopram; Clomipramine; Dry Eye Syndromes; Evoked Potentials, Visual; Lacrimal Apparatus; Methacholine Chloride; Miotics; Rats; Tears
PubMed: 34096973
DOI: 10.1167/iovs.62.7.8 -
Respiratory Medicine Sep 2021Bronchial hyperresponsiveness (BHR) is a key pathophysiological feature of asthma. Methacholine challenge test (MCT) is a common bronchoprovocation test useful for...
BACKGROUND
Bronchial hyperresponsiveness (BHR) is a key pathophysiological feature of asthma. Methacholine challenge test (MCT) is a common bronchoprovocation test useful for confirming a diagnosis of asthma. Studies of BHR in the general population of Asian countries are rare.
AIM
To estimate prevalence and determinants of BHR in Hanoi, Vietnam, and to study the association between BHR and symptoms common in asthma and previously diagnosed asthma.
METHODS
1500 out of 5872 randomly selected adults in urban and rural Hanoi, who had participated in a questionnaire survey (83% participated), were randomly selected and invited to clinical examinations. Totally 684 subjects (46%) participated. MCT was performed in 366 subjects. BHR was defined as a FEV-decrease of ≥20% from baseline following methacholine inhalations (PC). Cut offs used in the analyses were PC ≤ 1 mg/ml, ≤2 mg/ml and ≤8 mg/ml.
RESULTS
The prevalence of BHR was 16.4% at doses ≤8 mg/ml, while 9.6% reacted on doses ≤2 mg/ml. PC ≤ 2 mg/ml was associated with FEV <80% of predicted. PC ≤ 2 mg/ml, but not PC ≤ 8 mg/ml, was associated with multi-sensitization to airborne allergens. BHR defined as PC ≤ 8 mg/ml was associated with age >45y. The combination of asthmatic wheeze (wheezing with breathlessness apart from colds) and BHR, irrespectively of magnitude of BHR, was more common than the combination of BHR with previously diagnosed asthma.
CONCLUSIONS
The results indicate BHR to be more common in Hanoi than previously found in south-east Asia. Although the prevalence of physician diagnosed asthma has increased in Vietnam, our results indicate that asthma still may be underdiagnosed in Vietnam.
Topics: Adult; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Middle Aged; Prevalence; Surveys and Questionnaires; Vietnam
PubMed: 34246130
DOI: 10.1016/j.rmed.2021.106513 -
Annals of Cardiac Anaesthesia 2015Exertional-induced bronchoconstriction is a condition in which the physical activity causes constriction of airways in patients with airway hyper- responsiveness. In... (Comparative Study)
Comparative Study
INTRODUCTION
Exertional-induced bronchoconstriction is a condition in which the physical activity causes constriction of airways in patients with airway hyper- responsiveness. In this study, we tried to study and evaluate any relationship between the findings of cardiopulmonary exercise testing (CPET) and the response to methacholine challenge test (MCT) in patients with dyspnea after activity.
MATERIALS AND METHODS
Thirty patients with complaints of dyspnea following activity referred to "Lung Clinic" of Baqiyatallah Hospital but not suffering from asthma were entered into the study. The subjects were excluded from the study if: Suffering from any other pulmonary diseases, smoking more than 1 cigarette a week in the last year, having a history of smoking more than 10 packets of cigarettes/year, having respiratory infection in the past 4 weeks, having abnormal chest X-ray or electrocardiogram, and cannot discontinue the use of medicines interfering with bronchial provocation. Baseline spirometry was performed for all the patients, and the values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV/FVC were recorded. The MCT and then the CPET were performed on all patients.
RESULTS
The mean VO 2 (volume oxygen) in patients with positive methacholine test (20.45 mL/kg/min) was significantly lower than patients with negative MCT (28.69 mL/kg/min) (P = 0.000). Respiratory rates per minute (RR) and minute ventilation in the group with positive MCT (38.85 and 1.636 L) were significantly lower than the group with negative methacholine test (46.78 and 2.114 L) (P < 0.05). Also, the O 2 pulse rate in the group with negative methacholine test (116.27 mL/beat) was significantly higher than the group with positive methacholine test (84.26 mL/beat) (P < 0.001).
CONCLUSION
Pulmonary response to exercise in patients with positive methacholine test is insufficient. The dead space ventilation in these patients has increased. Also, dynamic hyperinflation in patients with positive methacholine test causes the reduced stroke volume and O 2 pulse in these patients.
Topics: Adolescent; Adult; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Exercise Test; Female; Humans; Male; Methacholine Chloride; Middle Aged; Young Adult
PubMed: 26440232
DOI: 10.4103/0971-9784.166443 -
American Journal of Respiratory Cell... Aug 2016Obese asthma presents with inherent hyperresponsiveness to methacholine or augmented allergen-driven allergic asthma, with an even greater magnitude of methacholine...
Obese asthma presents with inherent hyperresponsiveness to methacholine or augmented allergen-driven allergic asthma, with an even greater magnitude of methacholine hyperresponsiveness. These physiologic parameters and accompanying obese asthma symptoms can be reduced by successful weight loss, yet the underlying mechanisms remain incompletely understood. We implemented mouse models of diet-induced obesity, dietary and surgical weight loss, and environmental allergen exposure to examine the mechanisms and mediators of inherent and allergic obese asthma. We report that the methacholine hyperresponsiveness in these models of inherent obese asthma and obese allergic asthma manifests in distinct anatomical compartments but that both are amenable to interventions that induce substantial weight loss. The inherent obese asthma phenotype, with characteristic increases in distal airspace tissue resistance and tissue elastance, is associated with elevated proinflammatory cytokines that are reduced with dietary weight loss. Surprisingly, bariatric surgery-induced weight loss further elevates these cytokines while reducing methacholine responsiveness to levels similar to those in lean mice or in formerly obese mice rendered lean through dietary intervention. In contrast, the obese allergic asthma phenotype, with characteristic increases in central airway resistance, is not associated with increased adaptive immune responses, yet diet-induced weight loss reduces methacholine hyperresponsiveness without altering immunological variables. Diet-induced weight loss is effective in models of both inherent and allergic obese asthma, and our examination of the fecal microbiome revealed that the obesogenic Firmicutes/Bacteroidetes ratio was normalized after diet-induced weight loss. Our results suggest that structural, immunological, and microbiological factors contribute to the manifold presentations of obese asthma.
Topics: Animals; Asthma; Bacteria; Bariatric Surgery; Bronchial Hyperreactivity; Cytokines; Diet; Disease Models, Animal; Hypersensitivity; Inflammation Mediators; Intestines; Male; Methacholine Chloride; Mice, Inbred C57BL; Mice, Obese; Obesity; Weight Loss
PubMed: 27064658
DOI: 10.1165/rcmb.2016-0070OC -
Journal of Applied Physiology... May 2019Overnight analysis of tidal breathing flow volume (TBFV) loops, recorded by impedance pneumography (IP), has been successfully applied in the home monitoring of children...
Overnight analysis of tidal breathing flow volume (TBFV) loops, recorded by impedance pneumography (IP), has been successfully applied in the home monitoring of children with wheezing disorders. However, little is known on how sleep physiology modifies the relationship between TBFV profiles and wheeze. We studied such interactions in wheezing infants. Forty-three infants recruited because of recurrent lower airway symptoms were divided into three groups based on their risk of asthma: high (HR), intermediate (IR), or low (LR). Sedated patients underwent infant lung function testing including assessment of airway responsiveness to methacholine at the hospital and a full-night recording of TBFV profiles at home with IP during natural sleep. Overnight TBFV indexes were estimated from periods of higher and lower respiration variability, presumably belonging to active [rapid eye movement (REM)] and quiet [non-REM (NREM)] sleep, respectively. From 35 valid recordings, absolute time indexes showed intrasubject sleep phase differences. Peak flow relative to time and volume was lower in HR compared with LR only during REM, suggesting altered expiratory control. Indexes estimating the concavity/convexity of flow decrease during exhalation suggested limited flow during passive exhale in HR compared with IR and LR, similarly during NREM and REM. Moreover, during REM convexity was negatively correlated with maximal flow at functional residual capacity and methacholine responsiveness. We conclude that TBFV profiles determined from overnight IP recordings vary because of sleep phase and asthma risk. Physiological changes during REM, most likely decrease in respiratory muscle tone, accentuate the changes in TBFV profiles caused by airway obstruction. Impedance pneumography was used to investigate overnight tidal breathing flow volume (TBFV) indexes and their interactions with sleep phase [rapid eye movement (REM) vs. non-REM] at home in wheezing infants. The study shows that TBFV indexes vary significantly because of sleep phase and asthma risk of the infant and that during REM the changes in TBFV indexes caused by airway obstruction are accentuated and better associated with lung function of the infant.
Topics: Airway Obstruction; Asthma; Electric Impedance; Exhalation; Female; Functional Residual Capacity; Humans; Infant; Male; Methacholine Chloride; Peak Expiratory Flow Rate; Respiration; Respiratory Function Tests; Respiratory Sounds; Respiratory System; Sleep; Tidal Volume
PubMed: 30763165
DOI: 10.1152/japplphysiol.01007.2018 -
Journal of Applied Physiology... Jan 2020Obesity is associated with reduced operating lung volumes that may contribute to increased airway closure during tidal breathing and abnormalities in ventilation...
Obesity is associated with reduced operating lung volumes that may contribute to increased airway closure during tidal breathing and abnormalities in ventilation distribution. We investigated the effect of obesity on the topographical distribution of ventilation before and after methacholine-induced bronchoconstriction using single-photon emission computed tomography (SPECT)-computed tomography (CT) in healthy subjects. Subjects with obesity ( = 9) and subjects without obesity ( = 10) underwent baseline and postbronchoprovocation SPECT-CT imaging, in which Technegas was inhaled upright and followed by supine scanning. Lung regions that were nonventilated (Vent), low ventilated (Vent), or well ventilated (Vent) were calculated using an adaptive threshold method and were expressed as a percentage of total lung volume. To determine regional ventilation, lungs were divided into upper, middle, and lower thirds of axial length, derived from CT. At baseline, Vent and Vent for the entire lung were similar in subjects with and without obesity. However, in the upper lung zone, Vent (17.5 ± 10.6% vs. 34.7 ± 7.8%, < 0.001) and Vent (25.7 ± 6.3% vs. 33.6 ± 5.1%, < 0.05) were decreased in subjects with obesity, with a consequent increase in Vent (56.8 ± 9.2% vs. 31.7 ± 10.1%, < 0.001). The greater diversion of ventilation to the upper zone was correlated with body mass index ( = 0.74, < 0.001), respiratory system resistance ( = 0.72, < 0.001), and respiratory system reactance ( = -0.64, = 0.003) but not with lung volumes or basal airway closure. Following bronchoprovocation, overall Vent increased similarly in both groups; however, in subjects without obesity, Vent only increased in the lower zone, whereas in subjects with obesity, Vent increased more evenly across all lung zones. In conclusion, obesity is associated with altered ventilation distribution during baseline and following bronchoprovocation, independent of reduced lung volumes. Using ventilation SPECT-computed tomography imaging in healthy subjects, we demonstrate that ventilation in obesity is diverted to the upper lung zone and that this is strongly correlated with body mass index but is independent of operating lung volumes and of airway closure. Furthermore, methacholine-induced bronchoconstriction only occurred in the lower lung zone in individuals who were not obese, whereas in subjects who were obese, it occurred more evenly across all lung zones. These findings show that obesity-associated factors alter the topographical distribution of ventilation.
Topics: Adolescent; Adult; Aged; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Female; Humans; Lung Volume Measurements; Male; Methacholine Chloride; Middle Aged; Obesity; Pulmonary Ventilation; Respiratory Physiological Phenomena; Single Photon Emission Computed Tomography Computed Tomography; Young Adult
PubMed: 31751179
DOI: 10.1152/japplphysiol.00482.2019