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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 -
American Journal of Physiology. Lung... Oct 2020Cobalt has been associated with allergic contact dermatitis and occupational asthma. However, the link between skin exposure and lung responses to cobalt is currently...
Cobalt has been associated with allergic contact dermatitis and occupational asthma. However, the link between skin exposure and lung responses to cobalt is currently unknown. We investigated the effect of prior dermal sensitization to cobalt on pulmonary physiological and immunological responses after subsequent challenge with cobalt via the airways. BALB/c mice received epicutaneous applications (25 μL/ear) with 5% CoCl6HO (Co) or the vehicle (Veh) dimethyl sulfoxide (DMSO) twice; they then received oropharyngeal challenges with 0.05% CoCl6HO or saline five times, thereby obtaining four groups: Veh/Veh, Co/Veh, Veh/Co, and Co/Co. To detect early respiratory responses noninvasively, we performed sequential in vivo microcomputed tomography (µCT). One day after the last challenge, we assessed airway hyperreactivity (AHR) to methacholine, inflammation in bronchoalveolar lavage (BAL), innate lymphoid cells (ILCs) and dendritic cells (DCs) in the lungs, and serum IgE. Compared with the Veh/Veh group, the Co/Co group showed increased µCT-derived lung response, increased AHR to methacholine, mixed neutrophilic and eosinophilic inflammation, elevated monocyte chemoattractant protein-1 (MCP-1), and elevated keratinocyte chemoattractant (KC) in BAL. Flow cytometry in the Co/Co group demonstrated increased DC, type 1 and type 2 conventional DC (cDC1/cDC2), monocyte-derived DC, increased ILC , and natural cytotoxicity receptorILC . The Veh/Co group showed only increased AHR to methacholine and elevated MCP-1 in BAL, whereas the Co/Veh group showed increased cDC1 and ILC2 in lung. We conclude that dermal sensitization to cobalt may increase the susceptibility of the lungs to inhaling cobalt. Mechanistically, this enhanced susceptibility involves changes in pulmonary DCs and ILCs.
Topics: Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cobalt; Disease Models, Animal; Inflammation; Lung; Lymphocytes; Methacholine Chloride; Mice, Inbred BALB C
PubMed: 32726143
DOI: 10.1152/ajplung.00265.2020 -
Allergy and Asthma Proceedings Sep 2021The bronchial provocation test (BPT) performed by using the forced oscillation technique (FOT) is cooperated without forced expiratory effort. However, a comparison of... (Randomized Controlled Trial)
Randomized Controlled Trial
The bronchial provocation test (BPT) performed by using the forced oscillation technique (FOT) is cooperated without forced expiratory effort. However, a comparison of the application value and safety of BPTs measured by using the FOT and the standardized dosimeter method is lacking, which limits its clinical practice. We aimed to analyze the diagnostic value and safety of the BPT as measured by the FOT in patients with asthma and in healthy subjects. This was a randomized cross-over clinical study. Airway responsiveness was measured by using the FOT and the aerosol provocation system (APS) dosimeter method in all the participants. The between-test interval was 24 hours. The diagnostic value and safety of the two tests were analyzed. Asthma control status was assessed based on ACT scores, and patients with asthma (including 27 uncontrolled, 34 partially controlled, and 32 controlled) were collected, and 69 healthy subjects were recruited. Receiver operating characteristic curves revealed slightly superior screening capability of cumulative dose of methacholine causing a 20% decrease (PD)-forced expiratory volume in the first second of expiration when measured by using the APS-dosimeter method (area under the curve [AUC] 0.981 [95% confidence interval {CI}, 0.952-1.000]) over that of cumulative dose of inhaled methacholine at the inflection point when respiratory resistance began to increase continuously (Dmin) by using the FOT (AUC 0.959 [95% CI, 0.924-0.994]). The sensitivity and specificity were 98.9% and 98.6%, respectively, with the APS-dosimeter method, and 100% and 87.0%, respectively, with the FOT. It took an average of 9.0 minutes (range, 6.0-11.0 minutes) when using the FOT and an average of 17.0 minutes (range, 14.0-25.0 minutes) when using APS-dosimeter method ( < 0.01) in all the participants. The measurement time for the FOT was reduced by 47.1% than the APS-dosimeter. The incidence rate of the adverse events with the FOT was slightly higher than that with the APS-dosimeter method ( < 0.05). Both tests were well tolerated. No serious adverse event was found. The FOT, characterized as being simple, safe, and time saving, could be used to assess airway hyperresponsiveness in patients with asthma and worthy of clinical application.
Topics: Asthma; Bronchial Provocation Tests; Forced Expiratory Volume; Humans; Methacholine Chloride; Respiratory System
PubMed: 34474715
DOI: 10.2500/aap.2021.42.210044 -
Experimental Physiology Feb 2020What is the central question of this study? We evaluated whether regional variations exist in NO-dependent cutaneous vasodilatation and sweating during cholinergic...
NEW FINDINGS
What is the central question of this study? We evaluated whether regional variations exist in NO-dependent cutaneous vasodilatation and sweating during cholinergic stimulation. What is the main finding and its importance? Peak cutaneous vasodilatation and sweating were greater on the torso than the forearm. Furthermore, we found that NO was an important modulator of cholinergic cutaneous vasodilatation, but not sweating, across body regions, with a greater contribution of NO to cutaneous vasodilatation in the limb compared with the torso. These findings advance our understanding of the mechanisms influencing regional variations in cutaneous vasodilator and sweating responses to pharmacological stimulation.
ABSTRACT
Regional variations in cutaneous vasodilatation and sweating exist across the body. Nitric oxide (NO) is an important modulator of these heat loss responses in the forearm. However, whether regional differences in NO-dependent cutaneous vasodilatation and sweating exist remain uncertain. In 14 habitually active young men (23 ± 4 years of age), cutaneous vascular conductance (CVC ) and local sweat rates were assessed at six skin sites. On each of the dorsal forearm, chest and upper back (trapezius), sites were continuously perfused with either lactated Ringer solution (control) or 10 mm N -nitro-l-arginine (l-NNA; an NO synthase inhibitor) dissolved in Ringer solution, via microdialysis. At all sites, cutaneous vasodilatation and sweating were induced by co-administration of the cholinergic agonist methacholine (1, 10, 100, 1000 and 2000 mm; 25 min per dose) followed by 50 mm sodium nitroprusside (20-25 min) to induce maximal vasodilatation. The l-NNA attenuated CVC relative to the control conditions for all regions (all P < 0.05), and NO-dependent vasodilatation was greater at the forearm compared with the back and chest (both P < 0.05). Furthermore, maximal vasodilatation was higher at the back and chest relative to the forearm (both P < 0.05). Conversely, l-NNA had negligible effects on sweating across the body (all P > 0.05). Peak local sweat rate was higher at the back relative to the forearm (P < 0.05), with a similar trend observed for the chest. In habitually active young men, NO-dependent cholinergic cutaneous vasodilatation varied across the body, and the contribution to cholinergic sweating was negligible. These findings advance our understanding of the mechanisms influencing regional variations in cutaneous vasodilatation and sweating during pharmacological stimulation.
Topics: Adult; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Injections, Subcutaneous; Male; Methacholine Chloride; Muscarinic Agonists; Nitric Oxide Synthase; Nitroarginine; Skin; Sweating; Vasodilation; Young Adult
PubMed: 31821642
DOI: 10.1113/EP088295 -
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 -
The Journal of Asthma : Official... Apr 2022Evaluation of airway inflammation and dysfunction is important in management of allergic rhinitis (AR) since AR is a risk factor for developing asthma. Theoretical...
OBJECTIVE
Evaluation of airway inflammation and dysfunction is important in management of allergic rhinitis (AR) since AR is a risk factor for developing asthma. Theoretical nonlinear modeling of exhaled nitric oxide (NO) has revealed extended flow-independent NO parameters that could explain where or how NO metabolism was altered. We aimed to evaluate the association between extended NO parameters and bronchial hyperresponsiveness (BHR) in children with AR.
METHODS
Exhaled NO was measured in 74 children with AR on the same day they underwent the provocholine challenge test (PCT). Extended NO was measured in three different exhaled flow rates (30, 100, 200 mL/s) and calculated using the Högman-Meriläinen model. We compared the extended NO parameters including bronchial NO (JawNO), airway tissue NO (CawNO), alveolar tissue NO (CaNO), and diffusing capacity of NO (DawNO) between AR with and without BHR groups, and analyzed the correlation between extended NO parameters and the response-dose ratio (RDR) of the PCT. We additionally evaluated 49 respiratory healthy controls.
RESULTS
Among the 74 children with AR, nine showed BHR. JawNO increased more in children with AR than the control group. In children with AR, JawNO was higher in the AR with BHR than without BHR group, and was correlated positively with log RDR ( = 0.373, = .001).
CONCLUSIONS
Extended NO analysis including JawNO can be a useful tool for assessing BHR in AR.
Topics: Asthma; Bronchi; Bronchial Hyperreactivity; Child; Humans; Methacholine Chloride; Nitric Oxide; Rhinitis, Allergic
PubMed: 33210567
DOI: 10.1080/02770903.2020.1845724 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Jun 2022To investigate the roles of angiotensin-converting enzyme 2 (ACE2) in ozone-induced pulmonary inflammation and airway remodeling in mice.
OBJECTIVE
To investigate the roles of angiotensin-converting enzyme 2 (ACE2) in ozone-induced pulmonary inflammation and airway remodeling in mice.
METHODS
Sixteen wild-type (WT) C57BL/6J mice and 16 ACE2 knock-out (KO) mice were exposed to either filtered air or ozone (0.8 ppm) for 3 h per day for 5 consecutive days. Masson's staining and HE staining were used to observe lung pathologies. Bronchoalveolar lavage fluid (BALF) was collected and the total cell count was determined. The total proteins and cytokines in BALF were determined by BCA and ELISA method. The transcription levels of airway remodeling-related indicators in the lung tissues were detected using real-time quantitative PCR. The airway resistance of the mice was measured using a small animal ventilator with methacholine stimulation.
RESULTS
Following ozoneexposure ACE2 KO mice had significantly higher lung pathological scores than WT mice ( < 0.05). Masson staining results showed that compared with ozone-exposed WT mice, ozone-exposed ACE2 KO mice presented with significantly larger area of collagen deposition in the bronchi [(19.62±3.16)% (6.49±1.34)%, < 0.05] and alveoli [(21.63±3.78)% (4.44±0.99)%, < 0.05]. The total cell count and total protein contents in the BALF were both higher in ozone-exposed ACE2 KO mice than in WT mice, but these differences were not statistically significant ( > 0.05). The concentrations of IL-6, IL-1β, TNF-, CXCL1/KC and MCP-1 in the BALF were all higher in ozone-exposed ACE2 KO mice than in ozone-exposed WT mice, but only the difference in IL-1β was statistically significant ( < 0.05). The transcription levels of MMP-9, MMP-13, TIMP 4, COL1A1, and TGF-β in the lung tissues were all significantly higher in ozone-exposed ACE2 KO mice ( < 0.01). No significant difference was found in airway resistance between ozone-exposed ACE KO mice and WT mice after challenge with 0, 10, 25, or 100 mg/mL of methacholine.
CONCLUSION
ACE2 participates in ozone-induced lung inflammation and airway remodeling in mice.
Topics: Airway Remodeling; Angiotensin-Converting Enzyme 2; Animals; Methacholine Chloride; Mice; Mice, Inbred C57BL; Mice, Knockout; Ozone; Pneumonia
PubMed: 35790436
DOI: 10.12122/j.issn.1673-4254.2022.06.09 -
The British Journal of Nutrition Sep 2021PUFA modulate immune function and have been associated with the risk of childhood atopy and asthma. We investigated the effect of maternal fat intake in mice on PUFA...
PUFA modulate immune function and have been associated with the risk of childhood atopy and asthma. We investigated the effect of maternal fat intake in mice on PUFA status, elongase and desaturase gene expression, inflammatory markers and lung function in the offspring. C57BL/6J mice (n 32) were fed either standard chow (C, 20·4 % energy as fat) or a high-fat diet (HFD, 39·9 % energy as fat) for 4 weeks prior to conception and during gestation and lactation. At 21 d of age, offspring were weaned onto either the HFD or C, generating four experimental groups: C/C, C/HF, HF/C and HF/HF. Plasma and liver fatty acid composition were measured by GC and gene expression by quantitative PCR. Lung resistance to methacholine was assessed. Arachidonic acid concentrations in offspring plasma and liver phospholipids were increased by HFD; this effect was greater in the post-natal HFD group. DHA concentration in offspring liver phospholipids was increased in response to HFD and was higher in the post-natal HFD group. Post-natal HFD increased hepatic fatty acid desaturase (FADS) 2 and elongation of very long-chain fatty acid 5 expression in male offspring, whereas maternal HFD elevated expression of FADS1 and FADS2 in female offspring compared with males. Post-natal HFD increased expression of IL-6 and C-C motif chemokine ligand 2 (CCL2) in perivascular adipose tissue. The HFD lowered lung resistance to methacholine. Excessive maternal fat intake during development modifies hepatic PUFA status in offspring through regulation of gene expression of enzymes that are involved in PUFA biosynthesis and modifies the development of the offspring lungs leading to respiratory dysfunction.
Topics: Animals; Arachidonic Acid; Diet, High-Fat; Female; Liver; Lung; Male; Maternal Nutritional Physiological Phenomena; Methacholine Chloride; Mice; Mice, Inbred C57BL; Phospholipids; Pregnancy
PubMed: 33243305
DOI: 10.1017/S0007114520004742 -
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