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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 -
Journal of Applied Physiology... Jan 2021The obesity epidemic is causing a rise in asthma incidence due to the appearance of an obesity-specific late-onset nonallergic (LONA) phenotype. We investigated why only...
The obesity epidemic is causing a rise in asthma incidence due to the appearance of an obesity-specific late-onset nonallergic (LONA) phenotype. We investigated why only a subset of obese participants develop LONA asthma by determining how obesity, both alone and in combination with LONA asthma, affects the volume dependence of respiratory system impedance. We also determined how obesity and asthma affect impedance during and following challenge with the PC dose of methacholine. We found during passive exhalation that all obese participants, in contrast to lean controls and lean asthmatics, experienced similarly profound elevations in lung elastance as they approached functional residual capacity. We also found, however, that the LONA asthmatics had a greater negative dependence of airway resistance on lung volume over the middle of the volume range compared with the other groups. Methacholine challenge with the PC dose led to comparable changes in respiratory system impedance in the four study groups, but the doses themselves were substantially lower in both obese and lean asthmatic participants compared with obese and lean controls. Also, the obese LONA asthmatics had higher breathing frequencies and lower tidal volumes postchallenge compared with the other participants. Taken together, these results suggest that all obese individuals experience substantial lung collapse as they approach functional residual capacity, presumably due to the weight of the chest wall. It remains unclear why obese LONA asthmatics are hyperresponsive to methacholine while obese nonasthmatic individuals are not. Why only a subset of severely obese subjects develop late-onset nonallergic (LONA) asthma remains unknown, although it is widely assumed that compression of the lungs by the chest wall is somehow involved. We show that lung compression is common to obese individuals both without asthma and with LONA asthma but that those with LONA asthma may have increased airway wall compliance and possibly also a reduced ability to recruit collapsed lung.
Topics: Asthma; Bronchial Provocation Tests; Forced Expiratory Volume; Humans; Methacholine Chloride; Obesity
PubMed: 33119471
DOI: 10.1152/japplphysiol.00666.2020 -
Toxicology and Applied Pharmacology Dec 2020Hydraulic fracturing creates fissures in subterranean rock to increase the flow and retrieval of natural gas. Sand ("proppant") in fracking fluid injected into the well...
Hydraulic fracturing creates fissures in subterranean rock to increase the flow and retrieval of natural gas. Sand ("proppant") in fracking fluid injected into the well bore maintains fissure patency. Fracking sand dust (FSD) is generated during manipulation of sand to prepare the fracking fluid. Containing respirable crystalline silica, FSD could pose hazards similar to those found in work sites where silica inhalation induces lung disease such as silicosis. This study was performed to evaluate the possible toxic effects following inhalation of a FSD (FSD 8) in the lung and airways. Rats were exposed (6 h/d × 4 d) to 10 or 30 mg/m of a FSD collected at a gas well, and measurements were performed 1, 7, 27 and, in one series of experiments, 90 d post-exposure. The following ventilatory and non-ventilatory parameters were measured in vivo and/or in vitro: 1) lung mechanics (respiratory system resistance and elastance, tissue damping, tissue elastance, Newtonian resistance and hysteresivity); 2) airway reactivity to inhaled methacholine (MCh); airway epithelium integrity (isolated, perfused trachea); airway efferent motor nerve activity (electric field stimulation in vitro); airway smooth muscle contractility; ion transport in intact and cultured epithelium; airway effector and sensory nerves; tracheal particle deposition; and neurogenic inflammation/vascular permeability. FSD 8 was without large effect on most parameters, and was not pro-inflammatory, as judged histologically and in cultured epithelial cells, but increased reactivity to inhaled MCh at some post-exposure time points and affected Na transport in airway epithelial cells.
Topics: Administration, Inhalation; Animals; Dust; Epithelial Cells; Hydraulic Fracking; Inhalation Exposure; Lung; Male; Methacholine Chloride; Occupational Exposure; Rats; Rats, Sprague-Dawley; Respiratory Mucosa; Sand; Silicon Dioxide; Trachea
PubMed: 33068619
DOI: 10.1016/j.taap.2020.115284 -
Respiratory Physiology & Neurobiology Nov 2020Oxygen therapy and mechanical ventilation are important predisposing factors for the development of bronchopulmonary dysplasia (BPD), leading to increased morbidity and...
BACKGROUND
Oxygen therapy and mechanical ventilation are important predisposing factors for the development of bronchopulmonary dysplasia (BPD), leading to increased morbidity and mortality in premature infants. Oxygen toxicity mediated by reactive oxygen species (ROS) may play an important part in the development of BPD. We studied the effects of MnTBAP, a catalytic antioxidant on airway responsiveness and alveolar simplification in adult mice following neonatal hyperoxia.
METHODS
Mice litters were randomized to 85 %O or room air (RA) on D3 for 12 days to receive either MnTBAP (10 mg/kg/d) or saline intraperitoneally. Methacholine challenge (MCC) performed at 8 and 12 weeks of age by whole-body plethysmography to assess airway reactivity. Alveolarization quantified on lung sections by radial alveolar count (RAC) and mean linear intercept (MLI). Cell counts assessed from bronchoalveolar lavage (BAL) performed at 15 weeks.
RESULTS
Mice exposed to hyperoxia and MnTBAP (OXMN) had significantly higher airway reactivity post-MCC at 8 weeks compared to RA and O groups. At 12 weeks, airway reactivity was higher post-MCC in both hyperoxia and OXMN groups. MnTBAP did not attenuate hyperoxia-induced airway reactivity in adult mice. Hyperoxia exposed mice demonstrated large and distended alveoli on histopathology at 2 and 15 weeks. MnTBAP did not ameliorate hyperoxia-induced lung injury as assessed by RAC/MLI. Absolute lymphocyte count was significantly higher in BAL in the hyperoxia and OXMN groups.
CONCLUSIONS
MnTBAP, a catalytic antioxidant, did not afford protection from hyperoxia-induced lung injury in adult mice.
Topics: Animals; Animals, Newborn; Antioxidants; Bronchoconstrictor Agents; Bronchopulmonary Dysplasia; Disease Models, Animal; Female; Hyperoxia; Male; Metalloporphyrins; Methacholine Chloride; Mice; Mice, Inbred C57BL; Plethysmography, Whole Body; Pregnancy
PubMed: 32927098
DOI: 10.1016/j.resp.2020.103545 -
Molecules (Basel, Switzerland) Sep 2020Allergic rhinitis and asthma are common chronic allergic diseases of the respiratory tract, which are accompanied by immunoglobulin E (IgE)-mediated inflammation and the...
Allergic rhinitis and asthma are common chronic allergic diseases of the respiratory tract, which are accompanied by immunoglobulin E (IgE)-mediated inflammation and the involvement of type 2 T helper cells, mast cells, and eosinophils. (Berk.) Sacc is a fungal parasite on the larva of Lepidoptera. It has been considered to be a health-promoting food and, also, one of the best-known herbal remedies for the treatment of airway diseases, such as asthma and lung inflammation. In the present study, we demonstrated the antiallergic rhinitis effect of Cs-4, a water extract prepared from the mycelium culture of (Berk) Sacc, on ovalbumin (OVA)-induced allergic rhinitis in mice and the anti-asthmatic effect of Cs-4 in a rat model of asthma. Treatment with Cs-4 suppressed the nasal symptoms induced in OVA-sensitized and challenged mice. The inhibition was associated with a reduction in IgE/OVA-IgE and interleukin (IL)-4/IL-13 levels in the nasal fluid. Cs-4 treatment also decreased airway responsiveness and ameliorated the scratching behavior in capsaicin-challenged rats. It also reduced plasma IgE levels, as well as IgE and eosinophil peroxidase levels, in the bronchoalveolar fluid. Cs-4 treatment completely suppressed the increases in IL-4, IL-5, and IL-13 levels in rat lung tissue. In conclusion, our results suggest that Cs-4 has the potential to alleviate immune hypersensitivity reactions in allergic rhinitis and asthma.
Topics: Animals; Anti-Inflammatory Agents; Asthma; Body Weight; Bronchi; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Capsaicin; Cordyceps; Cytokines; Disease Models, Animal; Eosinophil Peroxidase; Female; Histamine Release; Immunization; Immunoglobulin E; Mast Cells; Methacholine Chloride; Mice, Inbred BALB C; Mycelium; Nasal Lavage; Ovalbumin; Rats, Sprague-Dawley; Rhinitis, Allergic; Skin; Spleen; Trachea; beta-N-Acetylhexosaminidases
PubMed: 32899766
DOI: 10.3390/molecules25184051 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Jun 2020To explore the value of leukotriene D4 (LTD4) bronchial provocation test (BPT) in detection of airway hyper-responsiveness (AHR) in children. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To explore the value of leukotriene D4 (LTD4) bronchial provocation test (BPT) in detection of airway hyper-responsiveness (AHR) in children.
METHODS
A total of 151 children aged 6 to 14 years, including 86 in remission of asthma and 65 with acute bronchitis, who were followed up in our respiratory clinic between November, 2017 and August, 2018. The children were randomly divided into LTD4 group (78 cases) and methacholine (MCH) group (73 cases). In LTD4 group, the 78 children underwent LTD4-BPT, including 46 with asthma and 32 children having re-examination for previous episodes of acute bronchitis; in MCH group, the 73 children underwent MCH-BPT, including 40 with asthma and 33 with acute bronchitis. MCH-BPT was also performed in the asthmatic children in the LTD4 group who had negative responses to LTD4 after an elution period. The major adverse reactions of the children to the two BPT were recorded. The diagnostic values of the two BPT were evaluated using receiver-operating characteristic (ROC) curve.
RESULTS
There was no significant difference in the results of basic lung function tests between LTD4 group and MCH group (>0.05). The positive rate of BPT in asthmatic children in the LTD4 group was significantly lower than that in the MCH group (26.1% 72.5%; < 0.05). The positive rate of BPT in children with previous acute bronchitis in the LTD4 group was lower than that in the MCH group (3.1% 15.2%). The positive rate of MCH-BPT in asthmatic children had negative BPT results in LTD4 group was 58.8%, and their asthma was mostly mild. The sensitivity was lower in LTD4 group than in MCH group (0.2609 0.725), but the specificity was slightly higher in LTD4 group (0.9688 vs 0.8485).The area under ROC curvein LTD4 group was lower than that in MCH group (0.635 0.787). In children with asthma in the LTD4 group, the main adverse reactions in BPT included cough (34.8%), shortness of breath (19.6%), chest tightness (15.2%), and wheezing (10.9%). The incidence of these adverse reactions was significantly lower in LTD4 group than in MCH group ( < 0.05). Serious adverse reactions occurred in neither of the two groups.
CONCLUSIONS
LTD4-BPT had high safety in clinical application of children and was similar to the specificity of MCH-BPT. However, it had low sensitivity, low diagnostic value, and limited application value in children's AHR detection.
Topics: Adolescent; Asthma; Bronchial Provocation Tests; Child; Humans; Leukotriene D4; Methacholine Chloride; Respiratory Hypersensitivity
PubMed: 32895196
DOI: 10.12122/j.issn.1673-4254.2020.06.04 -
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 Medicine 2020Within asthma, the small airways (≤2 mm in diameter) play an important role in pathophysiology. Using a combined clinical-computational approach, we sought to more...
BACKGROUND
Within asthma, the small airways (≤2 mm in diameter) play an important role in pathophysiology. Using a combined clinical-computational approach, we sought to more precisely evaluate the contribution of the small airways to deep-breath induced airway dilation (in the absence of bronchial challenge), which may be impaired in severe asthma.
METHODS
A patient-based computational model of the FOT was used to examine the sensitivity and specificity of FOT signals to small airways constriction at frequencies of 2 & 8 Hz. A clinical study of moderate to severe asthmatics (n = 24), and healthy volunteers (n = 10) was performed to evaluate correlations between baseline and post deep inspiration (following bronchodilator withhold and in the absence of prior bronchial challenge) forced oscillation technique (FOT) responses (at 2Hz and 8Hz) and asthma treatment intensity, spirometry, airway hyper-responsiveness and airway inflammation.
RESULTS
Computational modelling demonstrated that baseline resistance measures at 2Hz are both sensitive and specific to anatomical narrowing in the small airways. Furthermore, small airways resistance was significantly increased in asthmatics compared to health. Despite these differences, there were no noticeable differences between asthmatics and healthy volunteers in resistive measures following deep inspiration (DI) and DI responses of small airways were amplified in the presence of spirometry defined airflow limitation.
CONCLUSIONS
These results suggest that the small airways demonstrate increased resistance in moderate-to-severe asthma but dilate normally in response to deep inspirations in the absence of bronchial challenge. This suggests that effective targeting of the small airways is required to achieve functional improvements in moderate-severe asthmatic patients.
Topics: Adult; Aged; Airway Resistance; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Female; Humans; Male; Methacholine Chloride; Middle Aged; Patient-Specific Modeling; Sensitivity and Specificity; Severity of Illness Index; Spirometry
PubMed: 32843165
DOI: 10.1016/j.rmed.2020.106022 -
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 -
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