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The European Respiratory Journal Sep 2017The association between obesity and bronchial hyperresponsiveness (BHR) is incompletely characterised. Using the 2006 follow-up of the Tasmanian Longitudinal Health...
The association between obesity and bronchial hyperresponsiveness (BHR) is incompletely characterised. Using the 2006 follow-up of the Tasmanian Longitudinal Health Study, we measured the association between obesity and BHR and whether it was mediated by small airway closure or modified by asthma and sex of the patient.A methacholine challenge measured BHR. Multivariable logistic regression measured associations between body mass index (BMI) and BHR, adjusting for sex, asthma, smoking, corticosteroid use, family history and lung function. Mediation by airway closure was also measured.Each increase in BMI of 1 kg·m was associated with a 5% increase in the odds of BHR (OR 1.05, 95% CI 1.01-1.09) and 43% of this association was mediated by airway closure. In a multivariable model, BMI (OR 1.06, 95% CI 1.00-1.16) was associated with BHR independent of female sex (OR 3.26, 95% CI 1.95-5.45), atopy (OR 2.30, 95% CI 1.34-3.94), current asthma (OR 5.74, 95% CI 2.79-11.82), remitted asthma (OR 2.35, 95% CI 1.27-4.35), low socioeconomic status (OR 2.11, 95% CI 1.03-4.31) and forced expiratory volume in 1 s/forced vital capacity (OR 0.86, 95% CI 0.82-0.91). Asthma modified the association with an increasing probability of BHR as BMI increased, only in those with no or remitted asthma.An important fraction of the BMI/BHR association was mediated airway closure. Conflicting findings in previous studies could be explained by failure to consider this intermediate step.
Topics: Adult; Asthma; Australia; Body Mass Index; Bronchial Hyperreactivity; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Immunoglobulin E; Logistic Models; Longitudinal Studies; Male; Methacholine Chloride; Middle Aged; Multivariate Analysis; Obesity; Smoking; Social Class; Vital Capacity
PubMed: 28899934
DOI: 10.1183/13993003.02181-2016 -
Role of hyperpnea in the relaxant effect of inspired CO on methacholine-induced bronchoconstriction.Journal of Applied Physiology... May 2022Inhaling carbon dioxide (CO) in humans is known to cause inconsistent effects on airway function. These could be due to direct effects of CO on airway smooth muscle or...
Inhaling carbon dioxide (CO) in humans is known to cause inconsistent effects on airway function. These could be due to direct effects of CO on airway smooth muscle or to changes in minute ventilation (V̇e). To address this issue, we examined the responses of the respiratory system to inhaled methacholine in healthy subjects and subjects with mild asthma while breathing air or gas mixtures containing 2% or 4% CO. Respiratory mechanics were measured by a forced oscillation technique at 5 Hz during tidal breathing. At baseline, respiratory resistance (R) was significantly higher in subjects with asthma (2.53 ± 0.38 cmHO·L·s) than healthy subjects (2.11 ± 0.42 cmHO·L·s) ( = 0.008) with room air. Similar values were observed with CO 2% or 4% in the two groups. V̇e, tidal volume (V), and breathing frequency (BF) significantly increased with CO-containing mixtures ( < 0.001) with insignificant differences between groups. After methacholine, the increase in R and the decrease in respiratory reactance (X) were significantly attenuated up to about 50% with CO-containing mixtures instead of room air in both asthmatic ( < 0.001) and controls ( < 0.001). Mediation analysis showed that the attenuation of methacholine-induced changes in respiratory mechanics by CO was due to the increase in V̇e ( = 0.006 for R and = 0.014 for X) independently of the increase in V or BF, rather than a direct effect of CO. These findings suggest that the increased stretching of airway smooth muscle by the CO-induced increase in V̇e is a mechanism through which hypercapnia can attenuate bronchoconstrictor responses in healthy subjects and subjects with mild asthma. The main results of the present study are as follows: ) breathing gas mixtures containing 2% or 4% CO significantly attenuated bronchoconstrictor responses to methacholine, not differently in healthy subjects and subjects with mild asthma, and ) the causal inhibitory effect of CO was significantly mediated via an indirect effect of the increment of V̇e in response to intrapulmonary hypercapnia.
Topics: Airway Resistance; Asthma; Bronchoconstriction; Bronchoconstrictor Agents; Carbon Dioxide; Humans; Hypercapnia; Hyperventilation; Methacholine Chloride
PubMed: 35358399
DOI: 10.1152/japplphysiol.00763.2021 -
American Journal of Physiology. Lung... Apr 2015Airway hyperresponsiveness often constitutes a primary outcome in respiratory studies in mice. The procedure commonly employs aerosolized challenges, and results are...
Airway hyperresponsiveness often constitutes a primary outcome in respiratory studies in mice. The procedure commonly employs aerosolized challenges, and results are typically reported in terms of bronchoconstrictor concentrations loaded into the nebulizer. Yet, because protocols frequently differ across studies, especially in terms of aerosol generation and delivery, direct study comparisons are difficult. We hypothesized that protocol variations could lead to differences in aerosol delivery efficiency and, consequently, in the dose delivered to the subject, as well as in the response. Thirteen nebulization patterns containing common protocol variations (nebulization time, duty cycle, particle size spectrum, air humidity, and/or ventilation profile) and using increasing concentrations of methacholine and broadband forced oscillations (flexiVent, SCIREQ, Montreal, Qc, Canada) were created, characterized, and studied in anesthetized naïve A/J mice. A delivered dose estimate calculated from nebulizer-, ventilator-, and subject-specific characteristics was introduced and used to account for protocol variations. Results showed that nebulization protocol variations significantly affected the fraction of aerosol reaching the subject site and the delivered dose, as well as methacholine reactivity and sensitivity in mice. From the protocol variants studied, addition of a slow deep ventilation profile during nebulization was identified as a key factor for optimization of the technique. The study also highlighted sensitivity differences within the lung, as well as the possibility that airway responses could be selectively enhanced by adequate control of nebulizer and ventilator settings. Reporting results in terms of delivered doses represents an important standardizing element for assessment of airway hyperresponsiveness in mice.
Topics: Administration, Inhalation; Aerosols; Animals; Disease Models, Animal; Humans; Male; Methacholine Chloride; Mice; Nebulizers and Vaporizers; Reference Standards; Research Design; Respiratory Hypersensitivity
PubMed: 25637610
DOI: 10.1152/ajplung.00343.2014 -
The Journal of Allergy and Clinical... Nov 2023Exposure to certain agents in the workplace can trigger occupational asthma or work-exacerbated asthma, both of which come under the heading of work-related asthma...
BACKGROUND
Exposure to certain agents in the workplace can trigger occupational asthma or work-exacerbated asthma, both of which come under the heading of work-related asthma (WRA). Understanding the burden that WRA represents can help in the management of these patients.
OBJECTIVE
To assess the influence of occupation on asthma in real life and analyze the characteristics of patients with WRA included in an asthma cohort.
METHODS
This was a prospective multicenter study of a cohort of consecutive patients with asthma. A standardized clinical history was completed. Patients were classified as having WRA or non-WRA. All patients underwent respiratory function tests, FeNO test, and methacholine challenge (methacholine concentration that causes a 20% drop in FEV) at the beginning of the study. They were classified into two groups, depending on their employment status: employed (group 1) or unemployed (group 2).
RESULTS
Of the 480 patients included in the cohort, 82 (17%) received the diagnosis of WRA. Fifty-seven patients (70%) were still working. Mean age (SD) was 46 (10.69) years in group 1 and 57 (9.91) years in group 2 (P < .0001). Significant differences were observed in adherence to treatment (64.9% in group 1 vs 88% in group 2; P = .0354) and in severe asthma exacerbations (35.7% in group 1 vs 0% in group 2; P = .0172). No significant differences were observed in the rest of the variables analyzed.
CONCLUSIONS
The burden of WRA in specialized asthma units is not negligible. The absence of differences in the severity of asthma, the treatment administered, alterations in lung function, and the number of exacerbations in those working versus not working may support the idea that advice regarding changing jobs should be customized for individual patients.
Topics: Humans; Middle Aged; Asthma, Occupational; Bronchial Provocation Tests; Methacholine Chloride; Occupational Diseases; Occupational Exposure; Prospective Studies; Adult
PubMed: 37391017
DOI: 10.1016/j.jaip.2023.06.040 -
BMC Pulmonary Medicine Feb 2021Cough variant asthma (CVA) is one of the special populations of asthma. The aim of the study was to compare small airways, the degree of bronchial hyperresponsiveness...
BACKGROUND
Cough variant asthma (CVA) is one of the special populations of asthma. The aim of the study was to compare small airways, the degree of bronchial hyperresponsiveness (BHR) and airway inflammatory subtypes between CVA and classic asthma (CA), and investigate the relationship between these markers to determine the accuracy as indicators of CVA.
METHODS
A total of 825 asthmatic patients participated in the study and 614 were included. 614 patients underwent spirometry and a bronchial challenge with methacholine and 459 patients performed induction sputum cell test.
RESULTS
The number of CVA patients showed less small airway dysfunction than those of CA patients (p < 0.005). The degree of small airways dysfunction was higher in the CA group compared with the CVA group (p < 0.001). Small airways dysfunction was severer in the eosinophilic airway inflammatory subtype compared with other subtypes (p < 0.05).The area under curve of MMEF, FEF and FEF (% predicted) was 0.615, 0.621, 0.606, respectively. 0.17mcg of PD and 4.7% of sputum eosinophils was the best diagnostic value for CVA with an AUC of 0.582 and 0.575 (p = 0.001 and p = 0.005, respectively).
CONCLUSIONS
The eosinophilic airway inflammatory subtype may be increased small airway dysfunction. The value of small airways, BHR and induction sputum cells in CVA prediction, which reflected significant, but not enough to be clinically useful.
Topics: Adult; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Cough; Dose-Response Relationship, Drug; Eosinophil Cationic Protein; Eosinophils; Female; Forced Expiratory Volume; Humans; Leukocyte Count; Male; Methacholine Chloride; Middle Aged; Multivariate Analysis; Retrospective Studies; Sputum
PubMed: 33536015
DOI: 10.1186/s12890-021-01419-4 -
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 -
Respirology (Carlton, Vic.) Oct 2014Ventilation heterogeneity (VH) has been linked to airway responsiveness (AR) based on various measures of VH involving inert gas washout, forced oscillation and lung...
BACKGROUND AND OBJECTIVE
Ventilation heterogeneity (VH) has been linked to airway responsiveness (AR) based on various measures of VH involving inert gas washout, forced oscillation and lung imaging. We explore whether VH at baseline, as measured by the simple ratio of single breath alveolar volume to plethysmographically determined total lung capacity (VA/TLC), would correlate with AR as measured by methacholine challenge testing.
METHODS
We analysed data from spirometry, lung volumes, diffusing capacity and methacholine challenge to derive the VA/TLC and the dose-response slope (DRS) of forced expiratory volume in 1 s (DRS-FEV1) during methacholine challenge from 136 patients. We separated out airway closure versus narrowing by examining the DRS for forced vital capacity (DRS-FVC) and the DRS for FEV1/FVC (DRS-FEV1/FVC), respectively. Similarly, we calculated the DRS for sGaw (DRS-sGaw) as another measure of airway narrowing. We performed statistical analysis using Spearman rank correlation and multifactor linear regression using a backward stepwise modelling procedure.
RESULTS
We found that the DRS-FEV1 correlated with baseline VA/TLC (rho = -0.26, P < 0.01), and VA/TLC and FEV1 were independently associated with DRS-FEV1 (R(2) = 0.14, P = 0.01). In addition, VA/TLC was associated with both airway narrowing and closure in response to methacholine.
CONCLUSIONS
These results confirm that baseline VA/TLC is associated with AR, and reflects both airway closure and airway narrowing following methacholine challenge.
Topics: Adult; Aged; Airway Remodeling; Airway Resistance; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Cohort Studies; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Middle Aged; Pulmonary Diffusing Capacity; Spirometry; Total Lung Capacity
PubMed: 24995907
DOI: 10.1111/resp.12347 -
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 -
The Journal of Physiology Jun 2016Endothelin-1 (ET-1) is a potent endothelial-derived vasoconstrictor that may modulate cholinergic cutaneous vascular regulation. Endothelin receptors are also expressed...
KEY POINTS
Endothelin-1 (ET-1) is a potent endothelial-derived vasoconstrictor that may modulate cholinergic cutaneous vascular regulation. Endothelin receptors are also expressed on the human eccrine sweat gland, although it remains unclear whether ET-1 modulates cholinergic sweating. We investigated whether ET-1 attenuates cholinergic cutaneous vasodilatation and sweating through a nitric oxide synthase (NOS)-dependent mechanism. Our findings show that ET-1 attenuates methacholine-induced cutaneous vasodilatation through a NOS-independent mechanism. We also demonstrate that ET-1 attenuates cutaneous vasodilatation in response to sodium nitroprusside, suggesting that ET-1 diminishes the dilatation capacity of vascular smooth muscle cells. We show that ET-1 does not modulate methacholine-induced sweating at any of the administered concentrations. Our findings advance our knowledge pertaining to the peripheral control underpinning the regulation of cutaneous blood flow and sweating and infer that ET-1 may attenuate the heat loss responses of cutaneous blood flow, but not sweating.
ABSTRACT
The present study investigated the effect of endothelin-1 (ET-1) on cholinergic mechanisms of end-organs (i.e. skin blood vessels and sweat glands) for heat dissipation. We evaluated the hypothesis that ET-1 attenuates cholinergic cutaneous vasodilatation and sweating through a nitric oxide synthase (NOS)-dependent mechanism. Cutaneous vascular conductance (CVC) and sweat rate were assessed in three protocols: in Protocol 1 (n = 8), microdialysis sites were perfused with lactated Ringer solution (Control), 40 pm, 4 nm or 400 nm ET-1; in Protocol 2 (n = 11) sites were perfused with lactated Ringer solution (Control), 400 nm ET-1, 10 mm N(G) -nitro-l-arginine (l-NNA; a NOS inhibitor) or a combination of 400 nm ET-1 and 10 mm l-NNA; in Protocol 3 (n = 8), only two sites (Control and 400 nm ET-1) were utilized to assess the influence of ET-1 on the dilatation capacity of vascular smooth muscle cells (sodium nitroprusside; SNP). Methacholine (MCh) was co-administered in a dose-dependent manner (0.0125, 0.25, 5, 100, 2000 mm, each for 25 min) at all skin sites. ET-1 at 400 nm (P < 0.05) compared to lower doses (40 pm and 4 nm) (all P > 0.05) significantly attenuated increases in CVC in response to 0.25 and 5 mm MCh. A high dose of ET-1 (400 nm) co-infused with l-NNA further attenuated CVC during 0.25, 5 and 100 mm MCh administration relative to the ET-1 site (all P < 0.05). Cutaneous vasodilatation in response to SNP was significantly blunted after administration of 400 nm ET-1 (P < 0.05). We show that ET-1 attenuates cutaneous vasodilatation through a NOS-independent mechanism, possibly through a vascular smooth muscle cell-dependent mechanism, and methacholine-induced sweating is not altered by ET-1.
Topics: Adolescent; Adult; Endothelin-1; Female; Humans; Male; Methacholine Chloride; Nitroprusside; Skin; Skin Physiological Phenomena; Sweating; Vasodilation; Vasodilator Agents; Young Adult
PubMed: 26846374
DOI: 10.1113/JP271735 -
American Journal of Physiology. Lung... Nov 2018Isolated human airway smooth muscle (ASM) tissue contractility studies are essential for understanding the role of ASM in respiratory disease, but limited availability...
Isolated human airway smooth muscle (ASM) tissue contractility studies are essential for understanding the role of ASM in respiratory disease, but limited availability and cost render storage options necessary for optimal use. However, to our knowledge, no comprehensive study of cryopreservation protocols for isolated ASM has been performed to date. We tested several cryostorage protocols on equine trachealis ASM using different cryostorage media [1.8 M dimethyl sulfoxide and fetal bovine serum (FBS) or Krebs-Henseleit (KH)] and different degrees of dissection (with or without epithelium and connective tissues attached) before storage. We measured methacholine (MCh), histamine, and isoproterenol (Iso) dose-responses and electrical field stimulation (EFS) and MCh force-velocity curves. We confirmed our findings in human trachealis ASM stored undissected in FBS. Maximal stress response to MCh was decreased more in dissected than undissected equine tissues. EFS force was decreased in all equine but not in human cryostored tissues. Furthermore, in human cryostored tissues, EFS maximal shortening velocity was decreased, and Iso response was potentiated after cryostorage. Overnight incubation with 0.5 or 10% FBS did not recover contractility in the equine tissues but potentiated Iso response. Overnight incubation with 10% FBS in human tissues showed maximal stress recovery and maintenance of other contractile parameters. ASM tissues can be cryostored while maintaining most contractile function. We propose an optimal protocol for cryostorage of ASM as undissected tissues in FBS or KH solution followed by dissection of the ASM bundles and a 24-h incubation with 10% FBS before mechanics measurements.
Topics: Animals; Cryopreservation; Cryoprotective Agents; Dimethyl Sulfoxide; Histamine; Horses; Methacholine Chloride; Muscle Contraction; Muscle, Smooth; Trachea
PubMed: 30091377
DOI: 10.1152/ajplung.00064.2018