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Pulmonary Pharmacology & Therapeutics Feb 2023Allergic asthma is a heterogeneous disease involving a variety of inflammatory cells. Immune imbalance or changes in the immune microenvironment are the essential causes...
Allergic asthma is a heterogeneous disease involving a variety of inflammatory cells. Immune imbalance or changes in the immune microenvironment are the essential causes that promote inflammation in allergic asthma. Tetraspanin CD81 can be used as a platform for receptor clustering and signal transmission owing to its special transmembrane structure and is known to participate in the physiological processes of cell proliferation, differentiation, adhesion, and migration. Previous studies have shown that CD81-targeting peptidomimetics exhibit anti-allergic lung inflammation. However, due to the low metabolic stability of peptide drugs, their druggability is limited. Here, we aimed to generate a metabolically stable anti-CD81 peptide, evaluate its anti-inflammatory action and establish its mechanism of action. Based on previous reports, we applied retro-inverse peptide modification to obtain a new compound, PD00 (NH2-D-Gly-D-Ser-D-Thr-D-Tyr-D-Thr-D-Gln-D-Gly-COOH), with high metabolic stability. Enhanced ultraperformance liquid chromatography-tandem mass spectrometry was used to investigate the in vitro and in vivo metabolic stabilities of PD00. The affinities of PD00 and CD81 were studied using molecular docking and surface plasmon resonance techniques. An ovalbumin (OVA)-induced asthma model was used to evaluate the effects of PD00 in vivo. Mice were treated with different concentrations of PD00 (175 and 350 μg/kg) for 10 days. Airway hyperresponsiveness (AHR) to acetyl-β-methacholine (Mch), inflammatory cell counts in the bronchoalveolar lavage fluid, and serum OVA-specific IgE levels were detected in the mice at the end of the experiment. Lung tissues were collected for haematoxylin and eosin staining, untargeted metabolomic analysis, and single-cell transcriptome sequencing. PD00 has a high affinity for CD81; therefore, administration of PD00 markedly ameliorated AHR and airway inflammation in mice after OVA sensitisation and exposure. Serum OVA-specific IgE levels decreased considerably. In addition, PD00 treatment increased glycerophospholipid and purine metabolism in immune cells. Collectively, PD00 may regulate the glycerophospholipid and purine metabolism pathways to ameliorate the pathophysiological features of asthma. These findings suggest that PD00 is a potential compound for the treatment of asthma.
Topics: Animals; Mice; Ovalbumin; Molecular Docking Simulation; Asthma; Lung; Bronchoalveolar Lavage Fluid; Methacholine Chloride; Inflammation; Immunoglobulin E; Purines; Disease Models, Animal; Mice, Inbred BALB C; Cytokines
PubMed: 36563740
DOI: 10.1016/j.pupt.2022.102185 -
Validation of the clinical utility of sGaw as a response variable in methacholine challenge testing.Respirology (Carlton, Vic.) May 2023Airway hyperresponsiveness (AHR) is commonly assessed by a methacholine challenge test (MCT), during which a provocative concentration causing a 20% reduction in forced...
BACKGROUND AND OBJECTIVE
Airway hyperresponsiveness (AHR) is commonly assessed by a methacholine challenge test (MCT), during which a provocative concentration causing a 20% reduction in forced expiratory volume in 1 second (FEV ) (PC ) < 8 mg/ml is considered a positive response. However, a fall in specific airway conductance (sGaw) may also have clinical significance. The purpose of this study was to assess whether AHR determined by a provocative concentration causing a 40% reduction in sGaw (PC ) < 8 mg/ml corresponds to a clinical diagnosis of asthma.
METHODS
We analysed the changes in spirometry, lung volumes and sGaw during MCT in 211 randomly selected patients being evaluated for AHR to support a clinical diagnosis of asthma.
RESULTS
The mean (SD) age of the group was 53 (15) years, with 141 women (67%). Overall lung function was normal, with FEV = 92 (15) % predicted, total lung capacity = 97 (13) % predicted and sGaw = 0.19 (0.15-0.23) L/s/cm H O/L, (median, 25-75 IQR). There were many more patients who responded by PC only (n = 120) than who responded by PC (n = 52). There was no significant difference in asthma diagnosis between the PC (98%) and PC (93%) groups, and we estimate 34% of patients with a diagnosis of asthma would have been classified as having no AHR if only the FEV criterion was used.
CONCLUSION
Changes in sGaw during MCT indicate clinically significant AHR in support of a clinical diagnosis of asthma among patients being evaluated for asthma.
Topics: Humans; Female; Middle Aged; Methacholine Chloride; Bronchoconstrictor Agents; Asthma; Bronchial Provocation Tests; Respiratory Hypersensitivity; Forced Expiratory Volume
PubMed: 36478621
DOI: 10.1111/resp.14431 -
Respirology (Carlton, Vic.) Mar 2023
Topics: Humans; Methacholine Chloride; Asthma; Bronchial Provocation Tests
PubMed: 36411237
DOI: 10.1111/resp.14416 -
The European Respiratory Journal Mar 2023Subjects without a previous history of asthma, presenting with unexplained respiratory symptoms and normal spirometry, may exhibit airway hyperresponsiveness (AHR) in... (Observational Study)
Observational Study
BACKGROUND
Subjects without a previous history of asthma, presenting with unexplained respiratory symptoms and normal spirometry, may exhibit airway hyperresponsiveness (AHR) in association with underlying eosinophilic (type 2 (T2)) inflammation, consistent with undiagnosed asthma. However, the prevalence of undiagnosed asthma in these subjects is unknown.
METHODS
In this observational study, inhaled corticosteroid-naïve adults without previously diagnosed lung disease reporting current respiratory symptoms and showing normal pre- and post-bronchodilator spirometry underwent fractional exhaled nitric oxide ( ) measurement, methacholine challenge testing and induced sputum analysis. AHR was defined as a provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC) <16 mg·mL and T2 inflammation was defined as sputum eosinophils >2% and/or >25 ppb.
RESULTS
Out of 132 subjects (mean±sd age 57.6±14.2 years, 52% female), 47 (36% (95% CI 28-44%)) showed AHR: 20/132 (15% (95% CI 9-21%)) with PC <4 mg·mL and 27/132 (21% (95% CI 14-28%)) with PC 4-15.9 mg·mL. Of 130 participants for whom sputum eosinophils, or both results were obtained, 45 (35% (95% CI 27-43%)) had T2 inflammation. 14 participants (11% (95% CI 6-16%)) had sputum eosinophils >2% and PC ≥16 mg·mL, suggesting eosinophilic bronchitis. The prevalence of T2 inflammation was significantly higher in subjects with PC <4 mg·mL (12/20 (60%)) than in those with PC 4-15.9 mg·mL (8/27 (30%)) or ≥16 mg·mL (25/85 (29%)) (p=0.01).
CONCLUSIONS
Asthma, underlying T2 airway inflammation and eosinophilic bronchitis may remain undiagnosed in a high proportion of symptomatic subjects in the community who have normal pre- and post-bronchodilator spirometry.
Topics: Adult; Humans; Female; Middle Aged; Aged; Male; Methacholine Chloride; Bronchodilator Agents; Nitric Oxide; Asthma; Inflammation; Eosinophils; Forced Expiratory Volume; Bronchial Provocation Tests; Spirometry; Sputum; Bronchitis
PubMed: 36396140
DOI: 10.1183/13993003.01194-2022 -
Archivos de Bronconeumologia Feb 2023The role of bronchial provocation tests in the diagnosis of asthma remains to be fully explored. We aimed to evaluate methacholine and mannitol challenge testing, and... (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
INTRODUCTION
The role of bronchial provocation tests in the diagnosis of asthma remains to be fully explored. We aimed to evaluate methacholine and mannitol challenge testing, and explore the factors associated with this broncoprovocation response.
METHODS
Observational, cross-over, randomized trial evaluating adult cases with suspected asthma, naïve to treatment, with normal pre-bronchodilator spirometry, and negative bronchodilator test. Patients were randomized to start with methacholine or mannitol. The diagnosis of bronchial asthma was confirmed if there was a good functional and clinical response to one month with twice daily formoterol/budesonide 9/320. The diagnostic profile and the concordance were calculated. Factors associated with a positive provocation test were entered into a multivariate binomial logistic regression analysis, and classification trees were created for both tests.
RESULTS
The study included 108 cases (50.0% diagnosed with asthma and 51.9% cases starting with methacholine). The percentage of cases positive to methacholine and mannitol were 30.6% and 25.0% respectively. Kappa values were 0.40 (p<0.001). The diagnostic profile for methacholine was sensitivity 59.3% and specificity 98.1%, while for mannitol it was sensitivity 48.1% and specificity 98.1%. Variables associated with a positive methacholine response included sex, atopy, FEV, FEV/FVC and FENO, whereas they were FEV/FVC and FENO for mannitol. A FENO value>26ppb, FEV1≤103.3% and female sex correctly classified 78.7% of methacholine responders. FENO value>26ppb was enough to correctly classify 81.5% of mannitol responders.
CONCLUSIONS
Our study confirms the diagnostic profile of methacholine and mannitol challenge tests and describes the variable associated to their positivity with new proposed cutoff values.
Topics: Adult; Humans; Bronchial Provocation Tests; Methacholine Chloride; Bronchodilator Agents; Cross-Over Studies; Nitric Oxide; Asthma; Mannitol
PubMed: 36371327
DOI: 10.1016/j.arbres.2022.10.008 -
Pulmonary Pharmacology & Therapeutics Dec 2022Loss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta-agonists occurs with both short and long-acting formulations.... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Loss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta-agonists occurs with both short and long-acting formulations. Comparatively little is known about the development of tolerance following regular use of inhaled muscarinic receptor antagonists. Two investigations with the short-acting muscarinic receptor antagonist ipratropium bromide have reported no tolerance after regular use against inhaled methacholine. To our knowledge, there are no data regarding loss of bronchoprotection following regular use of long-acting muscarinic receptor antagonist. We therefore looked at the effect of daily dosing with tiotropium on methacholine induced bronchoconstriction in a population of mild asthmatics.
METHODS
We performed a randomized, double-blind, placebo-controlled cross-over study comparing tiotropium Respimat® 5 μg to placebo in adult asthmatics. Each treatment arm began with baseline methacholine challenge followed immediately by treatment administration. One hour later a post treatment methacholine challenge was performed. Participants dosed daily (two puffs) at home for the next six days and returned to the lab on Day 8 for a final dose of treatment 1 h prior to methacholine challenge.
RESULTS
The average doubling dose increase in methacholine PD following a single dose of tiotropium was 3.9 doubling doses whereas that following placebo was 0.93 (p = 0.003). After regular use, methacholine PD was further increased to 6.4 doubling doses following tiotropium whereas that following placebo decreased by 0.57 doubling doses (p < 0.001).
CONCLUSION
LAMA are indicated for use as add-on monotherapy or in triple therapy combination for poorly controlled asthma. It may be reassuring to know therefore, that regular use does not result in loss of bronchoprotection like that which occurs with beta-agonist bronchodilators.
Topics: Adult; Humans; Methacholine Chloride; Tiotropium Bromide; Bronchoconstriction; Cross-Over Studies; Bronchodilator Agents; Asthma; Muscarinic Antagonists; Receptors, Muscarinic; Double-Blind Method; Administration, Inhalation
PubMed: 36343758
DOI: 10.1016/j.pupt.2022.102174 -
Biomechanics and Modeling in... Feb 2023Even though cigarette smoking (CS) has been on the decline over the past 50 years, it is still the leading cause of preventable premature death in the United States....
Even though cigarette smoking (CS) has been on the decline over the past 50 years, it is still the leading cause of preventable premature death in the United States. Preclinical models have investigated the cardiopulmonary effects of CS exposure (CSE), but the structure-function relationship in the respiratory system has not yet been fully explored. To evaluate these relationships, we exposed female apolipoprotein E-deficient (Apoe[Formula: see text]) mice to mainstream CS ([Formula: see text]) for 5 days/week over 24 weeks with room air as a control (AE, [Formula: see text]). To contextualize the impact of CSE, we also assessed the natural aging effects over 24 weeks of air exposure (baseline, [Formula: see text]). Functional assessments were performed on a small animal mechanical ventilator (flexiVent, SCIREQ), where pressure-volume curves and impedance data at four levels of positive end-expiratory pressure ([Formula: see text]) and with increasing doses of methacholine were collected. Constant phase model parameters ([Formula: see text]: Newtonian resistance, H: coefficient of tissue elastance, and G: coefficient of tissue resistance) were calculated from the impedance data. Perfusion fixed-left lung tissue was utilized for quantification of parenchyma airspace size and tissue thickness, airway wall thickness, and measurements of elastin, cytoplasm + nucleus, fibrin, and collagen content for the parenchyma and airways. Aging caused the lung to become more compliant, with an upward-leftward shift of the pressure-volume curve and a reduction in all constant phase model parameters. This was supported by larger parenchyma airspace sizes, with a reduction in cell cytoplasm + nucleus area. Airway walls became thinner, even though low-density collagen content increased. In contrast, CSE caused a downward-rightward shift of the pressure-volume curve along with an increase in H, G, and hysteresivity ([Formula: see text]). Organ stiffening was accompanied by enhanced airway hyper-responsiveness following methacholine challenge. Structurally, parenchyma airspaces enlarged, as indicated by an increase in equivalent airspace diameter ([Formula: see text]), and the septum thickened with significant deposition of low-density collagen along with an influx of cells. Airway walls thickened due to deposition of both high and low-density collagen, infiltration of cells, and epithelial cell elongation. In all, our data suggest that CSE in female Apoe[Formula: see text] mice reduces respiratory functionality and causes morphological alterations in both central and peripheral airways that results in lung stiffening, compared to AE controls.
Topics: Female; Animals; Mice; United States; Cigarette Smoking; Methacholine Chloride; Collagen; Respiratory Mechanics; Apolipoproteins E
PubMed: 36335185
DOI: 10.1007/s10237-022-01644-8 -
Respiratory Physiology & Neurobiology Jan 2023Clinical case series suggest beneficial effects of low-dose intermittent hypoxia in asthma. We tested cardiopulmonary effects of repetitive acute hypoxic preconditioning...
Clinical case series suggest beneficial effects of low-dose intermittent hypoxia in asthma. We tested cardiopulmonary effects of repetitive acute hypoxic preconditioning (RAHP) during allergic inflammation. Brown Norway rats were sensitized to house dust mites (HDM) and exposed to 4-week RAHP or normoxia (SHAM), concurrent with weekly HDM or saline (SAL) challenges. We assessed methacholine responses and lung HIF-1α expression at endpoint, and weekly blood pressure (BP). RAHP relative to SHAM: 1) in HDM-challenged rats, showed no protection against HDM-induced airway dysfunction and did not significantly impact BP (week 4 mean BP difference = 10.51 mmHg, p = 0.09) or HIF-1α expression; 2) in SAL-challenged rats, attenuated airway responses to methacholine, reduced BP (week 4 mean BP average difference = -8.72 mmHg, p = 0.04) and amplified HIF-1α expression (p = 0.0086). Four weeks of RAHP did not mitigate the allergen-induced lower airway dysfunction and may detrimentally affect BP. However, it elicited beneficial cardiopulmonary responses in SAL-challenged rats, concurrent with increased HIF-1α expression.
Topics: Rats; Animals; Allergens; Methacholine Chloride; Pyroglyphidae; Hypoxia; Lung
PubMed: 36332748
DOI: 10.1016/j.resp.2022.103982 -
Scientific Reports Oct 2022Cholinergic urticaria (CholU) is classified into several subtypes: (1) conventional sweat allergy-type CholU (conventional SAT-CholU), (2) CholU with palpebral...
Cholinergic urticaria (CholU) is classified into several subtypes: (1) conventional sweat allergy-type CholU (conventional SAT-CholU), (2) CholU with palpebral angioedema (CholU-PA), 3) CholU with acquired anhidrosis and/or hypohidrosis (CholU-Anhd); 1) and 2) include SAT based on pathogenesis. There have been no studies on differences in the prevalence of bronchial asthma among the subtypes. We analyzed bronchial responsiveness using the methacholine dose indicator D, respiratory symptoms, and exhaled nitric oxide (FeNO). Median log10 D (interquartile range) of patients with conventional SAT-CholU (n = 11), CholU-PA (n = 11), and CholU-Anhd (n = 11) was 0.381 (- 0.829, 1.079), 0.717 (0.249, 0.787), and 1.318 (0.121, 1.699), respectively (p = 0.516). Respiratory symptoms were less frequently observed in CholU-Anhd than in conventional SAT-CholU or CholU-PA. FeNO of patients with conventional SAT-CholU, CholU-PA, and CholU-Anhd was 23 (18.5, 65.0), 39 (32.0, 59.5), and 25 (19.0, 33.0) ppb, respectively (p = 0.237). Nine% of conventional SAT-CholU patients and more than half of CholU-PA patients required treatment for asthma. Log D tended to be lower in patients with SAT-CholU than in those with CholU-Anhd. CholU-PA might be associated with asthma.
Topics: Humans; Cross-Sectional Studies; Bronchial Hyperreactivity; Methacholine Chloride; Urticaria; Asthma; Nitric Oxide; Cholinergic Agents
PubMed: 36302805
DOI: 10.1038/s41598-022-22655-6 -
American Journal of Physiology.... Dec 2022Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a...
Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a respiratory disease, is notably characterized by reversible airway obstruction, persistent lung inflammation, and airway hyperresponsiveness (AHR). Nasal insufflation of IL-11 causes AHR in wild-type mice while lung inflammation induced by antigen sensitization and challenge, which mimics features of atopic asthma in humans, is attenuated in mice genetically deficient in IL-11 receptor subunit α-1 (IL-11Rα1-deficient mice), a transmembrane receptor that is required conjointly with glycoprotein 130 to transduce IL-11 signaling. Nevertheless, the contribution of IL-11Rα1 to characteristics of nonatopic asthma is unknown. Thus, based on the aforementioned observations, we hypothesized that genetic deficiency of IL-11Rα1 attenuates lung inflammation and increases airway responsiveness after acute inhalation exposure to ozone (O), a criteria pollutant and nonatopic asthma stimulus. Accordingly, 4 and/or 24 h after cessation of exposure to filtered room air or O, we assessed lung inflammation and airway responsiveness in wild-type and IL-11Rα1-deficient mice. With the exception of bronchoalveolar lavage macrophages and adiponectin, which were significantly increased and decreased, respectively, in O-exposed IL-11Rα1-deficient as compared with O-exposed wild-type mice, no other genotype-related differences in lung inflammation indices that we quantified were observed in O-exposed mice. However, airway responsiveness to acetyl-β-methylcholine chloride (methacholine) was significantly diminished in IL-11Rα1-deficient as compared with wild-type mice after O exposure. In conclusion, these results demonstrate that IL-11Rα1 minimally contributes to lung inflammation but is required for maximal airway responsiveness to methacholine in a mouse model of nonatopic asthma.
Topics: Humans; Mice; Animals; Methacholine Chloride; Ozone; Interleukin-11; Asthma; Pneumonia; Receptors, Interleukin-11; Bronchoalveolar Lavage Fluid
PubMed: 36283092
DOI: 10.1152/ajpregu.00213.2022