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Diagnosis of asthma can be confirmed based on variability in peak expiratory flow (PEF) or changes in forced expiratory volume in 1 s (FEV 1 ) measured with spirometry. Our aim was to use methacholine challenge as a model of induced airway obstruction to assess how well relative changes in PEF reflect airway obstruction in comparison to relative changes in FEV 1 . We retrospectively studied 878 patients who completed a methacholine challenge test. To assess congruency along with differences between relative changes in FEV 1 and PEF during airway obstruction, a regression analysis was performed, and a Bland & Altman plot was constructed. ROC analysis, sensitivity, specificity, positive and negative predictive values and κ-coefficient were used to analyze how decrease in PEF predicts decrease of 10% or 15% in FEV 1 . The relative change in PEF was on average less than the relative change in FEV 1 . In the ROC analysis areas under the curve were 0.844 and 0.893 for PEF decrease to predict a 10% and 15% decrease in FEV 1 , respectively. The agreement between changes in PEF and FEV 1 varied from fair to moderate. Airway obstruction detected by change in PEF was false in about 40% of cases when compared to change in FEV 1 . Change in PEF is not a very accurate measure of airway obstruction when compared to change in FEV 1 . Replacing peak flow metre with a handheld spirometer might improve diagnostic accuracy of home monitoring in asthma., (© 2024 The Author(s). Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Background: Specific inhalation challenge (SIC) tests are still the reference test for diagnosing sensitizer-induced occupational asthma (SIOA). The European Respiratory Society recommends the cessation of inhaled corticosteroids (ICS) 72 hours before SIC., Objective: To assess the effect of an ongoing ICS treatment during SIC on the maximum fall in forced expiratory volume in 1 second (FEV 1 ), the change in methacholine provocative concentration of methacholine inducing a 20% fall in FEV 1 (PC 20 ), and sputum eosinophil counts after exposure to the suspected agent., Methods: We performed a retrospective analysis using a database of cases referred to our center for suspected SIOA from 1999 to 2022. The results of the SIC were compared between subjects treated with ICS during SIC and steroid-naïve subjects., Results: Six hundred and seventy-one individuals underwent SIC in the laboratory. Three hundred and eighteen were treated with ICS, whereas 353 were steroid naïve. The proportion of subjects with a positive SIC was greater among ICS-treated subjects (39. 6%) compared with steroid-naïve subjects (27.5%, P < .001). A treatment with ICS did not influence the outcome of the SIC. There was no difference in the change in PC 20 or the percentage of sputum eosinophils after SIC between steroid-treated and steroid-naïve subjects., Conclusions: An ongoing ICS treatment during an SIC did not affect the occurrence of an asthmatic reaction, the change in airway responsiveness, or eosinophilic inflammation after exposure to the suspected agent in subjects who have been treated with ICS for a long period of time., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Preliminary data in a randomly selected pediatric cohort study in 8-year-olds suggested a rate of positivity to a methacholine challenge test that was unexpectedly high, roughly 30%. The current recommendation for a negative methacholine test is a 20% decrease in the forced expiratory volume in one second at a dose greater than 400 μg. This was derived from studies in adults using the obsolete English Wright nebulizer. One explanation for the high incidence of positivity in the study in 8-year-olds could be that children deposit more methacholine on a μg/kg basis than adults, due to differences in their breathing patterns. The purpose of this study was to determine if pediatric breathing patterns could result in a higher dose of methacholine depositing in the lungs of children based on μg/kg body weight compared with adults. Methods: An AeroEclipse Breath Actuated nebulizer delivered methacholine aerosol, generated from a 16 mg/mL solution, for one minute, using age-appropriate breathing patterns for a 70 kg adult and a 30 and 50 kg child produced by a breathing simulator. Predicted lung deposition was calculated from the collected dose of methacholine on a filter placed at the nebulizer outport, multiplied by the fraction of the aerosol mass contained in particles ≤5 μm. The dose of methacholine on the inspiratory filter was assayed by high performance liquid chromatography (HPLC). Particle size was measured using laser diffraction technology. Results: The mean (95% confidence intervals) predicted pulmonary dose of methacholine was 46.1 (45.4, 46.8), 48.6 (45.3, 51.9), and 36.1 (34.2, 37.9) μg/kg body weight for the 30 kg child, 50 kg child, and 70 kg adult, respectively. Conclusions: On a μg/kg body weight, the predicted pulmonary dose of methacholine was greater with the pediatric breathing patterns than with the adult pattern.

Background: Increasing functional residual capacity (FRC) or tidal volume (V T ) reduces airway resistance and attenuates the response to bronchoconstrictor stimuli in animals and humans. What is unknown is which one of the above mechanisms is more effective in modulating airway caliber and whether their combination yields additive or synergistic effects. To address this question, we investigated the effects of increased FRC and increased V T in attenuating the bronchoconstriction induced by inhaled methacholine (MCh) in healthy humans., Methods: Nineteen healthy volunteers were challenged with a single-dose of MCh and forced oscillation was used to measure inspiratory resistance at 5 and 19 Hz (R 5 and R 19 ), their difference (R 5-19 ), and reactance at 5 Hz (X 5 ) during spontaneous breathing and during imposed breathing patterns with increased FRC, or V T , or both. Importantly, in our experimental design we held the product of V T and breathing frequency (BF), i.e, minute ventilation (V E ) fixed so as to better isolate the effects of changes in V T alone., Results: Tripling V T from baseline FRC significantly attenuated the effects of MCh on R 5 , R 19 , R 5-19 and X 5 . Doubling V T while halving BF had insignificant effects. Increasing FRC by either one or two V T significantly attenuated the effects of MCh on R 5, R 19 , R 5-19 and X 5 . Increasing both V T and FRC had additive effects on R 5 , R 19 , R 5-19 and X 5 , but the effect of increasing FRC was more consistent than increasing V T thus suggesting larger bronchodilation. When compared at iso-volume, there were no differences among breathing patterns with the exception of when V T was three times larger than during spontaneous breathing., Conclusions: These data show that increasing FRC and V T can attenuate induced bronchoconstriction in healthy humans by additive effects that are mainly related to an increase of mean operational lung volume. We suggest that static stretching as with increasing FRC is more effective than tidal stretching at constant V E , possibly through a combination of effects on airway geometry and airway smooth muscle dynamics., (© 2024. The Author(s).)

Background: Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs) offer an alternative, but concerns exist whether DPIs provide an effective relief during an obstructive event., Objective: We aimed to show non-inferiority of Salbutamol Easyhaler DPI compared to pMDI with spacer in treating methacholine-induced bronchoconstriction. Applicability of Budesonide-formoterol Easyhaler DPI as a reliever was also assessed., Methods: This was a randomized, parallel-group trial in subjects sent to methacholine challenge (MC) test for asthma diagnostics. Participants with at least 20 % decrease in forced expiratory volume in 1 s (FEV 1 ) were randomized to receive Salbutamol Easyhaler (2 × 200 μg), Ventoline Evohaler with spacer (4 × 100 μg) or Budesonide-formoterol Easyhaler (2 × 160/4.5 μg) as a reliever. The treatment was repeated if FEV 1 did not recover to at least -10 % of baseline., Results: 180 participants (69 % females, mean age 46 yrs [range 18-80], FEV 1 %pred 89.5 [62-142] %) completed the trial. Salbutamol Easyhaler was non-inferior to pMDI with spacer in acute relief of bronchoconstriction showing a -0.083 (95 % LCL -0.146) L FEV 1 difference after the first dose and -0.032 (-0.071) L after the last dose. The differences in FEV 1 between Budesonide-formoterol Easyhaler and Salbutamol pMDI with spacer were -0.163 (-0.225) L after the first and -0.092 (-0.131) L after the last dose., Conclusion: The study confirms non-inferiority of Salbutamol Easyhaler to Ventoline Evohaler with spacer in relieving acute bronchoconstriction, making Easyhaler a sustainable and safe reliever for MC test and supports its use during asthma attacks., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. JK reports payment or honoraria for lectures, presentations or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MSD, Novartis and Orion Pharma and participation on an Advisory Board from GlaxoSmithKline and MSD. VV reports being former employee of Orion Pharma and having received personal consultation and lecture fees from Orion Pharma and having been in sustainability advisory board of Orion Pharma. AT reports payments for lectures or presentations from Chiesi and GlaxoSmithKline and participation on an Advisory Board from Chiesi. LPM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chiesi and Orion Pharma. LV reports research grant from Tuberculosis foundation of Tampere. LL reports personal fees for lecturers and/or advisory board meetings from ALK, Astra Zeneca, Berlin Chemie, Boehringer Ingelheim, Chiesi, GSK, Menarini, Orion Pharma and Sanofi. SL, US and MV are employees of Orion Pharma., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Nocturia with or without asthma is one of the aging diseases. Desmopressin has been used as a nasal spray for patients who are suffering from nocturia. This study determined the effects of desmopressin on isolated tracheal smooth muscle in vitro . Methods: We evaluated desmopressin's efficiency on isolated rat tracheal smooth muscle. Desmopressin was evaluated for the following effects on tracheal smooth muscle: (1) effect on resting tension; (2) effect on contraction brought on by parasympathetic mimetic 10 -6 M methacholine; and (3) effect on electrically produced tracheal smooth muscle contractions. Results: As the concentration grew, desmopressin by itself had no impact on the trachea's baseline tension. Addition of desmopressin at doses of 10 -5 M or above elicited a significant relaxation response to 10 -6 M methacholine-induced contraction. Desmopressin could also inhibit spike contraction of the trachea induced by electrical field. Conclusion: According to this study, desmopressin at high quantities may prevent the trachea's parasympathetic activity. Due to its ability to block parasympathetic activity and lessen the contraction of the tracheal smooth muscle brought on by methacholine, Desmopressin nasal spray might help nocturia sufferers experience fewer asthma attacks., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Methods used to assess ventilation heterogeneity through inert gas washout have been standardised and showed high sensitivity in diagnosing many respiratory diseases. We hypothesised that nitrogen single or multiple breath washout tests, respectively nitrogen single breath washout (N 2 SBW) and nitrogen multiple breath washout (N 2 MBW), may be pathological in patients with clinical suspicion of asthma but normal spirometry. Our aim was to assess whether N 2 SBW and N 2 MBW are associated with methacholine challenge test (MCT) results in this population. We also postulated that an alteration in S III at N 2 SBW could be detected before the 20% fall of forced expiratory volume in the first second (FEV 1 ) in MCT., Study Design and Methods: This prospective, observational, single-centre study included patients with suspicion of asthma with normal spirometry. Patients completed questionnaires on symptoms and health-related quality-of-life and underwent the following lung function tests: N 2 SBW (S III ), N 2 MBW (Lung clearance index (LCI), S cond , S acin ), MCT (FEV 1 and sGeff) as well as N 2 SBW between each methacholine dose., Results: 182 patients were screened and 106 were included in the study, with mean age of 41.8±14 years. The majority were never-smokers (58%) and women (61%). MCT was abnormal in 48% of participants, N 2 SBW was pathological in 10.6% at baseline and N 2 MBW abnormality ranged widely (LCI 81%, S cond 18%, S acin 43%). The dose response rate of the MCT showed weak to moderate correlation with the subsequent N 2 SBW measurements during the provocation phases (ρ 0.34-0.50) but no correlation with N 2 MBW., Conclusions: Both MCT and N 2 washout tests are frequently pathological in patients with suspicion of asthma with normal spirometry. The weak association and lack of concordance across the tests highlight that they reflect different but not interchangeable pathological pathways of the disease., Competing Interests: Competing interests: DS (second author) is currently employed at Tillotts Pharma AG, however, during the period of the study was an employee of the University Hospital of Basel. AMD has received a grant from University Hospital Basel, PL has a grant/contract to Vertex and OM Pharma. DS (last author) reports grants from Astra-Zeneca AG, Curetis AG, BostonScientific, Novartis AG, GSK AG, Roche AG, Zambon, Pfizer, Schwabe Pharma AG, Vifor AG. Other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The multiple forced expiratory maneuvers that must be performed during methacholine test require a high degree of collaboration and can lead to fatigue. However, impulse oscillometry (IOS) is a noninvasive test, quick and easy to perform, that does not require effort-dependent maneuvers. Objectives: The primary endpoint was to evaluate the relationship between IOS and spirometry during the methacholine test. The secondary endpoint was to study the predictive value of baseline IOS in the development of bronchial hyperreactivity. Methods: Observational, prospective, cross-sectional study, with recruitment of consecutive patients from the pulmonology department with clinical suspicion of bronchial asthma with negative bronchodilator test and normal FeNO. Results: Twenty-five patients were included, with a mean age of 49 ± 18 years. Thirteen patients (52%) had a positive methacholine test. The correlation between IOS indices and FEV1 was significant ( p < 0.05) in all cases. The indices with the highest predictive power were R5-20 and AX. The optimal cutoff points were an increase of greater than 32.96% in R5, greater than 120.83% for X5, an increase of 30.30 [kPa l-1s-1] in R5-20, and an increase of 1.01 [kPa l-1] for AX. Baseline oscillometry demonstrated a strong predictive value in the development of bronchial hyperreactivity, with a sensitivity of 61.5% and a specificity of 91.7%, using the cut-off point of 160.0% for R5. Conclusions: IOS may be a valuable alternative to forced spirometry in detecting bronchial hyperreactivity during the methacholine test, showing a good correlation between both tests.

Balb/c mice respiratory mechanics was studied in two intravenous methacholine (MCh) protocols: bolus and continuous infusion. The Constant Phase Model (CPM) was used in this study. The harmonic distortion index (k d ) was used to assess the respiratory system nonlinearity. The analysis of variance showed difference between groups (OVA vs control) and among doses for both protocols. Bolus protocol posttest: there was a difference between OVA and control at 0.3 and 1 mg/kg doses (p<0.0001 and p<0.001) for R n . Infusion: there was a difference between OVA and control at 192 μg.kg -1 .min -1 dose for R n , G and H, (p<0.01; p<0.001; p<0.001). An increment was found in k d values near to the observed peak values in bolus protocol. The bolus protocol could better differentiate inflamed and non-inflamed airway resistance, whereas the differences between OVA and control in continuous infusion protocol were associated to airway- and, mainly, parenchyma-related parameters. Moreover, the bolus protocol presented a higher nonlinear degree compared to the infusion protocol., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Type 2 low (T2-low) asthma is reported to respond less to anti-inflammatory treatment compared with Type 2 high (T2-high) asthma. Airway hyperresponsiveness (AHR) to mannitol, a marker of airway mast cell activation, may be indicative of response to treatment in patients with T2-low disease. We investigated whether AHR to mannitol improves in patients with T2-low asthma after specialist management., Methods: Patients with asthma or suspected asthma, referred to our specialist outpatient clinic, were enrolled consecutively and assessed with FeNO, asthma control, blood eosinophils, mannitol and methacholine tests and induced sputum. T2-low asthma was defined in patients with FeNO < 25ppb and sputum eosinophils < 3% and blood eosinophils < 300µl -1 at inclusion. Patients with asthma and AHR to mannitol (PD15 ≤ 635 mg) were followed and reassessed after 12 months of specialist management., Results: Thirty-two patients (Females: 56%, age: 22 years (15-59)) were followed. Fourteen (44%) with T2-high and 18 (56%) with T2-low asthma. Baseline AHR to mannitol was comparable: G mean PD15: 150 mg (95% CI 61-368) and 214 mg (95% CI 106-432) for T2-high and T2-low asthma respectively ( P  = 0.51). Both groups improved equally: G mean PD15: 488 mg (95% CI 311-767) and 507 mg (95% CI 345-746); corresponding to a doubling-dose of: 3.00 (95% CI 1.58-5.74, P  = 0.003) and 2.28 (95% CI 1.47-3.53, P  = 0.001) respectively. There were no concomitant improvements in AHR to methacholine., Conclusion: Patients with asthma and AHR to mannitol improve similarly in responsiveness to mannitol after 12 months of specialist management regardless of Type 2 inflammatory biomarker levels. Mechanisms driving AHR in T2-low asthma need to be further elucidated.

In this study we assessed the effects of antigen exposure in mice pre-sensitized with allergen following viral infection on changes in lung function, cellular responses and tight junction expression. Female BALB/c mice were sensitized to ovalbumin and infected with influenza A before receiving a second ovalbumin sensitization and challenge with saline, ovalbumin (OVA) or house dust mite (HDM). Fifteen days post-infection, bronchoalveolar inflammation, serum antibodies, responsiveness to methacholine and barrier integrity were assessed. There was no effect of infection alone on bronchoalveolar lavage cellular inflammation 15 days post-infection; however, OVA or HDM challenge resulted in increased bronchoalveolar inflammation dominated by eosinophils/neutrophils or neutrophils, respectively. Previously infected mice had higher serum OVA-specific IgE compared with uninfected mice. Mice previously infected, sensitized and challenged with OVA were most responsive to methacholine with respect to airway resistance, while HDM challenge caused significant increases in both tissue damping and tissue elastance regardless of previous infection status. Previous influenza infection was associated with decreased claudin-1 expression in all groups and decreased occludin expression in OVA or HDM-challenged mice. This study demonstrates the importance of the respiratory epithelium in pre-sensitized individuals, where influenza-infection-induced barrier disruption resulted in increased systemic OVA sensitization and downstream effects on lung function.

Background: Most epidemiological studies depend on the subjects' response to asthma symptom questionnaires. Questionnaire-based study for childhood asthma prevalence may overestimate the true prevalence. The aim of this study was to investigate the prevalence of "Current asthma" using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and methacholine challenge test in Korean children., Methods: Our survey on allergic disease included 4,791 children (age 7-12 years) from 2010 to 2014 in Korean elementary schools. Bronchial hyperresponsiveness (BHR) was defined as provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) (PC20) ≤ 16 mg/mL. "Current asthma symptoms" was defined as positive response to "Wheezing, current," "Treatment, current," or "Exercise, current." "Current asthma" was defined when the subjects with "Current asthma symptoms" showed BHR on the methacholine challenge test or had less than 70% of predicted FEV1 value., Results: The prevalence of "Wheezing, ever," "Wheezing, current," "Diagnosis, ever," "Treatment, current," "Exercise, current," and "Current asthma symptoms" was 19.6%, 6.9%, 10.0%, 3.3%, 3.5%, and 9.6%, respectively, in our cross-sectional study of Korean elementary school students. The prevalence of BHR in elementary school students was 14.5%. The prevalence of BHR in children with "Wheezing, ever," "Wheezing, current," "Diagnosis, ever," "Treatment, current," and "Exercise, current" was 22.3%, 30.5%, 22.4%, 28.8%, and 29.9%, respectively. BHR was 26.1% in those with "Current asthma symptoms." The prevalence of "Current asthma" was 2.7%., Conclusions: Our large-scale study provides 2.7% prevalence of current asthma in Korean elementary school children. Since approximately one third of the children who have "Current asthma symptoms" present BHR, both subjective and objective methods are required to accurately predict asthma in subjects with asthma symptoms., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Background: Methacholine challenge tests (MCTs) are used to diagnose airway hyperresponsiveness (AHR) in patients with suspected asthma where previous diagnostic testing has been inconclusive. The test is time consuming and usually requires referral to specialized centers. Simple methods to predict AHR could help determine which patients should be referred to MCTs, thus avoiding unnecessary testing. Here we investigated the potential use of baseline spirometry variables as surrogate markers for AHR in adults with suspected asthma., Methods: Baseline spirometry and MCTs performed between 2013 and 2019 in a large tertiary center were retrospectively evaluated. Receiver-operating characteristic curves for the maximal expiratory flow-volume curve indices (angle β, FEV1, FVC, FEV1/FVC, FEF 50% , FEF 25-75% ) were constructed to assess their overall accuracy in predicting AHR and optimal cutoff values were identified., Results: A total of 2983 tests were analyzed in adults aged 18-40 years. In total, 14% of all MCTs were positive (PC20 ≤ 16 mg/ml). All baseline spirometry parameters were significantly lower in the positive group (p < 0.001). FEF 50% showed the best overall accuracy (AUC = 0.688) and proved to be useful as a negative predictor when applying FEF 50%  ≥ 110% as a cutoff level., Conclusions: This study highlights the role of FEF 50% in predicting AHR in patients with suspected asthma. A value of ≥ 110% for baseline FEF 50% could be used to exclude AHR and would lead to a substantial decrease in MCT referrals.

Objective: This study aimed to evaluate the diagnostic value of the modified hypertonic saline bronchial provocation test (HS-BPT) for children with asthma by using the high-power Aerosol Provocation System (APS). Methods : A total of 330 children suspected of having asthma and receiving HS-BPT-APS were included in this prospective survey conducted in Guangzhou, China from February 2017 to September 2018. The positive rate of HS-BPT-APS and the volume and types of adverse reactions were observed. There was also a retrospective cohort of 123 children with suspected asthma who underwent a methacholine BPT from 2015 to 2017. Using the method of nearest neighbor matching, a comparison was made of the positive rate and adverse reaction between the methacholine BPT group and HS-BPT-APS group. Results : The total positive rate of HS-BPT-APS was 43.9%. Common adverse reactions included cough, wheezing and chest tightness. There were no serious adverse reactions. Results of nearest neighbor matching showed a difference in the positive rate between the methacholine BPT group and HS-BPT-APS group (8.1% vs 18.2%, p  = 0.026), but there was no statistically significant difference between the age groups in patients who received the methacholine BPT or HS-BPT-APS. There was a similar adverse reaction rate in the two groups ( p  = 0.609). Conclusions : HS-BPT-APS is simple, safe, and time-saving, with few adverse reactions. The positive rate of HS-BPT-APS was higher than that of methacholine BPT in children with asthma. HS-BPT-APS may be a valuable tool in the diagnosis of children with asthma, and further study is required.

Introduction: Airway hyper-responsiveness (AHR) is a characteristic feature of asthma. The aim of this study was to compare the impulse oscillometry (IOS) and spirometry to methacholine for AHR detection among individuals with clinically hyper-reactive airway disease suggestive of bronchial asthma and baseline spirometry were normal., Materials and Methods: Adults with symptoms suggestive of AHR and normal baseline spirometry test were selected. The short protocol of methacholine challenge test (MCT) was performed for all subjects using IOS and spirometry simultaneously. The primary endpoint was to compare the methacholine dosage causing a 20% drop in forced expiratory volume in one second (FEV1), with methacholine dosage that causing 40% increasing the baseline respiratory resistance at 5 hertz (R5), as measured by IOS., Result: A total of 235 participants were analyzed, 184 (78.2%) had positive test results with R5, while 81 (34.4%) had positive MCT results with FEV1.The sensitivity and specificity of MCT with R5were 87.3%, 64.6%, and MCT with FEV1 were 39.1%, 85.4%, respectively. The area under the receiver operating characteristic (ROC) curve was greater at lower doses of MCT at R5, (AUROC: 0.653; p= 0.01)., Conclusions: The results showed higher sensitivity, negative predictive value, and earlier response of the short protocol of MCT with IOS, compared to MCT with spirometry. Our study suggested the utility of IOS in addition to conventional spirometry as a method of choice in MCT for detection of AHR.

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 50 and FEF 75 (% predicted) was 0.615, 0.621, 0.606, respectively. 0.17mcg of PD 20 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.

Objective: Interpretation of methacholine challenge testing (MCT) results depends on the patient's pretest probability of asthma as well as the provocative concentration (PC 20 ); however, ordering providers rarely understand the complexity associated with its interpretation. This study investigated the clinical utility and efficiency of MCT at a tertiary center in evaluating pediatric asthma., Methods: Retrospective chart review was done for all MCT done at a tertiary center over a six year period (2011-2017). Demographics, referring provider, referral diagnosis, current symptoms with and without exercise, and baseline spirometry were collected. Pretest probability of asthma was assigned by author (RB) who was blinded to MCT results and PC 20 . Post-test probability of asthma was assigned based on pretest probability, MCT result (+/-), and PC 20 . Three assigned asthma probability categories were "unlikely" "likely", and "very likely"., Results: Of 172 subjects (91 Females, age range 5-21 years), 64.9% of MCT results ( n  = 111)) were negative and 35.1% ( n  = 60)) were positive. One was inconclusive. Those who tested positive were shorter, lighter, younger and had lower forced expiratory volume in one second/forced vital capacity (FEV 1 /FVC) ratio than those who tested negative ( p  < 0.05). Subjects with exercise symptoms only were less likely to test positive (OR 0.2, CI 0.1-0.5). In a majority of subjects (91.8%; 157/171), MCT increased the certainty of presence or absence of asthma., Conclusions: In our subject population, MCT could be useful in evaluating pediatric asthma if subject's pretest probability of asthma and PC 20 was taken into account. It was not as useful for subjects with exercise symptoms only.

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 2 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 2 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., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Asthma is characterized by airway inflammation, variable airflow obstruction, and airway hyperresponsiveness (AHR). Generally, AHR takes longer to resolve than does airflow obstruction or clinical symptoms. AHR occasionally persists despite adequate asthma treatment. Objective: To evaluate factors which associates with residual AHR in patients with seemingly remitted airway inflammation. Methods: Patients who exhibited high fractional exhaled nitric oxide (FeNO) levels (>25 ppb) at the first visit (Visit 1) and normalized FeNO levels (<25 ppb) after adequate asthma treatment, including inhaled corticosteroid administration (Visit 2), were analyzed. Patients underwent a blood test, FeNO and small airway/alveolar nitric oxide concentration (CANO) measurements and a methacholine challenge test (continuous inhalation method) at both visits. Clinical indices were compared between patients with and without residual AHR. Results: Fifty patients were analyzed. All exhibited high FeNO levels at Visit 1 [mean, 54.0 ppb (95% confidence interval, 42.4-65.5)] and improvement of FeNO levels at Visit 2 [20.4 (19.2-21.6)] ( p  < 0.0001). Thirty-three patients (66%) had remission of AHR at Visit 2. No significant differences were observed between patients with and without residual AHR in terms of FeNO levels, lung function parameters and blood eosinophil counts at both visits. CANO level at Visit 2 was the only factor that significantly differed between patients with residual AHR [2.7 (1.9-3.6)] and those who achieved AHR remission [0.8 (0.5-1.0)] ( p  < 0.0001). Conclusion: Small airway inflammation, as assessed by CANO, was associated with residual AHR in patients with Th2-high asthma.

Objective: To assess the predictive value of bronchial hyper-responsiveness (BHR) for the subsequent development of respiratory symptoms, airflow limitation and decline in lung function among aluminium smelter workers., Methods: An inception cohort study of new employees at two Australian aluminium smelters was conducted. Participants completed a modified British Medical Research Council respiratory questionnaire, spirometry and a methacholine bronchial challenge test at baseline and at annual follow-up reviews. BHR was defined as PD 20 ≤4000 µg. Poisson and mixed effects models were fitted to respiratory symptoms and lung function (forced expiratory volume in 1 s (FEV 1 ) and FEV 1 /forced vital capacity (FVC))., Results: Baseline interview and lung function testing were completed by 278 workers, who were followed for a median of 4 years. BHR at baseline, present in 82 workers, was not associated with incident wheeze risk ratio (RR)=1.07 (95% CI 0.74 to 1.55) and cough RR=0.78 (95% CI 0.45, 1.35), but there was some increased risk of chest tightness RR=1.40 (95% CI 0.99, 1.98) after adjustment for age, sex, smoking and atopy. BHR at baseline was associated with lower FEV 1 and FVC, although the rate of annual decline in FEV 1 or FVC was similar between those with or without BHR. The specificity of BHR was 77% for wheeze, 70% for cough and 77% for chest tightness, but the sensitivity was poor, at 33%, 24% and 39%, respectively., Conclusion: Methacholine challenge testing at entry to employment was not sufficiently predictive of later adverse respiratory outcomes, and notwithstanding the study limitations is unlikely to be a useful pre-employment or preplacement screening test in the aluminium smelting industry., Competing Interests: Competing interests: MJA holds investigator initiated grants from Pfizer and Boehringer-Ingelheim for unrelated research. He has undertaken an unrelated consultancy for and received assistance with conference attendance from Sanofi. He has received a speaker's fee from GSK. The other authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Supplemental oxygen exposure administered to premature infants is associated with chronic lung disease and abnormal pulmonary function. This study used mild (40%), moderate (60%), and severe (80%) oxygen to determine how hyperoxia-induced changes in lung structure impact pulmonary mechanics in mice., Methods: C57BL/6J mice were exposed to room air or hyperoxia from birth through postnatal day 8. Baseline pulmonary function and methacholine challenge was assessed at 4 and 8 weeks of age, accompanied by immunohistochemical assessments of both airway (smooth muscle, tethering) and alveolar (simplification, elastin deposition) structure., Results: Mild/moderate hyperoxia increased baseline airway resistance (40% only) and airway hyperreactivity (40 and 60%) at 4 weeks accompanied by increased airway smooth muscle deposition, which resolved at 8 weeks. Severe hyperoxia increased baseline compliance, baseline resistance, and total elastin/surface area ratio without increasing airway hyperreactivity, and was accompanied by increased alveolar simplification, decreased airway tethering, and changes in elastin distribution at both time points., Conclusions: Mild to moderate hyperoxia causes changes in airway function and airway hyperreactivity with minimal parenchymal response. Severe hyperoxia drives its functional changes through alveolar simplification, airway tethering, and elastin redistribution. These differential responses can be leveraged to further develop hyperoxia mouse models.

Background: The relationship of airway hyperresponsiveness to airway remodeling and inflammation in infants with wheeze is unclear., Objective: To investigate airway hyperresponsiveness, remodeling and inflammation in infants with wheeze and troublesome breathing., Methods: Inclusion criteria were as follows: full-term, 3-23 months of age; doctor -diagnosed wheeze and persistent recurrent troublesome breathing; without obvious structural defect, suspicion of ciliary dyskinesia, cystic fibrosis, immune deficiency or specified use of corticosteroids. Airway hyperresponsiveness (AHR) was evaluated by performing a methacholine bronchial challenge test combined with whole body plethysmography and rapid thoracoabdominal compression. Endobronchial biopsies were analysed for remodeling (thickness of reticular basement membrane and amount of airway smooth muscle) and for inflammation (numbers of inflammatory cells). Correlation analyses were performed., Results: Forty-nine infants fulfilled the inclusion criteria for the present study. Median age was 1.06 years (IQR 0.6; 1.5). Lung function was impaired in 39/49 (80%) children, at the median age of 1.1 years. Methacholine challenge was successfully performed in 38/49 children. Impaired baseline lung function was correlated with AHR (P = .047, Spearman). In children with the most sensitive quartile of AHR, the percentage of median bronchial airway smooth muscle % and the number of bronchial mast cells in airway smooth muscle were not significantly higher compared to others (P = .057 and 0.056, respectively). No association was found between AHR and thickness of reticular basement membrane or inflammatory cells. Only a small group of children with both atopy and AHR (the most reactive quartile) had thicker airway smooth muscle area than non-atopics with AHR (P = .031)., Conclusions and Clinical Relevance: These findings do not support the concept that AHR in very young children with wheeze is determined by eosinophilic inflammation or clear-cut remodeling although it is associated with impaired baseline lung function. The possible association of increased airway smooth muscle area among atopic children with AHR remains to be confirmed., (© 2020 John Wiley & Sons Ltd.)

Clinical testing of bronchial hyperreactivity (BHR) provides valuable information in asthma diagnostics. Nevertheless, the test results depend to a great extent on the testing procedure: test substance, apparatus and protocol. In Nordic countries, three protocols predominate in the testing field: Per Malmberg, Nieminen and Sovijärvi methods. However, knowledge of their equivalence is limited. We aimed to find equivalent provocative doses (PD) to obtain similar bronchoconstrictive responses for the three protocols. We recruited 31 patients with suspected asthma and health care workers and performed BHR testing with methacholine according to Malmberg and Nieminen methods, and with histamine according to Sovijärvi. We obtained the individual response-dose slopes for each method and predicted equivalent PD values. Applying a mixed-model, we found significant differences in the mean (standard error of mean) response-dose (forced expiratory volume in one second (FEV 1 )%/mg): Sovijärvi 7.2 (1.5), Nieminen 13.8 (4.2) and Malmberg 26 (7.3). We found that the earlier reported cut-point values for moderate BHR and marked BHR between the Sovijärvi (PD 15 ) and Nieminen (PD 20 ) methods were similar, but with the Malmberg method a significant bronchoconstrictive reaction was measured with lower PD 20 values. We obtained a relationship between slope values and PD (mg) between different methods, useful in epidemiological research and clinical practice.

Introduction and Objectives: Functional and inflammatory measures have been recommended to corroborate asthma diagnosis in schoolchildren, but the evidence in this regard is conflicting. We aimed to determine, in real-life clinical situation, the value of spirometry, spirometric bronchial reversibility to salbutamol (BDR), bronchial responsiveness to methacholine (MCT) and fractional exhaled nitric oxide (FENO), to corroborate the diagnosis of asthma in children on regular inhaled corticosteroids (ICS) referred from primary care., Methods: One hundred and seventy-seven schoolchildren with mild-moderate persistent asthma, on treatment with regular ICS, participated in the study. Abnormal tests were defined as FENO ≥ 27 ppb, BDR (FEV1 ≥ 12%) and methacholine PC20 ≤ 4 mg/mL., Results: The proportions of positive BDR, FENO and MCT, were 16.4%, 33.3%, and 87.0%, respectively. MCT was associated with FENO (p < 0.03) and BDR (p = 0.001); FENO was associated with BDR (p = 0.045), family history of asthma (p = 0.003) and use of asthma medication in the first two years of life (p = 0.004). BDR was significantly related with passive tobacco exposure (p = 0.003)., Conclusions: Spirometry, BDR and BDR had a poor performance for corroborating diagnosis in our asthmatic children on ICS treatment; on the contrary, MCT was positive in most of them, which agrees with previous reports. Although asthma tests are useful to corroborate asthma when positive, clinical diagnosis remains the best current approach for asthma diagnosis, at least while better objective and feasible measurements at the daily practice are available. At present, these tests may have a better role for assessing the management and progression of the condition., (Copyright © 2020 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Impact Statement: Respiratory mechanics studies are associated with fundamental research and translational studies; the present work thus investigates this particular matter. Our current research describes differences and similarities between two different ways of administrating a very prevalent bronchoconstrictor (methacholine) in an aging process scenario. The core issue of our work is related with troubles we find with the bolus protocol and the application of the mathematical model used to assess the respiratory mechanics. Our findings reveal the continuous infusion as an alternative to these problems and we hope to provide the proper foundations to a more reliable assessment in the respiratory field.

Objectives: Various indirect or direct airway challenge tests are used to measure nonspecific bronchial hyper-responsiveness (NSBHR). The evaluation of NSBHR in diagnosing occupational asthma (OA) is performed, e.g., to monitor the specific inhalation challenge test (SICT). The aim of this study was to preliminarily compare the results of methacholine and mannitol inhalation challenge tests in SICT monitoring in bakers with work-related airway symptoms., Material and Methods: Four bakery workers with a suspicion of OA underwent single-blind placebo-controlled SICTs involving workplace allergens, accompanied by the evaluation of NSBHR with mannitol and methacholine, both before and after SICTs. Clinical examinations, spirometry tests, skin prick tests (SPTs) to common aeroallergens and occupational allergens, as well as tests to determine serum specific IgE antibodies to occupational aeroallergens were also performed., Results: Positive SPTs results to occupational aeroallergens were found in all bakery workers, and specific IgE antibodies to flour were detected in 2 subjects. Three patients displayed positive SICT reactions. In all of these 3 patients, airway responsiveness to methacholine increased significantly. In 2 patients, airway reaction to mannitol was significant, whereas in 1 subject there was no increase in NSBHR after mannitol inhalation. The patient with a negative SICT result did not reveal any changes in NSBHR before and after the test, either to methacholine or mannitol., Conclusions: The data obtained by the authors show that there is no clear correlation between the methacholine and mannitol inhalation challenge tests in SICT monitoring. Preliminary results indicate the need for further investigations to evaluate the usefulness of the mannitol challenge test in the diagnostics of OA. Int J Occup Med Environ Health. 2020;33(2):235-9., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

Objectives: The aim of this study was to investigate airway responsiveness and eosinophil and neutrophil inflammatory markers in clinically confirmed nonasthmatic adolescents with elevated fractional exhaled nitric oxide (FeNO), a marker of type-2 inflammation in the airways., Methodology: A total of 959 subjects from a general population, aged 12 to 15 years, answered a standardised questionnaire and underwent FeNO measurements at a screening visit at school. Adolescents without asthma, who had elevated FeNO (FeNO 100  > 15 ppb) (n = 19), and control subjects, with low FeNO (FeNO 100  < 5 ppb) and without reported symptoms of asthma or allergy (n = 28), participated in a follow-up study where FeNO 50 , airway responsiveness to methacholine (PD 20 ), blood eosinophil counts, and serum neutrophil lipocalin (HNL) and myeloperoxidase (MPO) levels were measured. Questionnaire follow-ups were performed 4 and 16 years later., Results: Airway responsiveness (PD 20 : 6.94 [1.87, 11.39] vs 11.42 [6.33, 59.4] µmol; P < .05) and blood eosinophil counts (0.31 [0.20, 0.44] vs 0.13 [0.1, 0.22] 10 9 /L; P < .001) (geometric mean [95% CI]) were higher among cases than controls. A significant correlation between blood eosinophils and FeNO was found (rho = 0.41; P = .005). In contrast, serum HNL and MPO were lower in cases than controls (P < .05 both), and there was a negative correlation between HNL and FeNO (r = -0.31; P = .04). At both follow-ups, a higher proportion of subjects reported allergic symptoms compared with baseline (P = .02, P = .01)., Conclusions: Elevated FeNO in nonasthmatic adolescents was associated with airway hyperresponsiveness, elevated blood eosinophil counts, and lower systemic activation of neutrophils., (© 2020 Wiley Periodicals, Inc.)

Nocturnal worsening of asthma may be due to reduced lung volumes and fewer sigh breaths, which have been shown to increase airway resistance and bronchoreactivity. We hypothesized that mimicking deep inspiration using nocturnal mechanical support would improve symptoms in patients with asthma. Subjects with asthma underwent usual care and bilevel positive airway pressure (PAP) therapy for 4 weeks, separated by 4 weeks, and methacholine challenge (PC 20 ) and subjective assessments. 13 patients with asthma alone and 8 with asthma + OSA completed the protocol. Change in bronchoreactivity (ratio of Post/Pre PC 20 ) was not significantly different during usual care and bilevel PAP [0.86 (IQR 0.19, 1.82) vs 0.94 (IQR 0.56, 2.5), p = 0.88], nor was the change in Asthma Control Test different: 0.1 ± 2.2 vs. -0.2 ± 2.9, p = 0.79, respectively. Bilevel PAP therapy for four weeks did not improve subjective or objective measures of asthma severity in patients with asthma or those with asthma and OSA, although there was heterogeneity in response., Competing Interests: Declaration of Competing Interest RLO previously consulted for Philips Respironics. Philips Respironics provided the bilevel positive airway pressure machines and related equipment used in the study. As an Officer of the ATS, Dr. Malhotra relinquished all outside personal income in 2012. ResMed provided a philanthropic donation to UC San Diego for a Sleep Center. The other authors report no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Hesperetin-5,7,3'- O -trimethylether (HTME), a synthetic liposoluble hesperetin, has been reported to be a dual phosphodiesterase (PDE)3/4 inhibitor. We investigated its inhibitory effects on methacholine (MCh)-induced airway hyperresponsiveness (AHR) and its potential for treating atypical asthma and COPD., Methods: FlexiVent system was used to determine AHR in ovalbumin (OVA) sensitized and challenged mice. Determination of cytokines was performed by using mouse T helper (Th)1/Th2 cytokine CBA kits, and of total immunoglobulin (Ig)E and OVA-specific IgE using ELISA kits. The number of inflammatory cells was counted using a hemocytometer. Xylazine/ketamine-induced anesthesia was to assess nausea, vomiting, and gastric hypersecretion in these mice., Results: HTME dually and competitively inhibited PDE3/4 activities in the Lineweaver-Burk analysis. HTME (30 and 100 μmol/kg) dose-dependently and significantly decreased the airway resistance (R L ) and increased lung dynamic compliance (C dyn ) values induced by MCh. It significantly suppressed numbers of total inflammatory cells and neutrophils, and levels of cytokines in bronchoalveolar lavage fluid (BALF). HTME dose-dependently and significantly inhibited total and OVA-specific IgE levels in the BALF and serum. However, HTME did not influence xylazine/ketamine-induced anesthesia., Conclusion: HTME exerted anti-inflammatory and bronchodilator effects and may be useful in treating chronic obstructive pulmonary disease and allergic atypical asthma with no gastrointestinal side effects., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Shih et al.)

Aim: This study aimed to analyze the Constant Phase Model (CPM) Coefficient of Determination (COD) and an index of harmonic distortion ([Formula: see text]) behavior in intravenous methacholine dose response curve. We studied the COD and [Formula: see text] behavior of Control and Lung Inflammation (OVA) groups of mice and we proposed an alternative for moments when the CPM should not be applied. Methods: 9-week female BALB/c mice were studied, 8 of the control group (23.11 ± 1.27 g) and 11 of the lung inflammation group (OVA) (21.45 ± 2.16 g). The COD values were obtained during the respiratory mechanics assessment via Forced Oscillation Technique (FOT) and the [Formula: see text] was estimated a posteriori. Both control and OVA groups were submitted to 4 doses of Methacholine (MCh) protocol. Results: A strong correlation between COD and [Formula: see text] was present at the last two doses (0.3 mg/kg: r = -0.75, p  = 0.0013 and 1 mg/kg: r = -0.91; p  < 0.0001) in the OVA group. Differences were found in doses of 0.3 mg/kg between control and OVA for the maximum values of Rn (Newtonian Resistance) and G (tissue viscous); and between groups at PBS and doses of 0.03, 0.1 and 0.3 mg/kg for H (Elastance). A similar behavior was observed for the analysis of Area Under the Curve with the exclusion of the 3 first measurements of each dose. However, in this scenario, the comparison with the maximum value presented a higher discriminatory capacity of the parameters associated with the parenchyma. Conclusions: During severe bronchoconstriction there is a strong negative correlation between model goodness of fit and nonlinearities levels, reinforcing that COD is a robust acceptance criterion, whether still simple and easily obtained from the ventilator. We also pointed out the area under the CPM parameters dose response curve is a useful and can be used as a complementary analysis to peak comparison following bolus injections of methacholine.

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 %max ) 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 ω -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 %max 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., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Background: Methacholine challenges have been used in clinical trials to assess therapeutic effects and potential adverse reactions of interventions on pulmonary function in a sensitive population, such as in subjects with asthma. Here, we evaluate the variability of the methacholine challenge recovery model, and compare the results obtained for both incremental and bolus challenge methods., Methods: The extent, time course and variability of change in forced expiratory volume in 1 s (FEV 1 ) following repeated methacholine challenges in subjects with mild asthma were investigated in an open-label, four-period, fixed-sequence, two-method, replicate crossover study. At Visits 1 and 2, subjects underwent an incremental challenge using doubling doses of methacholine until a ≥20% decrease in FEV 1 was observed; at Visits 3 and 4, subjects underwent a bolus challenge, inhaling a single dose of methacholine calculated from the cumulative dose established during Visit 1., Results: A total of 19 subjects were included in the study. Both the mean FEV 1 area under the curve (FEV 1 AUC 0-tz ) and mean maximum reductions in FEV 1 (absolute and relative) 120 min post-challenge values were higher for the incremental challenges than the bolus challenges, with no reported difference between repetitions of the same methodology. FEV 1 AUC 0-tz decrease 120 min post challenge demonstrated an intra-subject coefficient of variation (CV) of 47.2% (incremental) and 78.3% (bolus), suggesting considerable between-visit variability. The mean absolute, and similarly relative, maximum reductions in FEV 1 compared with post-diluent baseline values demonstrated lower intra-subject variability (incremental 21.16%, bolus 40.67%) than the FEV 1 AUC 0-tz -based endpoint. There was a trend towards faster recovery following the bolus challenge than with the incremental challenge. The provocative dose of methacholine inducing a ≥20% decrease in FEV 1 resulted in a between-group mean difference of 27.20% in the incremental challenge periods, with a high intra-subject CV of 80.64%, demonstrating considerable variability., Conclusion: Maximum reduction in FEV 1 had the lowest variability. There was little difference between repetitions of the same methodology, as indicated by overlapping confidence intervals. There was a trend towards faster recovery following bolus challenge than with the incremental challenge. The results of this trial could be of value when designing future clinical trials using the methacholine challenge methodology., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: New treatments are needed for cases of asthma that are refractory to traditional therapies. In this study, we examined the effect of oral nintedanib, an intracellular inhibitor of tyrosine kinases, on airway hyper-responsiveness (AHR) and airway smooth muscle cells, using a mouse model of experimental asthma. Methods: Asthma was experimentally induced in mice via subcutaneous injection of ovalbumin (OVA). A group of saline-injected mice served as a control group. The OVA mice were then divided into four treatment groups according to the dose of nintedanib. AHR was examined via exposure to vaporized methacholine. Airway inflammation was assessed via bronchoalveolar lavage fluid (BALF) cell counts and Th2 cytokine concentrations. Results: Baseline levels of AHR and airway inflammation were higher in OVA mice than in the control group. Treatment with nintedanib lowered AHR, BALF cell counts and BALF cytokine levels in a dose-dependent fashion. The effect of nintedanib was comparable to that of dexamethasone. In particular, treatment with nintedanib lowered the expression of transforming growth factor-β1 and inhibited the expression and phosphorylation of platelet-derived growth factor receptor-β, vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, fibroblast growth factor receptor 2 (FGFR2), FGFR3, and extracellular signal-regulated kinase. Conclusions: Nintedanib lowered AHR and the expression of factors associated with airway inflammation and remodeling in a mouse model of experimental asthma. Our results suggest that nintedanib may be useful in the treatment of asthma.

Introduction: Bronchoconstriction was recently shown to cause airway remodeling and induce allergic airway inflammation in asthma. However, the mechanisms how mechanical stress via bronchoconstriction could induce airway inflammation and remodeling remain unclear., Objective: We investigated the effect of bronchoconstriction induced by methacholine inhalation in a murine model of asthma., Methods: BALB/c female mice were sensitized and challenged with ovalbumin (OVA), followed by treatment with methacholine by a nebulizer twice a day for 7 days. Twenty-four hours after the last methacholine treatment, the bronchoalveolar lavage fluid (BALF) and lung tissues were collected. The BALF was analyzed for total and differential cell counts and cytokine levels. The lung tissues were analyzed for goblet cell metaplasia, thickness of the smooth muscle, and lung fibrosis. The expression of cytokines in the lung was also examined., Results: OVA sensitization and challenge induced infiltration of total cells, macrophages, and eosinophils in the BALF along with goblet cell metaplasia and increased airway smooth muscle hypertrophy. Seven days after the last OVA challenge, untreated mice achieved reduction in airway inflammation, while methacholine maintained the number of BALF total cells, macrophages, and eosinophils. The percentage of goblet cells and the thickness of airway smooth muscle were also maintained by methacholine. Moreover, the treatment of methacholine induced the expression of transforming growth factor (TGF)-β in the lung. This result indicates that the production of TGF-β is involved in induction of airway remodeling caused by bronchoconstriction with methacholine., Conclusions: Repeated bronchoconstriction caused by methacholine inhalation elicited allergic airway inflammation and airway remodeling., (© 2020 S. Karger AG, Basel.)

Background: Factors attributable to the level of fraction of exhaled nitric oxide (FeNO) in different age groups of asthmatic children are still lack of report., Objective: To evaluate factors associated with FeNO and the response of FeNO to inhaled steroid in different age groups of asthmatic children with allergic rhinitis., Methods: Asthmatic children aged 5 to 12 years were recruited. FeNO, lung function and bronchial hyperresponsiveness (BHR) to methacholine, skin prick testing to a panel of aeroallergens, total immunoglobulin E (T-IgE) in serum and eosinophils in blood were tested. Correlations between FeNO and the measured parameters were assessed. FeNO was measured again after the treatment of combined inhaled corticosteroid and long-acting beta-agonist (ICS/LABA) for 4 weeks. Changes in FeNO between different age groups were compared., Results: A total of 121 eligible subjects were enrolled in and completed this study. Asthmatic children aged 10 to 12 years old had significantly higher FeNO than those between 8 and 9 years and 5 to 7 years of children (both P < 0.01). Greater height/age (P < 0.01) and higher level of total allergen IgE (P < 0.01) are associated with a higher value of FeNO. After 4 weeks of treatment with ICS/LABA, asthma control test scores were significantly increased in all age groups (P < 0.01), while the level of FeNO significantly decreased in the elder age group only (P < 0.01)., Conclusions: Height and T-IgE are well correlated with FeNO in asthmatic children aged 5 to 12 years. Measurement of FeNO is more suitable for evaluating the efficacy of ICS/LABA in elder asthmatic children., (© 2019 John Wiley & Sons Ltd.)

Introduction: There are few data on the usefulness of different tests to diagnose asthma in children., Aim: We assessed the contribution of a detailed history and a variety of diagnostic tests for diagnosing asthma in children., Methods: We studied children aged 6-16 years referred consecutively for evaluation of suspected asthma to two pulmonary outpatient clinics. Symptoms were assessed by parental questionnaire. The clinical evaluation included skin-prick tests, measurement of exhaled nitric oxide fraction ( F eNO ), spirometry, bronchodilator reversibility and bronchial provocation tests (BPT) by exercise, methacholine and mannitol. Asthma was diagnosed by the physicians at the end of the visit. We assessed diagnostic accuracy of symptoms and tests by calculating sensitivity, specificity, positive and negative predictive values and area under the curve (AUC)., Results: Of the 111 participants, 80 (72%) were diagnosed with asthma. The combined sensitivity and specificity was highest for reported frequent wheeze (more than three attacks per year) (sensitivity 0.44, specificity 0.90), awakening due to wheeze (0.41, 0.90) and wheeze triggered by pollen (0.46, 0.83) or by pets (0.29, 0.99). Of the diagnostic tests, the AUC was highest for F eNO measurement (0.80) and BPT by methacholine (0.81) or exercise (0.74), and lowest for forced expiratory volume in 1 s (FEV 1 ) (0.62) and FEV 1 /forced vital capacity ratio (0.66), assessed by spirometry., Conclusion: This study suggests that specific questions about triggers and severity of wheeze, measurement of F eNO and BPT by methacholine or exercise contribute more to the diagnosis of asthma in school-aged children than spirometry, bronchodilator reversibility and skin-prick tests., Competing Interests: Conflict of interest: C.C.M. de Jong has nothing to disclose. Conflict of interest: E.S.L. Pedersen has nothing to disclose. Conflict of interest: R. Mozun has nothing to disclose. Conflict of interest: M. Goutaki has nothing to disclose. Conflict of interest: D. Trachsel has nothing to disclose. Conflict of interest: J. Barben has nothing to disclose. Conflict of interest: C.E. Kuehni has nothing to disclose., (Copyright ©ERS 2019.)

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta agonist (LABA) combinations, for example, fluticasone propionate/salmeterol (FPS) dry powder inhaler, marketed as Advair ® Diskus ® . Some regulators require generics to demonstrate local (lung) therapeutic equivalence (LTE) for each component of the FPS reference, ideally with a dose-response within the approved FPS dose range. We sought to develop a methacholine challenge (MeCh) LTE methodology for assessing the LABA (salmeterol) component of FPS. Methods: Forty-six patients with asthma received single doses of albuterol (active control; 90 or 180 μg), FPS (100/50 or 200/100 μg), and placebo on 5 separate study days. Spirometry and MeCh were performed 1, 6, and 10 hours after study drug inhalation. Primary endpoint was provocative concentration of methacholine producing a 20% fall in forced expiratory volume in 1 second (PC 20 ). Study entry required screening PC 20 ≤8 mg/mL, with a greater than fourfold increase (and PC 20 ≤128 mg/mL) after 180 μg albuterol. Results: Both albuterol (90 and 180 μg) and FPS (100/50 and 200/100 μg) significantly increased PC 20 compared with placebo (sustained 6 and 10 hours postdose with FPS but not albuterol). The dose-response slopes (95% confidence interval) estimated 1 hour after treatment were 0.374 (-0.068 to 0.815) and 0.310 (-0.135 to 0.754) between low and high doses of albuterol and FPS, respectively, both nonsignificant. Slopes were shallower than those available in the literature for albuterol and formoterol, but similar to those for salmeterol. Conclusions: These data confirm that the bronchoprotective effect of FPS lasts longer than that of albuterol. The shallow dose-response slope we observed for albuterol is contrary to previous reports, probably due to the measurement of PC 20 beginning at 1 hour postdose. The results suggest that use of MeCh to assess LTE for salmeterol formulations may be more difficult to accomplish than it is for albuterol and formoterol products.

Statins provide greater protection than predicted from just cholesterol-lowering effects, which is possibly mediated by other pleiotropic actions. This study aimed to examine the possible interaction effect of asthma on lipid profiles and evaluate the effect of rosuvastatin treatment on asthma. The animals were assigned into (1) control, (2) asthmatic, (3) hyperlipidemic, (4) asthmatic-hyperlipidemic, (5) rosuvastatin (40 mg/kg/day intraperitoneally, for 3 weeks)-treated asthmatic, (6) rosuvastatin-treated hyperlipidemic and (7) rosuvastatin-treated asthmatic-hyperlipidemic groups. Tracheal responsiveness to methacholine and ovalbumin, total and differential WBC (white blood cell) counts, and oxidative stress markers in bronchoalveolar lavage fluid (BALF) were evaluated. In the asthmatic and asthmatic-hyperlipidemic groups, tracheal responsiveness to ovalbumin, total WBC count, numbers of eosinophils, neutrophils, and monocytes were higher than the control group (p<0.001). A left-ward shift in the concentration-response curves to methacholine, an increase in nitrite and malondialdehyde concentrations, and a decrease in total thiol content, superoxide dismutase and catalase activities were also observed in the asthmatic and asthmatic-hyperlipidemic groups compared to control group (p<0.01 to p<0.001). Beyond lipid-lowering effect in the treated hyperlipidemic and asthmatic-hyperlipidemic groups, rosuvastatin treatment decreased tracheal responsiveness to methacholine, reduced total WBC count, the numbers of eosinophils, neutrophils, and monocytes, as well as decreased malondialdehyde concentration, and increased total thiol content, superoxide dismutase and catalase activities in treated asthmatic and asthmatic-hyperlipidemic groups (p<0.05 to p<0.001). The improving effect of rosuvastatin on asthmatic and asthmatic-hyperlipidemic animals was shown due to pleiotropic mechanisms including the effect on airway hyperresponsiveness, lung inflammation, and oxidative stress.

Neurotensin (NT) demonstrates ambiguous activity on inflammatory processes. The present study was undertaken to test the potential anti-inflammatory activity of NT in a murine model of non-atopic asthma and to establish the contribution of NTR1 receptors. Asthma was induced in BALB/c mice by skin sensitization with dinitrofluorobenzene followed by intratracheal hapten provocation. The mice were treated intraperitoneally with NT, SR 142948 (NTR1 receptor antagonist) + NT or NaCl. Twenty-four hours after the challenge, airway responsiveness to nebulized methacholine was measured. Bronchoalveolar lavage fluid (BALF) and lungs were collected for biochemical and immunohistological analysis. NT alleviated airway hyperreactivity and reduced the number of inflammatory cells in BALF. These beneficial effects were inhibited by pretreatment with the NTR1 antagonist. Additionally, NT reduced levels of IL-13 and TNF-α in BALF and IL-17A, IL12p40, RANTES, mouse mast cell protease and malondialdehyde in lung homogenates. SR 142948 reverted only a post-NT TNF-α decrease. NT exhibited anti-inflammatory activity in the hapten-induced asthma. Reduced leukocyte accumulation and airway hyperresponsiveness indicate that this beneficial NT action is mediated through NTR1 receptors. A lack of effect by the NTR1 blockade on mast cell activation, oxidative stress marker and pro-inflammatory cytokine production suggests that other pathways can be involved, which requires further research.

Background: Forced expiratory maneuvers are usually difficult in young children. Impulse oscillometry (IOS) requires no active cooperation, is noninvasive, rapid, and easy to perform. This study aimed to compare IOS indexes and forced expiratory volume in 1 second (FEV1) in children for the assessment of bronchial hyperreactivity to methacholine, mannitol, and eucapnic voluntary hyperventilation (EVH)., Materials: Children aged 3-14 years (mean 10.0 ± 3.1) with symptoms suggestive of asthma were recruited. IOS measurements were taken before spirometry. Methacholine, mannitol, and EVH tests were performed without a specific order., Results: We included 190 children, whose mean age was 10.0 ± 3.1 years. Changes in FEV1 correlated significantly with variation in IOS indexes (P < .05). The indexes with the greatest discriminative capacity were Z5, R5, and X5. Optimal cut-offs were: for methacholine tests, ≧22% in R5, ≧82% for reactance area (AX), and ≦41% for X5; for the mannitol test, ≧18% in R5, ≧40% in AX, and ≦21% for X5. In the EVH test, ≧23% for R5, ≧40% for AX, and a fall of 29% for X5. When using the optimal cut-off points obtained from IOS, the mean number of steps and doses required for methacholine and mannitol tests to induce significant bronchoconstriction were significantly lower compared with spirometry ( P < .05)., Conclusions: The effectiveness of R5, X5, and AX indexes were comparable to FEV1 in assessing bronchial obstruction during bronchial challenge testing. Therefore, IOS may be useful in assessing bronchial obstruction in children who cannot reliably perform spirometric maneuvers during bronchial challenge testing., (© 2019 Wiley Periodicals, Inc.)

Background and Objective: The reduction of forced expiratory volume in 1 s (FEV 1 ) in response to methacholine challenge in asthma may reflect two components: airway narrowing, assessed by the change in FEV 1 /forced vital capacity (FVC), and airway closure, assessed by the change in FVC. The purpose of this study was to determine the degree and determinants of airway closure in response to methacholine in a large group of asthmatic patients participating in studies conducted by the American Lung Association-Airways Clinical Research Centers (ALA-ACRC)., Methods: We used the methacholine challenge data from participants in five studies of the ALA-ACRC to determine the closing index, defined as the contribution of airway closure to the decrease in FEV 1 , and calculated as %ΔFVC/%ΔFEV 1 ., Results: There were a total of 936 participants with asthma, among whom the median closing index was 0.67 relative to that of a published healthy population of 0.54. A higher closing index was associated with increased age (10-year increments) (0.04, 95% CI = 0.02, 0.05, P < 0.005) and obesity (0.07, 95% CI = 0.03, 0.10, P < 0.001). There was no association between the closing index and asthma control., Conclusion: Our findings confirm that airway closure in response to methacholine occurs in a large, diverse population of asthmatic participants, and that increased airway closure is associated with older age and obesity. These findings suggest that therapies targeting airway closure may be important in patients with a high closing index., (© 2019 Asian Pacific Society of Respirology.)

Airway narrowing due to hyperresponsiveness severely limits gas exchange in patients with asthma. Imaging studies in humans and animals have shown that bronchoconstriction causes patchy patterns of ventilation defects throughout the lungs, and several computational models have predicted that these regions are due to constriction of smaller airways. However, these imaging approaches are often limited in their ability to capture dynamic changes in small airways, and the patterns of constriction are heterogeneous. To directly investigate regional variations in airway narrowing and the response to deep inspirations (DIs), we utilized tantalum dust and microfocal X-ray imaging of rat lungs to obtain dynamic images of airways in an intact animal model. Airway resistance was simultaneously measured using the flexiVent system. Custom-developed software was used to track changes in airway diameters up to generation 19 (~0.3-3 mm). Changes in diameter during bronchoconstriction were then measured in response to methacholine (MCh) challenge. In contrast with the model predictions, we observed significantly greater percent constriction in larger airways in response to MCh challenge. Although there was a dose-dependent increase in total respiratory resistance with MCh, the percent change in airway diameters was similar for increasing doses. A single DI following MCh caused a significant reduction in resistance but did not cause a significant increase in airway diameters. Multiple DIs did, however, cause significant increases in airway diameters. These measurements allowed us to directly quantify dynamic changes in airways during bronchoconstriction and demonstrated greater constriction in larger airways.

Background: Recurrent wheezing in early life is transient in most children. The significance of airway hyperresponsiveness (AHR) in persistence of respiratory symptoms from infancy to early childhood is controversial., Objective: We evaluated whether AHR in wheezy infants predicts doctor-diagnosed asthma (DDA) or AHR at the age of 6 years., Methods: Sixty-one wheezy infants (age 6-24 months) were followed up to the median age of 6 years. Lung function and AHR with methacholine challenge test were assessed at infancy and 6 years. The exercise challenge test was performed at the age of 6 years. Atopy was assessed with skin prick tests., Results: At 6 years, 21 (34%) of the children had DDA. Children with DDA had higher logarithmic transformed dose-response slope (LOGDRS) to methacholine in infancy than children without DDA (0.047 vs 0.025; P = .033). Furthermore, AHR to methacholine in infancy and at 6 years were associated with each other (r = 0.324, P = .011). Children with exercise-induced bronchoconstriction (EIB) at 6 years were more reactive to methacholine in infancy than those without EIB (P = .019)., Conclusion: Increased AHR in symptomatic infants was associated with increased AHR, DDA, and EIB at median the age of 6 years, suggesting early establishment of AHR., (Copyright © 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aims: To demonstrate the noninferiority of extrafine beclomethasone/formoterol fumarate (BDP/FF) dry powder inhaler (DPI) vs. extrafine BDP/FF pressurized metered dose inhaler (pMDI; Foster® 100/6 μg NEXThaler and pMDI, respectively) in the onset of reliever effect after methacholine induced bronchospasm in asthmatic patients, evaluated in terms of forced expiratory volume in 1 s (FEV 1 ) at 5 min postdose. The DPI provides an alternative device option for patients who cannot use a pMDI properly during an acute asthma attack., Methods: Sixty-five patients received one inhalation of BDP/FF DPI, BDP/FF pMDI or placebo after methacholine challenge, according to a double-blind, double-dummy, cross-over design. Lung function and Borg dyspnoea score were assessed up to 30 min postdose., Results: FEV 1 adjusted mean difference between BDP/FF DPI and BDP/FF pMDI at 5 min postdose was 2 ml (95% confidence interval: -0.060; 0.065). A similar result was observed at the other time points. Median time to 85% recovery in FEV 1 was 8 min for BDP/FF DPI, 7.5 min for BDP/FF pMDI and 28 min for placebo (P = 0.554 DPI vs. pMDI). The Borg score improved after treatment with both BDP/FF DPI and pMDI and the effect was greater than after placebo. Median time to reach 50% recovery was 4.2 min for BDP/FF DPI, 4.0 min for BDP/FF pMDI and 10.0 min for placebo (P = 0.609 DPI vs. pMDI)., Conclusions: Extrafine Foster® NEXThaler, a flow-independent DPI, is comparable to extrafine Foster® pMDI when administered as reliever therapy after methacholine challenge, thus supporting the maintenance and reliever therapy approach also with Foster® NEXThaler., (© 2018 Chiesi Farmaceutici S.p.A. The British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Incorporation of multi-wall carbon nanotubes (MWCNT) into materials has raised concerns about their potential hazards to manufacturing workers. In animal models, airway inflammation and lung fibrosis follow aspiration, instillation, and inhalation exposures to MWCNT. However, the effects of MWCNT on pulmonary function, airway reactivity and airway epithelium function following inhalation exposure has not been studied. We investigated whether inhaled MWCNT affects lung resistance (R L ) and dynamic compliance (C dyn ), reactivity to inhaled methacholine (MCh), epithelial regulation of airway reactivity to MCh in vitro, and airway epithelial ion transport. Male rats were exposed by whole body inhalation for 6 h to air or aerosolized MWCNT (0.5, 1 or 5 mg/m 3 ) for one or nine days. Eighteen h after 1 d exposure to 5 mg/m 3 MWCNT, basal R L was increased and basal C dyn was decreased; changes did not persist for 7 d. Reactivity to MCh (R L ) was increased and C dyn responses were decreased at 18 h, but not 7 d after exposure to 1 and 5 mg/m 3 MWCNT. The effects of i.t.-instilled MWCNT and nitrogen-doped MWCNT (N-MWCNT) on pulmonary function and reactivity to MCh at doses comparable to deposition after inhalation of 5 mg/m 3 at 1 d and 0.5, 1, and 5 mg/m 3 MWCNT 9 d-exposures were compared. Both nanoparticles increased airway reactivity (R L ); N-MWCNT did not affect C dyn responses. Lung function and airway reactivity are altered following a single MWCNT inhalation and generally subside over time. Given i.t., MWCNT's and N-MWCNT's effects were comparable, but N-MWCNT evoke smaller changes in C dyn responses., (Published by Elsevier Inc.)

The clinical relevance of cough during methacholine challenge in individuals with normal airway sensitivity is unknown. We compared responses of individuals with chronic cough who cough during high-dose methacholine bronchoprovocation and have normal versus increased airway sensitivity to healthy controls. Fifteen healthy participants (CONTROL) aged 26 ± 7 yr (mean ± SD) and 32 participants aged 42 ± 14 yr with chronic cough and suspected asthma completed high-dose methacholine challenge testing. Three participants who did not cough and had normal airway sensitivity were excluded. Spirometry and lung volumes were compared at the maximum response (MAX) among 1) ASTHMA [ n = 15, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (FEV 1 ) from baseline (PC 20 ) 4.71 ± 1.37 mg/ml], 2) methacholine-induced cough with normal airway sensitivity (COUGH, n = 14, PC 20 41.2 ± 18.7 mg/ml for 3 participants with a measurable PC 20 ), and 3) CONTROL ( n = 15; PC 20 93.4 ± 95.4 mg/ml for 4 participants with a measurable PC 20 ). Esophageal pressure-derived pulmonary mechanics were compared at MAX for the ASTHMA and COUGH groups. From baseline to MAX, FEV 1 and forced expiratory flow between 25% and 75% of forced vital capacity decreased more in ASTHMA (-36.2 ± 3.8 %pr; -47.1 ± 6.9 %pr, respectively) than COUGH (-12.2 ± 3.0 %pr ( P < 0.001); -24.7 ± 6.5 %pr ( P < 0.001), respectively) and CONTROL (-13.7 ± 2.0 %pr ( P < 0.001); -32.8 ± 5.4 %pr ( P < 0.017), respectively). In both ASTHMA and COUGH, inspiratory capacity decreased by 500-800 ml, and functional residual capacity and residual volume increased by ~800 ml. Individuals with COUGH develop dynamic hyperinflation and gas trapping comparable to individuals with ASTHMA despite less bronchoconstriction and smaller reductions in mid-to-late expiratory flows, which leads us to believe that COUGH is a distinct phenotype. NEW & NOTEWORTHY Healthy individuals and individuals with chronic cough who demonstrate normal airway sensitivity but cough during methacholine bronchoprovocation bronchoconstrict less than individuals with mild asthma. However, those who cough and have normal airway sensitivity develop dynamic hyperinflation and gas trapping comparable to individuals with mild asthma. Thus, methacholine-induced cough with normal airway sensitivity may be clinically relevant, related to reversible small airway obstruction and preservation of the bronchodilating and/or bronchoprotective effects of deep inspirations.

The present study aimed to investigate the role of microRNA-146a and its adapter proteins [interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6)] in the pathogenesis of ovalbumin (OVA)-sensitized rats in association with the diet-induced obesity condition. Twenty male Wistar rats were divided into four groups: control with normal diet (ND), OVA-sensitized with normal diet (S + ND), high-fat diet (HFD), and OVA-sensitized with high-fat diet (S + HFD). All the animals were fed for 8 weeks with standard pelts or high-fat diet, and were then sensitized and challenged with OVA or saline for another 4 weeks. The tracheal responsiveness to methacholine, serum protein levels, and lipid profile levels was measured by the ELISA method. Moreover, the gene expression level of microRNA-146a (miR-146a) was measured in the lung tissue of the rats using the real-time PCR method. Maximum response to methacholin increased in the S + HFD group in compared with ND, S + ND, and HFD groups (P < 0.05 to P < 0.001). Moreover, in the S + HFD group the mRNA expression levels of miRNA-146a increased in the lung tissue (P < 0.001). In addition, the protein analysis results showed that IRAK1, TRAF6, NF-kB, and IL-1β protein levels were high in the S + HFD group compared to the ND and HFD groups; however, in compared with the S + ND group, only the IL-1β protein level was higher in the S + HFD group (P < 0.05). These results suggest that a defect in the NF-kB-miR-146a negative feedback loop may be involved in the pathogenesis of obesity associated with OVA-sensitized condition. © 2018 BioFactors, 45(1):75-84, 2019., (© 2018 International Union of Biochemistry and Molecular Biology.)