Effects of increasing tidal volume and end-expiratory lung volume on induced bronchoconstriction in healthy humans.

BACKGROUND: Increasing functional residual capacity (FRC) or tidal volume (VT) 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 VT 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 (R5 and R19), their difference (R5-19), and reactance at 5 Hz (X5) during spontaneous breathing and during imposed breathing patterns with increased FRC, or VT, or both. Importantly, in our experimental design we held the product of VT and breathing frequency (BF), i.e, minute ventilation (VE) fixed so as to better isolate the effects of changes in VT alone. RESULTS: Tripling VT from baseline FRC significantly attenuated the effects of MCh on R5, R19, R5-19 and X5. Doubling VT while halving BF had insignificant effects. Increasing FRC by either one or two VT significantly attenuated the effects of MCh on R5, R19, R5-19 and X5. Increasing both VT and FRC had additive effects on R5, R19, R5-19 and X5, but the effect of increasing FRC was more consistent than increasing VT thus suggesting larger bronchodilation. When compared at iso-volume, there were no differences among breathing patterns with the exception of when VT was three times larger than during spontaneous breathing. CONCLUSIONS: These data show that increasing FRC and VT 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 VE, possibly through a combination of effects on airway geometry and airway smooth muscle dynamics.

Desmopressin nasal spray inhibiting parasympathetic function on isolated tracheal smooth muscle.

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.

Salbutamol Easyhaler provides non-inferior relief of methacholine induced bronchoconstriction in comparison to Ventoline Evohaler with spacer: A randomized trial.

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 (FEV1) 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 FEV1 did not recover to at least -10 % of baseline. RESULTS: 180 participants (69 % females, mean age 46 yrs [range 18-80], FEV1%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 FEV1 difference after the first dose and -0.032 (-0.071) L after the last dose. The differences in FEV1 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.

Single and multiple breath nitrogen washout compared with the methacholine test in patients with suspected asthma and normal spirometry.

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 (N2SBW) and nitrogen multiple breath washout (N2MBW), may be pathological in patients with clinical suspicion of asthma but normal spirometry. Our aim was to assess whether N2SBW and N2MBW are associated with methacholine challenge test (MCT) results in this population. We also postulated that an alteration in SIII at N2SBW could be detected before the 20% fall of forced expiratory volume in the first second (FEV1) 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: N2SBW (SIII), N2MBW (Lung clearance index (LCI), Scond, Sacin), MCT (FEV1 and sGeff) as well as N2SBW 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, N2SBW was pathological in 10.6% at baseline and N2MBW abnormality ranged widely (LCI 81%, Scond 18%, Sacin 43%). The dose response rate of the MCT showed weak to moderate correlation with the subsequent N2SBW measurements during the provocation phases (ρ 0.34-0.50) but no correlation with N2MBW. CONCLUSIONS: Both MCT and N2 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.

Previous Influenza Infection Exacerbates Allergen Specific Response and Impairs Airway Barrier Integrity in Pre-Sensitized Mice.

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.

Respiratory mechanics during methacholine bolus and continuous infusion protocols in asthma model.

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 (kd) 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 Rn. Infusion: there was a difference between OVA and control at 192 µg.kg-1.min-1 dose for Rn, G and H, (p<0.01; p<0.001; p<0.001). An increment was found in kd 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.

Current Asthma Prevalence Using Methacholine Challenge Test in Korean Children from 2010 to 2014.

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.

Baseline spirometry parameters as predictors of airway hyperreactivity in adults with suspected asthma.

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 ß, FEV1, FVC, FEV1/FVC, FEF50%, FEF25-75%) 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). FEF50% showed the best overall accuracy (AUC = 0.688) and proved to be useful as a negative predictor when applying FEF50% ≥ 110% as a cutoff level. CONCLUSIONS: This study highlights the role of FEF50% in predicting AHR in patients with suspected asthma. A value of ≥ 110% for baseline FEF50% could be used to exclude AHR and would lead to a substantial decrease in MCT referrals.

Comparison of spirometry and impulse oscillometry in methacholine challenge test for the detection of airway hyperresponsiveness in adults.

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.

Small airway dysfunction in patients with cough variant asthma: a retrospective cohort study.

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, FEF50 and FEF75 (% predicted) was 0.615, 0.621, 0.606, respectively. 0.17mcg of PD20 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.

Airway hyperresponsiveness to mannitol improves in both type 2 high and type 2 low asthma after specialist management.

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: Gmean 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: Gmean 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.

Diagnostic value of the hypertonic saline bronchial provocation test in children with asthma using the high-power aerosol provocation system.

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.

Utility and efficiency of methacholine challenge testing in evaluating pediatric asthma: unraveling the diagnostic conundrum.

OBJECTIVE: Interpretation of methacholine challenge testing (MCT) results depends on the patient's pretest probability of asthma as well as the provocative concentration (PC20); 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 PC20. Post-test probability of asthma was assigned based on pretest probability, MCT result (+/-), and PC20. 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 (FEV1/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 PC20 was taken into account. It was not as useful for subjects with exercise symptoms only.

Antioxidant MnTBAP does not protect adult mice from neonatal hyperoxic lung injury.

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 %O2 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 O2 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.

The Effect of Bronchoconstriction by Methacholine Inhalation in a Murine Model 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)-ß in the lung. This result indicates that the production of TGF-ß 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.

Predictive value of non-specific bronchial challenge testing for respiratory symptoms and lung function in aluminium smelter workers.

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 PD20 ≤4000 µg. Poisson and mixed effects models were fitted to respiratory symptoms and lung function (forced expiratory volume in 1 s (FEV1) and FEV1/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 FEV1 and FVC, although the rate of annual decline in FEV1 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.

Respiratory mechanics evaluation of mice submitted to intravenous methacholine: Bolus vs. continuous infusion.

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.

Airway hyperresponsiveness, remodeling and inflammation in infants with wheeze.

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.

Hesperetin-5,7,3'-O-Trimethylether Dually Inhibits Phosphodiesterase 3/4 and Methacholine-Induced Airway Hyperresponsiveness in Sensitized and Challenged Mice.

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 (RL) and increased lung dynamic compliance (Cdyn) 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.