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Approximately 4% of the Japanese population genetically lack plasma platelet activating factor acetylhydrolase (PAF-AH) and show a higher prevalence of thromboembolic disease, but whether they are susceptible to another PAF-related disease, asthma, remains controversial. To determine the role of plasma PAF-AH in airway physiology, we performed PAF bronchoprovocation tests in 8 plasma PAF-AH-deficient subjects and 16 control subjects. Serial inhalation of PAF (1–1000 μg/ml) concentration-dependently induced acute bronchoconstriction, but there was no significant difference between PAF-AH-deficient and control subjects (11.7 ± 4.6% vs. 9.6 ± 2.8% decrease in forced expiratory volume in 1 s). Transient neutropenia after single inhalation of PAF (1000 μg/ml) showed no significant difference between the groups either in its magnitude (72 ± 11% vs. 65 ± 9% decrease) or duration (4.1 ± 1.0 vs. 3.3 ± 0.8 min). In conclusion, a lack of plasma PAF-AH activity alone does not augment physiological responses to PAF in the airway. [Copyright &y& Elsevier]

Despite the controversy of airway responsiveness to β2-agonist drugs in asthma, in a previous study we showed increased responsiveness of asthmatic airways to isoprenaline. Therefore, in the present study of airway sensitivity to other β2-agonists, salbutamol and its relationship to histamine responsiveness was reexamined. The threshold bronchodilator concentrations of inhaled salbutamol required for a 20% increase in forced expiratory flow in 1 sec (FEV1), (PC20) was measured in 20 normal and 19 asthmatic adults. Airway responsiveness to histamine, as the concentration that caused a 20% decrease in FEV1, was also measured in 11 normal and 12 asthmatic subjects; and the correlation between PC20 salbutamol and PC20 histamine was evaluated. Sensitivity to salbutamol was greater in asthmatics (PC20 = 7.24 mg/L) than in non-asthmatics (PC20 = 124.25 mg/L, p < 0.001). Airway responsiveness to histamine in asthmatics (PC20 = 0.18 g/L) was also significantly greater than in normal subjects (PC20 = 19.46 g/L, p < 0.001). There was a significant correlation between PC20 salbutamol and histamine (Rs = 0.6052, p < 0.005). Maximum response to both salbutamol and histamine and slope of concentration-response curves of both agents were significantly greater in patients with asthma than in normal subjects (p < 0.001 and p < 0.005 for maximum response and slope, respectively). The increased sensitivity of asthmatics to inhaled salbutamol suggests that they also may be more sensitive to their endogenous adrenaline, which may thus dilate and stabilize their airways. [ABSTRACT FROM AUTHOR]

Summary Background Some studies have reported that the levels of exhaled nitric oxide (ENO) in asthmatics are similar to those in subjects with allergic rhinitis, and it has been postulated that atopic status might be the determinant of enhanced nitric oxide production in asthma. Objectives The aim of this study was to determine differences in ENO levels between asthmatics and subjects with allergic rhinitis sensitized to the same allergen, and to correlate these levels with airway responsiveness. Methods Nineteen patients with asthma and 18 subjects with allergic rhinitis monosensitized to Parietaria pollen were enrolled in the study. ENO values and airway responsiveness to methacholine and adenosine 5′-monophosphate (AMP) were measured during the pollen season. The response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall in FEV1 (PC20 ). ENO was measured with the single-exhalation method. Results The geometric mean (95% confidence interval) ENO values were significantly higher in asthmatics than in subjects with allergic rhinitis: 72.4 p.p.b. (54.9–93.3 p.p.b) vs. 44.7 p.p.b. (30.9–64.6 p.p.b., P = 0.03). In asthmatics, a significant correlation was found between ENO and PC20 AMP values (ρ = -0.57, P = 0.02), whereas no correlation was detected between ENO and PC20 methacholine (ρ =- 0.35, P = 0.14). Conclusions Our results suggest that atopy is not the only determinant of increased ENO levels detected in subjects with asthma, and that responsiveness to AMP may be a more sensitive marker for assessing airway inflammation in asthma compared to methacholine. [ABSTRACT FROM AUTHOR]

Summary Background Some studies have reported that the levels of exhaled nitric oxide (ENO) in asthmatics are similar to those in subjects with allergic rhinitis, and it has been postulated that atopic status might be the determinant of enhanced nitric oxide production in asthma. Objectives The aim of this study was to determine differences in ENO levels between asthmatics and subjects with allergic rhinitis sensitized to the same allergen, and to correlate these levels with airway responsiveness. Methods Nineteen patients with asthma and 18 subjects with allergic rhinitis monosensitized to Parietaria pollen were enrolled in the study. ENO values and airway responsiveness to methacholine and adenosine 5′-monophosphate (AMP) were measured during the pollen season. The response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall in FEV1 (PC20 ). ENO was measured with the single-exhalation method. Results The geometric mean (95% confidence interval) ENO values were significantly higher in asthmatics than in subjects with allergic rhinitis: 72.4 p.p.b. (54.9–93.3 p.p.b) vs. 44.7 p.p.b. (30.9–64.6 p.p.b., P = 0.03). In asthmatics, a significant correlation was found between ENO and PC20 AMP values (ρ = -0.57, P = 0.02), whereas no correlation was detected between ENO and PC20 methacholine (ρ =- 0.35, P = 0.14). Conclusions Our results suggest that atopy is not the only determinant of increased ENO levels detected in subjects with asthma, and that responsiveness to AMP may be a more sensitive marker for assessing airway inflammation in asthma compared to methacholine. [ABSTRACT FROM AUTHOR]

To date, few animal models of chronic obstructive pulmonary disease (COPD) exist that are ideal for the evaluation of pathophysiology, as they typically require many months of cigarette smoke exposure in inhalation facilities. Here we show that pulmonary inflammation and some of the inflammatory hallmarks of COPD can be induced in mice by cigarette smoke-conditioned media (CS) administered by the intranasal route. Balb/c mice were challenged with CS for up to 40 days. At the end of smoke treatment, mice were sacrificed and bronchoalveolar lavage (BAL) fluid collected. Total cell counts and cell differentials were performed. Enzyme-linked immunosorbent assays (ELISAs) for KC and tumor necrosis factor alpha (TNF-α) were performed on BAL fluid. Lungs and nasal cavities were examined histologically. Intranasal CS treatment significantly increased BAL neutrophils, lymphocytes, KC, TNF-α, and mucin. Changes in pulmonary reactivity to methacholine were also observed in mice challenged with CS for 40 days. The model described above demonstrates that within 1 to 8 weeks of intranasal instillation of CS, mice develop pulmonary inflammation and cellular lung changes that are characteristic of human COPD and therefore may be a good short-term in vivo model that can be utilized to monitor intervention strategies targeted for COPD. [ABSTRACT FROM AUTHOR]

Because eosinophilic airway inflammation is a characteristic of bronchial asthma, the treatment of such inflammation is important in the management of this disease. Suplatast tosilate is a novel anti-asthma drug that suppresses eosinophil proliferation and infiltration through selective inhibition of Th2 cytokine synthesis. We investigated the effect of oral suplatast tosilate therapy in patients with mild and moderate asthma. Twenty-eight asthma patients were randomized into two groups with or without suplatast tosilate treatment (100 mg t.i.d. for 28 days). We examined the blood eosinophil counts, eosinophilic cationic protein level, sputum eosinophil count, exhaled nitric oxide level, and airway responsiveness before and after treatment. In patients treated with suplatast tosilate, the eosinophil count in the blood and sputum was significantly decreased after treatment, while there was no such change in the patients without suplatast treatment. The exhaled nitric oxide level and airway responsiveness (measured using an Astograph) were also decreased after treatment with suplatast tosilate, while there were no significant changes in patients without suplatast tosilate. These results strongly suggest that oral administration of suplatast tosilate suppresses airway hyperresponsiveness in asthma patients by reducing eosinophilic inflammation in the airways. [ABSTRACT FROM AUTHOR]

Objective: To examine differences in the rates of respiratory symptoms, asthma and levels of lung function in two remote Aboriginal communities. Methodology: Respiratory symptoms, smoking history, skin prick test responses to common allergens, serum IgE, lung function, airway responsiveness to methacholine and white blood cell counts were compared in two Aboriginal communities, one from the central desert (n = 84) and another from the tropical north (n = 209) of Western Australia. Results: Compared with the tropical community, chest tightness and dyspnoea were more frequent and forced expiratory volume in 1 s and forced vital capacity were lower in the desert community, despite similar levels of wheeze, doctor-diagnosed asthma and skin prick test responses and lower levels of airway responsiveness and smoking. The total white cell and neutrophil counts were greater in the desert community. Serum IgE was very high and similar in both communities. Conclusions: Our findings show a low prevalence of asthma in children, a high prevalence of respiratory symptoms and low levels of lung function in remote Aboriginal communities. The greater prevalence of respiratory morbidity in the desert community was not explained by diagnosed asthma, airway hyperresponsiveness or cigarette smoking. The role of infection requires further investigation. The results suggest that the lower lung function observed in Aboriginal communities (compared with non-Aboriginal communities) results at least partly from environmental factors. [ABSTRACT FROM AUTHOR]

Background: Atopy may be a risk factor in the development of asthma. Indoor allergens are considered to be more potent asthma inducers than outdoor ones such as pollens. Lower airway inflammation may be present in non-asthmatic subjects during natural exposure to relevant allergens and may eventually lead to the development of asthma. Aims: To document seasonal variation in lower airway responsiveness and inflammation in sensitized non-asthmatic subjects, during natural exposure to allergens, and to determine whether it is more marked in those exposed to animals to which they are sensitized. Methods: Twenty-two atopic subjects were seen during and out of the pollen season. All (but the controls) were sensitized to domestic animals, and to trees, grasses or ragweed. Eleven were not exposed to animals at home and 8 were exposed. They were compared with 3 normal controls. A respiratory questionnaire was administered, allergy skin prick tests, spirometry, methacholine challenge, blood and induced sputum with differential cell counts were obtained during the pollen season for all subjects. These tests were repeated out of the pollen season. Results: Throughout the study, none of the subjects had asthma symptoms. Mean PC[sub 20] was significantly lower in subjects exposed to animals compared with unexposed subjects or controls, both during and out of the pollen season. In season, subjects exposed to animals had significantly higher sputum eosinophil numbers than unexposed or normal control subjects. Conclusions: Non-asthmatic atopic subjects show variable degrees of airway responsiveness and inflammation. However, subjects exposed to animals show higher airway eosinophilia, which may suggest they are at increased risk of developing airway hyperresponsiveness and asthma.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is an important cause of childhood respiratory disease as well as exacerbations of asthma. Although previous studies have demonstrated that a DNA vaccine encoding the RSV G protein can inhibit RSV replication in mouse models of RSV infection, studies have not been performed to determine whether a DNA vaccine encoding the RSV G protein can protect against RSV induced mucus expression and airway hyperresponsiveness which was the focus of this study. The DNA-G vaccine we constructed significantly inhibited RSV viral replication, mucus expression, and importantly was associated with inhibition of RSV induced airway responsiveness. [Copyright &y& Elsevier]

ABSTRACTBackground: Interferon (IFN)-α is the only approved treatment for chronic hepatitis C. Interstitial pneumonia and, rarely, exacerbation of bronchial asthma have been reported as adverse pulmonary effects of IFN-α treatment. The purpose of the present study was to clarify whether IFN-α treatment affects pulmonary function and airway responsiveness in patients with chronic hepatitis C. Methods: We studied 17 patients (nine males and eight females; mean age 46 years; range 30–62 years) with chronic active hepatitis C diagnosed by serum tests and liver biopsy. Pulmonary function tests included vital capacity (VC), forced expiratory volume in 1 s (FEV1), forced expiratory flow in the middle half of the forced vital capacity (FVC25–75%), total lung capacity and carbon monoxide diffusing capacity of the lung (DLCO), which was adjusted for hemoglobin concentration. Airway responsiveness was measured by methacholine inhalation challenge and determination of the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20). These tests were performed before and 3 months after initiation of IFN-α therapy. Results: No patient developed interstitial pneumonia, although there was a tendency for the hemoglobin-adjusted DLCO to decrease. Other pulmonary function test parameters were not affected. Overall, there was no significant change in PC20 (from 15.0 to 11.4 mg/ mL). In three patients whose initial PC20 was within the normal range, airway hyperresponsiveness was induced and one patient developed bronchial asthma after IFN-α therapy. Conclusions: These findings suggest that IFN-α induces airway hyperresponsiveness to methacholine in a few patients with chronic hepatitis C. [ABSTRACT FROM AUTHOR]

Background Increased vascularity in airway mucosa is a distinctive feature of airway remodelling in asthma. While corticosteroids have proved most effective in modifying airway inflammation, the effect of inhaled corticosteroids on increased airway mucosal vascularity in asthmatics has been little studied. Objective We examined the effect of inhaled corticosteroid on airway vascularity in bronchial biopsy specimens taken from asthmatic patients. Subjects and methods We studied bronchial biopsies from 28 asthmatic patients before and after treatment with inhaled beclomethasone dipropionate (BDP) 800 µg/daily, or placebo, for 6 months in a double-blind manner. Biopsy specimens were evaluated for number of vessels and percentage of area occupied by vessels, using computerized image analysis after staining for type IV collagen in vessel walls. Specimens were also examined for extent of collagen III in the subepithelial basement membrane. In addition, we compared asthmatic specimens with biopsy specimens taken from non-asthmatic control subjects. Results There was a significant increase in number of vessels (P < 0.01) and percent vascularity (P < 0.001) in the submucosa of asthmatic patients compared with control subjects. After 6 months of treatment, we observed significant improvements in forced expiratory volume in 1 s (FEV1), FEV1% and airway responsiveness (P < 0.05, each) in the BDP treatment group compared with the placebo group. This was accompanied by significant decreases in both vessel number and percent vascularity in the airways of BDP-treated patients (P < 0.05, each). We also observed a significant correlation between change in percent vascularity and change in collagen III thickness in the BDP-treated patients (rs = 0.90, P < 0.001). Furthermore, the change in percent vascularity was inversely correlated with both FEV1 (rs = -0.49, P < 0.05) and airway responsiveness (rs = -0.36, P < 0.05). Conclusion These findings suggest that inhaled corticosteroid treatment of asthma reduced airway wall vascularity during airway remodelling. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the effects of non-bronchoconstrictive doses of propranolol on airway hyperresponsiveness to methacholine. Methods: Double increasing concentrations (from 0.03 to 64 µg/ml) of inhaled propranolol were administered to a study population which included ten patients with mild asthma, ten rhinitics, and ten healthy control subjects. After the baseline bronchial responses to propranolol and methacholine, expressed as the cumulative provocative dose producing a 20% fall in forced expiratory volume in 1 s (PD20FEV1), were assessed, methacholine challenge was repeated after pretreatment with non-bronchoconstrictive doses of propranolol. Results: The pharmacologically induced β-blockade did not cause any effect in normal individuals, but it worsened airway responsiveness to methacholine in all asthmatics (geometric mean PD20 FEV1: 257 and 87 µg, respectively) and some rhinitics (geometric mean PD20 FEV1: 724 and 446 µg, respectively). Conclusion: Asthmatic patients were extremely sensitive to β-blockers, whereas we observed a variable response to propranolol within the group of rhinitic subjects. This variability in the latter group is possibly because these individuals had different degrees of airway inflammation, increased parasympathetic activity, and β-adrenoceptor dysfunction. [ABSTRACT FROM AUTHOR]

Inhalation provocation tests were used to assess whether the volatile products of an activated resin had caused occupational asthma in a non‐random sample of six asthmatic coal miners. The resin system uses the polymerization of polyester and styrene under the influence of the cross‐linking agent dibenzoyl peroxide to secure roof, wall and floor bolts in mine tunnels. The tests were conducted sequentially in a double‐blind fashion over a ‘dose’ range which extended just beyond the maximum likely to have been experienced occupationally during a single day's work. The tests were monitored by symptoms, changes in the forced expiratory volume in 1 s (FEV1) and changes in airway responsiveness. All subjects completed the series of tests without any significant decrements in FEV1 or significant increases in airway responsiveness. We conclude that the use of this resin system is not likely to have been the cause of the asthma in the test subjects, nor in the larger group of miners of which they were a sample, but neither possibility is fully excluded and the participants may not have been adequately representative of other asthmatic coal miners. [ABSTRACT FROM PUBLISHER]

Investigates the effects of methacholine and Provocholine, a methacholine formulation, on airway responses. Uses of the compounds; Comparison of the bronchoconstriction produced by the two compounds; Absence of product impurities in both compunds; Similarity of structures and effects.

BackgroundThe airway inflammation observed in asthma is orchestrated by activated Th-2 lymphocytes relevant for the induction of altered airway responsiveness. An increasing body of evidence is accumulating that not only the pro-inflammatory cytokines interleukin (IL)-4 and IL-5 but also the immunomodulating cytokines IL-12 and possibly IL-10 are crucial for regulating the allergic airway inflammation. ObjectiveSince IL-10 is capable of downregulating a broad spectrum of pro-inflammatory cytokines, we wanted to address the role of endogenously produced IL-10 in vivo in allergic asthma. MethodsKnockout (IL-10-/-) mice (C57BL/6-IL10tm1Cgn) and wild-type (WT) counterparts were immunized (day 0) and exposed (day 14–21) to ovalbumin (OVA). Airway inflammation and reactivity (AR), serum allergen-specific IgE responses and cytokine profiles in the bronchoalveolar lavage fluid (BALF) were studied. ResultsThe IL-10-/- mice had more eosinophilic airway inflammation but comparable levels of allergen-specific serum IgE compared to the WT mice after allergen challenge. The AR was comparably increased in the OVA challenged WT and IL-10-/- mice vs sham-exposed WT, but not vs sham-exposed IL-10-/- mice since these showed a higher baseline AR. IFN γ, IL-4 and IL-13 were comparable and IL-5 was even lower in the BALF of the in IL-10-/- mice compared to the similarly exposed WT mice. ConclusionThese results indicate that IL-10 plays an important and possibly direct role in the control of airway inflammation and responsiveness in an in vivo mouse model of allergy. [ABSTRACT FROM AUTHOR]

Background: Different mechanisms may underlie bronchial hyperresponsiveness (BHR) in different diseases. The aim of this study was to investigate the bronchial responsiveness profile produced by three different challenge tests, methacholine, a direct simulus, and two indirect stimuli, adenosine 5′‐monophosphate (AMP) and cold air, in subjects with asthma and patients with Sjögren's syndrome. Methods: The study population comprised 40 adult patients with asthma, 18 subjects with Sjögren's syndrome, and 20 controls. Blood samples were collected before each challenge for measurements of serum eosinophil peroxidase (S‐EPO) and eosinophil cationic protein (S‐ECP). The investigated subjects recorded peak expiratory flow and kept a symptom diary. Results: Atopic subjects with asthma were significantly more hyperresponsive to AMP than nonatopic subjects with asthma (P=0.01) and subjects with Sjögren's syndrome (P=0.02). No difference was seen between atopic and nonatopic subjects with asthma in the case of challenges with methacholine or cold air. In atopic subjects with asthma, a significant correlation was found between challenges with methacholine and AMP (r=0.91, P=0.0001) and methacholine and cold air (r=0.83, P=0.004), but, in nonatopic subjects with asthma, no significant correlation was seen between methacholine and AMP or cold air challenges. In atopic subjects with asthma, the dose‐response slope for AMP was correlated to S‐EPO (r=-0.56; P=0.01) and S‐ECP (r=-0.51, P=0.02), while no correlation between BHR and inflammation markers was found in the two other patient groups. Conclusions: The results of this study suggest that patients with asthma and subjects with Sjögren's syndrome display different bronchial responsiveness profiles for different challenge agents. Atopic subjects with asthma are more hyperresponsive to AMP than nonatopic subjects and patients with Sjögren's syndrome.... [ABSTRACT FROM AUTHOR]

Background Although airway hyperresponsiveness to inhaled acetaldehyde has been documented in Japanese patients with asthma, the response to this bronchoconstrictor agent has never been studied in Caucasians. Objectives The objectives of the study were to determine differences in airway responsiveness to acetaldehyde between asthmatic and healthy subjects, and to examine the relationship between acetaldehyde responsiveness and the variability of peak expiratory flow (PEF). Methods The response to methacholine and acetaldehyde challenges was measured in 81 non-smoking adults (61 asthmatics and 20 normal controls). Subjects recorded PEF morning and evening for 14 days. The response to both bronchoconstrictor agents was measured by the PC20 (provocative concentration required to produce a 20% fall in FEV1). PEF variation was expressed as amplitude percentage mean, and as low percentage best (lowest PEF expressed as a percentage of the best PEF recorded). Results The two types of challenge yielded a similarly high level of sensitivity (100% for methacholine and 92% for acetaldehyde) and specificity (90 and 100%, respectively) to distinguish between asthma and controls. Asthmatic subjects were on average 265-fold less sensitive to acetaldehyde than to methacholine. PC20 acetaldehyde correlated weakly but significantly with both indices of PEF variation (amplitude percentage mean: ρ = - 0.36, P = 0.004; low percentage best: ρ = 0.42, P = 0.001). Conclusions These results indicate that airway hyperresponsiveness to acetaldehyde is a sensitive and specific indicator for separating asthmatic and normal subjects. Airway responsiveness to methacholine or acetaldehyde and PEF variation are not reflecting the same pathophysiological process in the airways. [ABSTRACT FROM AUTHOR]

Background Airway hyperresponsiveness to pharmacological agonists is a common feature in subjects with allergic rhinitis. Objective The aim of this study was to investigate differences in threshold value and shape of the concentration-response curves to methacholine between subjects with perennial allergic rhinitis and subjects with seasonal rhinitis. Methods We studied a sample of 72 non-asthmatic patients with allergic rhinitis. They were subdivided into two groups: subjects with only seasonal symptoms and skin sensitization to grass and/or Parietaria pollen allergens (seasonal group, n = 38), and subjects with perennial symptoms and skin sensitization to house dust mite, alone or with other allergens (perennial group, n = 34). They were challenged with methacholine (up to 200mg/mL), and concentration-response curves were characterized by the threshold value (PC20 = provocative concentration of methacholine required to produce a 20% fall in FEV1) and maximal response plateau, if possible. The measurements in the seasonal group were done within the pollen season. Results The geometric mean methacholine PC20 for subjects of the perennial group was 6.9 mg/mL, compared with 23.4mg/mL in subjects of the seasonal group (P < 0.01). A plateau response was detected in 16 subjects of the perennial group and in 28 subjects of the seasonal group (P < 0.05). Moreover, the level of plateau was higher in subjects of the perennial group when compared with subjects of the seasonal group (23.8 ± 2.0% vs 19.2 ± 1.6%, P < 0.05). Conclusion In subjects with allergic rhinitis, sensitization to perennial allergens is associated not only with lower methacholine threshold values, but also with lower prevalence and higher level of plateau than sensitization to pollen allergens. [ABSTRACT FROM AUTHOR]

To study the effect of environmental tobacco smoke (ETS) exposure in the evening on nocturnal changes in airway tone and responsiveness, 17 subjects with mild asthma (mean±SD age, 26±5 years, FEV% pred., 89±14%) were exposed to either ambient air (sham) or ETS (20 ppm CO) for 3 h (7:00 to 10:00 p.m.). Seven subjects had a history of ETS-induced respiratory symptoms. Spirometry was performed 2 h before exposure (5:00 p.m.), every 30 min during exposure, and at 11:00 p.m., 3:00 a.m., and 7:00 a.m. The provocative concentrations of methacholine necessary to decrease FEV by 20%, PCFEV, were assessed at 5:00 p.m., 11:00 p.m., 3:00 a.m., and 7:00 a.m. Compared with pre-exposure measurements, mean FEV values during and after ETS exposure were significantly lower than with sham exposure=0.013 and 0.026). This effect, however, was due to a significant response in single individuals. The higher bronchial responsiveness after ETS than after sham exceeded one doubling concentration in 4, 5, and 4 patients at 11:00 p.m., 3:00 a.m., and 7:00 a.m., respectively. The opposite effect was observed in 2, 2, and 2 patients, respectively. There was no statistically significant mean effect of ETS on airway responsiveness during night; however, there was significant heterogeneity in individual responses ( P=0.0002). Patients with and without a history of ETS-induced symptoms did not show different responses to experimental ETS exposure. In conclusion, our data suggest that in single adult subjects with mild asthma, acute exposure to ETS in the evening can produce a deterioration of airway tone and responsiveness during the night, with wide interindividual variability in the response. [ABSTRACT FROM AUTHOR]

We determined the effect of an inhibitor of neutral endopeptidase, acetorphan, on the skin responses to substance P and on the bronchostrictor effects of sodium metabisulphite aerosol in asthmatic subjects. One hour following ingestion of acetorphan (200 mg) or placebo tablets, cutaneous responses to substance P were performed in four subjects. In seven subjects, bronchial challenge with increasing concentrations of sodium metabisulphite solutions was performed and the concentration required to cause a 20% fall in baseline FEV determined (PC). On the acetorphan day, there was a significant increase in the wheal and flare responses to substance P and to the diluent (0.9% NaCl) alone. However, there was no significant effect of acetorphan on the PC metabisulphite. We conclude that metabisulphite airway challenge in vivo may not invoke the release of endogenous neuropeptides. However, the degree of inhibition of neuropeptide breakdown by the oral dose of acetorphan used may not have been optimal. [ABSTRACT FROM AUTHOR]

We studied the effective site of an inhaled aerosol of procaterol, a β-selective adrenergic bronchodilator, in 8 asthmatic patients whose basal lung functions are almost within the normal range in both slow vital capacity (VC) and forced expiratory volume in one second (FEV), and are free from asthmatic attack. In patients who had received procaterol 30 min after inhalation of aerosol, there was no significant change in VC, although FEV, maximal expiratory flow at 50% VC $$(\dot V_{50} )$$ , maximal expiratory flow at 25% VC $$(\dot V_{25} )$$ and maximal expiratory flow at 30% VC of partial maximal expiratory flow volume curve $$(\dot V_{30p} )$$ improved significantly. On the other hand, in those who had received placebo, none of the parameters changed. Furthermore, Rl decreased and C increased significantly during the first 5 min after inhalation of procaterol aerosol. After an interval of 5 min, Rl did not change any further, while C continued to improve until 30 min after inhalation of procaterol. These results suggest that procaterol may first dilate the large airway and then may gradually dilate the small airway in bronchial asthma. [ABSTRACT FROM AUTHOR]

We compared the protective effect and duration of action of inhaled formoterol with salbutamol and placebo in 16 asthmatic children in a double-blind, cross-over study. All had an FEV ≥ 70% predicted normal and a provocative concentration of methacholine (MCh) required to decrease their FEV by 20% (PC) ≤ 4 mg/ml. On each study day, FEV was within 10% and PC within one doubling-dose of the initial visit. Patients received either placebo, salbutamol 200 µg, formoterol 12 µg, or formoterol 24 µg by metered-dose inhaler. FEV and PC were measured repeatedly over 12 h. After salbutamol, peak FEV was 120% of baseline at 30 min and returned to baseline in 3 h. After formoterol (12 or 24 µg) peak FEV was 118% at 3 h and remained above baseline for at least 12 h. Protection from MCh by both doses of formoterol was significantly better than by salbutamol. Protection from formoterol 12 and 24 µg at 12 h was equivalent to that from salbutamol at 3 h. The PC of four children 48 h after formoterol 24 µg was more than twice their baseline PC. Formoterol by inhalation is potent and long-acting and provides significantly better antiasthma protection than salbutamol. [ABSTRACT FROM AUTHOR]

To examine the effect of breathing pattern on the dose-response curve, 4 mild asthmatic and 9 normal subjects inhaled increasing concentrations of methacholine (0.03-256 mg/ml) using a quiet tidal breathing pattern or tidal breathing with a forced expiratory phase. The provocative concentration of methacholine causing a 20% decrease in the forced expired volume in 1 s (PCFEV) or a 200% increase in pulmonary resistance (PC 200R) was determined. In addition, the maximal change in FEV and R and the slopes of the dose-response curves were measured. The forced expiratory pattern caused an increase in the central/peripheral deposition ratio of a [99]technetium-labeled aerosol (n=3). There were no differences in mean tidal volume, minute ventilation, inspiratory flow rates, or baseline FEV or R between the quiet breathing or forced expiration studies, although mean expiratory flows were increased in the latter ( p<0.001). PCFEV and PC R decreased ( p<0.001) but the maximal change in FEV and R was unchanged in the forced expiration studies. Forced expiration during inhalation challenge did not alter the slope of FEV or R dose-response curves. These results suggest that the sensitivity (PC, PC) and maximal response of in vivo dose-response curves may be affected independently by factors such as aerosol deposition. [ABSTRACT FROM AUTHOR]

Airways responsiveness of chronic smokers to an aerosolized bronchodilator and to breathing at increased lung volume (one liter above Functional Residual Capacity) was compared using a modified flow body plethysmograph to measure large airway resistance (R) and distribution of the evenness of the ventilation (PD) of smaller airways simultaneously during normal breathing. The magnitude of the decrease of R after bronchodilator administration (M) was significantly correlated with the decrease of R after breathing at increased lung volume (r=0.61, P<0.01). Similarly, the magnitude of the decrease of PD after M was significantly correlated with the decrease noted after breathing at increased lung volume (r=0.65, P<0.01). The responsiveness of the individual subject was related to smoking and respiratory disease (RD) history. The heaviest smokers (pack-year history=37.8 years) had more responsive large airways and apparently less responsive small airways than did lighter smokers (pack-year history=14.3 years). Subjects with a past history of RD were more responsive to bronchodilator than subjects without a history of RD even though the smoking history of the two groups was not significantly different. [ABSTRACT FROM AUTHOR]

Background: Nitric oxide (NO) may be bronchoprotective in asthma, possibly due to a direct action on airway smooth muscle or through mast cell stabilisation. To investigate this the effects of two doses of nebulised NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase (NOS) inhibitor, on exhaled NO levels and airway responsiveness to histamine, a direct smooth muscle spasmogen, and adenosine-5'-monophosphate (AMP), an indirect spasmogen which activates mast cells, were evaluated in patients with mild asthma.Methods: The study consisted of two phases each with a double blind, randomised, crossover design. In phase 1, 15 subjects inhaled either L-NAME 54 mg or 0.9% saline 30 minutes before histamine challenge. Nine of these subjects were studied in a similar fashion but were also challenged with AMP. In phase 2, 13 subjects (eight from phase 1) performed the same protocol but inhaled L-NAME in a dose of 170 mg or 0.9% saline before being challenged with histamine and AMP.Results: The mean (95% CI) reduction in exhaled NO levels after L-NAME 54 mg was 78% (66 to 90) but this did not alter airway responsiveness; the geometric mean (SE) concentration provoking a fall of 20% or more in forced expiratory volume in one second (PC20) after L-NAME and saline was 0.59 (1.26) and 0.81 (1.26) mg/ml, respectively, for histamine and 20.2 (1.7) and 17.2 (1.6) mg/ml, respectively, for AMP. In contrast, L-NAME 170 mg reduced NO levels to a similar extent (81% (95% CI 76 to 87)) but increased airway responsiveness by approximately one doubling dose to both spasmogens; the geometric mean (SE) PC20 for histamine after L-NAME 170 mg and saline was 0.82 (1.29) and 1.78 (1.19) mg/ml, respectively (p < 0.001), and for AMP was 11.8 (1.5) and 24.3 (1.4) mg/ml, respectively (p < 0.001).Conclusions: These results suggest that L-NAME increases airway responsiveness in asthma. This may occur through mechanisms separate from NO inhibition or through pathways independent of those responsible for production of NO measured in exhaled air. [ABSTRACT FROM AUTHOR]

Background: Regular, inhaled beta 2 agonists may increase airway responsiveness in asthmatic subjects. The mechanism is not known but may be via an increase in airway inflammation. A study was undertaken to examine the effect of regular inhaled salbutamol on airway responsiveness to methacholine and hypertonic saline, on the maximal response plateau to methacholine, and on inflammatory cells in induced sputum in rhinitic non-asthmatic subjects.Methods: Thirty subjects with a baseline maximal response plateau of > 15% fall in forced expiratory volume in one second (FEV1) entered a randomised, placebo controlled, parallel trial consisting of two weeks run in, four weeks of treatment, and two weeks washout. Methacholine challenges were performed at the beginning of the run in period, before treatment, after treatment, and after washout. Hypertonic saline challenges were performed before and after treatment and induced sputum samples were collected for differential cell counting.Results: There was no change in airway responsiveness, maximal response plateau to methacholine, or in induced sputum eosinophils or mast cells. The maximum fall in FEV1 after hypertonic saline increased in the salbutamol group (median change 6.0%, interquartile range (IQR) 11.0) but did not change in the placebo group (median change 1.3%, IQR 5.5).Conclusions: Regular inhaled salbutamol for four weeks increases airway responsiveness to hypertonic saline but does not alter airway responsiveness to methacholine or cells in induced sputum in non-asthmatic individuals with rhinitis. The relevance of these findings to asthmatic subjects has not been established. [ABSTRACT FROM AUTHOR]

The effects of inhaled allergen on airway responsiveness and on β- and α-1-adrenergic receptors on lung membrane were investigated in guinea pigs. After measuring the respiratory threshold to histamine (RT-HIS), one group of guinea pigs passively sensitized for ovalbumin was challenged by allergen inhalation (challenged group). Measurement of the RT-HIS 24 h following challenge revealed a significant decrease from 687 µg/ml (mean, n = 16) to 407 µg/ml (P < 0.05). In addition the RT-HIS 24 h after challenge was also significantly lower in the challenged group than in controls (n = 9, P < 0.05). The density of β-adrenergic receptors on the lung membrane of the challenged group was 594 ± 32 (mean ± SE) fmol/mg protein (n = 11) compared with 712 ± 24 fmol/mg protein (n = 9) in the controls, a statistically significant difference (P < 0.05). A significant correlation was found between the RT-HIS and density of β-adrenergic receptors. From these results, we concluded that the exaggerated airway responsiveness 24 h after allergen challenge is in part due to a decrease in the density of β-adrenergic receptors. There was no difference in the density of α-1-adrenergic receptors nor a significant correlation between the RT-HIS and the number of α-1-adrenergic receptors in the challenged vs the control groups. [ABSTRACT FROM AUTHOR]

Objectives: To assess the relation between measured levels of exposure to soluble oil mists in a plant manufacturing ball bearings, and both respiratory symptoms and airway responsiveness in the workforce.Methods: 114 male workers exposed to oil mist and 55 unexposed male controls from nearby factories were studied. Soluble oil mist concentrations were measured with area samplers. Respiratory symptoms were assessed by questionnaire and measurement of airway responsiveness to methacholine with an abbreviated method. Subjects were labelled positive to methacholine airway challenge (MAC+) if forced expiratory volume in one second (FEV1) fell by > or = 20%. The linear dose-response slope was calculated as the percentage fall in FEV1 at the last dose divided by the total dose given.Results: Geometric mean concentrations of oil mists ranged from 0.65 mg/m3 (GSD 1.29) to 2.20 mg/m3 (GSD 1.55) based on 92 measurements obtained from 1979-93. The prevalence of chronic cough or phlegm, bouts of bronchitis, and dyspnoea was greater among exposed workers than among controls (odds ratio (OR) 4.64, P = 0.002 for chronic cough and phlegm). After adjustment for smoking and age, dyspnoea was significantly related to an index of cumulative exposure to oil mist (OR 1.44, P = 0.006/10 y.mg/m3). The proportion of MAC+ subjects was similar in the two groups. However, after adjustment for baseline FEV1 and age, the dose-response slope was significantly steeper among exposed workers than among controls (P = 0.01), a finding indicating airway hyperresponsiveness in the exposed workers. Furthermore, the dose-response slope was significantly related to baseline FEV1, age, and, after adjustment for FEV1, the index of cumulative exposure to oil (P = 0.004).Conclusion: Subjects with exposure to soluble oil mist in the metal industry are at risk of developing both respiratory symptoms and airway hyperresponsiveness. [ABSTRACT FROM AUTHOR]

Intratracheal Parainfluenza type 3 (PI-3) virus inoculation of guinea pigs leads to a non-specific airway hyperresponsiveness in vivo and in vitro which coincides with a significant increase in the number of inflammatory cells in the broncho-alveolar lavage fluid (90% increase, 4 days after inoculation). The activity of the bronchoalveolar cells, as measured by the chemiluminescence production of infected animals is significantly diminished (34.2%, 4 days after inoculation) after renewed stimulation with PI-3 virus in vitro as compared to the chemiluminescence production by bronchoalveolar cells obtained from control guinea pigs. Pretreatment of the guinea-pigs with the antitussive agent levodropropizine, administered intra-peritoneally twice a day for five successive days at a dose of 10 mg/kg, prevents the virus-induced airway hyperresponsiveness in vivo and in vitro, and inhibits the influx of broncho-alveolar cells. Levodropropizine at a dose of 1 mg/kg did not modulate these responses. Further, the decrease in chemiluminescence production of broncho-alveolar cells obtained from virus-infected animals after PI-3 virus stimulation in vitro was inhibited by levodropropizine (10 mg/kg). These data demonstrate the ability of levodropropizine to counteract the hyperresponsiveness phenomenon and the associated inflammatory event induced by PI-3 virus, an effect which may be due to its capacity to act on the peptidergic system or may be due to the anti-allergic/bronchoconstrictor property of this compound. [ABSTRACT FROM AUTHOR]

Adenosine, a naturally occurring purine nucleoside, elicits dose-related bronchoconstriction in asthmatic subjects when administered by inhalation and it is recovered in increased amounts from the bronchial lavage fluid of subjects with active asthma when compared to normal controls. Although the mechanism by which adenosine mediates bronchoconstriction in asthmatic subjects is not clear, recent data indicate an important role for mast cell mediator release. We have recently shown that local airway challenge with adenosine in subjects with asthma and rhinitis provokes an increase in the levels of PGD2, histamine and tryptase. However, airway responsiveness and atopic status are the most important determinants of adenosine-induced responses, regardless of any increases in mast cell mediators in airway fluids. New discoveries suggest that the airway response to adenosine may be an index of mast cell priming and therefore may provide a useful tool to further explore the inflammatory processes in allergic asthma and rhinitis. Therefore adenosine provocation may gain increasing acceptance as an additional measure of disease activity in asthma and rhinitis. [ABSTRACT FROM AUTHOR]

There are renewed interests in using the parameter K of Salazar-Knowles' equation to assess lung tissue compliance. K either decreases or increases when the lung's parenchyma stiffens or loosens, respectively. However, whether K is affected by other common features of respiratory diseases, such as inflammation and airway smooth muscle (ASM) contraction, is unknown. Herein, male C57BL/6 mice were treated intranasally with either saline or lipopolysaccharide (LPS) at 1 mg/kg to induce pulmonary inflammation. They were then subjected to either a multiple or a single-dose challenge with methacholine to activate ASM to different degrees. A quasi-static pressure-driven partial pressure-volume (P-V) maneuver was performed before and after methacholine. The Salazar-Knowles' equation was then fitted to the deflation limb of the P-V loop to obtain K, as well as the parameter A, an estimate of lung volume (inspiratory capacity). The fitted curve was also used to derive the quasi-static elastance (E st ) at 5 cmH 2 O. The results demonstrate that LPS and both methacholine challenges increased E st . LPS also decreased A, but did not affect K. In contradistinction, methacholine decreased both A and K in the multiple-dose challenge, whereas it decreased K but not A in the single-dose challenge. These results suggest that LPS increases E st by reducing the open lung volume (A) and without affecting tissue compliance (K), whereas methacholine increases E st by decreasing tissue compliance with or without affecting lung volume. We conclude that lung tissue compliance, assessed using the parameter K of Salazar-Knowles' equation, is insensitive to inflammation but sensitive to ASM contraction.

Background: Airway obstruction (AO) in asthma is driven by airway smooth muscle (ASM) contraction. AO can be induced extrinsically by direct stimulation of ASM with contractile agonists as histamine, or by indirect provocation with antigens as ovalbumin, while the airway tone is dependent on intrinsic mechanisms. The association of the ASM phenotypes involved in different types of AO and airway tone in guinea pigs was evaluated., Methods: Guinea pigs were sensitized to ovalbumin and challenged with antigen. In each challenge, the maximum OA response to ovalbumin was determined, and before the challenges, the tone of the airways. At third challenge, airway responsiveness (AR) to histamine was evaluated and ASM cells from trachea were disaggregated to determinate: (a) by flow cytometry, the percentage of cells that express transforming growth factor-β1 (TGF-β1), interleukin-13 (IL-13) and sarco-endoplasmic Ca 2+ ATPase-2b (SERCA2b), (b) by RT-PCR, the SERCA2B gene expression, (c) by ELISA, reduced glutathione (GSH) and, (d) Ca 2+ sarcoplasmic reticulum refilling rate by microfluorometry. Control guinea pig group received saline instead ovalbumin., Results: Antigenic challenges in sensitized guinea pigs induced indirect AO, AR to histamine and increment in airway tone at third challenge. No relationship was observed between AO induced by antigen and AR to histamine with changes in airway tone. The extent of antigen-induced AO was associated with both, TGF-β1 expression in ASM and AR degree. The magnitude of AR and antigen-induced AO showed an inverse correlation with GSH levels in ASM. The airway tone showed an inverse association with SERCA2b expression., Conclusions: Our data suggest that each type of AO and airway tone depends on different ASM phenotypes: direct and indirect AO seems to be sensitive to the level of oxidative stress; indirect obstruction induced by antigen appears to be influenced by the expression of TGF-β1 and the SERCA2b expression level plays a role in the airway tone., (© 2022. The Author(s).)

Expression of bronchodilatory β2-adrenoceptors and bronchoconstrictive muscarinic M3-receptors alter with airway size. In COPD, (a combination of) β2-agonists and muscarinic M3-antagonists (anticholinergics) are used as bronchodilators. We studied whether differential receptor expression in large and small airways affects the response to β2-agonists and anticholinergics in COPD. Bronchoprotection by indacaterol (β2-agonist) and glycopyrrolate (anticholinergic) against methacholine- and EFS-induced constrictions of large and small airways was measured in guinea pig and human lung slices using video-assisted microscopy. In guinea pig lung slices, glycopyrrolate (1, 3 and 10 nM) concentration-dependently protected against methacholine- and EFS-induced constrictions, with no differences between large and small intrapulmonary airways. Indacaterol (0.01, 0.1, 1 and 10 μM) also provided concentration-dependent protection, which was greater in large airways against methacholine and in small airways against EFS. Indacaterol (10 μM) and glycopyrrolate (10 nM) normalized small airway hyperresponsiveness in COPD lung slices. Synergy of low indacaterol (10 nM) and glycopyrrolate (1 nM) concentrations was greater in LPS-challenged guinea pigs (COPD model) compared to saline-challenged controls. In conclusion, glycopyrrolate similarly protects large and small airways, whereas the protective effect of indacaterol in the small, but not the large, airways depends on the contractile stimulus used. Moreover, findings in a guinea pig model indicate that the synergistic bronchoprotective effect of indacaterol and glycopyrrolate is enhanced in COPD. [ABSTRACT FROM AUTHOR]

Asthma is an important cause of subacute cough. The concentration of alveolar nitric oxide (CANO) is a sensitive inflammatory indicator in peripheral airways, and it has received much less attention than the fraction of exhaled nitric oxide (FeNO 50 ). The main objective of this study was to explore the correlation between CANO and clinical parameters in asthmatic and non-asthmatic subacute cough, which might promote understanding of the clinical utility of CANO in these special patient populations. 155 patients with subacute cough were included consecutively, of which 25 were diagnosed as asthmatic. Data for demographic characteristics, FeNO 50 , CANO, baseline spirometry, bronchial provocation test (or bronchodilation test) and response dose ratio (RDR) were collected. Differences between the asthmatic and non-asthmatic groups were analyzed. Spearman's correlation coefficient ( ρ ) was used to evaluate the correlation between FeNO 50 , CANO and other clinical parameters. In patients with subacute cough, baseline CANO values did not differ between asthmatic and non-asthmatic patients (4.4(1.3, 11.4) versus 4.0(2.1, 6.8) ppb, P > 0.05). Besides, CANO exhibited a stronger association with pulmonary function parameters when compared with FeNO 50 . For asthmatic subacute cough, CANO was inversely correlated with FEV 1 /FVC ( ρ = -0.69, P < 0.01) and small airway parameters including MEF25 ( ρ = -0.47, P < 0.05) and MMEF ( ρ = -0.45, P < 0.05). For non-asthmatic subacute cough, CANO was inversely correlated with MEF25 ( ρ = -0.19, P < 0.05) and RDR ( ρ = -0.21, P < 0.05). In subacute cough, asthmatic and non-asthmatic patients had similar values of baseline CANO. In both asthmatic and non-asthmatic subacute cough, CANO exhibited a stronger association with pulmonary function parameters when compared with FeNO 50 . A low CANO value in non-asthmatic subacute cough corresponded to a higher value of RDR, which implied a stronger tendency towards airway responsiveness., (© 2021 IOP Publishing Ltd.)

Background: Small plateau (SP) on the flow-volume curve was found in parts of patients with suspected asthma or upper airway abnormalities, but it lacks clear scientific proof. Therefore, we aimed to characterize its clinical features., Methods: We involved patients by reviewing the bronchoprovocation test (BPT) and bronchodilator test (BDT) completed between October 2017 and October 2020 to assess the characteristics of the sign. Patients who underwent laryngoscopy were assigned to perform spirometry to analyze the relationship of the sign and upper airway abnormalities. SP-Network was developed to recognition of the sign using flow-volume curves., Results: Of 13,661 BPTs and 8,168 BDTs completed, we labeled 2,123 (15.5%) and 219 (2.7%) patients with the sign, respectively. Among them, there were 1,782 (83.9%) with the negative-BPT and 194 (88.6%) with the negative-BDT. Patients with SP sign had higher median FVC and FEV 1 % predicted (both P < .0001). Of 48 patients (16 with and 32 without the sign) who performed laryngoscopy and spirometry, the rate of laryngoscopy-diagnosis upper airway abnormalities in patients with the sign (63%) was higher than those without the sign (31%) (P = 0.038). SP-Network achieved an accuracy of 95.2% in the task of automatic recognition of the sign., Conclusions: SP sign is featured on the flow-volume curve and recognized by the SP-Network model. Patients with the sign are less likely to have airway hyperresponsiveness, automatic visualizing of this sign is helpful for primary care centers where BPT cannot available., (© 2021. The Author(s).)