Histamine release from blood cells and serum ECP in patients with asthma, during and after a mild pollen season.
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Asthma↗
Biomedical subjects
B Schmekel
Publications and source records attributed to B Schmekel.
Eosinophil cationic protein (ECP) in saliva: a new marker of disease activity in bronchial asthma.
Eosinophil cells play a crucial role in the pathogenesis of asthma, and concentration of eosinophil cationic protein (ECP) in serum has been used to monitor activity of the disease. Our aim was to determine the feasibility and usefulness of measuring ECP in saliva and to use it as a marker of the disease. Thirty-eight patients with asthma and 16 healthy volunteers were included in this study. Repeatability of measurements of ECP in saliva was acceptable [intra-class correlation coefficients (Ri) = 0.74 and coefficients of repeatability (CR) = 0.37 in five healthy subjects]. Levels of ECP in saliva were higher in asthmatics than in volunteers (P < 0.01). There was a significant inverse association between a surrogate variable reflecting disease activity (i.e. change over a few weeks in dose of inhaled corticosteroid required by a change in clinical status of asthma) and a change over the same time period in salivary ECP in 19 patients with stable asthma (r = -0.64, P = 0.02). Our findings indicate that levels of salivary ECP are elevated in patients with asthma and associated with presumed activity of disease as recorded by alteration of taken dose of inhaled corticosteroid.
Acute Disease↗
Human neutrophil lipocalin (HNL) and myeloperoxidase (MPO). Studies of lung lavage fluid and lung tissue.
Myeloperoxidase (MPO) and human neutrophil lipocalin (HNL) are proteins which are stored in neutrophil granulocytes, in the primary and secondary granules, respectively. These granules or their contents of MPO and HNL are secreted upon activation of the cells, and measurement of these soluble markers in biological fluids, such as bronchoalveolar lavage (BAL), has been proposed to mirror the degree of neutrophil activity in the tissue. We conducted a BAL study in 10 healthy volunteers, with the aim to evaluate the intra-individual variability of the concentration of HNL and MPO recovered in sequential aspirations, during a time period when the concentrations of HNL and MPO in BAL fluids were considered to have equilibrated with those in the underlying tissues. The concentrations of HNL were less variable than those of MPO (coefficients of variability 0.33 +/- 0.07 vs. 0.92 +/- 0.28; P = 0.01), suggesting HNL to be a more useful marker of neutrophil activity within the airspace. The specificity of HNL as a selective index of neutrophil cells was confirmed by means of immunohistochemical staining of uninvolved lung tissue specimens obtained from patients referred to pulmonectomy due to carcinoma. While HNL was located only to intracellular spaces of neutrophils, MPO was in addition located to other cells as well. We speculate that the dynamic changes of pressure across the membranes and flow of solutes during a lavage process might mobilize particulate matter and adherent cells, some of which may be loaded with MPO, and that this may introduce larger variability in the recovery of MPO than of HNL. We conclude that using HNL as a soluble indicator of neutrophil presence is more feasible than using MPO.
Acute-Phase Proteins↗
Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers.
Racemic R,S-salbutamol is taken to relieve bronchial constriction. Only the R-enantiomer has bronchodilating properties. The S-enantiomer has been proposed to cause in vitro bronchial hyperreactivity in guinea-pigs. Stereoselective elimination of salbutamol has been shown, with S-salbutamol being eliminated at a slower rate than R-salbutamol. This study questioned whether rates of stereoselective elimination were similar after oral or lung delivery, and whether the S:R ratio would increase after repeated inhalations in a situation resembling a common clinical use. Eighteen healthy volunteers received single-dose racemic salbutamol as a solution instilled in the trachea during anaesthesia, as inhaled micronized powder and/or as ingested tablets. Five volunteers inhaled repeated doses of racemic salbutamol. Concentrations in plasma and urine were measured using a technique which allowed chiral separation of samples with concentrations as low as 0.1 ng x mL(-1). The bioavailability of S-salbutamol was significantly higher than that of R-salbutamol after the different modes of administration. Stereoselective elimination was more pronounced after oral administration than after inhalation. Repeated inhalations resulted in successive increases in the S:R ratio as steady state was approached. In conclusion, the clinical consequences of increasing plasma concentrations of S-salbutamol need to be further assessed.
Administration, Inhalation↗
The diagnostic capacity of forced oscillation and forced expiration techniques in identifying asthma by isocapnic hyperpnoea of cold air.
The measurement of forced expiratory volume in one second (FEV1) is often used to assess the effect of bronchial provocations, and deep inspiration is required beforehand. This may briefly alter the bronchial tone in a variable way in some subjects. The forced oscillation technique (FOT) is a test used to characterize the mechanical impedance of the respiratory system, and prior deep inspiration is not required. We tested the hypothesis that measurable bronchoconstriction would occur in all asthmatic subjects stimulated with isocapnic hyperventilation of dry cold air (IHCA). Twenty patients with mild asthma and nine healthy controls were exposed to IHCA, at 70% of their maximal voluntary ventilatory capacity for 4 min and the results were assessed both by applying the FOT and by measuring FEV1. Optimal cut-off levels were defined by receiver operating characteristic (ROC) curve analyses of the changes in respiratory resistance and reactance at 5-35 Hz, resonant frequency (fres) and FEV1. A positive result was present in the asthmatics when measured by FOT, and using ROC analyses the discriminative capacity to correctly diagnose asthma was greatest for responses in fres; the sensitivity was 89% and the specificity 100%. The sensitivity of FEV1 to correctly diagnose asthma was only 73%, and the specificity 88%. In conclusion, the results of this study suggest that the use of forced expiratory volume in one second for bronchial provocation tests by isocapnic hyperventilation of dry cold air may be misleading and that the bronchoconstriction thus elicited is measured with greater sensitivity and specificity by the forced oscillation technique than by forced expiratory volume in one second.
Adult↗
Relative effects of inhaled corticosteroids on immunopathology and physiology in asthma: a controlled study.
BACKGROUND: Although corticosteroids are recognised as the most efficacious treatment for bronchial asthma, their mode of action remains unclear. A placebo controlled trial was undertaken of the effect of inhaled corticosteroids on physiological and immmunopathological parameters in asthmatic patients in whom the correlations between these indices were tested after treatment. METHODS: Sixteen patients (two women) with asthma entered a double blind, placebo controlled, parallel study during which they inhaled either budesonide 800 micrograms twice daily or matching placebo for six weeks. Spirometric parameters and bronchial reactivity to histamine and terbutaline were measured and endobronchial biopsy samples were taken before and after treatment. Patients recorded morning and evening flow rates during the treatment period. The biopsy samples were subjected to immunohistological analysis to determine the disposition of inflammatory cells within the bronchial wall. RESULTS: Treatment with budesonide resulted in a significant improvement in the 25-75% forced expiratory flow (FEF25-75) from a mean of 133 l/min before treatment to 169 l/min after treatment, and in the morning peak expiratory flow rate (PEFR) from a mean of 384 l/min before treatment to 415 l/min after treatment. No changes were seen in the placebo group. Comparison between the changes in the immunopathological indices after six weeks of treatment with placebo or budesonide showed a significant reduction in the numbers of mast cells (0.5/unit area to 0.2/ unit area), activated eosinophils, and the expression of HLA-DR antigens (relative density -1.9 before to 1.02 after treatment) on inflammatory cells in response to treatment with budesonide. Although reductions in the numbers of other inflammatory cells within the bronchial wall were recorded using immunohistological analysis, these changes were not statistically significant. Significant correlations were found between changing immunological indices and lung physiology. CONCLUSIONS: This controlled study shows that inhaled corticosteroids cause improvement in physiological and immunopathological parameters in patients with stable asthma that are not seen with placebo, and that cause and effect relationships may exist between these two measures of disease status.
Adolescent↗
Interinstrument variability of three portable peak flow meters.
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Adult↗
Increased adhesion to vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 of eosinophils from patients with asthma.
Adhesion of peripheral blood eosinophil and neutrophil granulocytes to the endothelial cell adherence receptors E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 has been measured. The study included patients with allergic rhinitis, patients with mild allergic and nonallergic asthma, and healthy individuals; 10 persons were in each group. In addition, assay of eosinophil and neutrophil cell surface expression of the receptor complex CD11b/CD18 was performed. Increased eosinophil adhesion to vascular cell adhesion molecule-1 (p < 0.05) and intercellular adhesion molecule-1 (p < 0.05) was demonstrated in the patients with a more labile asthma, that is, a peak expiratory flow rate variability of more than 10%, suggesting a relationship to the degree of ongoing inflammation in the airways of the patients. The increased eosinophil adhesion was most probably due to a functional upregulation of the CD11b/CD18 and very late activation antigen-4 receptors, because the number of receptors measured as cell surface expression was unaltered. The increased eosinophil adhesion in the patients with high peak expiratory flow rate variability appeared independent of atopy. The increased adhesion was not entirely specific to the eosinophils, because neutrophils from patients with a peak expiratory flow rate variability of more than 10% also demonstrated increased adhesion to intercellular adhesion molecule-1 (p < 0.05) when compared with neutrophils from the patients with low peak expiratory flow rate variability. In conclusion, the demonstrated priming of eosinophil adhesion to vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 might be one contributing mechanism behind the selective accumulation of eosinophils in the lung tissue of patients with asthma.
Adult↗
Kinetic retrieval of eosinophil cationic protein, hyaluronan, secretory IgA, albumin, and urea during BAL in healthy subjects.
Determination of absolute concentrations of various soluble components of the epithelial lining fluid (ELF) may be valuable to estimate inflammatory activities within the underlying lung tissue. Internal standards may then be used as markers of dilution of bronchoalveolar lavage (BAL). The aim of this study was to determine whether different dwell times would affect the relationship between the concentrations of any of the three potential internal standards (secretory IgA [SIgA], albumin, and urea), and the concentrations of two potential markers of inflammation (eosinophil cationic protein [ECP] and hyaluronan [HA]) in BAL. A series of aliquots of BAL fluid were aspirated every 60 s up to 8 min after a bolus instillation of saline solution in 20 healthy subjects (10 smokers). The BAL concentrations of albumin and urea increased with time, consistent with continuous diffusion from the body water pool, absorption of the BAL fluid, or both. The rate constant of diffusion was 1,000 times higher for urea than for albumin (3.38 x 10(-1) and 3.64 x 10(-4), respectively), reflecting the difference in molecular weights, and in agreement with the notion that albumin and urea appeared in BAL fluid by a rate-limited procedure related to osmotic transfer. Biexponential increases of SIgA were recorded, suggesting a two-compartmental origin of this compound, normally located to mucosal membranes and presumed to be dissolved in ELF. Time-dependent increases in BAL fluid of HA also were recorded, but on the other hand, the ECP concentrations tended to level off after an initial increase, suggesting that the bulk of ECP appeared in BAL by a nonosmotic mechanism. We conclude that the kinetics of these three internal standards in BAL fluid differs greatly from each other and from the kinetics of the two selected markers of inflammation. Consequently, internal standards for determination of absolute concentrations of markers of inflammation in ELF should be carefully selected because of the requirement of matched kinetics of the markers.
Adult↗
The bronchial response, but not the pulmonary response to inhaled methacholine is dependent on the aerosol deposition pattern.
The clinical effect of inhaled radio-labeled (Technetium-99m diethylenetriamine-pentaacetic acid) methacholine was studied in two separate experiments performed in eight symptom-free asthmatics with bronchial hyperresponsiveness. Aerosols were formed by two different nebulizers, producing either mainly small aerosol particles (2-microns mass median aerodynamic diameter [MMAD]) for peripheral, or mainly large aerosol particles (9-microns MMAD) for large airway deposition. The intended site of deposition was confirmed by gamma camera recordings. Changes in specific airway conductance (sGaw) were set as an index of central airway constriction, and functional alterations in the gas exchanging parts of the lung were estimated by multiple inert gas elimination technique (MIGET) and arterial blood gas analyses. The main finding was that the responses, as measured by the changes in arterial blood gases and by MIGET, were similar in the two experiments, while the fall in sGaw was significantly larger after deposition in the main bronchi than in the peripheral airways (p < 0.05). The time courses of the abnormalities in the gas exchanging elements were much longer than those of the responses of the central airways, and the abnormalities were recorded still at the end of the experiment 2 h after challenge in most patients. A discrepancy in dose dependency and time courses suggests differences in mechanism and/or dynamics of the responses exerted by the various target organs. Interaction in the process of clearance from the lung of inhaled methacholine by the bronchial circulation may have contributed to the observed discrepancies.
Adult↗
Determination of theophylline in plasma using different capillary electrophoretic systems.
Theophylline was determined in human plasma by capillary electrophoresis (CE). The drug was used as a model substance to study a simple sample pretreatment often used in HPLC: to 200 microliters of plasma were added 400 microliters of acetonitrile to precipitate the plasma proteins and the supernatant was injected into the capillary after centrifugation. Three capillary electrophoretic systems were compared with respect to migration time and electrophoretic migration reproducibility. UV detection at 280 nm was applied. The separation was preferably made in an uncoated fused-silica capillary (57 cm x 75 microns I.D.) with 10 mM phosphate-borate buffer (pH 9.0) as the electrophoretic buffer. A linear calibration graph was obtained in the concentration range studied, 1.8-36 micrograms/ml (10-200 microM). The method permits the determination of theophylline in plasma at therapeutic concentrations of 4.5-20 micrograms/ml (25-110 microM) with acceptable precision.
Electrophoresis↗
Tremor in healthy volunteers after bambuterol and terbutaline CR-tablets.
Bambuterol tablets, 10 and 20 mg, and terbutaline CR-tablets, 5 and 7.5 mg, have been compared for their capacity to produce subjectively determined tremor in a randomised, double-blind, cross-over study in 40 healthy volunteers. The duration of each treatment was one week, with an intervening washout period of at least 2 weeks. On the second and the last treatment days in each period, tremor was subjectively assessed on six occasions. In addition, an overall assessment of night and day tremor was made each morning and evening. Analyses were made for the second and last treatment days and during the treatment week. Paired comparisons for tremor during daytime showed a significant difference between the treatments, with the exception of bambuterol 20 mg and terbutaline 5 mg. Bambuterol 10 mg caused less tremor and terbutaline 7.5 mg caused more tremor than the other treatments. At the end of the week, the differences were smaller and were only significant when comparing bambuterol 10 mg with the 20 mg dose and with high dose terbutaline. Terbutaline 7.5 mg caused more tremor at night than the other treatments. The tremor experienced was generally mild, and after bambuterol 10 mg it was almost negligible (mean 0.13 after the first dose). Two subjects recorded a score of 3 after terbutaline 7.5 mg. The results indicate that, in doses equipotent with regard to bronchodilation, tremor is less pronounced after bambuterol as compared to controlled release tablets of terbutaline.
Administration, Oral↗
Markers for eosinophils and T-lymphocytes as predictors of late asthmatic response.
Bronchial allergen challenge was performed on 12 allergic asthmatics during a stable phase of their disease. After resolution of the immediate bronchial response, fractional lung lavage was performed twice, two and 24 h post-challenge. The recovery of eosinophils, eosinophil cationic protein (ECP), eosinophil chemotactic activity (ECA) and immunohistochemical staining of the phenotypically distinct population stainable by the monoclonal antibody CD45RO, agreed to indicate T-memory cells, were assessed in the two lavages. Serial measurements of lung function, and serum concentration of ECP were also done. We found that although the recoveries in bronchial washes of eosinophil cells and ECP tended to increase during the trial, none of these variables predicted the emergence of late phase bronchial response (LPR). Instead, the proportion in the 2-h lavages, of memory-cells or ECA predicted the LPR. These two variables were inversely correlated to each other in the first lavage, suggesting the T-cells to be potential major sources of ECA. The fact that T-cells and ECA, but not markers for eosinophil activation in lavage, predicted the LPR, may suggest T-cell activation to precede the activation of the eosinophils within the lung after a bronchial allergen challenge. There was a close correlation between LPR and serum concentration of ECP obtained at the end of the trial, 24 h post-challenge, suggesting either a delayed or a continuous activation of circulating eosinophils after bronchial allergen challenge.
Asthma↗
[Current aspects of asthma].
Knowledge of the pathophysiology and aetiology of asthma has expanded greatly during recent years, and hopes are strong that within the foreseeable future it will be possible to alleviate asthmatic symptoms even more effectively. This review covers some of this new knowledge, and presents viewpoints on the practical clinical management of asthma patients.
Adrenal Cortex Hormones↗
Integrity of the alveolar-capillary barrier and alveolar surfactant system in smokers.
BACKGROUND: The permeability of the alveolar-capillary barrier to technetium-99m labelled diethylenetriamine pentaacetate (99mTc DTPA) is known to be greatly increased in smokers, but the underlying mechanism is poorly understood. Abnormal permeability of the alveolar epithelium as well as impaired surfactant function has been suggested. The purpose of this study was to examine transudation of urea and albumin into the alveoli and alveolar surfactant function in smokers and non-smokers and to relate these variables to the rate of alveolar-capillary transfer of 99mTc DTPA. METHODS: Standardised bronchoalveolar lavage was performed and the yield of urea and albumin measured in the lavage fluid. The integrity of the alveolar surfactant system was assessed by measurement of the surface activity and of the yield of phospholipids in alveolar lavage fluid. RESULTS: The mean decay constant for the pulmonary clearance of 99mTc DTPA was 0.028/min in the smokers and 0.009/min in the non-smokers. The recovery of albumin and urea in alveolar lavage fluid was very similar in the two groups. The surface activity of alveolar lavage fluid was lower in smokers than in non-smokers (minimum surface tension 37.9 versus 28.6 mN/m) and the yield of phospholipids was reduced (2.08 versus 3.86 mg). The rate constant for the pulmonary clearance of 99mTc DTPA correlated with the yield of phospholipids at bronchoalveolar lavage. CONCLUSIONS: The study shows that increased alveolar-capillary transfer of 99mTc DTPA in smokers is not accompanied by increased transudation of small or large molecules into the alveoli. The findings support the hypothesis that increased clearance of 99mTc DTPA in smokers is related to surfactant dysfunction.
Adult↗
Increased eosinophil chemotactic activity in bronchial washes obtained from patients with asymptomatic allergic alveolitis.
The chemotactic activities of eosinophils and neutrophils were measured in bronchial washes obtained from 6 symptom-free patients with previous extrinsic allergic alveolitis and 9 healthy volunteers. An increased chemotactic activity was found in the washes obtained from the patients, and the recovery of eosinophils was correlated with the eosinophil chemotactic activity, suggesting a causal relationship. Chromatography of the fluids obtained suggested that low molecular weight compounds were principally responsible for the increased chemotactic activity. A mild disturbance of the integrity of the alveolocapillary barrier could to some extent add to the explanation of the increased chemotactic activity in the washes obtained from the patients.
Adult↗
Exercise increases the rate of pulmonary absorption of inhaled terbutaline.
The purpose of the study was to investigate whether a constant submaximal exercise challenge affected the plasma pharmacokinetics of an inhaled beta 2-adrenoceptor agonist, terbutaline sulfate. Eight healthy nonsmokers participated in a study comprising measurements of plasma concentrations of terbutaline on two separate study days. Plasma samples were frequently collected at rest during study day 1, and on the second study day, during and after a 30-min exercise challenge, which was performed immediately after inhalation of the drug. The rate of increase of plasma concentrations and the maximal plasma concentrations were higher during exercise than during rest (p less than 0.01 and p less than 0.05, respectively). The plasma concentration fell rapidly after cessation of the exercise and approached those obtained at rest. We suggest that increased pulmonary and/or bronchial blood flow and altered surface tension of the liquid lining of the air space may contribute to the enhancement of absorption of this hydrophilic compound during exercise. Based on the levels of the maximal plasma concentrations reached during exercise in this study, the results would be to increase the frequency of administration of the drug, rather than to increase the administered doses, if the aim is to prevent or ameliorate exercise-induced asthma and potential systemic side effects.
Absorption↗
T-cell dominated inflammatory reactions in the bronchi of asthmatics are not reflected in matched bronchoalveolar lavage specimens.
Samples of bronchoalveolar lavage (BAL) and endobronchial biopsies were obtained from five patients with clinically diagnosed asthma (ATS criteria). A comparison was made of the presence and distribution of immunocompetent lymphocytes and macrophages within each sample. Significantly raised numbers of T lymphocytes, CD45RO+ lymphocytes, RFD1+ macrophage-like cells and RFD7+ macrophages were seen in the bronchial biopsies. In contrast four out of five of the BAL specimens showed a normal differential cell count, the one exception being a patient exhibiting a degree of lymphocytosis. Further, immunocytological investigation demonstrated a normal distribution of T-cell subsets and macrophage subsets in asthmatic BAL with the exception that in four out of five of these patients a raised number of macrophage-like cells exhibiting phenotypic markers of monocytes was observed. Correlation between BAL and biopsy data was seen in the number of CD45RO+ T-cells present. No other parameters exhibited a significant correlation. Raised expression of HLA-DR was recorded in all asthmatic biopsies, yet lavage cells from the same patients failed to exhibit any increase of HLA-DR density over normal. It is concluded that the immune-associated inflammation present in endobronchial biopsies of clinically stable asthmatics is not reflected in bronchoalveolar lavage samples taken from the same patients.
Acute-Phase Reaction↗