Therapeutic applications of BAL.
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Asthma↗
Biomedical subjects
L M Fabbri
Publications and source records attributed to L M Fabbri.
Guidelines for bronchoprovocation on the investigation of occupational asthma. Report of the Subcommittee on Bronchoprovocation for Occupational Asthma.
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Asthma↗
Ketotifen does not inhibit asthmatic reactions induced by toluene di-isocyanate in sensitized subjects.
In order to determine whether treatment with ketotifen inhibits asthmatic reactions induced by toluene di-isocyanate (TDI), we studied six sensitized subjects with previously demonstrated dual or late asthmatic reaction after inhalation challenge with TDI. Ketotifen (1 mg b.i.d., orally) or placebo was administered for 7 days to the examined subjects, according to a double-blind, cross-over, placebo-controlled study design. When the subjects were treated with either ketotifen or placebo, FEV1 markedly decreased after exposure to TDI. These results suggest that the anti-asthmatic agent ketotifen is not effective in TDI-induced asthma and suggest that it should not be used in the prophylaxis of asthmatic reactions induced by TDI in sensitized subjects.
Asthma↗
Response to acetylcholine and myosin content of isolated canine airways.
Contractility of tracheal smooth muscle strips and spiral strips of fourth to fifth generation bronchi was studied in organ baths. The relationship among contractility, airway smooth muscle myosin, and smooth muscle thickness was also examined. The trachea was divided into three segments, each consisting of 12-14 rings. Smooth muscle strips from each of the three regions (top, middle, and bottom of the trachea) and from fourth to fifth generation bronchi were studied. Acetylcholine (ACh) sensitivity (-log EC50) was 8.1, 7.1, 7.9, and 6.1 for the top, middle, and bottom of the trachea and the bronchi, respectively. At P = 0.01, the EC50 ACh value of the top of the trachea differed from the EC50 value of the bronchi. Maximal tension (Tmax) generated in bronchi (3.2 g) was lower (P less than 0.01) than in the top (10.4 g), middle (7.1 g), and bottom of the trachea (5.1 g). Differences between trachea and bronchi disappeared when Tmax was corrected for smooth muscle myosin content. Thickness of smooth muscle in bronchi was less (P less than 0.01) than in the three regions of trachea. Tmax was significantly correlated with airway smooth muscle thickness (r = 0.56; P less than 0.05). These results suggest that in mongrel dogs sensitivity to ACh shows a gradient from the top of the trachea to the bronchi and that Tmax is greater in the trachea than in the bronchi and is significantly correlated with thickness of smooth muscle.
Acetylcholine↗
Ambroxol inhibits airway hyperresponsiveness induced by ozone in dogs.
To follow up previous observations that airway hyperresponsiveness induced by ozone is linked to airway inflammation and particularly to the release of arachidonic acid metabolites, we investigated the effect of ambroxol (a mucoactive and surfactant-stimulating drug that has recently been discovered to inhibit the release of arachidonic acid from cell membrane phospholipids) on airway hyperresponsiveness and bronchoalveolar neutrophilia induced by ozone in dogs. One group of 5 dogs was studied before treatment with nebulized saline and then after exposure to ozone (3 ppm, 1 h); another group of 6 dogs was studied before treatment with ambroxol (100 breaths of a 1% solution) and after exposure to ozone. On each occasion, we measured airway responsiveness to acetylcholine and counted the number of cells in bronchoalveolar lavage fluid. When the dogs were given the saline placebo, ozone induced a marked increase in airway responsiveness to acetylcholine and a marked influx of neutrophils in the airways. When the dogs were given ambroxol, ozone induced the same increase in the number of neutrophils in bronchoalveolar lavage, but did not increase the degree of airway responsiveness to acetylcholine. We conclude that ambroxol inhibits ozone-induced airway hyperresponsiveness in dogs, probably by inhibiting the formation and release of oxygenation products of arachidonic acid from neutrophils.
Acetylcholine↗
Dexamethasone isonicotinate inhibits dual and late asthmatic reactions but not the increase of airway responsiveness induced by toluene diisocyanate in sensitized subjects.
To determine whether treatment with aerosolized dexamethasone isonicotinate inhibits asthmatic reactions and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied six sensitized subjects with previously demonstrated dual or late asthmatic reaction after inhalation challenge with TDI. Dexamethasone isonicotinate (four puffs bid for seven days, ie, 0.5 mg bid for seven days; last four puffs 30 minutes before TDI) was administered for seven days before the inhalation challenge with TDI (0.010 to 0.015 ppm for 10 to 30 minutes) to each subject, according to a single-blind study design. When the subjects received no treatment, FEV1 markedly decreased and airway responsiveness increased after exposure to TDI. By contrast, when the subjects were treated with dexamethasone-isonicotinate, FEV1 decreased significantly less, but airway responsiveness still significantly increased after exposure to TDI. These results suggest that aerosolized dexamethasone isonicotinate may be used in the prophylaxis of TDI-induced late asthmatic reactions.
Adult↗
Fatal asthma in a young patient with severe bronchial hyperresponsiveness but stable peak flow records.
We report the sudden death of a 16 yr old boy with asthma. At presentation, the patient had symptoms of active asthma, mild bronchoconstriction, severe airway hyperresponsiveness to methacholine, and increased variability of peak expiratory flow records. After the patient was placed on inhaled beclomethasone (1 mg b.i.d preceded by inhaled fenoterol 0.4 mg b.i.d) he rapidly felt better, lung function improved, but airway responsiveness remained severe. Four months later, on the day he died, he was well until a fatal attack of asthma occurred around midnight without identifiable precipitating factors. Taken to hospital, he was dead on arrival. Necroscopy and microscopy showed the characteristic features of asthma death. This case report suggests that; a) asthma death may occur suddenly and unexpectedly; b) asthma death may not be prevented by long-term treatment with high-dose inhaled beclomethasone; c) severe bronchial hyperresponsiveness, even in the presence of stable peak flow records, may identify asthmatic patients at risk of sudden death.
Adolescent↗
[Non-allergic factors of bronchial asthma].
The functional characteristic of all forms of asthma is the airway hyperresponsiveness to several stimuli. Airway hyperresponsiveness is always present in current asthmatics and can be also documented in some subjects during the symptom-free periods. The mechanisms of the spontaneous or induced increases of airway hyperresponsiveness are probably different from those responsible for stable airway hyperresponsiveness. The transitory increases in airway hyperresponsiveness are associated with an acute inflammatory response of the bronchial mucosa, whereas airway inflammation is not a constant finding in subjects with stable airway hyperresponsiveness. The mechanisms involved in the latter condition might be a functional and/or structural derangement of bronchial epithelium, a functional or structural alteration of airway smooth muscle or alteration in the function of the autonomic nervous system.
Asthma↗
Neutrophils and asthma.
The importance of inflammation in asthma has been recognized for a long time and recently proved in man and animal models. All inflammatory cells are probably involved in exacerbations of asthma. Neutrophils in particular are present in the airways during and after the spontaneous asthma attacks in man and during asthmatic reactions and airway hyperresponsiveness induced experimentally in man and animals. Depletion of neutrophils prevents these effects and repletion with neutrophils reconstitutes them. Moreover, the supernatant from stimulated human neutrophils causes transient hyperresponsiveness. However, neutrophils are not increased in stable asthmatics with hyperreactive airways and are not involved in airway hyperresponsiveness induced experimentally in some animals (e.g. guinea-pigs). The studies reviewed suggest that neutrophils may be involved in the transient increases of airway responsiveness associated with exacerbations of asthma, but not in the long-lasting hyperresponsiveness of stable asthmatics.
Animals↗
Bronchial epithelium and asthma.
The bronchial epithelium has a number of mechanical functions, including mucociliary clearance and protection against noxious agents. It may also modulate the function of the underlying smooth muscle by metabolism and regulation of mediators and the production of relaxant or constrictor substances, and regulate the activation and differentiation of lymphocytes and mast cells by releasing chemotactic factors and cytokines. It is possible that epithelial structural and functional abnormalities may lead via several mechanisms to increased bronchial responsiveness in asthmatic subjects.
Asthma↗
Airway smooth muscle biochemistry and asthma.
The contractile properties of muscle cells are related to the molecular structure of myosin. The molecular structure and the antigenicity of myosin isoforms is different in skeletal, cardiac, and smooth muscle. We investigated whether different isoforms of myosin heavy chains are present in smooth muscle from human lungs. We observed that the distribution of three isoforms of smooth muscle myosin heavy chains is different in airways compared to pulmonary arteries, and in central airways and arteries compared to lung parenchyma. We also observed that asthmatic subjects have a similar distribution, but different immunoreactivity of myosin heavy chains in bronchial smooth muscle compared to normal subjects. These data suggest that changes in the contractile properties of smooth muscle in human lungs may be associated with changes in myosin heavy chain isoforms.
Actins↗
Pathology of bronchial asthma and animal models of asthma.
We reviewed studies on pathology of status asthmaticus, asymptomatic asthma, and of animal models developed to study the pathogenesis of asthma. In status asthmaticus airway occlusion by mucous plugs, desquamed epithelium, goblet cell hyperplasia, submucosal glands hypertrophy, increased smooth muscle, basal membrane thickening, inflammatory infiltration of the bronchial mucosa are observed, together with focal areas of alveolar wall destruction in lung parenchyma. At variance with active asthma, in which almost invariably inflammatory cells infiltrate the mucosa, only scarce airway inflammation is reported in asthmatics between attacks. The majority of the animal models developed so far have been addressed to investigate the mechanism of the transient hyperreactivity that is associated with exacerbations of asthma, while little information is available on the structure-function relationship on long-lasting hyperresponsiveness.
Airway Obstruction↗
Steroid and non-steroid anti-inflammatory agents in asthma.
Anti-inflammatory steroids are the principal agents for the treatment of asthma. Systemic corticosteroids are recommended for the treatment of acute episodes of asthma, whereas inhaled steroids should be used in the long-term prophylaxis of asthma. Because of their side-effects, there is a need for additional research and development of steroids without systemic activity, and/or other anti-inflammatory agents for use in the long-term prophylaxis of asthma.
Administration, Inhalation↗
Dose-dependent inhibitory effect of inhaled beclomethasone on late asthmatic reactions and increased responsiveness to methacholine induced by toluene diisocyanate in sensitised subjects.
To determine whether inhaled beclomethasone, both at low and at high doses, inhibits late asthmatic reactions and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied 9 sensitised subjects. Low dose beclomethasone (200 micrograms bid), high dose beclomethasone aerosol (1000 micrograms bid), and placebo were administered for 7 days before TDI inhalation challenge to each subject, according to a double-blind, crossover study design. The washout period between the treatments was at least 1 week. When the subjects were treated with placebo, forced expiratory volume in 1 sec (FEV1) markedly decreased after exposure to TDI. By contrast, high dose beclomethasone prevented the late asthmatic reaction and the low dose partially inhibited the reaction. With placebo the mean (+/- SE) value of FEV1 4 h after exposure to TDI was 2.6 +/- 0.17 L, which went to 3.3 +/- 0.12 after low dose beclomethasone, and to 3.5 +/- 0.15 L after high dose of beclomethasone (significant difference in the decrease of FEV1 in the 8 h after exposure to TDI, between treatments: F = 9.87, (P less than 0.001), After treatment with placebo or with low dose beclomethasone, airway responsiveness to methacholine increased 8 h after exposure to TDI. With placebo, the PD20 decreased from 0.66 mg (Geometric Standard Error of the Mean [GSEM], 1.38) to 0.18 mg (GSEM, 1.46); with low dose inhaled beclomethasone, the PD20 decreased from 0.93 mg (GSEM, 1.42) to 0.36 mg (GSEM, 1.63).(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
Pathogenesis of bronchial hyperresponsiveness.
In asthmatic subjects, the degree of bronchial hyperresponsiveness correlates with the severity of asthma and the amount of treatment required to control asthma. Both in normal and in asthmatic subjects, the degree of airway responsiveness may increase after viral infections, exposure to oxidant pollutants and allergens or sensitizing agents; however, airway hyperresponsiveness is quite stable in the absence of exposure to inflammatory stimuli, suggesting that there are at least two components in airway hyperresponsiveness: a transient component, caused by airway inflammation, and a long-lasting one, unrelated to exposure to acute inflammatory stimuli, which is hypothesized to be due to changes in the autonomic innervation or in the smooth muscle itself.
Animals↗
Fatal asthma in a subject sensitized to toluene diisocyanate.
We report the case of a 43-yr-old car painter who died within 1 h of exposure to a polyurethane paint in the workplace. A diagnosis of asthma induced by toluene diisocyanate (TDI) had been established 6 yr before, when he underwent inhalation challenges with carbachol and with TDI. The subject had airway hyperresponsiveness to carbachol (PD20FEV1 carbachol = 0.32 mg; normal value greater than 1.0 mg) and developed an early and long-lasting asthmatic reaction after exposure to TDI in the laboratory. Although it was recommended that he change his job or stop using paints containing isocyanates, he continued to work as a car painter, taking antiasthmatic drugs both at work and at home to control asthma symptoms. On Monday, October 6, 1986, at 11:30 A. M., he developed a severe attack of asthma while he was mixing the 2 components of a polyurethane paint. Taken to hospital, he was dead on arrival. Autopsy showed no evidence of cardiac or brain disease; lungs were overinflated, the cut surface showed grey glistening mucous plugs in in the airways. Histologic examination showed denudation of airway epithelium and thickening of the basement membrane with infiltration of the lamina propria by polymorphonuclear leukocytes, mainly eosinophils, and diffuse mucous plugging of bronchioles. Bronchial smooth muscle appeared hyperplastic and disarrayed, and lung parenchyma showed focal areas of alveolar destruction adjacent to areas of perfectly intact alveolar walls.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Occupational asthma due to isocyanates.
162 subjects who had been exposed to isocyanates, who had developed symptoms during the exposure period, or in the evening or night and, therefore, had a history compatible with isocyanate-induced asthma, were studied with inhalation challenge testing to isocyanates (toluene diisocyanate and methylene diphenyl diisocyanate) and methacholine, because they were suspected of having occupational asthma. None of these subjects had symptomatic asthma before employment. The diagnosis of occupational asthma was delayed (duration of symptoms before diagnosis: 3.9 +/- 0.4 yrs). Isocyanate-asthma documented by a positive inhalation challenge to isocyanates was present in 57.4% of the subjects. A higher degree of airway responsiveness to methacholine was present in subjects with a positive isocyanate inhalation challenge compared to subjects with a negative challenge (Gmean and GESM: 0.407 (1.14) vs 0.942 (1.14) mg). The majority of the subjects complained of shortness of breath and cough. The low proportion of atopic subjects (21.5%) and of smokers (7.5%), and the high proportion of subjects with the late component in the asthmatic reaction (71%) appear to be common features in this disease.
Adult↗