Biomedical subjects

P Boschetto

Publications and source records attributed to P Boschetto.

At least 19 recordsLinked to original sources

PubMed1992

Theophylline inhibits late asthmatic reactions induced by toluene diisocyanate in sensitised subjects.

Toluene diisocyanate (TDI)-induced asthma is a frequent occupational airway disease. To determine whether a calibrated dosage of oral slow-release theophylline inhibits asthmatic reactions and the associated increase of airway responsiveness to methacholine induced by TDI, we examined six asthmatic subjects who developed a late or a dual asthmatic reaction after TDI inhalation challenge. We administered oral slow-release theophylline or placebo to each subject for 7 days according to a double-blind, randomized, cross-over study design. When the subjects received a placebo, TDI caused a late or a dual asthmatic reaction. When the subjects received theophylline. TDI caused significantly reduced late asthmatic reactions. Mean serum theophylline concentrations were within the therapeutic range. Theophylline neither modified the baseline airway responsiveness to methacholine, nor the increase of airway responsiveness to methacholine induced by TDI. These results suggest that slow-release theophylline may improve TDI-induced late asthmatic reactions, but it does not change the baseline airway responsiveness to methacholine and the increase of airway responsiveness to methacholine induced by TDI.

Administration, Inhalation↗

PubMed1992

Increase in vascular permeability produced in rat airways by PAF: potentiation by adrenalectomy.

1. The effect of bilateral adrenalectomy on the sensitivity of blood vessels in rat airways to mediators that increase vascular permeability was examined. 2. An increase in vascular permeability was induced by intravenous platelet activating factor (PAF, 50, 100, 500, 1000 ng kg-1) and measured by quantifying the extravasation of Evans blue dye. 3. PAF consistently increased the amount of Evans blue extravasation in the larynx, trachea, main bronchi and intrapulmonary airways in sham-operated rats. 4. The magnitude of this extravasation was significantly greater in the larynx (P less than 0.05), trachea (P less than 0.05) and main bronchi (P less than 0.05) of the adrenalectomized rats than it was in these tissues of the sham-operated rats. 5. When adrenalectomized rats were given subcutaneous dexamethasone (0.2 mg kg-1 4 h before PAF) the amount of plasma extravasation produced by PAF was decreased to the level of the sham-operated rats. 6. We conclude that adrenalectomy potentiates the increase in airway vascular permeability induced by PAF in rats and that this effect may be due to the depletion of endogenous corticosteroids.

Adrenalectomy↗

PubMed1991

Corticosteroid inhibition of airway microvascular leakage.

We studied the effect of dexamethasone on microvascular leakage (using Evans blue dye as a marker of plasma exudation) induced in rat airways by platelet-activating factor (PAF). Intravenously administered PAF caused a dose-related increase in plasma leakage over the range 0.1 to 1 micrograms/kg. At 500 ng/kg PAF, the response was maximal in the extrapulmonary airways examined with increases in leakage above those in control animals of 312% in the larynx, 295% in the trachea, and 167% in the main bronchi. A maximal response was not achieved in the intrapulmonary airways at the doses of PAF tested: at 1 microgram/kg the increase was 206% above that in control animals. Dexamethasone, given by intraperitoneal injection 24 h and 4 h before PAF at a dose of 0.2 mg/kg on each occasion, partially inhibited leakage induced by PAF (1 microgram/kg) in all airway levels studied by 43 to 65%. At each level the tissue concentration of dye was reduced to a value that was significantly (p less than 0.05) different from either PAF or control values. We also determined whether a high dose (8 mg/kg) of dexamethasone given intraperitoneally would inhibit plasma leakage of dye induced by either PAF or antigen-challenge of sensitized rats. When given 4 h before antigen, dexamethasone completely prevented allergen-induced leakage in the airways showing significant leakage (larynx, trachea, and intrapulmonary airways). Similarly, dexamethasone (4 h before) partially inhibited PAF-induced leakage in the trachea and main bronchi. In summary, in rat airways, both low and high doses of dexamethasone markedly inhibit mediator-induced plasma exudation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Theophylline inhibits early and late asthmatic reactions induced by allergens in asthmatic subjects.

To determine whether oral slow-release theophylline inhibits asthmatic reactions and the associated increase of airway responsiveness to methacholine induced by allergens, we examined six asthmatic subjects who developed a dual asthmatic reactions after allergen bronchoprovocation with Dermatophagoides pteronyssinus or with grass pollen. We gave oral slow-release theophylline and placebo to each subject for seven days in two series of experiments in a double-blind, randomized, crossover study. The individual daily dose of theophylline (4.7 to 16.6 mg/kg/day, divided into two doses) was calculated for each subject by measuring individual theophylline clearance and optimal daily dosage. During treatment with placebo, the subjects developed dual asthmatic reactions, ie, FEV1 decreased from 4.1 +/- 0.17 L before bronchoprovocation to 3.2 +/- 0.14 L at 15 minutes and to 3.2 +/- 0.19 L at seven hours after allergen bronchoprovocation. By contrast, during active treatment FEV1 decreased from 4.2 +/- 0.28 L to 3.9 +/- 0.26 L at 15 minutes, and to 3.8 +/- 0.13 L at seven hours (both cases, P less than .03 compared with placebo). Mean serum theophylline concentration was 13.2 +/- 0.6 mg/L. Although 1 week's treatment with slow-release theophylline did not modify significantly either prechallenge airway responsiveness to methacholine or its increase after allergen inhalation challenge, in five out of six subjects theophylline significantly inhibited the increase of airway responsiveness to methacholine induced by allergens compared to placebo and control day (P less than .05). These results suggest that slow-release theophylline may inhibit allergen-induced asthmatic reactions and the associated increase of airway responsiveness, suggesting some antiinflammatory effects for this drug.

Administration, Oral↗

PubMed1990

Venous blood platelets decrease during allergen-induced asthmatic reactions.

To determine whether circulating platelets alter during asthmatic reactions induced by allergens, we studied nine subjects previously shown to develop an early or dual asthmatic reaction after inhalation challenge with extracts of house dust mite or grass pollen. In each subject, FEV1, circulating platelets and leucocytes were measured before, 15, 30 and 60 min, and 2, 4, 6 and 8 hr after inhalation of allergen and diluent control administered in a single-blind, randomized fashion. The same procedure was repeated in six of the nine subjects after bronchoconstriction induced by methacholine. Each subject developed an early asthmatic reaction after allergen inhalation challenge, which was followed by a late asthmatic reaction in six subjects and by an equivocal late asthmatic reaction in two of them (fall in FEV1 of 15 and 17% respectively). Compared with the control day, circulating platelets significantly decreased during the allergen-induced early asthmatic reaction (P less than 0.025, at 30 min). Platelet counts returned to baseline values within 4 hr and remained steady thereafter both in subjects who did and did not develop a late asthmatic reaction. No changes in platelet counts occurred after bronchoconstriction induced by methacholine. Diurnal increase of leucocyte numbers occurred after challenge with both allergen and diluent control. These results suggest that platelets may be involved in the pathogenesis of allergen-induced asthmatic reactions.

Adolescent↗

PubMed1990

Effect of platelet activating factor on formation and composition of airway fluid in the guinea-pig trachea.

1. We studied the effect of platelet activating factor (PAF) on leakage of albumin, and secretion of fucose (a marker for mucus glycoprotein) and protein into the tracheal lumen of the guinea-pig isolated in situ, and on bioelectric properties and fluxes of mannitol in vitro. We also studied the effect of PAF on mucus secretion in human bronchi in vitro. 2. In guinea-pig, intravenous PAF markedly increased the luminal concentration of protein but did not significantly increase fucose concentrations. Increased albumin leakage (274% above controls at a dose of 50 ng/kg PAF) was associated with the increased luminal content of protein (248% above controls at the same dose of PAF). 3. Leakage of albumin was maximal 10 min after PAF, was significantly reduced by 20 min and had returned to baseline by 30 min. This pattern of leakage could be repeated with successive administrations of PAF. 4. PAF induced small but significant biphasic changes in bioelectric properties in vitro. The initial response was rapid in onset and characterized by maximal increases in short-circuit current (Isc) of 6.5% above controls at 7.5 min and in conductance (G) of 7% at 20 min. Both responses were blocked by the PAF receptor antagonist WEB 2086. Amiloride blocked the increase in Isc. Permeability of the tissue to mannitol (Pmann) was unaltered. The delayed response was characterized by maximal increases in Isc and G of 10% above controls at 60-90 min which were not significantly affected by WEB 2086 or amiloride. Pmann was increased by 38% at 90 min. 5. PAF increased fucose secretion in human bronchi in vitro. 6. Lyso-PAF in vitro caused changes similar to those induced by PAF on bioelectric properties and mucus secretion, but had no significant effects in vivo. 7. Light microscopy showed no evidence of epithelial disruption in animals given intravenous PAF at a dose causing significant albumin transudation. 8. We conclude that PAF increases the protein content of guinea-pig tracheal fluid principally by inducing plasma leakage rather than mucus secretion and that the small changes in ion transport and epithelial conductance may reduce the tendency to epithelial disruption during plasma leakage.

Action Potentials↗

PubMed1990

Leukotriene B4 and late asthmatic reactions induced by toluene diisocyanate.

We investigated whether leukotriene B4 (LTB4) is released from the lungs of sensitized subjects during asthmatic reactions induced by toluene diisocyanate (TDI). We examined three groups of TDI-sensitized subjects, one after no exposure to TDI, the second 8 h after an exposure to TDI that caused an early asthmatic reaction, and the third 8 h after an exposure to TDI that caused a late asthmatic reaction. We analyzed bronchoalveolar lavage (BAL) fluid by reverse-phase high-performance liquid chromatography and by specific radioimmunoassay. The mean concentration of LTB4 was higher [0.31 +/- 0.09 (SE) ng/ml, range 0.15-0.51] in BAL fluid of sensitized subjects who developed a late asthmatic reaction than in BAL fluid of subjects who developed an early asthmatic reaction (0.05 +/- 0.04 ng/ml, range 0-0.224), and no LTB4 was detectable in the control subjects. We also performed BAL 8 h after TDI exposure on four TDI-sensitized late-dual reactors who were on steroid treatment. In this group of subjects no LTB4 was detectable. These results suggest that LTB4 may be involved in late asthmatic reactions induced by TDI.

Adult↗

PubMed1990

Effects of treatment on airway microvascular leakage.

Microvascular leakage, an essential component of inflammation, probably plays a critical role in asthma in producing plasma exudation and thickening of the bronchial mucosa which may underlie airway hyperresponsiveness. Several therapeutic approaches are possible to reduce this leakage, by blocking either the effects or the release of inflammatory mediators which induce the leakage. Drugs with these actions might be too specific to be of therapeutic value if many mediators are involved, as seems increasingly likely. Reduction of blood flow using selective vasoconstrictors is a more attractive approach and alpha 1-adrenoceptor agonists may be of value. Drugs that act directly on endothelial cells are probably the most useful, since they would be effective irrespective of the mechanism of leakage. Corticosteroids probably have this property, but whether beta-agonists or theophylline are clinically effective against airway microvascular leakage is not yet certain. The development of new drugs which can inhibit microvascular leakage is an important therapeutic approach for the future.

Adrenal Cortex Hormones↗

PubMed1989

Plasma exudation. Correlation between Evans blue dye and radiolabeled albumin in guinea pig airways in vivo.

We quantified the tissue exudation and luminal transudation of two plasma markers, Evans blue (EB) dye and [125I]-human serum albumin (HSA), into the airways of the anesthetized guinea pig in response to platelet activating factor (PAF). There was a highly significant correlation between the tissue content of EB and [125I]-HSA in all airways studied. Significant correlation for transudation of the two markers was limited to high rates of plasma leakage. [125I]-HSA was the more sensitive marker for the association between exudation and transudation and the effect of PAF on transudation. EB was the better marker for assessing the relationship between the dose of PAF and plasma exudation.

Animals↗

PubMed1989

Effect of antiasthma drugs on microvascular leakage in guinea pig airways.

We have studied the effect of intravenous epinephrine, albuterol, verapamil, and aminophylline on airway microvascular leakage in guinea pigs. Microvascular leakage was induced by platelet-activating factor (PAF; 50 ng/kg intravenously), which acts directly on venular endothelial cells, and measured by quantifying extravasation of Evans blue (EB) dye. Epinephrine (20 micrograms/kg) inhibited PAF-induced changes in dye leakage in larynx and main bronchi; at 80 and 160 micrograms/kg, significant inhibition was observed in all airways studied. This effect was reversed by phentolamine (2.5 mg/kg) or prazosin (100 micrograms/kg). By contrast, albuterol (20 to 320 micrograms/kg) and aminophylline (12.5 to 50 mg/kg) failed to inhibit dye leakage at any dose studied. Verapamil inhibited PAF-increased leakage in larynx, main bronchi, and intrapulmonary airways at the lowest dose tested (125 micrograms/kg), although inhibition was not dose dependent. These results suggest that the antiedema effect of epinephrine may be due to vasoconstriction rather than to a direct effect on endothelial cell contractility and that neither beta-agonists nor theophylline have an inhibitory effect. The inhibitory effect of epinephrine on airway microvascular leakage may have therapeutic implications for asthma.

Adrenergic alpha-Agonists↗

PubMed1989

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↗

PubMed1989

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↗

PubMed1989

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↗

PubMed1988

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↗

PubMed1988

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↗

PubMed1987

Prednisone inhibits late asthmatic reactions and airway inflammation induced by toluene diisocyanate in sensitized subjects.

To determine the importance of airway inflammation for late asthmatic reactions induced by toluene diisocyanate (TDI), we investigated whether prednisone prevented them [corrected] by modifying the associated airway inflammatory reaction. We measured FEV1 before and at regular intervals after exposure to TDI and performed bronchoalveolar lavage at 8 hours after TDI in two groups of subjects with previously documented late asthmatic reactions, in one group, after no treatment, and in the other group, after treatment with prednisone (50 mg/day for 4 days). After no treatment, each subject developed a late asthmatic reaction, an increase in airway responsiveness, polymorphonuclear leukocytosis, and increased albumin in bronchoalveolar lavage. By contrast, after treatment with prednisone, no subject developed a late asthmatic reaction or an increase in airway responsiveness, and the number of leukocytes and the concentration of albumin were normal in bronchoalveolar lavage. These results suggest that late asthmatic reactions induced by TDI may be caused by airway inflammation and that prednisone may block them [corrected] by inhibiting the inflammatory reaction of the airway induced by TDI in sensitized subjects.

Adult↗

PubMed1987

Bronchoalveolar neutrophilia during late asthmatic reactions induced by toluene diisocyanate.

The mechanism by which late asthmatic reactions are induced by toluene diisocyanate (TDI), a low molecular weight chemical that causes occupational asthma in exposed subjects, is unknown. We investigated whether early and late asthmatic reactions induced by TDI are associated with changes in airway responsiveness to methacholine and airway inflammation as determined by bronchoalveolar lavage. We measured FEV1 before and at regular intervals after exposure to TDI, and performed dose-response curves to methacholine and bronchoalveolar lavage at 8 h after TDI in a group of 6 subjects with late asthmatic reactions and in 6 subjects with only early asthmatic reactions. The same procedure was followed 2 h after TDI in a group of 6 subjects with previously documented late asthmatic reactions and in a group of 6 subjects without any previously documented asthmatic reaction after TDI. In subjects with late asthmatic reactions, neutrophils were increased at both 2 and 8 h, and eosinophils and airway responsiveness were increased only at 8 h. By contrast, neutrophils, eosinophils and airway responsiveness were not increased at 8 h after TDI in subjects with an early asthmatic reaction or at 2 h after TDI in normal control subjects. These results suggest that late asthmatic reactions to TDI, and the associated increase in airway responsiveness, may be caused by airway inflammation.

Asthma↗

PubMed1987

Protective effect of antiasthma drugs on late asthmatic reactions and increased airway responsiveness induced by toluene diisocyanate in sensitized subjects.

To determine whether 4 drugs used in the treatment of asthma inhibit the late asthmatic reaction and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied 24 sensitized subjects divided into 4 groups. Beclomethasone aerosol (1 mg bid), slow-release theophylline (6.5 mg/kg bid), slow-release verapamil (120 mg bid), and cromolyn (20 mg qid via spinhaler), were administered for 7 days, respectively, to 1 of the 4 groups, according to a double-blind, crossover, placebo-controlled study design. When the subjects were treated with placebo, verapamil, or cromolyn, FEV1 markedly decreased and airway responsiveness increased after exposure to TDI. By contrast, beclomethasone prevented the late asthmatic reaction and the associated increase in airway responsiveness to methacholine induced by TDI. Slow-release theophylline partially inhibited both the immediate and the late asthmatic reactions but had no effect on airway hyperresponsiveness to methacholine. These results suggest that only high-dose inhaled steroids can completely block TDI-induced late asthmatic reactions.

Asthma↗