Bronchial hyperresponsiveness, airway inflammation and occupational asthma induced by toluene diisocyanate.
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Animals↗
Biomedical subjects
L M Fabbri
Publications and source records attributed to L M Fabbri.
Prostacyclin activates tachykinin release from capsaicin-sensitive afferents in guinea-pig bronchi through a ruthenium red-sensitive pathway.
1. We have investigated the ability of prostacyclin (PGI2) to contract guinea-pig isolated bronchi and the possible involvement of capsaicin-sensitive primary afferents in the response to PGI2. 2. PGI2 (0.1-100 microM) produced concentration-dependent contractions of the guinea-pig isolated bronchi. In vitro capsaicin desensitization (10 microM for 30 min followed by washing) significantly reduced the PGI2-induced contraction at all concentrations tested. A capsaicin-resistant component of contraction (40-60% of the overall response) was also evident. 3. Ruthenium red (3 microM), an inorganic dye which acts as a selective functional antagonist of capsaicin, significantly decreased PGI2-induced contractions, without affecting the response to substance P, neurokinin A or acetylcholine. 4. MEN 10, 207, (Tyr5, D-Trp6,8,9, Arg10)-neurokinin A (4-10) (3 microM), a selective antagonist of NK2-tachykinin receptors, significantly decreased PGI2-induced contractions and neurokinin A-induced contractions, without affecting the response to acetylcholine. 5. The effect of ruthenium red and MEN 10,207 on the one hand, and that of ruthenium red and capsaicin on the other was non additive. 6. These results indicate that PGI2-induced contraction of the guinea-pig isolated bronchi involves two distinct mechanisms, one of which involves transmitter (tachykinins) release from peripheral endings of capsaicin-sensitive primary afferents. In as much as PGI2-activation of primary afferents is sensitive to ruthenium red, we suggest that PGI2 shares a common mechanism of tachykinin release with that activated by capsaicin.
Animals↗
Increase in numbers of CD8 positive lymphocytes and eosinophils in peripheral blood of subjects with late asthmatic reactions induced by toluene diisocyanate.
Occupational asthma induced by toluene diisocyanate (TDI) shares several features with allergic asthma, but the mechanism of action of TDI is poorly understood. Ten sensitised subjects, previously shown to develop a dual or late asthmatic reaction after inhaling TDI were examined. In each subject, forced expiratory volume in one second (FEV1) was measured and venous blood was taken before, and 30 minutes and eight, 24, 48, and 72 hours after exposure to TDI (0.005-0.015 ppm for 10-30 minutes). Filtered air was used as a control. Differential leucocyte counts were determined and phenotypic analysis was performed by immunofluorescence on mononuclear cells using monoclonal antibodies (anti-CD3, anti-CD4, anti-CD8, and anti-HLA-DR). Five subjects developed a dual asthmatic reaction and five had a late reaction. Percentage of CD8 positive lymphocytes increased significantly eight hours after exposure to TDI (from 27 +/- 3 (SEM) % to 42.1 +/- 5%) in the subjects with an isolated late reaction. A delayed significant further increase in suppressor/cytotoxic T lymphocytes was seen in seven of the 10 subjects 48 hours after active exposure (from 27 +/- 2% to 42 +/- 4.8%), irrespective of the type of asthmatic reaction developed after exposure to TDI. Eosinophil percentage increased from 2.5% +/- 1.0 to 6.4% +/- 1.2 24 hours after exposure to TDI and the increase was sustained for up to 48 hours (4.7 +/- 1.1%). No significant variations of FEV1 or cell percentages were seen in the controls. In conclusion, the events triggered by exposure to TDI in sensitised subjects included changes in lung function and systemic effects which lasted longer than bonchoconstriction and concerned suppressor/cytotoxic lymphocytes and eosinophils. These results suggest that TDI induced late asthmatic reactions may be associated with an immunological response to TDI or to its products.
Adult↗
Late asthmatic reactions, airway inflammation and chronic asthma in toluene-diisocyanate-sensitized subjects.
To determine the importance of airway inflammation for exacerbation and prognosis of asthma induced by toluene diisocyanate (TDI), we first examined sensitized subjects during asthmatic reactions induced by exposure to TDI in the laboratory. We observed that late and dual, but not early, asthmatic reactions induced by TDI are accompanied by a transient increase of airway responsiveness, bronchoalveolar neutrophilia followed by eosinophilia and by an increase of LTB4 and albumin in bronchoalveolar lavage fluid. All these effects were prevented by pretreatment with prednisone. In addition, we examined the lung pathology of 1 sensitized subject who died after exposure at work. The pathologic features of fatal asthma induced by TDI and of chronic asthma induced by TDI suggest the importance of inflammation for the exacerbation and prognosis of the disease.
Asthma↗
Quantitative structural analysis of peripheral airways and arteries in sudden fatal asthma.
The peripheral airways and the adjacent muscular pulmonary arteries were studied by morphometric methods in the autopsy lungs of six asthmatic subjects who died suddenly during an asthma attack, and they were compared with those of six control subjects who died of other causes and had no history of respiratory diseases. Bronchioles of asthmatic subjects had an increased amount of lumen occlusion (p less than 0.01), smooth muscle thickness (p less than 0.001), and inflammatory infiltrate (p less than 0.001), and both mononuclear cells and eosinophils contributed to this increased inflammation. The muscular pulmonary arteries adjacent to occluded and inflamed bronchioles did not have the morphologic features of chronic hypoxia, as shown by the normal medial and intimal thickness, but they had an important inflammatory process in their walls that was particularly marked at sites adjacent to airways. Although the functional significance of these findings is unknown, they may be responsible in part for the gas exchange abnormalities observed in acute severe asthma.
Adolescent↗
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↗
Airway inflammation during late asthmatic reactions induced by toluene diisocyanate.
To determine the importance of airway inflammation for the development of late asthmatic reactions, we examined sensitized subjects during late asthmatic reactions induced by exposure to toluene diisocyanate (TDI) in the laboratory. Late asthmatic reactions are associated with a transient increase of bronchial responsiveness and, at the same time, with an increase of neutrophils followed by eosinophils, and of LTB4 and albumin in bronchoalveolar lavage fluid. Late asthmatic reactions, increased bronchial responsiveness, and increase of neutrophils, eosinophils, LTB4, and albumin concentration in bronchoalveolar lavage induced by exposure to TDI are all prevented by pretreatment with prednisone but not with the nonsteroidal anti-inflammatory agent indomethacin. Aerosolized steroids (beclomethasone and dexamethasone isonicotinate) completely inhibit late asthmatic reactions induced by TDI, whereas theophylline has a partial, and verapamil, ketotifen, and cromolyn have no protective effect. These results suggest that late asthmatic reactions induced by TDI may be caused by airway inflammation, and that anti-inflammatory steroids should be recommended in the prophylaxis of TDI asthma.
Asthma↗
Late asthmatic reactions, airway inflammation and chronic asthma in TDI sensitized subjects.
Sensitized subjects may develop symptoms of asthma after exposure to isocyanates in their place of work. After challenge with isocyanates in the laboratory, sensitized subjects develop immediate, late and dual asthmatic reactions. We speculated that toluene diisocyanate (TDI) might cause late asthmatic reactions and increase bronchial responsiveness by causing an acute inflammatory reaction in the airways, and that airway inflammation may be responsible for persistence of occupational asthma induced by isocyanates. To test these hypotheses, we examined sensitized subjects during asthmatic reactions induced by exposure to toluene diisocyanate in the laboratory. We observed that late and dual, but not early, asthmatic reactions are associated with a transient increase of bronchial responsiveness which is associated with an acute inflammatory reaction of the airways characterized by an increase of neutrophils followed by eosinophils, by an increase of leukotriene B4 and albumin in bronchoalveolar lavage fluid, and that all these effects are inhibited by steroids. Longitudinal studies suggest that the majority of subjects with occupational asthma continue to have persistent asthma months and years after the cessation of exposure, and the results of our studies combined with the results of studies performed by others suggest that the persistence of asthma may be related to the persistence of airway inflammation.
Asthma↗
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↗
Evidence that toluene diisocyanate activates the efferent function of capsaicin-sensitive primary afferents.
Isocyanates are an important cause of occupational asthma. The mechanism of isocyanate-induced asthma is still unknown. To determine whether toluene diisocyanate stimulates the 'efferent' function of peripheral endings of capsaicin-sensitive sensory nerves, we investigated the effect of toluene diisocyanate in the rat isolated urinary bladder, a preparation in which the action of capsaicin has been well characterized. Toluene diisocyanate (0.03-3 mM) produced a concentration-dependent contraction of the bladder strips. Its maximal effect was about 50% of the response to capsaicin (1 microM). Previous exposure of the strips to capsaicin followed by washing out produced complete unresponsiveness, both to the first exposure to toluene diisocyanate and to a second exposure of capsaicin. Further, the response to both toluene diisocyanate and capsaicin was completely prevented by extrinsic bladder denervation, achieved by bilateral removal of pelvic ganglia (72 h before). Repeated exposure of the rat bladder to toluene diisocyanate reduced the capsaicin-evoked release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI), taken as biochemical marker of activation of these sensory nerves. These experiments provide the first evidence that toluene diisocyanate activates directly or indirectly the efferent function of capsaicin-sensitive primary sensory nerves.
Animals↗
Effect of antiasthma drugs on asthmatic reactions induced by toluene diisocyanate in sensitized subjects.
To determine the effect of antiasthma drugs on asthmatic reactions and airway inflammation, we studied several groups of sensitized subjects treated with active drugs or placebo before and after exposure to toluene diisocyanate in the laboratory. We observed that the steroidal anti-inflammatory agent prednisone, but not the nonsteroidal anti-inflammatory agent indomethacin, inhibits the late (but not the early) asthmatic reactions induced by TDI. Prednisone also inhibits the increase of bronchial responsiveness and the increase of neutrophils, eosinophils, and albumin in bronchoalveolar lavage fluid that are associated with late asthmatic reactions induced by exposure to TDI. Beclomethasone has a dose-dependent inhibitory effect on TDI-induced late asthmatic reactions, whereas theophylline has a partial inhibitory effect on both early and late asthmatic reactions, and verapamil, ketotifen, cromolyn. Beta 2-adrenergic agonists have variable effects: salbutamol has no effect on early and late asthmatic reactions by itself, but it potentiates the inhibitory effect of low doses of beclomethasone. Broxaterol inhibits early asthmatic reactions, but has no effect on the late asthmatic reactions and the associated inflammatory response. These results suggest that, in sensitized subjects, late asthmatic reactions induced by toluene diisocyanate can be prevented by steroidal anti-inflammatory agents, whereas early asthmatic reactions may be prevented either by an association of inhaled steroids and beta-adrenergic agonists, or by beta-adrenergic agonists (e.g., broxaterol) with more complex mechanisms of action.
Adrenergic beta-Agonists↗
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↗
Pharmacological modulation of the contractile response to toluene diisocyanate in the rat isolated urinary bladder.
1. Toluene diisocyanate produced concentration-dependent contractions of the rat isolated urinary bladder. 2. The contractions were tetrodotoxin-resistant and were abolished by previous exposure of the strips to capsaicin. 3. Indomethacin (5 microM) and ruthenium red (30 microM) inhibited toluene diisocyanate-induced contractions. Responses expressed as a percentage of the response obtained with substance P, 30 nM, were respectively 141.6 +/- 24.8% and 20.1 +/- 5.1% in control and indomethacin-treated strips (P less than 0.005); 123.0 +/- 30.2% and 14.0 +/- 6.5% in control and ruthenium red-treated strips (0.01 less than P less than 0.05). 4. These results suggest that toluene diisocyanate-induced contractions of the rat isolated bladder are the result of the release of cyclo-oxygenase products which may act by activating the capsaicin receptor.
Animals↗
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↗
Airway inflammation and late asthmatic reactions.
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Asthma↗
Increased bronchial responsiveness in primary and secondary Sjögren's syndrome.
We examined one group of 33 patients with primary Sjögren's syndrome, one group of 17 patients with secondary Sjögren's syndrome, i.e. associated with other connective tissue diseases, and one group of 14 patients with connective tissue diseases but without Sjögren's syndrome. In each patient we obtained chest radiographs and measured lung volumes, carbon monoxide diffusing capacity and airway responsiveness to methacholine. We observed no difference in chest radiograph abnormalities, in lung volumes and in carbon monoxide diffusing capacity among the three groups. However, we found a slight but significant increase of bronchial responsiveness in patients with primary and secondary Sjögren's syndrome compared with patients with connective tissue disorders but without Sjögren's syndrome. Thus PD20FEV1 methacholine was 1.07 mg (1.2) (geometric mean and GSEM) in primary Sjögren's syndrome, 0.91 mg (1.4) in secondary Sjögren's syndrome (NS), and 2.24 mg (1.09) in patients with connective tissue diseases but without Sjögren's syndrome (t = 2.59 and t = 2.8, both p less than 0.05, vs primary and secondary Sjögren's syndrome, respectively). These results show that some patients with Sjögren's syndrome have mild bronchial hyperresponsiveness, which may be related to the specific airway abnormalities of this disease.
Bronchial Provocation Tests↗
Clinical guidelines and indications for bronchoalveolar lavage (BAL): bronchial asthma.
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Asthma↗
Clinical guidelines and indications for bronchoalveolar lavage (BAL): chronic bronchitis and emphysema.
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Bronchitis↗