Low molecular weight pollutants and asthma: pathogenetic mechanisms and genetic factors.
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Air Pollutants↗
Biomedical subjects
M Saetta
Publications and source records attributed to M Saetta.
CD8 T-cell clones producing interleukin-5 and interferon-gamma in bronchial mucosa of patients with asthma induced by toluene diisocyanate.
OBJECTIVES: The aims of the present study were to determine whether specific in vivo stimulation of asthmatics sensitized with toluene diisocyanate (TDI) induces the activation of T lymphocytes in bronchial mucosa and to characterize their phenotype and cytokine secretion profile. METHODS: Bronchial biopsies from two subjects with occupational asthma due to TDI were obtained 48 h after an asthmatic reaction induced by an inhalation challenge with TDI and after three months of no exposure to TDI, at the time when the subjects had recovered from their asthma. The fragments of bronchial mucosa were cultured in the presence of interleukin-2 so that the in vivo activated T cells present in the tissue would expand, and T blasts were then cloned under limiting dilution conditions. RESULTS: From the two 48-h specimens, 65 and 63 T-cell clones were obtained. Most of the clones exhibited the CD8 phenotype (82 and 83%). All of the CD8 clones produced interferon-gamma and 44% produced interleukin-5, but only 6% secreted interleukin-4 as well. Three months after the cessation of exposure, growing T cells could not be recovered from bronchial biopsies cultured in interleukin-2. CONCLUSIONS: The results suggest that, in sensitized subjects, exposure to TDI induces the activation of a subset of CD8 lymphocytes producing interferon-gamma and interleukin-5.
Adult↗
Structural aspects of airway inflammation in COPD.
Descriptions of pathology of chronic bronchitis in the past have been mainly focused on mucous gland hypertrophy, since this was considered the morphologic basis of the disease, but more recent studies have suggested a pathogenetic role for airway inflammation in subjects with chronic bronchitis. In the present review, we briefly summarize the results of these latter studies, which describe the nature of airway inflammation and the state of activation of inflammatory cells in the bronchial mucosa of subjects with chronic bronchitis.
Bronchitis↗
Toluene diisocyanate-stimulated release of arachidonic acid metabolites in the organ bath from guinea-pig airways.
This study was designed to evaluate whether metabolites of arachidonic acid play a role in the contractile response to toluene diisocyanate in isolated guinea pig airways. In control experiments we collected the supernatant from an organ bath over a time period of 2 h, after the addition of toluene diisocyanate (100 and 300 microM), and after the addition of toluene diisocyanate (300 microM) in the presence of indomethacin (5 microM). We measured prostaglandin E2, 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, thromboxane B2, leukotriene B4, leukotriene C4/D4/E4/F4 by radioimmunoassays. Levels of prostaglandin F2 alpha and 6-keto-prostaglandin F1 alpha increased significantly after addition of toluene diisocyanate in the absence of indomethacin. These results suggest that prostaglandins are involved in toluene diisocyanate-induced contractions in guinea-pig airways.
Animals↗
The effect of compound 48/80 on contractions induced by toluene diisocyanate in isolated guinea-pig bronchus.
We have investigated the ability of compound 48/80 and of histamine H1 and H2 receptor antagonists to inhibit toluene diisocyanate-induced contractions in isolated guinea-pig bronchi. Compound 48/80 (100 micrograms/ml) significantly inhibited toluene diisocyanate-induced contractions. By contrast, the two histamine H1 and H2 receptor antagonists, chlorpheniramine (10 microM) and cimetidine, (10 microM) did not affect toluene diisocyanate-induced contractions, but significantly inhibited contractions induced by exogenously applied histamine (100 microM) and by 48/80. We investigated which mechanisms 48/80 used to inhibit toluene diisocyanate-induced contractions, paying particular attention to the possible involvement of capsaicin-sensitive primary afferents. In vitro capsaicin desensitization (10 microM for 30 min followed by washing) significantly reduced compound 48/80-induced contractions. A capsaicin-resistant component of contraction was also evident. Ruthenium red (3 microM), an inorganic dye which acts as a selective functional antagonist of capsaicin, did not affect 48/80-induced contraction. MEN 10,207 (Tyr5,D-Trp6,8,9,Arg10)-neurokinin A (4-10) (3 microM) a selective antagonist of NK2-tachykinin receptors significantly reduced 48/80-induced contractions. These results show that compound 48/80 inhibits toluene diisocyanate-induced contractions in isolated guinea-pig bronchi. It is likely that two mechanisms are involved in the inhibition: (1) the release of mediators other than histamine by mast cells, (2) an effect of 48/80 on sensory nerves.
Animals↗
Occupational asthma and extrinsic alveolitis due to isocyanates: current status and perspectives.
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Alveolitis, Extrinsic Allergic↗
Effect of bumetanide on toluene diisocyanate induced contractions in guinea pig airways.
BACKGROUND: The loop diuretic frusemide has been shown to inhibit the bronchoconstrictor response to exercise, inhaled allergen, distilled water, adenosine, and sodium metabisulphite. Toluene diisocyanate contracts smooth muscle by activating capsaicin sensitive nerves and causes asthma that shares many features with allergen induced asthma. METHODS: The study was designed to assess the effect of two loop diuretics, bumetanide (10 and 100 microM) and frusemide (100 microM), on smooth muscle contraction induced by toluene diisocyanate (0.03-1000 microM) in guinea pig airways with and, in the case of bumetanide, without epithelium. The effect of bumetanide on the response to acetylcholine, neurokinin A, and electrical field stimulation in guinea pig bronchial smooth muscle rings was also examined. RESULTS: Bumetanide (10 and 100 microM) had no effect on toluene diisocyanate induced contraction whether airway epithelium was present or not. Frusemide (100 microM) caused no significant inhibition of toluene diisocyanate induced contraction (mean reduction on the entire curve 25%). Bumetanide inhibited non-adrenergic, non-cholinergic contraction induced by electrical field stimulation of bronchi pretreated with atropine (1 microM) and indomethacin (5 microM) and this inhibition was inversely related to the frequency of stimulation, suggesting that bumetanide may be inhibiting transmitter release at the prejunctional level. Bumetanide and frusemide did not inhibit the responses to exogenous acetylcholine (0.1 microM) or neurokinin A (1 nM). CONCLUSIONS: Bumetanide and frusemide in doses that are known to inhibit non-adrenergic, non-cholinergic contraction due to electrical field stimulation failed to inhibit the response to toluene diisocyanate in guinea pig airways.
Acetylcholine↗
Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis.
To examine the nature and the degree of leukocyte infiltration and to determine the state of activation of cells in bronchial mucosa of subjects with chronic bronchitis, bronchoscopy was performed in 10 subjects with a history of cigarette smoking and chronic sputum production and in six normal nonsmoking control subjects. Lobar bronchial biopsies were examined using histochemical and immunohistochemical techniques. Subjects with chronic bronchitis had an increased number of total leukocytes (CD45 positive cells), both in the epithelium and in the lamina propria, than did the control subjects (p < 0.05), whereas the numbers of neutrophils, eosinophils, and mast cells were similar in the two groups. There was a significant increase in the numbers of macrophages (p < 0.01) and of T-lymphocytes (CD3 positive cells) (p < 0.05) in the lamina propria of chronic bronchitics, whereas the relative proportions of CD4 and CD8 positive cells were similar in the bronchitics and the control subjects. Subjects with chronic bronchitis also had an increased expression of markers of lymphocyte activation, i.e., an increased number of interleukin-2 receptor positive cells (CD25 positive cells) (p < 0.05) and an increased number of very late activation antigen (VLA-1) positive cells (p < 0.05). In conclusion, the present study provides evidence for mononuclear cell infiltration and for T-cell activation in bronchial mucosa of subjects with chronic bronchitis, supporting the involvement of these cells in the pathogenesis of the disease.
Adult↗
Mast cells in the airway mucosa and rapid development of occupational asthma induced by toluene diisocyanate.
We examined lobar bronchial biopsies taken from 18 subjects with occupational asthma induced by toluene diisocyanate (TDI) and from nine nonasthmatic control subjects. Two groups of asthmatics were identified on the basis of the duration of exposure to TDI before the onset of symptoms of asthma. Group A (n = 8) developed asthma after 2.4 +/- 0.4 yr of exposure to TDI, and Group B (n = 10) developed asthma after 21.6 +/- 3.1 yr of exposure to TDI. Both groups of asthmatic subjects had increased numbers of inflammatory cells in the airway mucosa compared with subjects in the nonasthmatic control group. Comparison between Groups A and B showed that subjects who developed asthma after short-term exposure had a significantly increased number of mast cells both in epithelium and in lamina propria than did subjects who developed asthma after long-term exposure to TDI (p < 0.01). Interestingly, the numbers of mast cells both in the epithelium (rs = -0.52, p < 0.05) and in the lamina propria (rs = -0.81, p < 0.001) were inversely correlated with the length of exposure to TDI before the onset of asthma. In conclusion, subjects who develop asthma after short-term exposure to TDI have an increased number of mast cells in the airway mucosa, suggesting that these cells may be associated with individual susceptibility differences to offending agents.
Adult↗
Effects of inhaled beclomethasone on airway responsiveness in occupational asthma. Placebo-controlled study of subjects sensitized to toluene diisocyanate.
We investigated the effect of 5 months of treatment with inhaled beclomethasone dipropionate (BDP) on the airway responsiveness to methacholine (PD20 FEV1) and to toluene diisocyanate (TDI) in 15 sensitized asthmatic subjects who had been removed from occupational exposure to TDI. After the diagnosis was established by a positive inhalation challenge with TDI, each subject was removed from occupational exposure to isocyanates and treated with either BDP (1 mg twice per day, n = 7) or placebo (n = 8) for 5 months. The study was double blind for parallel groups. P20 FEV1 methacholine was measured before and three times during treatment and then at 6 months, that is, 4 wk after cessation of treatment. Airway sensitivity to TDI was assessed with specific inhalation challenge before treatment and at 6 months. Beclomethasone reduced the airway hyperresponsiveness to methacholine but did not affect the response to TDI. In fact, in the subjects on BDP, P20 FEV1 increased from 0.145 to 0.485 mg (p < 0.05) after 2 months of treatment. A further increase was observed at 4 and 5 months (0.548 and 0.629 mg, respectively, p < 0.01), and the improvement in nonspecific airway responsiveness was maintained after a 1-month washout period (0.637 mg, p < 0.01). In contrast, in the subjects on placebo, P20 FEV1 did not change significantly. At the end of the study, the severity of asthmatic reactions induced by bronchial challenge with TDI was significantly reduced in both groups, but no differences were observed between placebo and BDP.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Activated T-lymphocytes and eosinophils in the bronchial mucosa in isocyanate-induced asthma.
We have studied the phenotype and activation status of leukocytes in the bronchial mucosa in patients with isocyanate-induced asthma. Fiberoptic bronchial biopsy specimens were obtained from nine subjects with occupational (five toluene- and four methylene diisocyanate-sensitive) asthma, 10 subjects with extrinsic asthma, and 12 nonatopic healthy control subjects. Bronchial biopsy specimens were examined by immunohistology with a panel of monoclonal antibodies and the alkaline phosphatase-antialkaline phosphatase method. There was a significant increase in the number of CD25+ cells (interleukin-2 receptor-bearing cells, presumed "activated" T-lymphocytes; p less than 0.01) in isocyanate-induced asthma compared with that of control subjects. There were also significant increases in major basic protein (BMK-13)-positive (p less than 0.02) and EG2-positive (p less than 0.01) cells that represent total and "activated" eosinophil cationic protein-secreting eosinophils, respectively. In agreement with our previous findings, CD25+ (p less than 0.01), BMK-13 (p less than 0.03), and EG2+ (p less than 0.01) cells were also elevated in extrinsic asthma. No significant differences were observed in the numbers of T-lymphocyte phenotypic markers (CD3, CD4, and CD8) between subjects with asthma (isocyanate-induced and extrinsic) and control subjects. Similarly, no significant differences in immunostaining for neutrophil elastase (neutrophils) or CD68 (macrophages) were observed. The results suggest that isocyanate-induced occupational asthma and atopic (extrinsic) asthma have a similar pattern of inflammatory cell infiltrate. The results support the view that T-lymphocyte activation and eosinophil recruitment may be important in asthma of diverse etiology.
Adult↗
Airway mucosal inflammation in occupational asthma induced by toluene diisocyanate.
We examined the light and electron microscopic structure of lobar bronchial biopsies of nine subjects with occupational asthma induced by toluene diisocyanate (TDI) and of four control nonasthmatic subjects who had never been exposed to TDI. Inflammatory cell numbers were separately assessed in the intact epithelium, in the more superficial layer of the submucosa, and in the total submucosa. Asthmatic subjects had an increased number of inflammatory cells in the airway mucosa compared with control subjects. Eosinophils were significantly increased in all compartments, CD45-positive cells were significantly increased in the epithelium and in the more superficial layer of the submucosa, and mast cells were significantly increased only in epithelium. By electron microscopy eosinophils and mast cells appeared degranulated only in asthmatic patients. In the areas of epithelium that appeared intact by light microscopy, electron microscopy showed that, although the intercellular spaces between columnar cells were similar in asthmatic and control groups, the intercellular spaces between basal cells were significantly wider in patients with asthma. Patients with TDI-induced asthma also had a thicker subepithelial reticular layer, where immunohistochemistry showed the presence of collagen III. In conclusion, in patients with asthma induced by TDI, the airway mucosa shows pathologic features, such as inflammatory cell infiltrate and thickening of subepithelial collagen, similar to those described in atopic asthma.
Adolescent↗
Effect of cessation of exposure to toluene diisocyanate (TDI) on bronchial mucosa of subjects with TDI-induced asthma.
The effect of cessation of exposure to toluene diisocyanate (TDI) was studied in six patients with TDI-induced asthma, proved by a positive inhalation challenge with TDI. Bronchial challenges with TDI and methacholine were performed, and lobar bronchial biopsies were taken at diagnosis and 6 months later, after cessation of exposure. Biopsies from four nonasthmatic control subjects were also examined. At diagnosis, asthmatic subjects had thickened reticular basement membrane (p less than 0.05) and increased numbers of mononuclear cells (p less than 0.05) and eosinophils (p less than 0.05) in the lamina propria when compared with control subjects. Electron microscopy showed degranulation of eosinophils and mast cells in asthmatics. Six months after cessation of exposure, the thickness of reticular basement membrane was significantly reduced compared with that at diagnosis (p less than 0.05), and it decreased to values similar to those of control biopsies. Inflammatory cell numbers in bronchial mucosa of asthmatic subjects did not change significantly 6 months after removal from exposure, and degranulation of eosinophils and mast cells was still present. At the end of the study, airway hyperresponsiveness to methacholine and/or sensitivity to TDI persisted in most of the asthmatic patients despite the cessation of exposure and the disappearance of asthmatic symptoms. In conclusion, in patients with occupational asthma induced by TDI, the avoidance of exposure to the sensitizing agent for 6 months is able to reverse the reticular basement membrane thickening in the bronchial mucosa, but the inflammatory cell infiltrate, the specific sensitivity to TDI, and the nonspecific airway hyperreactivity may persist.
Adult↗
The effect of phosphoramidon and epithelium removal on toluene diisocyanate-induced contractions in guinea-pig bronchi.
To evaluate the role of airway neutral endopeptidase 24.11 (NEP) and epithelium removal in the contraction of airway smooth muscle in response to toluene diisocyanate (TDI), we studied the effects of the NEP inhibitor, phosphoramidon, on TDI-induced contractions of guinea-pig bronchial rings with intact epithelium and without epithelium. In preparations with intact epithelium, phosphoramidon (10 microM) potentiated the contractile response to TDI (0.3 mM) (mean +/- SEM, 23.7 +/- 2.5% versus 67.9 +/- 10.3%, p less than 0.01). Phosphoramidon also increased TDI-induced contractions in tissues without epithelium (36.9 +/- 4.9% versus 52.5 +/- 7.1%, p less than 0.05). Removal of the epithelium increased the contractile response to TDI (23.7 +/- 2.5% versus 36.9 +/- 4.9%, p less than 0.05). These results demonstrate the response to TDI is increased in epithelium-free compared to intact bronchi and that NEP 24.11 modulates the effects of endogenously released tachykinins by TDI at all of the sites where NEP is found in the airways.
Animals↗
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↗
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↗
Assessment of induced bronchoconstriction in anesthetized cats by the end-inflation occlusion method.
Airway occlusion during constant flow inflation allows rapid determination of frequency-dependence of pulmonary resistance by estimating its extreme values: RL,max (zero frequency) and RL,min (high frequency). RL,max represents the maximum resistance value that can be obtained with the prevailing time constant inequalities and stress relaxation, while RL,min represents the resistance that would be obtained in the absence of time constant inequalities and stress relaxation. In 5 anesthetized, tracheostomized, paralyzed, and artificially ventilated cats, RL,min, RL,max, and static pulmonary elastance (EL,st) have been measured following airway occlusion at the end of constant flow tidal inflations. Measurements were made before and during continuous infusion of increasing doses of serotonin (10-100 micrograms/kg/min IV). The development of intrinsic positive end-expiratory pressure (PEEPi) was also assessed. Cats varied greatly in their responsiveness to serotonin, but RL,min, RL,max, and EL,st increased and PEEPi developed in all cats. Increases in RL,max did not always parallel increases in RL,min but were similar to those in EL,st, suggesting that altered viscoelastic properties of the lung contributed to the increases in RL,max. We conclude that time-constant inequalities, changes in the lung periphery, and hyperinflation probably all contribute to the observed increases in RL,max and will influence conventional methods of measuring RL. Measuring RL,min potentially provides a better method for assessing the reduction in caliber of the conducting airways in isolation.
Airway Obstruction↗