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Notes: To determine whether the measurement of specific markers of inflammatory cells in peripheral blood might be used to detect the inflammatory activity in the airways in asthma induced by toluene diisocyanate (TDI). we measured the levels of eosinophil cationic protein (ECP), histamine and tryplase in peripheral blood before and during inhalation challenge with TDI or methacholine in two groups of subjects who exhibited or did not exhibit an asthmatic reaction after exposure to toluene diisocyanate in the laboratory. When the subjects developed a late asthmatic reaction after exposure to TDI, the\ showed an increase in their ECP serum levels. By contrast, there were no signilicam changes in serum ECP levels after exposure to TDI in the control group or after methacholine challenge in either group. Tryptase levels in serum were not detectable before or during inhalation challenge with TDI or methacholinc. There was no significant increase in plasma histamine levels during inhalation challenge with TDJ or methacholine. These results suggest that eosinophils arc ‘activated’ in subjects who develop a late asthmatic reaction after exposure to TDI and that the measurement of ECP levels in peripheral blood may be a useful marker to monitor airway inflammation.

Notes: To assess the nature and the time–course of the cellular component of airway inflammation induced by isocyanates, we examined nine subjects with occupational asthma induced by toluene– or methylene diphenyl–diisocyanate (TDI, MDI) and four control subjects never exposed to isocyanates. Sputum was induced by inhalation of ultrasonically nebulized hypertonic saline (3–4% NaCl) before and 8, 24, 48 h after inhalation challenge with TDI or MDI. Expectorated samples were incubated with dithiothreitol, washed and cytocentrifuged. Differential cell counts were obtained on slides stained with May–Grünwald–Giemsa. Metachromatic cells (mast cells and basophils) were counted on slides stained with toluidine blue at pH 0.1. One occupational asthmatic exhibited a dual reaction to TDI, two exhibited a single early asthmatic reaction to M DI, six exhibited a late asthmatic reaction to TDI (n= 5) or M DI (n= 1), whereas no reactions were observed in control subjects after TDI challenge. In sensitized subjects eosinophils increased from a median value (interquartile range) of 5 (15)% before challenge to 29 (29)% (P= 0.014) and to 30 (31)% (P= 0.031) 8 and 24 h after TDI/MDI challenges, respectively. Sputum eosinophilia was observed both in early and late reactors and declined to near to baseline values 48 hr after challenge. Percentages of eosinophils in control subjects did not exceed 7% during the study. There was a significant correlation between the increase in eosinophil counts and the magnitude of the bronchoconstriction expressed as the area of FEV1 response to isocyanate challenge (rank correlation coefficient = 0–71, P= 0.014). No significant changes in sputum neutrophils, macrophages, lymphocytes and mast cells were detected. The results indicate that isocyanate–induced asthmatic responses are associated with influx of eosinophils in airway secretion lasting up to 24 h.

Notes: 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.

Notes: Background TDI-induced asthma exhibits clinical, functional and morphological similarities with allergen-induced asthma, suggesting that an immunological mechanism is involved in the sensitization to TDL In vitro studies using the technique of cloning lymphocytes demonstrated that a great proportion of T-cell clones derived from bronchial mucosa of subjects with TDI-induced asthma produced IL-5 and interferon-gamma, but not IL-4, upon in vitro stimulation.Objectives To investigate in vivo the role of IL-4 and IL-5 on the inflammatory response of the bronchial mucosa to TDI in sensitized subjects, we performed a quantitative analysis of bronchial biopsies.Methods We obtained bronchial biopsies from six subjects with TDI asthrha 48 h after an asthmatic reaction induced by TDI challenge (challenged group), in six subjects with TDI asthma 1–4 weeks after the last exposure to TDI (chronic group), and in six non-asthmatic controls. The number of eosinophils, mast cells, T-lymphocytes, and IL-4 and IL-5 protein positive cells was determined by immunohistochemistry in the area 100 μn beneath the epithelial basement membrane.Results The characteristic increase of submucosal eosinophils, but not of mast cells and T-lymphocytes, was observed in the subjects with TDI-induced asthma when compared with controls. No differences were detected between the two groups of asthmatics. In the subjects with TDI-induced asthma, cell immunoreactivity for IL-5 was increased when compared with normal controls. There was no difference in the expression of IL-5 protein between challenged and chronic asthmatics. In contrast, the expression of IL-4 protein was increased only in the asthmatic subjects tested after recent exposure to TDI.Conclusions We demonstrated that TDI asthma 48 h after specific bronchial challenge was associated with increased numbers of cells expressing IL-4 and IL-5, whereas chronic TDI asthma was associated with increased expression of IL-5, but not of IL-4. The results suggest that subjects who developed TDI asthma exhibit increased production of IL-5 even in the absence of a recent trigger by the exogenous sensitizer and that production of TH2-like cytokines in TDI-induced asthma may not always be co-ordinately regulated in vivo.

Notes: Background:  Toluene diisocyanate (TDI)-induced asthma is a common cause of occupational asthma and it affects 5–15% of the exposed population suggesting an underlying genetic susceptibility.Methods:  To investigate the role of genetic factors in the development of TDI-induced asthma, we analyzed the distribution of human leukocyte antigen (HLA) class I genes and of tumor necrosis factor (TNF)-α A-308G polymorphism in 142 patients with TDI-induced asthma and in 50 asymptomatic exposed subjects.Results:  Neither the distribution of HLA class I antigens nor the distribution of TNF-α A-308G polymorphism was different between patients with TDI-induced asthma and asymptomatic exposed subjects.Conclusions:  These results suggest that HLA class I antigens and TNF-α A-308G are not associated with susceptibility or resistance to the development of TDI-induced asthma.