Glutathione-conjugated toluene diisocyanate causes airway inflammation in sensitised mice

Abstract

Toluene diisocyanate (TDI) is a highly volatile compound that reacts readily with nucleophilic compounds, sulfhydryl groups in particular. Since the epithelial lining fluid of the airways contains high levels of the sulfhydryl, glutathione (GSH), inhalation of TDI is likely to result in the formation of GS-TDI conjugates. We therefore investigated whether GS-TDI is capable of provoking irritant and/or allergic reactions. Irritant effects of GS-TDI were studied after intratracheal administration of a range of doses of GS-TDI in saline to naive BALB/c mice. GS-TDI caused a dose-dependent increase in neutrophils in the lungs 24 h after instillation. A dose equivalent to 150 microg of TDI or lower had no effect. For provocation of allergic reactions, mice were sensitised by application of 1% TDI onto the skin on days 0 and 1, and challenged intratracheally with a sub-irritant dose of GS-TDI on day 8. GS-TDI did not induce non-specific tracheal hyperreactivity to carbachol 24 and 48 h after challenge in TDI-sensitised mice. However, it increased the numbers of neutrophils in the lungs as compared with the control mice. These findings suggest that GSH conjugation does not diminish the capacity of TDI to elicit irritant-induced inflammation in the lungs of mice at doses above 150 microg of TDI in the conjugate. Moreover, the capacity to induce allergic-specific inflammation was retained at concentrations of GS-TDI being devoid of irritant activity. However, the GS-TDI conjugate failed to induce non-specific tracheal hyperreactivity. This may be the consequence of the deposition of excess of GSH upon local dissociation of the conjugate.

Leukocyte nicotinamide adenine dinucleotide phosphate-reduced oxidase is required for isocyanate-induced lung inflammation

“…26 TDI and other isocyanates are oxidizing agents that react rapidly with cellular proteins and lead to molecular changes. 48,49 It has been reported that both immunologic and nonimmunologic effects of isocyanates may induce pathogenic mechanisms distinct from other airway inflammatory conditions. 46 Consistent with the strong oxidant activity of TDI, we found that after wild-type and Ncf1 -/-mice were repeatedly exposed to TDI, there was a marked increase in carbonylation, an irreversible oxidative change on proteins, in their lung tissue.…”

Airway Inflammation and Bronchial Remodelling in Toluene Diisocyanate‐exposed BALB/c Mouse Model

“…Although the pathogenic mechanism of TDI‐induced asthma is far from clear, it is regarded that specific sensitization to the compound involves binding of TDI to carrier molecules [7–9]. Specific IgE to isocyanate has been reported to be of benefit in the diagnosis of occupational asthma [10–12].…”

Risk assessment for consumer exposure to toluene diisocyanate (TDI) derived from polyurethane flexible foam

“…The data summarized above indicate that potential physiological exposures to TDI such as those reported here (i.e., inhalation and dermal contact) likely result in the formation of conjugates by the reaction of TDI with biological macromolecules (Brown and Burkert, 2002;De Marzo et al, 2000;Lange et al, 1999;Mráz et al, 1998Mráz et al, , 2000Ogawa et al, 2006;Valstar et al, 2004;Wisnewski et al, 2006;Ye et al, 2006), with no detectable free TDA (Mormann et al, 2006;Rosenberg and Savolainen, 1985;Skarping et al, 1994;Timchalk et al, 1994). Since inhalation exposures in rodents and humans are not associated with carcinogenic effects and do not produce detectable levels of free TDA in either species, the cancer risk posed by the inhalation of TDI is considered negligible and is not further evaluated herein.…”