title: 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.
authors.affiliation: Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands. d.l.valstar@pharm.uu.nl
authors.forename: D L
authors.initials: DL
authors.lastname: Valstar
authors.forename: M A
authors.initials: MA
authors.lastname: Schijf
authors.forename: F P
authors.initials: FP
authors.lastname: Nijkamp
authors.forename: N
authors.initials: N
authors.lastname: Bloksma
authors.forename: P A J
authors.initials: PA
authors.lastname: Henricks
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001985:Bronchial Provocation Tests; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000737:chemistry / Q000633:toxicity*; D007249:Inflammation / Q000276:immunology* / Q000503:physiopathology; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000503:physiopathology; D014051:Toluene 2,4-Diisocyanate / Q000737:chemistry / Q000633:toxicity*
chemical_list: D014051:Toluene 2,4-Diisocyanate; D005978:Glutathione