Isocyanate-induced asthma, which is the most common type of occupational asthma, has been difficult to diagnose and control, in part, because the biological mechanisms responsible for the disease and the determinants of exposure are not fully defined. To help address these issues, we recently established a murine model of toluene diisocyanate (TDI) asthma using inhalation exposure paradigms consistent with potential workplace exposure. In order to confirm our hypothesis that TDI-induce asthma, like allergic asthma, is predominantly a Th2 response, the ability of mice that were deficient in CD4 or CD8 cells or specific Th1 and Th2 cytokines to develop TDI asthma was examined. The development of allergic asthma was evaluated by monitoring lungs for the presence of eosinophilia, goblet cell metaplasia, epithelial cell alterations, airway hyperreactivity (AHR), and Th2 and Th1 cytokine expression, as well as serum IgE levels and TDI-specific IgG antibodies. Transgenic CD8 or CD4 knockout (KO) mice exhibited significant reductions in AHR, cytokine expression, serum antibody levels, airway inflammation, and histopathological lesions, although in a number of the endpoints the effects were more attenuated in CD4 KO mice. IFNgamma depletion ablated the increase in AHR in TDI-allergic mice, but had only slight to moderate effects on airway histopathology, serum antibody levels, and cytokine expression compared to sensitized/challenged controls. IL-4 and IL-13 deficiency had moderate inhibitory effects, while combined IL-4/IL-13 depletion effectively prevented almost all asthma-associated pathologies. Taken together, these results indicate that TDI asthma, like immune-mediated asthma produced by large-molecular-weight materials, is driven primarily by CD4+ T cells and is dependent upon the expression of Th2 cytokines. However, as with protein-induced asthma models, certain pathologies are influenced by CD8+ T cells and Th1-derived cytokines, such as AHR and cytokine production.
Models; Occupational-diseases; Bronchial-asthma; Isocyanates; Diseases; Inhalation-studies; Exposure-levels; Exposure-assessment; Work-environment; Occupational-exposure; Laboratory-animals; Animals; Animal-studies; Airway-resistance; Airway-obstruction; Lung-disorders; Pulmonary-system-disorders; Respiratory-system-disorders
Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505