Isocyanate-induced
asthma, the most commonly reported cause 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 have been difficult to define. Appropriate animals models of
isocyanate asthma will be instrumental to further our understanding of this disease. Previous studies have demonstrated that dermal exposure to
isocyanates in mice results in systemic sensitization that leads to eosinophilic airways
inflammation upon subsequent airway challenge. We hypothesized that inhalation of vapor phase
toluene diisocyante (TDI) will lead to immunologic sensitization in mice and that subsequent challenge will induce pathology and immune system alterations indicative of
asthma found in humans. To determine the impact of exposure dose as well as the involvement of immune (allergic) or nonimmune mechanisms, a murine model of TDI
asthma was established and characterized following either low-level subchronic or high-dose acute inhalation TDI exposure. C57BL/6 J mice were exposed to TDI by inhalation either subchronically for 6 weeks (20 ppb, 4 h/day, 5 days/week) or by a 2-h acute exposure at 500 ppb. Both groups were challenged 14 days later via inhalation with 20 ppb TDI for 1 h. Mice that underwent the subchronic exposure regimen demonstrated a marked allergic response evidenced by increases in airway
inflammation,
eosinophilia, goblet cell
metaplasia, epithelial cell alterations, airway hyperreponsiveness (AHR), T(H)1/T(H)2
cytokine expression in the lung, elevated levels of serum
IgE, and TDI-specific
IgG antibodies, as well as the ability to transfer these pathologies to naive mice with lymphocytes or sera from TDI exposed mice. In contrast, mice that received acute TDI exposure demonstrated increased AHR, specific
IgG antibodies, and pathology in the lung consistent with
asthma, but without the presence of elevated serum
IgE, lung eosionophilia, or increased expression of T(H)
cytokines. These results describe mouse models for TDI
asthma consistent with that found in workers with
occupational asthma and indicate that the pulmonary pathology associated with TDI can vary depending upon the exposure paradigm.