ToxSci Advance Access published online on December 8, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi050
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1 Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown WV 26505
* To whom correspondence should be addressed. 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 non-immune mechanisms, a murine model of TDI asthma was established and characterized following either low-level, subchronic or high-dose acute inhalation TDI exposure. C57BL/6J mice were exposed to TDI by inhalation either subchronically for 6 wks (20 ppb, 4 hrs/day, 5 days/week) or by a 2 hr acute exposure at 500 ppb. Both groups were challenged 14 days later via inhalation with 20 ppb TDI for 1 hr. 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), TH1/TH2 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 naïve 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 Th 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.
Received June 3, 2004
Accepted December 2, 2004
Immunotoxiocology
Exposure and Immunological Determinants in a Murine Model for Toluene Diisocyanate (TDI) Asthma
2 Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown WV 26505
Michael I. Luster, E-mail: mluster{at}cdc.gov
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