Long-term topical exposure to toluene diisocyanate in mice leads to antibody production and in vivo airway hyperresponsiveness three hours after intranasal challenge

Toluene diisocyanate (TDI) is a low-molecular-weight compound which is know n to cause occupational asthma in 5 to 10% of exposed workers. Previously, we developed a murine model to investigate TDI-induced occupational asthma. Short-term exposure to TDI (skin sensitization twice daily on Day 0 and Da y 1 and intranasal challenge on Day 8) led to a nonspecific tracheal hyperr activity 24 h after the challenge in TDI-sensitized mice when compared with nonsensitized mice whereas no TDI-specific IgE antibodies were found in th e serum. Because 20% of subjects with TDI-induced occupational asthma exhib it an increase in serum IgE antibodies, we exposed mice for a longer period of time to investigate whether this procedure could induce TDI-specific an tibody production in exposed mice. Long-term exposure (skin sensitization a n 6 consecutive weeks followed by intranasal challenge on Week 7) resulted in the production of total IgE and IgG and TDI-specific IgE and IgG antibod ies. Airway reactivity to various agonists was also measured in vitro and i n vivo in long-term exposed mice. TDI-sensitized mice exhibited in vitro tr acheal hyperreactivity to carbachol 3 h after the challenge when compared w ith the nonsensitized mice, Moreover, in vivo airway hyperresponsiveness to serotonin (5-hydroxytryptamine[5HT]) was found 3 h after the challenge In TDI-sensitized mice. interestingly, in vivo airway hyperresponsiveness was not observed are any time point in the mice exposed to TDI according to the short-term protocol. In conclusion, by altering the exposure time and/or c umulative dosage of TDI different biological reactions can be elicited in e xposed mice. This important finding might be a reflection of the diversity of symptoms found in patients suffering from TDI-induced asthma. Both the s hort-exposure and the long-exposure model will be useful to further investi gate the mechanisms of action of TDI.