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

Abstract

Toluene diisocyanate (TDI) is a low-molecular-weight compound which is known 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 Day 1 and intranasal challenge on Day 8) led to a nonspecific tracheal hyperractivity 24 h after the challenge in TDI-sensitized mice when compared with nonsensitized mice whereas no TDI-specific IgE antibodies were found in the serum. Because 20% of subjects with TDI-induced occupational asthma exhibit an increase in serum IgE antibodies, we exposed mice for a longer period of time to investigate whether this procedure could induce TDI-specific antibody production in exposed mice. Long-term exposure (skin sensitization on 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 antibodies. Airway reactivity to various agonists was also measured in vitro and in vivo in long-term exposed mice. TDI-sensitized mice exhibited in vitro tracheal hyperreactivity to carbachol 3 h after the challenge when compared with 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 at any time point in the mice exposed to TDI according to the short-term protocol. In conclusion, by altering the exposure time and/or cumulative dosage of TDI different biological reactions can be elicited in exposed mice. This important finding might be a reflection of the diversity of symptoms found in patients suffering from TDI-induced asthma. Both the short-exposure and the long-exposure model will be useful to further investigate the mechanisms of action of TDI.