Late respiratory response and associated eosinophilic inflammation induced by repeated exposure to toluene diisocyanate in guinea pigs

Objective: The study was designed to establish an animal model of toluene diisocyanate (TDI)-induced late respiratory response and to investigate airway inflammatory cell dynamics in this model. Methods: Guinea pigs were exposed to 2,4-TDI dissolved in ethyl acetate by nasal application according to three schedules. Schedule 1 consisted of sensitization and multiple challenge (n = 58): 10% TDI was applied once daily for 7 days (sensitization) followed by challenges with 5% TDI once weekly for 4 weeks. Schedule 2 consisted of sensitization only (n = 5). 10% TDI was applied once daily for 7 days. Schedule 3 consisted of single challenge only (n = 12): 5% TDI was applied only once. As controls, ethyl acetate was applied according to the three schedules described above. Each animal was premedicated with metyrapone before each challenge. Bronchoalveolar lavage and histologic examination were performed at various times after the last challenge. Results: Schedule 1 induced immediate and late respiratory responses at a prevalence of 63% and 56%, respectively. Schedules 2 and 3 induced an immediate response in some animals but no late response. Neither immediate nor late response was observed in control animals. All of the subgroups of schedule I that developed late responses (examined at 2, 3, 6, 24 and 168 hours) showed a significant increase of eosinophils in bronchoalveolar lavage fluid and tissue compared with the corresponding control of each (examined at the same time points). Two of the subgroups with late responses (examined at 3 and 6 hours) were compared with their corresponding subgroups, which were given the same treatment, failed to develop late response, and were examined at the same time points; they again proved to have a significant increase of eosinophils in both samples. Subgroups of schedule 1 without late response (30 minutes, 3 and 6 hours), schedule 2 (6 hours), or schedule 3 (2 and 6 hours) did not show significant changes in lavage or tissue cell composition, except for the schedule 1 subgroup examined at 6 hours, which showed a significant increase of eosinophils only in the tissue compared with its control. Conclusions: Sensitization and multiple challenge with TDI induced immediate and/or late respiratory responses at a high prevalence in guinea pigs. Eosinophilic but not neutrophilic inflammation was involved in the late response.