1097 Importance of skin exposure in a sub-chronic mouse model of chemical-induced asthma

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Abstract

Introduction

Toluene 2,4-toluene diisocyanate (TDI) is well-known chemical sensitizer and occupational asthmogen. In a chronic mouse model, with dermal sensitisation and five weeks of intranasal challenges with TDI we were able to induce several key hallmarks of occupational asthma, including airway hyperreactivity (AHR), and a predominant Th2 immune responses. Yet, no features of airway inflammation, nor airway remodelling were present. Therefore, we altered the TDI mouse model and introduced endotracheal challenge to investigate lung inflammation and remodelling.

Methods

On days 1 and 8, BALB/c mice were dermally treated (20 µl/ear) with 0.5% TDI or the vehicle AOO (3:2). From day 15, the mice received under light isoflurane anaesthesia, a total of five oropharyngeal challenges with 20 µl of the chemical or AOO (1:4) (days 15, 17, 19, 23 and 24). Two days after the last challenge, airway hyperreactivity (AHR) to methacholine was assessed, followed by an evaluation of pulmonary inflammation in bronchoalveolar lavage (BAL). As immunological parameters, lung dendritic cells, lymphocyte subpopulations (T- and B-cells) and the cytokine production profile (Th1 vs Th2) in auricular lymph nodes were measured. Blood was sampled to determine total serum IgE, IgG1 and IgG2a.

Results

Mice dermally sensitised and challenged with TDI showed significant increased proliferation of the auricular lymph nodes, characterised by Th-, Tc- and B-cells. The cytokine production profile of the auricular lymph nodes showed increased levels of IL4, IL13, IL10 and IFNλ. Furthermore, mice sensitised and challenged with TDI showed significantly increased serum IgE and IgG1 levels. These TDI-sensitised and challenged mice showed pronounced airway hyperreactivity, along with a mixed eosinophilic and neutrophilic inflammation and recruitment of several dendritic cell subpopulations. Mice that were not dermally sensitised, but only received the TDI challenges did not show airway hyperreactivity, but had a neutrophilic lung inflammation, compared to the complete control mice. These mice also did not show any signs of immune sensitisation, yet dendritic cell recruitment to the lungs was identical to the TDI-sensitised and TDI-challenged mice.

Conclusion

Endo-tracheal instillation with TDI leads to lung inflammation, without AHR, probably due to the irritant properties of TDI. Yet, mice dermally sensitised with TDI, followed by TDI challenges showed a predominant Th2 response, with AHR and eosinophilic inflammation. These data confirm the important role of dermal sensitisation in the development of chemical-induced asthma.

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