Isocyanates are a leading cause of occupation-related asthma. The pathophysiology of this condition, however, remains poorly understood, in part due to a lack of appropriate animal models. One critical question that is currently unanswered is what role different sites of exposure (i.e. lung versus skin) may play in subsequent development of reactive airway symptoms. In addition, it is unclear what particular antigenic form of an isocyanate is serving as the primary immunogen. Answers to these questions would have enormous impact on development of appropriate measures to protect workers. Our laboratory has recently established a mouse model of antigen-induced allergic asthma which involves sensitization through the skin, using a newly developed method of epicutaneous exposure to soluble protein under an occlusive skin patch. The systemic responses induced differ significantly from contact hypersensitivity responses induced by skin painting with haptens in that they involve preferential activations of Th2 cels. Intranasal antigen challenge of epicutaneously immunized mice in our system resulted in lung inflammatory responses with characteristics of human asthma, including airway eosinophilia and increased mucus production. In this pilot study, we proposed the development of a novel murine model of isocyanate-induced asthma, by adapting our epicutaneous protein immunization model. Specifically, hexamethylene diisocyante (HDI)-spcific responses will be established in mice by epicutaneous exposure to HDI-protein conjugates using an occlusive skin patch. The nature of these responses will be characterized and compared to responses induced by skin painting with HDI hapten alone. The relative strength and nature of lung inflammatory responses induced by intranasal HDI challenge of either epicutaneously immunized or airway sensitized mice will then be characterized. These studies will provide information about the effect of initial site of sensitization (skin versus lung) on the development of inflammatory responses upon subsequent airway exposure. Establishment of this mouse model will provide a means for future investigation of: 1) the pathophysiology of isocyanate asthma; 2) the relative immunogenicity of different of different classes or antigenic forms of isocyanates; and 3) the role of different sites of exposure in sensitization. This information will provide valuable insight into the pertinent risk factors for developing isocyanate asthma and will help guide development of appropriate strategies for protection in the workplace.
