Complications due to allergic airway inflammation have increased worldwide due to several pulmonary diseases, such as asthma and bronchopulmonary fungal diseases. The present treatment of choice for airway inflammation and hyperreactivity is glucocorticoid. However, the nonspecific nature of these agents reflect our limited knowledge regarding the mechanisms that mediate leukocyte-dependent airway inflammation leading to hyperreactivity. Our failure to fully understand these mechanisms may be due, in part, to the lack of appropriate animal models to study antigen- specific airway inflammation and hyperreactivity. The common link in the pathology of all of these diseases is the infiltration of the airways with large numbers of leukocytes, most characteristically eosinophils. The subsequent pathology in the airways is associated with a Th2-type response leading to peribronchial recruitment of eosinophils. We hypothesize that an antigenic challenge in a pre-sensitized host results in an inflammatory response leading to airway hyperreactivity. We further hypothesize that this response is initiated by early response cytokines, resulting in the production of C-C chemokines that facilitate the peribronchial recruitment of eosinophils and contribute to airway hyperreactivity. To test this postulate, we will focus on mechanisms of chemokine-induced eosinophil recruitment and airway hyperreactivity.
Our specific aims are the following: l) Determine the temporal production and cellular sources of the early response cytokines and C-C chemokines as they correlate with eosinophil infiltration and airway hyperreactivity; 2) Identify cytokine networks involved in the activation of C-C chemokines leading to airway eosinophilia and hyperreactivity; and 3) Elucidate the in vivo contribution of C-C chemokines to airway-associated eosinophil recruitment and hyperreactivity. The experimental murine model of eosinophilic airway inflammation will be generated using an established model of Schistosoma mansoni egg antigen (SEA)-induced Th2-type hypereosinophilic response localized to the airway with airway hyperreactivity. To assess the mechanisms of chemokine production leading to eosinophilic airway infiltration, we will employ Northern analysis (or RT-PCR) and in situ hybridization for analysis of steady-state levels of mRNA; ELISAs and immunohistochemistry for protein analysis. Chemotactic and proliferation assays will also be utilized as well as measurement of airway physiology. These studies will elucidate specific mechanisms operative in mediating eosinophil recruitment in antigen-specific airway inflammation, leading to airway hyperresponsiveness.
