This proposal seeks to define IL-5 effector functions in the lung leading to pulmonary pathology and lung dysfunction. The focus of the proposal is to identify IL-5-dependent cell and molecular pulmonary changes using a transgenic mouse model of asthma constitutively expressing IL-5 from the airwa epithelium (line NJ.1726). Specifically, this proposal will correlate induced pulmonary pathologies (including measurements of airway hyperresponsiveness) occurring in NJ.1726 mice with the recruitment of eosinophils and specific lymphocyte subpopulations. We will also determine if pulmonary changes induced by IL-5 expression in the lung """"""""sensitizes"""""""" individuals to exacerbating effect of exposure to aerosolized antigen (i.e., allergic inflammation) or environmental pollutants such as ozone. Moreover, the proposal outlines specific experiments to identify eosinophil-associated activities in the lung and to evaluate the synergistic effects of IL-5 expression on other inflammatory signaling cascades. An important intent of this proposal is to integrate our approaches to understand eosinophil effector function in the mouse with the downstream pulmonary consequences of the recruitment and activation of this cell type in the lung. The specific objectives of this proposal are: 1) to determine the lymphocyte dependence (i.e., the specific populations of T and B cells) of the pulmonary pathologies occurring in transgenic mice constitutively expressing IL-5 in the lung (line NJ.1736); 2) To test if IL-5 expression in the airway epithelium/lumen of NJ.1726 mice induces pulmonary immune changes that predispose individuals to exaggerated responses to exacerbating inflammatory stimuli; 3) To determine if the IL-5-dependent recruitment in eosinophils to the lung mucosa and airway lumen of mice is the causative event leading to pulmonary pathology; 4) To test if synergistic effects between IL-5 and chemokines expressed in the lung are responsible for lung pathologies observed in mice and asthmatic patients exposed to allergens and/or environmental pollutants.
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