Asthma is considered a chronic inflammatory disease and the airway hyperresponsiveness and bronchospasm that are characteristic of asthma are believed, to a significant extent, to be the result to this inflammatory process. Eosinophil infiltration, dysregulated cytokine production and subepithelial fibrosis are prominent features of asthmatic inflammation. The contribution that these and other abnormalities of the asthmatic airway make to asthmatic bronchospasm and airway hyperresponsiveness, however, have not been adequately defined. This is due, to a significant extent, to the complexity of asthmatic inflammation, the inability of present study techniques to successfully isolate and study individual components of the inflammatory response, and our incomplete ability to predict in vivo function from in vitro experimentation. We believe that eosinophils, are major regulators of airway physiology. In this grant we propose to dissect the role that eosinophils play in airway hyperresponsiveness and bronchospasm using transgenic animals in which specific cytokines are overexpressed in a lung airway-selective/specific manner. Our attention will be focused on the eosinophil regulators, Macrophage Inflammatory Protein (MIP)-1, RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), the eosinophil effector molecule Transforming Growth Factor (TGF)-beta1 and the regulator IL-6. We will: 1) Create transgenic mice using the CC10 ling-selective/specific promoter to express these cytokines in a lung/airway-specific/selective fashion. 2) Characterize the morphologic, immunologic and physiologic phenotype of these transgenic mice. 3) Determine if specific transgenic mice (when compared to their nontransgenic littermates) manifest heightened, diminished or altered pathologic, immunologic or physiologic responses to antigen (ovalbumin), hapten (picrylchloride) or virus (respiratory syncytial virus). 4) Determine if the cytokines interact with one another in the regulation of airway inflammation and/or physiology. These studies will increase our understanding of cytokine networking in asthmatic inflammation and hyperresponsiveness and may ultimately lead to improved treatment strategies for this disorder.
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