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 of this inflammatory process. Eosinophil infiltration and release of granule proteins, dysregulated cytokine production, epithelial desquamation and subepithelial fibrosis are prominent features of asthmatic inflammation. The contribution that these and other abnormalities of the asthmatic airway make to 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. The applicants believe that eosinophils, via their elaboration of granule proteins and bioactive cytokines, are major regulators of airway hyperresponsiveness and major inducers of bronchospasm. The applicants propose to dissect the role that eosinophil recruitment, activation and secretion play in airway hyperresponsiveness and bronchospasm using transgenic animals in which specific cytokines and/or proteins are over-expressed in a lung airway- selective/specific manner. Their attention will be focused on the airway eosinophil chemoattractants, Macrophage Inflammatory Protein (MIP)-1a, RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) and lymphocyte chemotactic factor (LCF), the eosinophil effector molecules Major Basic Protein (MPB) and Transforming Growth Factor (TGF)-B1 and the regulator IL-6. The applicants will: 1) Create transgenic mice using the CC10 lung- selective/specific promoter to express cytokines and/or eosinophil derived granule proteins in a lung/airway-specific fashion; 2) Characterize the morphologic and physiologic phenotype of these transgenic mice; 3) Determine if specific transgenic mice (when compared to their nontransgenic littermates) manifest heightened or diminished sensitivity to antigen-or viral-induced inflammation, bronchospasm and airway hyperresponsiveness; and 4) Determine if the cytokines and eosinophil-derived granule proteins interact with one another in the regulation of airways physiology. These studies will increase our understanding of cytokine networking in asthmatic inflammation and hyperresponsiveness and may ultimately lead to improved treatment strategies for asthma.
