Eosinophil Regulation of Pulmonary IL-13 Levels

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DESCRIPTION (provided by applicant): Despite numerous clinical investigations and basic research that describe a correlation between the pathologies associated with allergic respiratory inflammation and the accompanying pulmonary eosinophilia the specific role(s) of eosinophils and/or eosinophil effector functions (EEFs) in asthma are poorly understood. The central hypothesis of this proposal is that eosinophils recruited to the lung contribute to remodeling and airway dysfunction by modulating the Th2 character of the pulmonary micro-environment. This hypothesis will be tested using a novel double transgenic mouse model of chronic asthma co- expressing IL-5 and eotaxin 2 (I5/E2) that replicates the pulmonary eosinophilia characteristic of asthma patients, including evidence of extensive eosinophil degranulation. Specifically, we will determine the role(s) of eosinophil-derived IL-13 cytokine expression in the development of pulmonary pathologies in this model. The second aim will determine the kinetics and reversibility of eosinophil-dependent pulmonary remodeling and lung function using an doxycycline-inducible version of our double transgenic mouse model of asthma. Collectively, the completion of this proposal provides a "road map" to the definition of EEFs that mediate remodeling and lung dysfunction and, in turn, the potential for targeted therapies and improved long term care of chronic asthma patients.