Eosinophil Regulation of Pulmonary IL-13 Levels

描述（由申请人提供）：尽管大量的临床调查和基础研究描述了过敏性呼吸道炎症相关病理与伴随的肺嗜酸性粒细胞增多之间的相关性，但嗜酸性粒细胞和/或嗜酸性粒细胞效应功能（EEFs）在哮喘中的具体作用尚不清楚。该建议的中心假设是，嗜酸性粒细胞募集到肺部，通过调节肺微环境的Th2特征，有助于重塑和气道功能障碍。这一假设将通过一种新型的双转基因慢性哮喘小鼠模型进行验证，该模型共同表达IL-5和eotaxin 2 (I5/E2)，复制哮喘患者肺嗜酸性粒细胞的特征，包括广泛的嗜酸性粒细胞脱颗粒的证据。具体来说，我们将在该模型中确定嗜酸性粒细胞衍生的IL-13细胞因子表达在肺部病理发展中的作用。第二个目标是利用多西环素诱导的双转基因哮喘小鼠模型，确定嗜酸性粒细胞依赖的肺重塑和肺功能的动力学和可逆性。总的来说，该提案的完成为介导重塑和肺功能障碍的EEFs的定义提供了一个“路线图”，反过来，靶向治疗和改善慢性哮喘患者长期护理的潜力。

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.