Eosinophil Regulation of Pulmonary IL-13 Levels

描述(申请人提供)：尽管许多临床研究和基础研究描述了与过敏性呼吸道炎症相关的病理和伴随的肺嗜酸性粒细胞增多之间的关系，但嗜酸性粒细胞和/或嗜酸性粒细胞效应功能(EEF)在哮喘中的具体作用(S)尚不清楚。这一建议的中心假设是，招募到肺中的嗜酸性粒细胞通过调节肺微环境的Th2特征而促进重塑和气道功能障碍。这一假设将使用一种新的慢性哮喘双转基因小鼠模型来验证，该模型共表达IL-5和eoaxin 2(I5/E2)，复制了哮喘患者的肺嗜酸性粒细胞特征，包括广泛的嗜酸性粒细胞脱颗粒的证据。具体地说，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(S)。第二个目标将使用我们的双转基因哮喘小鼠模型的多西环素诱导版本来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。总而言之，这项提案的完成为EEFS的定义提供了一个“路线图”，该定义调解了重塑和肺功能障碍，进而为有针对性的治疗和改善慢性哮喘患者的长期护理提供了可能性。

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.