Project 2 - Postnatal Development of Pulmonary Immune Mechanisms

该计划自成立以来的总体目标是确定患者的病理生物学反应， 哺乳动物的呼吸系统吸入环境浓度的氧化剂空气污染物。 这次更新申请的重点将是年轻人环境诱发哮喘的机制， 儿童，使用我们开发的婴儿恒河猴环境过敏性哮喘模型， 通过这个项目的支持。在过去五年的资助中，我们使用这种模式， 关于慢性臭氧暴露对肺部发育的影响的一些惊人发现， 婴儿期生长，包括：气道生长发育迟缓，出生后气道世代丧失， 基底细胞FGF-2三元信号复合物的建立，上皮表面 神经支配，中枢神经控制受损，过敏反应增强，气道高反应性， 破坏肺泡形成和气道重塑所有研究报告提出的分析框架 进行这种更新的是上皮/间充质营养单位，其细胞成分 通过由基底膜调节的细胞外信号复合物建立营养相互作用 区 该计划的总体假设是，环境暴露于氧化剂空气污染物会促进 过敏性哮喘在幼儿肺发育中的发展，并通过以下方式加剧其严重程度：（1） 破坏上皮/间充质营养单位内的稳态，和（2）从根本上损害 促进正常气道生长的营养相互作用的建立和分化， 发展这些变化是急性损伤、炎症、 并修复对过敏原暴露的免疫反应。 本项目将重点关注上皮/间充质营养单位内的粘膜免疫， 具体目标： 1)确定偶发性臭氧暴露如何与屋尘螨（HDM）致敏相结合 过敏原可以在出生后发育期间启动哮喘表型。 2)确定间歇性臭氧暴露与HDM过敏原致敏作用的关系 哮喘表型的进展。 3)确定间歇性臭氧暴露与HDM过敏原致敏如何导致 哮喘表型持续到成年早期。

The overall goal of this program since its inception has been to define the pathobiological response of the mammalian respiratory system to the inhalation of ambient concentrations of oxidant air pollutants. The focus of this renewal application will be on mechanisms of environmentally induced asthma in young children, using the model of environmental allergic asthma in infant rhesus monkeys that we have developed through support of this program. Using this model over the previous five years of funding, we have made a number of startling discoveries regarding the effect of chronic ozone exposure on lung development and growth during infancy, including: stunting of airway growth, postnatal loss of airway generations, impaired establishment of the FGF-2 ternary signaling complex by basal cells, the failure of epithelial surfaces to innervate, impaired central nervous control, enhancement of the allergic response, airway hyperreactivity, disrupted alveolarization, and airway remodeling. The analytical framework in which all of the studies proposed for this renewal will be conducted is the epithelial/mesenchymal trophic unit, whose cellular components establish trophic interactions via an extracellular signaling complex modulated by the basement membrane zone. The overall hypothesis for this program is that environmental exposure to oxidant air pollutants promotes the development of allergic asthma in the developing lungs of young children and exacerbates its severity by: (1) disrupting the homeostasis within the epithelial/mesenchymal trophic unit and (2) fundamentally compromising the establishment and differentiation of the trophic interactions that promote normal airway growth and development. These changes result from the superimposition of continual cycles of acute injury, inflammation, and repair on the immune response to allergen exposure. This Project will focus on mucosal immunity within the epithelial/mesenchymal trophic unit, with the following specific aims: 1) Determine how episodic ozone exposure in conjunction with sensitization to house dust mite (HDM) allergen can initiate the asthma phenotype during postnatal development. 2) Determine how episodic ozone exposure in conjunction with sensitization to HDM allergen can contribute to the progression of the asthma phenotype. 3) Determine how episodic ozone exposure in conjunction with sensitization to HDM allergen can result in persistence of the asthma phenotype into early adulthood.