Pulmonary Effects of Environmental Oxidant Pollutants

描述(由申请人提供)：该计划的总体目标是确定哺乳动物呼吸系统对吸入环境中氧化性空气污染物浓度的病理生物学反应。此次更新申请的重点将是环境诱发幼儿哮喘的机制，使用研究人员通过该项目支持开发的幼年恒河猴环境哮喘模型。在过去五年的资助中，研究人员利用这个模型，在婴儿期慢性臭氧暴露对肺部发育和生长的影响方面取得了一些惊人的发现，包括：呼吸道生长迟缓，出生后气道代数减少，基底细胞建立成纤维细胞生长因子(FGF)-2三元信号复合体受损，上皮表面无法神经支配，中枢神经控制受损，过敏反应增强，呼吸道高反应性，肺泡化破坏，以及气道重塑。所有建议进行更新的研究的分析框架是上皮/间充质营养单元(EMTU)，其细胞成分通过基底膜带(BMZ)调节的细胞外信号复合体建立营养相互作用。总体假设是，环境中暴露于氧化性空气污染物会促进幼儿发育期肺部过敏性哮喘的发展，并通过以下方式加重其严重性：1)扰乱EMTU内的动态平衡；2)从根本上损害促进正常呼吸道生长和发育的营养相互作用的建立和分化。这些变化是由于急性损伤、炎症和修复的连续循环叠加在对过敏原暴露的免疫反应上的。该计划内的四个项目中的每一个都将侧重于EMTU的不同组成部分：项目1，上皮和间充质细胞(成纤维细胞、平滑肌)和BMZ；项目2，粘膜免疫系统；项目3，神经和神经控制；项目4，血管系统。

DESCRIPTION (provided by applicant): 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 asthma in infant rhesus monkeys that the investigators have developed through the support of this program. Using this model over the previous five years of funding, the investigators 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 fibroblast growth factor (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 (EMTU), whose cellular components establish trophic interactions via an extracellular signaling complex modulated by the basement membrane zone (BMZ). The overall hypothesis 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 EMTU 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. Each of the four projects within the program will focus on different components of the EMTU: Project 1, epithelial and mesenchymal cells (fibroblasts, smooth muscle) and the BMZ; Project 2, mucosal immune system; Project 3, innervation and neural control; and Project 4, vasculature.