Pulmonary Effects of Environmental Oxidant Pollutants

描述（由申请人提供）：本项目自成立以来的总体目标是确定哺乳动物呼吸系统对吸入环境浓度的氧化空气污染物的病理生物学反应。这项更新申请的重点将放在幼儿环境诱发哮喘的机制上，使用研究人员通过该计划的支持开发的婴儿恒河猴环境哮喘模型。在过去五年的资助中，研究人员使用这个模型，在长期接触臭氧对婴儿肺部发育和生长的影响方面取得了许多惊人的发现，包括：气道生长发育迟缓，出生后气道世代缺失，基底细胞对成纤维细胞生长因子(FGF)-2三元信号复合物的建立受损，上皮表面神经活化失败，中枢神经控制受损，过敏反应增强，气道高反应性，肺泡化破坏和气道重塑。所有关于这种更新的研究都将在上皮/间充质营养单位（EMTU）的分析框架中进行，其细胞成分通过基底膜区（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，暴露于氧化空气污染物的环境中会促进幼儿发育中的肺部过敏性哮喘的发展，并通过以下方式加剧其严重程度：1)破坏EMTU内的稳态；2)从根本上损害促进正常气道生长和发育的营养相互作用的建立和分化。这些变化是由于对过敏原暴露的免疫反应的急性损伤、炎症和修复的连续循环叠加造成的。该计划中的四个项目中的每一个都将专注于EMTU的不同组成部分：项目1，上皮细胞和间充质细胞（成纤维细胞、平滑肌）和BMZ；课题二，粘膜免疫系统；课题三，神经支配与神经控制；项目四，脉管系统。

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.