Project 2 - Local Biological Response Profiles in the Lower Respiratory Tract

大约一半的美国人口继续受到致病性空气污染物的影响， 臭氧（O3），最近的流行病学研究表明， 孩子暴露相关肺损伤的机制以及年龄和暴露史如何影响急性肺损伤 和纳塔尔后肺部的慢性易感性仍然知之甚少。新的证据文件， 出生后，间歇性O3暴露深刻地改变了非人类的肺生长，结构和功能 灵长类动物生物效应可能由O3肺内弥散和 在上皮细胞衬液（ELF）内的反应/扩散，导致局部剂量的产生。整体 该项目的假设是，年龄、部位、细胞和暴露史相关的急性 与情景O3的结果从差异ELF依赖的相互作用与空间 局部剂量的异质性与气道上皮细胞内的差异调节相结合， ELF抗氧化剂池。 项目2侧重于气管支气管气道。项目2的总体假设是 未成熟气道的四个特征导致婴儿对氧化剂的敏感性增加 暴露：1）不成熟的气道结构和细胞组织; 2）上皮厚度的改变 衬里层; 3）细胞和细胞外抗氧化剂水平的局部差异;和4）气道特异性 产生炎症反应能力的差异。 项目2将追求三个具体目标： 1)确定年龄相关差异对该部位特定损伤和炎症模式的影响 臭氧暴露急性发作后; 2)确定出生后肺发育期间的臭氧暴露是否会改变特定部位的肺发育。 在生命后期急性臭氧暴露后发现的损伤和炎症模式; 3)确定出生后肺发育期间臭氧暴露对肺功能的影响， 呼吸道感染，在以后的生活中对细菌脂多糖（LPS）产生急性炎症反应。 我们的努力将促进对O3相关的正常干扰的基本机制的理解。 肺发育、肺损伤和易感性;并生成肺结构的独特特征 和生物化学。

Approximately half of the US population continues to be impacted by pathogenic air pollutants such as ozone (O3), which recent epidemiologic studies suggest induces long term functional impairments in children. The mechanisms of exposure-related lung injury and how age and exposure history govern acute and chronic susceptibility in the post natal lung remain poorly understood. Novel evidence documents that postnatal, episodic O3 exposure profoundly alters lung growth, structure, and function in non-human primates. Biological effects are likely determined by the combination of O3 intrapulmonary dispersion and reaction/diffusion within the epithelial lining fluid (ELF), leading to generation of the local dose. The overall hypothesis of this program is that the age-, site-, cell-, and exposure history-related susceptibilities to acute versus episodic O3 result from differences in ELF-dependent interactions associated with spatial heterogeneities in the local dose coupled with differential regulation of the airway epithelial intracellular and ELF antioxidant pools. Project 2 focuses on the tracheobronchial airways. The overall hypothesis being addressed by Project 2 is that four characteristics of immature airways contribute to the heightened susceptibility of infants to oxidant exposure: 1) immature airway structure and cellular organization; 2) alterations in thickness of the epithelial lining layer; 3) local differences in levels of cellular and extracellular antioxidants; and 4) airway specific differences in the ability to generate an inflammatory response. Project 2 will pursue three specific aims: 1) Determine the impact of age-related differences on this site specific pattern of injury and inflammation following an acute episode of ozone exposure; 2) Determine if ozone exposure during the postnatal period of lung development alters the site specific pattern of injury and inflammation found after an acute episode of ozone exposure later in life; 3) Define the impact of ozone exposure during the postnatal period of lung development on the ability of airways to mount an acute inflammatory response to bacterial lipopolysaccharide (LPS) later in life. Our efforts will advance understanding of the fundamental mechanisms of O3-related disruption of normal lung development, lung injury, and susceptibility; and generate unique characterizations of lung structure and biochemistry.