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空气污染物的影响，如 臭氧(臭氧)，最近的流行病学研究表明，臭氧会导致长期的功能损害 孩子们。暴露性肺损伤的机制以及年龄和暴露史如何影响急性 对出生后肺部的慢性易感性仍然知之甚少。新奇的证据文件 出生后，间歇性臭氧暴露深刻改变了非人类的肺生长、结构和功能 灵长类动物。生物效应可能是由臭氧在肺内的弥散和 在上皮衬里液体(ELF)内的反应/扩散，导致局部剂量的产生。整体而言 该计划的假设是年龄、地点、细胞和接触史与急性胰腺炎的易感性相关 与间歇性臭氧的差异是由于与空间相关的ELF依赖的相互作用的差异 局部剂量的异质性与呼吸道上皮细胞内和细胞内的不同调节 精灵抗氧化剂池。 项目2的重点是气管、支气管腔。项目2正在解决的总体假设是 未成熟呼吸道的四个特征导致婴儿对氧化剂的易感性增加 暴露：1)未成熟的呼吸道结构和细胞组织；2)上皮厚度的变化 衬里层；3)细胞和细胞外抗氧化剂水平的局部差异；以及4)特定于呼吸道的 在产生炎症反应的能力上的差异。 项目2将追求三个具体目标： 1)确定与年龄相关的差异对该部位特定的损伤和炎症模式的影响 在经历了一次臭氧暴露期之后； 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 在生命后期的一次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 在以后的生活中，呼吸道对细菌脂多糖(LPS)会产生急性炎症反应。 我们的努力将促进对与臭氧相关的正常脑组织破坏的基本机制的理解 肺发育、肺损伤和易感性；并产生肺结构的独特特征 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.