Mechanisms of Species-Dependent Environmental Lung Injury

描述(由申请者提供)：这是计划项目的首次竞争性续签，最初资助的项目从2003年6月开始，为期三年。这一多机构、多研究人员项目的基本目标和创新的结构模式基本上保持不变。大约一半的美国人口继续受到臭氧(O3)等致病空气污染物的影响，最近的流行病学研究表明，臭氧会导致儿童长期的功能障碍。尽管进行了广泛的研究，但暴露相关肺损伤的机制以及年龄和暴露史如何决定出生后肺的急性和慢性易感性仍然知之甚少。新的证据证明，出生后，间歇性的臭氧暴露深刻地改变了非人类灵长类动物的肺生长、结构和功能。生物效应可能由臭氧在肺内的弥散和上皮衬里液体(ELF)内的反应/扩散共同决定，从而导致局部剂量的产生。因此，研究人员假设，年龄、部位、细胞和暴露史相关的急性和间歇性臭氧的易感性是由于局部剂量的空间异质性导致的ELF依赖的相互作用的差异，以及对呼吸道上皮细胞内和ELF抗氧化剂池的不同调节。代替最初提出的呼吸道致敏成分，研究人员优先考虑我们当前的目标，将重点放在年龄、生物变异和暴露史(包括恢复)相关的易感性上。研究人员的努力将促进对与臭氧相关的正常肺发育、肺损伤和易感性破坏的基本机制的理解；并产生肺结构和生化的独特特征。跨学科研究团队包括肺表面化学、病理生物学和定量形态学、成像和三维重建、剂量学、外推建模和生物统计学方面的专业知识。这个高度互动的计划将利用非人类灵长类动物(猕猴)，并将扩大数据库，包括老鼠，并包括相互依赖的项目(4)和核心(3)。研究人员打算描述ELF介导的局部剂量产生的特征；定义出生后易感性的机制；将呼吸道反应决定因素描述为急性暴露与间歇性暴露的函数；开发利用鼻子作为哨兵的肺损伤生物标志物；建立从3D重建中提取的结构图谱，并制定预测健康结果的模型。该计划涵盖从分子相互作用到完整的灵长类动物，与NIEHS目标高度相关，预计将扩展到人类群体，并将大大减少儿童群体中氧化剂空气污染对健康影响的不确定性。

DESCRIPTION (provided by applicant): This is the first competing renewal of a program project initially funded for three years starting in June 2003. The fundamental goals and innovative structural paradigm of this multi-institution, multi-investigator program remain essentially unchanged. Approximately half of the United States 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. Despite extensive research endeavors, 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. Thus, the investigators hypothesize 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. In lieu of the originally proposed airway sensitization component, the investigators have prioritized our current goals to focus on age, biological variation, and exposure history (including recovery) related susceptibilities. The investigators' 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. The interdisciplinary research team encompasses expertise in lung surface chemistry, pathobiology and quantitative morphology, imaging and 3-dimensional reconstruction, dosimetry, extrapolation modeling, and biostatistics. This highly interactive program will utilize non-human primates (rhesus monkeys) and, to expand the database, rats, and encompasses interdependent projects (4) and cores (3). the investigators intend to characterize the ELF-mediated local dose generation; define the mechanisms of postnatal susceptibility; characterize airway response determinants as a function of acute versus episodic exposures; develop lung injury biomarkers utilizing the nose as a sentinel; build structural atlases extracted from 3-D reconstructions, and, formulate models that predict health outcomes. The program spans from molecular interactions to the intact primate, is highly relevant to NIEHS goals, is anticipated to extend into the human population, and will substantially reduce the uncertainties regarding the health effects of oxidant air pollution in our childhood population.