Mechanism of Species Dependent Environmental Lung Injury

相当大比例的美国人口继续暴露在臭氧(O3)等有害空气污染物中。尽管进行了多年和大量的研究工作，但与暴露相关的肺损伤的机制、控制儿童暴露的易感性因素以及儿童暴露的长期健康后果仍然知之甚少。新的证据表明，婴儿非人类灵长类动物间歇性接触臭氧会导致肺生长、结构和功能的深刻变化，并加剧反应性呼吸道疾病的发展。因为臭氧与上皮衬里液体的成分发生反应 (ELF)决定了局部剂量的产生，我们假设，年龄、部位、细胞和疾病对急性和间歇性臭氧暴露的特异性易感性是由于局部剂量中与空间异质性相关的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。为了验证这一假说，这将进一步加深我们对臭氧相关的肺正常发育、肺损伤和易感性中断的基本机制的理解；我们召集了一个跨学科的研究团队，包括肺表面化学、病理生物学和定量形态学、剂量学和外推建模方面的专业知识。我们设计了一个高度互动的项目，利用非人类灵长类动物(恒河猴)，涉及四个相互依赖的项目和三个核心。我们最初的目标是表征ELF介导的跨年龄、暴露史和呼吸道敏化的局部剂量的产生；确定出生后肺中年龄依赖的易感性的机制；表征作为急性和间歇性暴露的函数的气道重塑的决定因素；开发以鼻子为哨点的肺损伤的非侵入性生物标志物；以及建立预测肺生长和呼吸道敏化的健康结果的模型。该计划涵盖从分子相互作用到完整的灵长类动物，与NIEHS的目标高度相关，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。

A substantial proportion of the US population continues to be exposed to harmful air pollutants such as ozone (O3). Despite the many years and extensive number of research efforts, the mechanisms of exposure-related lung injury, the factors that govern susceptibility, and the long-term health consequences of childhood exposures remain poorly understood. New evidence suggests that episodic O3 exposure of infant nonhuman primates results in profound alterations in lung growth, structure, and function, and exacerbates development of reactive airways disease. Because O3 reactions with constituents of the epithelial lining fluid (ELF) dictate generation of the local dose, we hypothesize that the age-, site-, cell-, and disease-specific susceptibilities to acute versus episodic O3 exposure result from differences in ELF-dependent interactions associated with spatial heterogeneities in the local dose coupled with differential regulation of the airway e pithelial intracellular and ELF a ntioxidant pools. To test this hypothesis, which will further our understanding of the fundamental mechanisms of O3-related disruption of normal lung development, lung injury, and susceptibility; we have brought together an interdisciplinary research team that encompasses expertise in lung surface chemistry, pathobiology and quantitative morphology, dosimetry, and extrapolation modeling. We have designed a highly interactive program that utilizes non-human primates (rhesus monkeys) and involves four interdependent projects and three cores. Our initial goals are to characterize the ELF-mediated generation of the local dose across age, exposure history, and airway sensitization; define the mechanisms of age-dependent susceptibility in the postnatal lung; characterize the determinants of airway remodeling as a function of acute versus episodic exposures; develop non-invasive biomarkers of lung injury utilizing the nose as a sentinel; and, formulate models that predict health outcomes across lung growth and airway sensitization. The program spans from molecular interactions to the intact primate, is highly relevant to the goals of NIEHS, 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.