Mechanism of Species Dependent Environmental Lung Injury

相当一部分美国人口继续暴露在臭氧（O3）等有害空气污染物中。尽管多年来进行了大量的研究工作，但暴露相关肺损伤的机制、控制易感性的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暴露于O3会导致肺部生长、结构和功能的深刻改变，并加剧反应性气道疾病的发展。因为O3会与上皮组织的液体成分发生反应

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.