Combustion Generated PM0.1 and Predisposition to Asthma

描述(由申请人提供)： 在过去十年中，哮喘等炎症性呼吸道疾病的发生急剧增加。这一增长率超过了基因漂移本身所能解释的范围，这表明了环境的作用。许多假说试图通过列举更好的卫生、环境污染、病毒呼吸道感染和/或农村生活方式中发现的一些保护作用的丧失来解释这一现象，这些都是疾病开始和恶化的罪魁祸首。这项建议旨在确定在新生儿早期接触超细颗粒物(PM0.1)是否会导致成人易患、发展或加重过敏性呼吸道疾病。我们的假设是，危险废物燃烧/热降解产生的PM0.1含有持久的、表面稳定的自由基，在新生儿中，这些自由基与上皮-粘膜表面相互作用，调节适应性免疫反应，导致成人呼吸道疾病，如哮喘。在短期内，这项建议将通过实现以下具体目标来探索这一假说的有效性：1)使用生化和蛋白质组方法表征PM0.1在肺内产生氧化应激的能力；2)确定PM0.1对新生大鼠肺病理生理学的影响；以及3)阐明PM0.1诱导的活性氧增加导致成年大鼠肺和/或免疫功能障碍的细胞和分子事件。我们实验室的长期目标是了解肺气道病早期免疫学和病理生理学改变的始发者，并最终了解哮喘的根本原因，以便开发更有效的干预和治疗方法。拟议研究的完成将深入了解废物的燃烧/热降解如何影响儿童炎症性呼吸道疾病的发展，并期望有效地推断人类炎症性呼吸道疾病，如哮喘。这些研究的结果不仅对公众健康有重要影响，而且对公共环境政策也有重要影响，因为目前还没有PM0.1的空气质量标准。

DESCRIPTION (provided by applicant): The occurrence of inflammatory respiratory diseases, such as asthma, has increased dramatically in the past decade. This rate of increase is more than can be accounted for by genetic drift alone and suggests a role for the environment. Many hypotheses attempt to explain this phenomenon by citing better hygiene, environmental pollution, viral respiratory tract infections, and/or loss of some protective effect found in a rural lifestyle as culprits in disease initiation and exacerbation. This proposal seeks to determine if exposure during early neonatal life to ultrafine particles (PM0.1) typically produced from thermal remediation of hazardous wastes leads to predisposition, development of, or exacerbation of allergic respiratory disease in the adult. Our hypothesis is that PM0.1 generated from the combustion/thermal degradation of hazardous wastes contains persistent, surface-stabilized free radicals that in neonates interact with epithelial-mucosal surfaces and modulate the adaptive immune response leading to adult airways disease such as asthma. In the short term, this proposal will explore the validity of this hypothesis by accomplishing the following specific aims: 1) characterize the ability of PM0.1 to produce oxidative stress within the lung using biochemical and proteomic approaches; 2) define the impact of PM0.1 on pulmonary pathophysiology of neonatal rats; and 3) elucidate the cellular and molecular events by which PM0.1-induced increases in reactive oxygen species lead to pulmonary and/or immune dysfunction in adults. The long-term objective of our laboratory is to realize the initiators of the immunological and pathophysiological changes that occur during the early stages of pulmonary airways disease and ultimately to understand the fundamental causes of asthma so that more effective interventions and therapy may be developed. Completion of the proposed studies will provide insight into how combustion/thermal degradation of waste affects the development of inflammatory airways disease in children with the expectation of valid extrapolation to human inflammatory airways disease, such as asthma. The outcome of these studies will not only have important implications for public health but also for public environmental policy, since currently there are no air quality standards for PM0.1.