Combustion Generated PM0.1 and Predisposition to Asthma

描述（由申请人提供）：

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.