Diesel Exhaust Particle Modulation of Inflammation

描述（由申请人提供）：暴露于高水平的空气污染显然有助于增加发病率和死亡率。这些健康影响的统计关联是特别好的相关性与暴露于高水平的颗粒材料的平均空气动力学直径小于2.5？m（PM2.5）。虽然造成这一部分的来源取决于当地环境，但这些颗粒大多数是燃烧产物。在城市地区，柴油机排气颗粒（DEP）通常是这种受管制污染物的主要成分。因此，人们对柴油机尾气和DEP的生物反应进行了广泛的研究。在受控的人体暴露研究和动物模型中，DEP明显诱导肺部炎症，至少部分是通过增加中性粒细胞化学吸引分子的表达。初步研究表明，人类趋化因子IL-8和啮齿动物趋化因子MIP-2与DEP相关，并且相关的趋化因子具有生物活性。该提议的工作假设是，这种新的关联（a）使趋化因子浓缩，导致嗜中性粒细胞的局部活化增加，和（B）延长趋化因子在肺中的半衰期，导致持续的炎症反应。这个建议的具体目标是首先，定义这种关联的机制，其次，确定这种关联如何影响对趋化因子的生物反应。定义协会的机制将通过化学和物理分析的DEP特性，有助于结合，并分析协会和释放动力学。对该联合的生物学效应的分析将利用对趋化因子、DEP和DEP-趋化因子复合物的炎症反应的体外和体内测定。这些研究将补充其他实验室正在进行的研究，这些研究侧重于DEP诱导的趋化因子产生的机制，通过表征这种创新机制，这些颗粒可能会增强对趋化因子的炎症反应。

DESCRIPTION (provided by applicant): Exposure to high levels of air pollution clearly contributes to increased morbidity and mortality. The statistical association of these health effects is especially well correlated with exposure to high levels of particulate material with a mean aerodynamic diameter less than 2.5 ?m (PM2.5). Although the sources that contribute to this fraction depend on the local environment, most of these particles are combustion products. In urban areas, diesel exhaust particles (DEP) are often a major constituent of this regulated pollutant. For this reason, the biological responses to diesel exhaust and DEP have been extensively studied. DEP clearly induce pulmonary inflammation in controlled human exposure studies and animal models, at least partly through increased expression of neutrophil chemattractant molecules. Preliminary studies indicate that the human chemokine IL-8 and the rodent chemokine MIP-2 associate with DEP and that the associated chemokine is biologically active. The working hypotheses for this proposal are that this novel association (a) concentrates the chemokine resulting in increased localized activation of neutrophils and (b) prolongs the half-life of the chemokine in the lung resulting in a sustained inflammatory response. The specific aims of this proposal are first, to define the mechanisms of this association and second, to determine how the association affects the biological response to the chemokine. Defining the mechanisms of the association will be approached through chemical and physical analyses of the DEP characteristics that contribute to the binding, and analyses of the association and release kinetics. Analysis of the biological effects of the association will utilize in vitro and in vivo assays of the inflammatory responses to the chemokines, the DEP, and the DEP-chemokine complex. These studies will complement ongoing studies in other laboratories, which focus on the mechanisms for DEP-induced chemokine production, by characterizing this innovative mechanism by which these particles might potentiate the inflammatory responses to the chemokines.