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会增加发病率和死亡率。这些健康影响的统计关联尤其与暴露于平均空气动力学直径小于2.5的高水平颗粒物质密切相关。米(PM2.5)。虽然造成这一比例的来源取决于当地环境，但这些颗粒中的大多数是燃烧产物。在城市地区，柴油废气颗粒（DEP）往往是这一受管制污染物的主要组成部分。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。在对照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引诱分子的表达。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，且相关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)集中了趋化因子，导致中性粒细胞的局部活化增加，(b)延长了趋化因子在肺部的半衰期，导致持续的炎症反应。本提案的具体目的是首先确定这种关联的机制，其次确定这种关联如何影响对趋化因子的生物反应。通过化学和物理分析导致结合的DEP特征，以及分析结合和释放动力学，可以确定这种结合的机制。该关联的生物学效应分析将利用体外和体内对趋化因子、DEP和DEP趋化因子复合物的炎症反应的分析。这些研究将补充其他实验室正在进行的研究，这些研究的重点是depp诱导趋化因子产生的机制，通过表征这些颗粒可能增强对趋化因子的炎症反应的创新机制。

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.