Key Events in Modulation of Lung Infection Susceptibility by Nanomaterials

项目摘要 我们已经表明，某些类型的工程纳米材料（ENM）诱导氧化应激，改变 巨噬细胞基因调控和吞噬功能，增加小鼠对链球菌的易感性 肺炎，社区获得性肺炎的主要原因。肺炎的风险增加是一个主要的 与人类暴露于超细环境颗粒物相关的健康结果，特别是在 老人我们的目标是开发和测试一个框架，用于预测ENM对感染易感性的影响， 使用基于机制的巨噬细胞功能体外测定。我们假设暴露于ENM 损害先天免疫功能，并通过氧化还原介导的 改变巨噬细胞极化和损害病原体的吞噬清除的信号传导机制。我们 还提出蛋白S-谷胱甘肽化（SSG），蛋白氧化修饰的主要形式， 调节先天免疫的多个方面，作为ENM毒性的分子主动事件做出贡献。要求1 将使用新的氧化还原蛋白质组学方法来鉴定ENMs诱导的SSG的蛋白质靶点， 对这些修饰最敏感的通路。目的2将确定巨噬细胞转录 途径的影响，以及如何暴露于ENMs调节吞噬活性对S。肺炎 我们将研究如何最强大的SSG修饰和mRNA通路受ENM的影响是共同的， 调节，并开发灵敏的测定方法来在体外和体内定量这些标志物。目标3将测试是否 目的1-2中鉴定的巨噬细胞功能和途径标志物的体外测定准确预测是否 吸入暴露于ENM调节用S. 肺炎先进的纳米材料剂量测定模型将用于推导等效的人体暴露量 这将是导致这些影响所需的水平。准确预测不良结局的能力 来自基于机制的体外研究的ENM将改变新兴ENM的危害和风险方法， 并且解决了与环境颗粒暴露相关的更广泛的人类健康问题。

PROJECT SUMMARY We have shown that some types of engineered nanomaterials (ENMs) induce oxidative stress, alter macrophage gene regulation and phagocytic function, and increase the susceptibility of mice to Streptococcus pneumonia, the leading cause of community-acquired pneumonia. Increased risks of pneumonia are a major health outcome associated with human exposure to ultrafine environmental particulates, particularly in the elderly. Our goal is to develop and test a framework for prediction of ENM effects on infection susceptibility, using mechanism-based in vitro assays of macrophage function. We hypothesize exposure to ENMs compromises innate immune function and enhances susceptibility to lung infections through redox-mediated signaling mechanisms that alter macrophage polarization and impair phagocytic clearance of pathogens. We also propose that protein S-glutathionylation (SSG), a major form of protein oxidative modification that regulates multiple aspects of innate immunity, contribute as molecular initiative events for ENM toxicity. Aim 1 will use novel redox protoemics methods to identify the protein targets of SSG induced by ENMs and the major pathways that are most sensitive to these modifications. Aim 2 will identify macrophage transcriptional pathways impacted by ENMs and how exposure to ENMs modulate phagocytic activity toward S. pneumonia. We will investigate how the most robust SSG modifications and mRNA pathways affected by ENMs are co- regulated, and develop sensitive assays to quantify these markers in vitro and in vivo. Aim 3 will test whether in vitro assays for macrophage function and pathway markers identified in Aims 1-2 accurately predict whether inhalation exposure to ENMs modulates lung infections in both young and aged mice challenged with S. pneumonia. Advanced nanomaterial dosimetry models will be used to derive equivalent human exposure levels that would be required to induce these effects. The ability to accurately predict adverse outcomes of ENMs from mechanism-based in vitro studies will transform hazard and risk approaches for emerging ENMs, and addresses a broader human health problem associated with environmental particulate exposures.