Mechanisms of particulate matter driven infant respiratory disease

项目摘要 子宫内暴露于环境颗粒物（PM）空气污染与增加的较低 婴儿呼吸道感染（LRTI）。尽管已知胎儿对环境的敏感性 与产前PM暴露和LRTI发病率相关的污染物和流行病学证据， PM增强的发病机制在免疫不成熟人群中相对未被探索。初步 来自我们新的宫内小鼠暴露模型的数据表明， 在子宫内暴露于PM以产生强烈的炎症反应。根据这些数据和类似的结果， 我们的新生儿（即，<7日龄）暴露模型，表明以下呼吸道感染严重程度增加 早期生活暴露于空气污染，我们假设这个免疫抑制窗口与以下因素相关： 后代对严重呼吸道合胞病毒（RSV）疾病的易感性。RSV感染代表一种 严重导致婴儿呼吸道疾病和死亡。已知其发病机制受到类似 受PM诱导的氧化应激影响的途径，即核因子红细胞2相关转录 因子（Nrf2）抗氧化反应途径。影响母体Nrf2信号传导的多态性最近被发现， 据报道，在子宫内暴露于PM的婴儿中，LRTI风险增加。因此，为了验证我们的假设， 母体对氧化应激的反应能力对后代RSV疾病严重程度的影响，我们将进行 项目的两个具体目标。在目标1中，我们将联合收割机结合我们的新型宫内暴露模型与 我们充分表征的RSV感染的新生小鼠模型来表征RSV感染的严重性。 具体来说，我们将确定肺T细胞谱的改变如何影响后代的适应性免疫， 应答在目标2中，我们将使用Nrf2缺陷型和野生型小鼠来研究母体Nrf2的作用。 表达对后代肺氧化应激反应的影响，以宫内PM和RSV易感性。我们 将进一步探索Nrf2的保护作用，通过母体膳食补充剂与已知的Nrf2 诱导剂。这项研究的结果将为理解基因间的相互作用提供重要的见解。 和RSV感染的免疫发病机制的环境决定因素。这些发现将有助于确定 易感儿童亚组，并建立针对Nrf2反应途径的原理验证 在暴露于空气污染的母亲中，为了防止儿童呼吸道疾病， 影响到全世界数百万儿童健康问题。

Project Summary Intrauterine exposure to ambient particulate matter (PM) air pollution has been associated with increased lower respiratory tract infections (LRTIs) in infants. Despite the known sensitivity of the fetus to environmental pollutants and epidemiological evidence correlating prenatal PM exposure and LRTI morbidity, mechanisms of PM enhanced pathogenesis are relatively unexplored in immunologically immature populations. Preliminary data from our novel intrauterine murine exposure model demonstrate the reduced ability of immature offspring exposed to PM in utero to develop a robust inflammatory response. Based on these data and similar results in our neonatal (i.e., <7 days of age) exposure model indicating increased respiratory infection severity following early life exposure to air pollution, we hypothesized this window of immunosuppression correlates with offspring susceptibility to severe respiratory syncytial virus (RSV) disease. RSV infection represents a significant cause infant respiratory morbidity and mortality. Its pathogenesis is known to be impacted by similar pathways affected by PM-induced oxidative stress, namely the nuclear factor erythroid 2-related transcription factor (Nrf2) antioxidant response pathway. Polymorphisms impacting maternal Nrf2 signaling have recently been reported to increase LRTI risk in infants exposed to PM in utero. Thus, to test our hypothesis and clarify the impact of maternal ability to respond to oxidative stress on offspring RSV disease severity, we will carry out two specific aims in the proposed project. In Aim 1, we will combine our novel intrauterine exposure model with our well-characterized neonatal mouse model of RSV infection to characterize RSV infection severity. Specifically, we will determine how altered pulmonary T cell profiles influence offspring adaptive immune responses. In Aim 2, we will use Nrf2-deficient and wild-type mice to investigate the role of maternal Nrf2 expression on offspring pulmonary oxidative stress responses to intrauterine PM and RSV susceptibility. We will further probe the protective role of Nrf2 through maternal dietary supplementation with a known Nrf2 inducer. Outcomes from this research will provide important insight to understand interactions between genetic and environmental determinants of immunopathogenesis of RSV infection. These findings will aid in identifying susceptible subgroups of children and establish the proof-of-principle for targeting the Nrf2 response pathway in mothers exposed to air pollution for the protection against childhood respiratory disease, a pervasive public health problem affecting millions of children worldwide.