Mechanisms of particulate matter driven infant respiratory disease

项目摘要 宫内暴露于环境颗粒物(PM)空气污染与更低的 婴儿呼吸道感染(LRTI)。尽管已知胎儿对环境的敏感性 污染物和流行病学证据与产前PM暴露和LRTI发病率的相关性， 在免疫不成熟的人群中，PM增强的发病机制相对尚不清楚。初步 来自我们新的小鼠宫内暴露模型的数据表明，未成熟后代的能力降低 在子宫内暴露于PM会产生强烈的炎症反应。基于这些数据和类似的结果 我们的新生儿(即7日龄)暴露模型显示以下呼吸道感染严重程度增加 早年暴露在空气污染中，我们假设这一免疫抑制窗口与 后代对严重呼吸道合胞病毒(RSV)疾病的易感性。RSV感染代表着一种 主要原因是婴儿呼吸道发病率和死亡率。已知其发病机制受类似的 PM诱导氧化应激影响的途径，即核因子红系2相关转录 因子(Nrf2)抗氧化反应途径。最近，影响母体Nrf2信号转导的基因多态性 据报道，在子宫内暴露于PM的婴儿会增加LRTI风险。因此，为了检验我们的假设并澄清 母体应对氧化应激能力对子代RSV疾病严重程度的影响，我们将开展 拟议项目中的两个具体目标。在目标1中，我们将把我们的新型宫内暴露模型与 我们建立了具有良好特性的新生小鼠RSV感染模型，以表征RSV感染的严重程度。 具体地说，我们将确定改变的肺T细胞特征如何影响后代的获得性免疫 回应。在目标2中，我们将使用Nrf2缺陷和野生型小鼠来研究母体Nrf2的作用 子代肺氧化应激对宫内PM和RSV易感性的表达我们 将通过母体饮食补充已知的Nrf2进一步探讨Nrf2的保护作用 诱导者。这项研究的结果将为理解基因之间的相互作用提供重要的见解 以及RSV感染免疫致病机制的环境决定因素。这些发现将有助于确定 并建立靶向Nrf2反应通路的原则证明 在暴露于空气污染中的母亲中，为预防儿童呼吸道疾病，公众普遍存在 影响全球数百万儿童的健康问题。

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.