Combustion Generated Particulate Pollution Affects Infant Respiratory Health

描述（由申请人提供）：流行病学数据支持暴露于颗粒物（PM）水平升高与儿童下呼吸道感染（LRTIs）增加之间的因果关系。在H1N1流感大流行期间，暴露于PM是墨西哥和美国观察到的H1N1引起的发病率和死亡率水平增加的差异的一个潜在促成因素。有趣的是，由于PM暴露导致下呼吸道感染的风险在婴儿中最高。尽管有强有力的证据表明PM暴露与婴儿的LRTI易感性、发病率和死亡率有关；关于这个问题的研究很少，这种现象背后的机制也是未知的。我们开发了一种新的新生儿（<7d龄）啮齿动物模型来研究PM暴露，我们在此应用该模型来了解PM对LRTI易感性增强的影响以及LRTI介导的疾病严重程度。我们发现暴露于PM的年龄在预测LRTI疾病后遗症方面很重要，并且婴儿暴露于PM引发了一些可能解释流行病学数据的事件。首先，新生小鼠暴露于PM会导致上皮破坏。其次，新生儿暴露于PM后的适应性免疫反应本质上是抑制性的（即IL10和Treg细胞增加，Th1、Tc1和Th17细胞数量减少），而不是保护性的。最终结果是增强了流感介导疾病的严重程度，如暴露于PM后感染的新生小鼠肺部病毒载量和死亡率增加所证明的那样。我们的数据进一步表明，pm诱导的细胞相关或分泌的上皮信号（即外免疫组）通过编程树突状细胞（dc）来指导这种对流感的异常免疫反应。因此，我们假设在婴儿期暴露于PM会通过一个涉及表观免疫组改变的过程增加传染性呼吸道疾病的严重程度。目的1将检验新生儿暴露于PM抑制肺宿主对流感的防御并增强疾病的假设。目的2将定义PM暴露诱导抑制流感免疫反应的下游调节性T细胞机制。我们的初步数据表明，il - 10和调节性T细胞在流感介导的疾病中发挥作用。我们将首先使用报告小鼠确定PM诱导的il - 10的来源，并使用il - 10缺陷小鼠和il - 10重建实验检查PM暴露中il - 10增强流感严重程度的必要性。目的3将确定PM改变气道上皮的上游信号，这些信号指示树突状细胞（DC）表型，进而影响T细胞反应。这些研究将使用DC特异性的¿-catenin敲除小鼠和我们最近开发的新生儿上皮：DC共培养系统来探索¿-catenin信号在DC功能中的作用。这些研究的完成将使我们了解损伤上皮细胞和dc之间的分子信号事件，这对于了解PM暴露如何改变婴儿流感发病机制以及确定治疗LRTI引起的环境诱导哮喘加重的药理学靶点至关重要。

DESCRIPTION (provided by applicant): Epidemiological data support a causal link between exposure to elevated levels of particulate matter (PM) and increased lower respiratory tract infections (LRTIs) in children. During the H1N1 influenza (Flu) pandemic, exposure to PM was a potential contributing factor to the disparity in the increased levels of H1N1-induced morbidity and mortality observed in Mexico and the United States. Interestingly, the risk of LRTIs due to PM exposure is highest in infants. Despite strong evidence associating PM exposure and LRTI susceptibility, morbidity, and mortality in infants; there is very little research on this subject nd the mechanisms underlying this phenomenon are unknown. We have developed a novel neonatal (<7d of age) rodent model for studying PM exposures, which we apply here to understand the effects of PM on enhanced susceptibility to LRTI and LRTI-mediated disease severity. We show that age of exposure to PM is important in predicting LRTI disease sequela and that infant exposure to PM initiated several events that may explain the epidemiological data. First, exposure of neonatal mice to PM results in epithelial disruption. Second, adaptive immune responses following PM exposure in neonates are suppressive in nature (i.e. increased IL10 and Treg cells and decreased Th1, Tc1, and Th17 cell numbers) and not protective. The end result is enhanced severity of Flumediated disease as evidenced by increased pulmonary viral loads and mortality in neonatal mice infected following exposure to PM. Our data further suggest that PM-induced epithelial signals either cell associated or secreted (i.e. epimmunome) are used to direct this aberrant immune response to Flu by programming dendritic cells (DCs). Thus, we hypothesize that exposure to PM during infancy increases the severity of infectious respiratory disease through a process involving alteration of the epimmunome. Aim 1 will test the hypothesis that neonatal exposure to PM suppresses pulmonary host defense against Flu and enhances disease. Aim 2 will define downstream regulatory T cell mechanisms induced by PM exposure which suppress the immune response to Flu. Our preliminary data indicate a role for IL10 and regulatory T cells in enhanced Flu-mediated disease. We will first determine the source of PM-induced IL10 using reporter mice and examine the necessity for IL10 in PM exposure enhanced Flu severity using IL10 deficient mice and IL10 reconstitution experiments. Aim 3 will determine the upstream signals from PM altered airway epithelium that dictate dendritic cell (DC) phenotype which in turn influences T cell responses. These studies will be accomplished using DC specific ¿-catenin knockout mice and our recently developed neonatal epithelial:DC co-culture system to explore the role of ¿-catenin signaling in DC function. Completion of these studies will provide us with an understanding of the molecular signaling events between injured epithelial cells and DCs crucial to understand how PM exposure alters Flu pathogenesis in infants and to identify pharmacologic targets for the treatment of environmentally-induced asthma exacerbations due to LRTI.