Combustion Generated Particulate Pollution Affects Infant Respiratory Health

燃烧产生的颗粒物污染影响婴儿呼吸系统健康

• 批准号: 9181413
• 负责人: Stephania A Cormier
• 金额: $ 16.05万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2017-12-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181413
• 关键词: Acute; Address; Affect; Age; Animal Model; Area; Asthma; Cell Count; Cell physiology; Cells; Child; Childhood Asthma; Coculture Techniques; Data; Dendritic Cells; Disease; Epithelial; Epithelial Cells; Epithelium; Event; Exposure to; Free Radicals; Functional disorder; Host Defense; Immune response; Immune system; Impairment; Infant; Infant Mortality; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Interleukin-10; Knockout Mice; Link; Lower Respiratory Tract Infection; Lung; Lung diseases; Mediating; Mesenchymal; Mexico; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Neonatal; Oxidative Stress; PPBP gene; Particulate; Particulate Matter; Pathogenesis; Penetrance; Pharmacology; Phenotype; Play; Pollution; Population; Predisposition; Process; Production; Public Health; Publishing; Regulatory T-Lymphocyte; Reporter; Research; Risk; Rodent Model; Role; Severities; Severity of illness; Signal Transduction; Source; Study models; System; T cell response; Testing; Therapeutic Intervention; United States; Viral; Viral Load result; Virus Diseases; adaptive immune response; airway epithelium; beta catenin; cytotoxic; epidemiologic data; experimental study; flu; immune function; infancy; injured; mortality; mouse model; neonatal exposure; neonate; novel; pandemic disease; programs; public health relevance; reconstitution; repaired; respiratory health; response

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.

描述（由申请方提供）：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（LRTI）增加之间的因果关系。在H1N1流感（Flu）大流行期间，暴露于PM是在墨西哥和美国观察到的H1N1诱导的发病率和死亡率增加水平差异的潜在促成因素。有趣的是，由于PM暴露导致的LRTI风险在婴儿中最高。尽管有强有力的证据表明PM暴露与婴儿下呼吸道感染的易感性、发病率和死亡率有关;但对该主题的研究很少，而且这种现象背后的机制尚不清楚。我们已经开发了一种新的新生儿（<7日龄）啮齿动物模型研究PM暴露，我们在这里应用，以了解PM对增强LRTI和LRTI介导的疾病严重程度的易感性的影响。我们发现，暴露于PM的年龄是重要的，在预测下呼吸道感染疾病后遗症和婴儿暴露于PM发起了几个事件，可以解释的流行病学数据。 首先，新生小鼠暴露于PM导致上皮破坏。其次，新生儿PM暴露后的适应性免疫应答本质上是抑制性的（即IL 10和Treg细胞增加，Th 1、Tc 1和Th 17细胞数量减少），而不是保护性的。最终结果是流感介导的疾病的严重程度增加，如暴露于PM后感染的新生小鼠的肺病毒载量和死亡率增加所证明的。我们的数据进一步表明，PM诱导的上皮细胞相关或分泌的信号（即表免疫组）用于通过编程树突状细胞（DC）来指导这种异常的免疫应答。因此，我们假设婴儿期暴露于PM通过涉及表免疫组改变的过程增加了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将确定PM暴露诱导的下游调节性T细胞机制，其抑制对流感的免疫应答。我们的初步数据表明IL 10和调节性T细胞在增强的流感介导的疾病中的作用。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重建实验来检查IL 10在PM暴露增强的流感严重性中的必要性。目的3将确定来自PM改变的气道上皮的上游信号，这些信号决定了树突状细胞（DC）表型，而树突状细胞（DC）表型反过来又影响T细胞反应。这些研究将使用DC特异性β-连环蛋白敲除小鼠和我们最近开发的新生儿上皮：DC共培养系统来完成，以探索β-连环蛋白信号传导在DC功能中的作用。这些研究的完成将使我们了解受损上皮细胞和DC之间的分子信号传导事件，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环境诱导的LRTI所致哮喘急性发作的药理学靶点至关重要。