Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice

摘要 肺炎是5岁以下儿童死亡的主要原因，也是最常见的 这是发展中国家儿童死亡的主要原因。每年估计有1.5亿例 全球儿童肺炎的流行每年导致大约一百万儿童死亡。虽然 疫苗和抗生素显著改善了下呼吸道感染的大龄儿童的预后 在受感染的儿童中，婴儿和幼儿的发病率和死亡率最高， 肺炎此外，儿童肺炎的长期影响可导致肺功能受损， 慢性阻塞性肺疾病的发病率是慢性阻塞性肺疾病的发病率。 考虑到这些非常重要的医疗和公共卫生成果，需要更深入地- 深入了解新生儿/婴儿肺部对肺炎的免疫反应。需要进一步解决的问题 研究包括：确定调节免疫应答中年龄和性别差异机制 下呼吸道感染（LRTI），这些变量如何影响短期和长期结果， LRTI以及是否可以改变肺部免疫反应的调节因子以减轻疾病 新生儿和幼儿的严重程度。从而确定可以增强新生儿免疫力的方法 下呼吸道疾病期间的系统可以潜在地改善结果。 我们的初步研究表明，新生儿肺CD 4 + T细胞对LRT E反应低下。杆菌 由于CD 4 + T细胞对于宿主对LRTI的反应性至关重要，如遗传和获得性免疫学所证实的， 缺乏，我们将重点关注新生儿CD 4 + T细胞反应性的调节机制， 肺。在本提案中，我们将以先前提案支持的研究为基础， 肺CD 4 + T细胞对E.大肠杆菌肺炎。我们将研究DNA的作用 甲基化组在调节新生儿肺CD 4 + T细胞对肺炎的反应中的作用， 甲基转移酶抑制剂可以破坏正常新生儿CD 4 + T细胞对LRTI的反应。最后我们将 检查成人H1N1呼吸结果的性别特异性差异是否由差异决定 CD 4 + T细胞基因中启动子位点的甲基化对宿主对流感的反应至关重要。在目标1中， 我们将重点关注CD 4 + T细胞来源的IL-22、IFN γ和AREG，以确定它们在肺的宿主反应中的作用 对新生儿和青少年的下呼吸道感染在目标2a中，我们将研究DNA甲基化组在调节 新生儿和青少年肺中的CD 4 + T细胞反应性在目标2b中，我们将确定是否暴露于LRT E。 在儿童期接种大肠杆菌可以改变成年人的肺CD 4 + T细胞反应性， 流感，通过DNA甲基化启动子位点的变化。这些研究将提供 对LRTI结果中年龄相关差异和儿童期细菌感染影响的机制性见解 暴露对成人肺部感染免疫反应的影响。

ABSTRACT Pneumonia is a leading cause of death in children less than 5 years of age and it is the most common cause of mortality in children living in developing countries. Each year there are an estimated 150 million cases of childhood pneumonia worldwide resulting in approximately one million children dying each year. Although vaccines and antibiotics have dramatically improved outcomes in older children with lower respiratory tract infections, infants and young children disproportionately suffer from the highest morbidity and mortality from pneumonia. In addition, the long-term effects of childhood pneumonia can lead to impaired lung function in adult life and increase the risk of developing chronic obstructive lung disease. With these highly significant medical and public health outcomes in mind, there is a need for a more in- depth understanding of the neonate/infant lung immune response to pneumonia. Questions that require further investigation include; identifying mechanisms that regulate age and sex differences in immune responsiveness to lower respiratory tract infections (LRTI), how these variables influence short and long-term outcomes to LRTIs and whether regulators of immune responsiveness in the lung can be altered to attenuate disease severity in the neonate and young child. Thus identifying approaches that can boost the neonatal immune system during lower respiratory tract illnesses could potentially improve outcomes. Our preliminary studies indicate that lung CD4+ T cells in neonates are hypo-responsive to LRT E. coli. Since CD4+ T cells are critically important for host responsiveness to LRTI as evident by genetic and acquired deficiencies, we will focus on regulatory mechanisms that underlie CD4+ T cell responsiveness in neonatal lung. In this proposal, we will build on studies supported by our previous proposal, to examine age-related differences in lung CD4+ T cell responsiveness to E. coli pneumonia. We will examine the role of the DNA methylome in regulating neonatal lung CD4+ T cell responses to pneumonia and determine if DNA methyltransferase inhibitors can disrupt the normal neonatal CD4+ T cell response to LRTI. Finally, we will examine if sex-specific differences in respiratory outcomes to H1N1 in adults are determined by differential methylation of promoter sites in CD4+ T cell genes that are critical to the host response to influenza. In aim 1, we will focus on CD4+ T cell-derived IL-22, IFN, and AREG to determine their role in the lung’s host response to LRTIs in the neonate and juvenile. In aim 2a, we will examine the role of the DNA methylome in regulating CD4+ T cell responsiveness in neonatal and juvenile lung. In aim 2b, we will determine if exposure to LRT E. coli during childhood can alter lung CD4+ T cell responsiveness in a sex-specific manner in adults with influenza, through changes in DNA methylation promoter sites. Together, these studies will provide mechanistic insights into age-related differences in LRTI outcomes and the influence of childhood bacterial exposures on the immune response to lung infections in adults.