Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice

新生小鼠弥漫性炎症性肺损伤的解决

• 批准号: 10226540
• 负责人: Sharon Ann McGrath-Morrow
• 金额: $ 45.41万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226540
• 关键词: 5 year old; Acute Lung Injury; Adolescent; Adoptive Cell Transfers; Adoptive Transfer; Adult; Age; Amphiregulin; Antibiotics; Antigen-Presenting Cells; Antigens; Attenuated; Bacteria; Bacterial Pneumonia; Biological Response Modifiers; CD4 Positive T Lymphocytes; Cause of Death; Cell Lineage; Cells; Child; Childhood; Chronic Obstructive Airway Disease; Clinical; DNA; DNA Methylation; DNA Methyltransferase Inhibitor; Data; Developing Countries; Development; Diffuse; Disease; Disease Outcome; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelial; Epithelium; Escherichia coli; Escherichia coli Infections; Exposure to; FOXP3 gene; Gene Expression; Gene Expression Profile; Genes; Genetic; Growth; IL2RA gene; Immune; Immune Response Genes; Immune response; Impairment; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Interferons; Investigation; Knockout Mice; Lead; Life; Ligands; Long-Term Effects; Lower Respiratory Tract Infection; Lower respiratory tract structure; Lung; Lung Inflammation; Lung infections; Medical; Methylation; Mind; Morbidity - disease rate; Mus; Neonatal; Outcome; Pathway interactions; Phenotype; Pneumonia; Public Health; Recovery; Regulation; Regulatory T-Lymphocyte; Reporting; Resolution; Respiratory physiology; Risk; Role; Severity of illness; Sex Differences; Site; T cell response; T-Lymphocyte; Testing; Time; Translating; Up-Regulation; Vaccines; Weight Gain; age difference; age related; antimicrobial; base; cytokine; early childhood; early life exposure; effector T cell; genome-wide; immunoregulation; improved; improved outcome; inhibitor/antagonist; insight; interleukin-22; lung injury; lung repair; methylome; mortality; neonatal immune system; neonate; pathogen; personalized approach; promoter; repaired; respiratory; response; sex; transcriptome sequencing

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.

摘要 肺炎是5岁以下儿童死亡的主要原因，也是最常见的。 生活在发展中国家的儿童死亡的原因。据估计，每年有1.5亿个病例 儿童肺炎在全世界每年造成约100万名儿童死亡。虽然 疫苗和抗生素极大地改善了患有下呼吸道的大龄儿童的预后 感染、婴幼儿发病率和死亡率最高的是 肺炎。此外，儿童肺炎的长期影响可导致儿童肺功能受损。 并增加患慢性阻塞性肺病的风险。 考虑到这些非常重要的医疗和公共卫生后果，有必要更多地- 深入了解新生儿/婴儿对肺炎的肺免疫反应。需要进一步解决的问题 研究包括：确定调节免疫反应性年龄和性别差异的机制 对于下呼吸道感染(LRTI)，这些变量如何影响短期和长期结果 肺内免疫反应调节因子是否可被改变以减轻疾病 新生儿和幼儿的严重程度。从而确定可以提高新生儿免疫力的方法 在下呼吸道疾病期间，预防和控制呼吸道疾病可能会改善预后。 我们的初步研究表明，新生儿肺内的CD4+T细胞对LRT-E.Coli反应迟钝。 由于CD4+T细胞对宿主对LRTI应答至关重要，这在遗传和获得性方面是显而易见的 缺陷，我们将重点研究新生儿CD4+T细胞反应性的调节机制 阿龙。在这项提案中，我们将在先前提案所支持的研究的基础上，审查与年龄有关的 肺内CD4+T细胞对大肠杆菌肺炎反应性的差异。我们将研究DNA的作用 甲基组在调节新生儿肺内CD4+T细胞对肺炎反应中的作用及DNA检测 甲基转移酶抑制剂可以破坏新生儿正常的CD4+T细胞对LRTI的反应。最后，我们会 检查不同性别的成年人感染H1N1病毒后的呼吸结果是否由性别差异决定 CD4+T细胞基因中对宿主对流感反应至关重要的启动子位置的甲基化。在目标1中， 我们将重点研究CD_4+T细胞衍生的IL-22、干扰素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甲基组在调节 新生儿和青少年肺组织中CD_4~+T细胞的反应性在目标2b中，我们将确定是否暴露于LRT E。 儿童时期的大肠杆菌可以性别特异性的方式改变成人肺脏CD4+T细胞的反应性 流感，通过DNA甲基化启动子位置的变化。总而言之，这些研究将提供 对与年龄相关的LRTI结局差异和儿童细菌影响的机制洞察 暴露于成人肺部感染的免疫反应。