Air Pollution Particle Effects on Human Antimycobacterial Immunity

空气污染颗粒物对人体抗分枝杆菌免疫的影响

• 批准号: 8538384
• 负责人: STEPHAN K SCHWANDER
• 金额: $ 4.66万
• 依托单位: UNIV OF MED/DENT NJ-SCH OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538384
• 关键词: 1-Nitropyrene; 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; 8-hydroxy-2' -deoxyguanosine; Abbreviations; Address; Air; Air Pollutants; Air Pollution; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Antimycobacterial Agents; Apoptosis; Bacteria; Biological Assay; Biological Markers; Biomass; Biostatistical Methods; Blood Cells; Body Burden; Bronchoalveolar Lavage; Caliber; Cell physiology; Cells; Cessation of life; Chinese Hamster; Chinese Hamster Ovary Cell; Cities; Colony-Forming Units Assay; Colony-forming units; Communities; Country; Development; Diesel Exhaust; Effector Cell; Environmental Pollutants; Epidemiologic Studies; Exposure to; Gene Expression; Gene Targeting; Grant; Growth; High Prevalence; Household; Human; IRF1 gene; Immune; Immune response; Immunity; Immunological Diagnosis; In Vitro; Incidence; Income; Individual; Indoor Air Pollution; Infection; Infectious Lung Disorder; Inflammatory; Institutes; Interferons; Knowledge; Lead; Link; Lipid Peroxidation; Lung; Lung diseases; Malignant Neoplasms; Malondialdehyde; Measurement; Measures; Mediating; Mexico; Mononuclear; Mycobacterium tuberculosis; NF-kappa B; National Cancer Institute; National Institute of Environmental Health Sciences; Necrosis; New Jersey; Occupational Exposure; Ovary; Oxidative Stress; Particulate Matter; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phagocytosis; Process; Production; Proxy; Pyrenes; Questionnaires; Reactive Oxygen Species; Recruitment Activity; Reporting; Risk; Risk Factors; Role; Signal Transduction; Silicon Dioxide; Site; Study Subject; Time; Toll-like receptors; Toxic effect; Tuberculin Test; Tuberculosis; World Health Organization; antimicrobial; base; burden of illness; chemokine; cigarette smoking; cytokine; enzyme linked immunospot assay; global health; in vivo; macrophage; migration; monocyte; mortality; oxidative DNA damage; particle; pathogen; pollutant; premature; receptor expression; scavenger receptor; time use; trafficking; urban ambient particulate matter; urinary

DESCRIPTION (provided by applicant): Air pollution and tuberculosis (TB) each contribute significantly to global disease burden as deteriorating air quality from rapid industrial growth and traffic collide with high levels of endemic TB in many parts of the world. Although epidemiological studies have shown associations of increased incidence of TB with cigarette smoking, occupational exposure to silica, or indoor air pollution, no studies to our knowledge have examined the role of urban air pollution exposure in the development of TB and underlying pathobiological mechanisms. The lungs are the primary portal of entry for fine urban particulate matter (PM2.5) and Mycobacterium tuberculosis (M.tb), the bacterium that causes TB, and the site of 85% of TB pathology. Studies evaluating PM2.5 effects on pathogen-specific innate and adaptive immune responses, particularly in the human lungs, are lacking. Our preliminary studies in primary human blood cells have shown that PM2.5 from diesel exhaust alters cytokine production and toll-like receptor (TLR)-mediated M.tb-specific cell activation pathways with suppression of several NF-kB and IRF-1-mediated target genes required for appropriate antimycobacterial host immune responses. Based on these studies, we hypothesize that exposure to PM2.5 impairs innate and adaptive antimycobacterial immune effector functions of primary human bronchoalveolar cells (BACs). Specific aims of this proposal are to examine i) PM2.5-induced cellular toxicity and PM2.5 effects on M.tb-specific immunity, ii) the role of PM2.5 in altering phagocytosis and growth control of M.tb by human BACs, and iii) personal in vivo PM2.5 exposure and its relationship to immune effector functions in BAC. These aims will be addressed as follows: PM2.5 will be collected and healthy M.tb-exposed and unexposed study subjects with and without immunodiagnostic evidence of latent M.tb infection recruited in a megacity known for its high prevalence of TB cases and high air pollution levels. PM2.5 effects will be studied on M.tb-induced pro- and anti-inflammatory cytokine production and gene expression, and on M.tb phagocytosis and growth control in BACs. Measurements of (1) urinary metabolites for major urban combustion pollutants and biomarkers of oxidative stress and (2) particulate matter load of alveolar macrophages and assessments of (3) time activity and (4) geographical indicators will be used to determine in vivo exposure of the study subjects. These parameters of exposure will be correlated with the antimycobacterial BAC effector functions using biostatistical methods. Thus, this proposal will address a crucial gap in knowledge about the effects of air pollution exposure on human antimicrobial lung immunity. PM2.5-induced alterations of innate and adaptive antimycobacterial immune responses may confer a major risk of loss of immunological control over M.tb infection. Given the wide geographical scales for both air pollution and M.tb infections, new knowledge to be gained from this study will have significant global health implications.

描述（由申请人提供）：空气污染和结核病（TB）各自对全球疾病负担有重大贡献，因为快速工业增长和交通导致的空气质量恶化与世界许多地区的高水平地方性结核病发生冲突。尽管流行病学研究表明结核病发病率的增加与吸烟、职业性二氧化硅暴露或室内空气污染有关，但据我们所知，还没有研究探讨城市空气污染暴露在结核病发展中的作用及其潜在的病理生物学机制。肺部是城市细颗粒物（PM2.5）和结核杆菌（M.tb）（导致结核病的细菌）的主要入口，也是85%结核病病理的发生部位。评估PM2.5对病原体特异性先天性和适应性免疫反应的影响，特别是在人类肺部，缺乏研究。我们在原代人血细胞中的初步研究表明，柴油机尾气中的PM2.5改变了细胞因子的产生和Toll样受体（TLR）介导的结核分枝杆菌特异性细胞活化途径，抑制了适当的抗分枝杆菌宿主免疫应答所需的几个NF-κ B和IRF-1介导的靶基因。基于这些研究，我们假设暴露于PM2.5会损害原代人支气管肺泡细胞（BAC）的先天性和适应性抗分枝杆菌免疫效应子功能。该提案的具体目的是检查i）PM2.5诱导的细胞毒性和PM2.5对结核分枝杆菌特异性免疫的影响，ii）PM2.5在改变人类BAC对结核分枝杆菌的吞噬作用和生长控制中的作用，以及iii）个人体内PM2.5暴露及其与BAC中免疫效应子功能的关系。这些目标将解决如下：PM2.5将被收集和健康的结核分枝杆菌暴露和未暴露的研究对象，有和没有免疫诊断证据的潜伏结核分枝杆菌感染招募在一个大城市，其结核病病例的高患病率和高空气污染水平。将研究PM2.5对结核分枝杆菌诱导的促炎和抗炎细胞因子产生和基因表达以及对结核分枝杆菌吞噬作用和BAC生长控制的影响。测量（1）主要城市燃烧污染物的尿液代谢物和氧化应激生物标志物，以及（2）肺泡巨噬细胞的颗粒物负荷，并评估（3）时间活动和（4）地理指标，以确定研究受试者的体内暴露量。使用生物统计学方法将这些暴露参数与抗结核杆菌BAC效应器功能相关。因此，该提案将解决空气污染暴露对人类抗微生物肺部免疫力影响的知识方面的关键空白。PM2.5诱导的先天性和适应性抗分枝杆菌免疫应答的改变可能赋予对结核分枝杆菌感染的免疫控制丧失的主要风险。鉴于空气污染和结核分枝杆菌感染的地理范围很广，从这项研究中获得的新知识将对全球健康产生重大影响。