PM exposure and changes in respiratory host defense responses

PM 暴露和呼吸道宿主防御反应的变化

• 批准号: 10320036
• 负责人: Neil Alexis
• 金额: $ 23.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-24 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320036
• 关键词: Acute; Address; Adverse effects; Affect; Age; Air Pollutants; Air Pollution; Area; Biochemical; Bioenergetics; Biological Products; Biological Response Modifiers; Bronchoalveolar Lavage; Cell physiology; Cells; Cessation of life; Child; China; Chinese; Chronic; Clinical; Collaborations; Collection; Country; Data; Disease; Epidemiology; Epithelial; Epithelial Cells; Equilibrium; Exposure to; Gene Expression; Genomics; Glycolysis; Health; Homeostasis; Host Defense; Human; Human Volunteers; Immune; Immune System Diseases; Immune system; Immunologic Markers; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Innate Immune Response; Invaded; Knowledge; Lead; Leukocytes; Life; Link; Lung; Measures; Mediating; Mediator of activation protein; Medical; Metabolism; Mitochondria; Modeling; Modification; Mucosal Immune Responses; Mucous Membrane; Nasal Epithelium; Nose; Oxidative Phosphorylation; Phenotype; Predisposition; Production; Respiration; Respiratory Mucosa; Respiratory System; Respiratory Tract Infections; Role; Sampling; Severities; Sputum; Structure of mucous membrane of nose; Surface; System; Translational Research; Universities; air sampling; airway immune response; antimicrobial; arm; base; cell type; defense response; epidemiology study; experimental study; fighting; fine particles; global health; healthy volunteer; immune function; immune health; immunoregulation; in vitro testing; in vivo; innovation; macrophage; monocyte; nasal microbiome; novel; pathogen; pollutant; premature; recruit; respiratory; response; volunteer

Project Summary It is well established that both acute and chronic exposure to PM significantly affects human health, causing 7 million premature deaths worldwide. It is becoming increasingly evident that PM modifies respiratory host defense responses, which would affect groups of all ages and could have significant implications for children with developing immune systems or susceptible individuals with pre-existing respiratory conditions. The host defense responses of the respiratory tract include innate resident immune cells, such as monocytes/macrophages, and epithelial cells, which provide the first line of defense in the airways against invading pollutants or pathogens. Pollutant-induced modifications of either or both of these components of respiratory host defense will have significant effects on the ability of the host airway to fight infections. While epidemiological studies have demonstrated the association between ambient PM exposure and enhanced susceptibility to infection, a critical knowledge gap exists regarding the mechanistic link between PM-induced immune dysfunction of epithelial cells and airway immune cells and in vivo evidence of respiratory immune health effects. The objective of this proposal is to address how PM modifies cellular mechanisms that are integral to maintaining respiratory immune function homeostasis and link these to observations made in humans in vivo. We hypothesize that PM samples collected during high (vs low) air pollution periods in China will 1) suppress respiratory immune function when tested in vitro (UNC), and 2) show similar deleterious effects when examined in vivo in exposed individuals in China (China collaborators). SA 1 will determine the effects of PM from China on epithelial cell immune and antiviral host defense function and identify the mechanisms mediating these responses. These studies will use our well-established system of differentiated human nasal epithelial cells, which will be exposed to PM collected in China and examined for changes in host defense function and bioenergetic modifications. SA 2 will determine PM-induced modifications of innate immune cell phenotype and functions and the mechanisms mediating these responses. These studies will use sputum and bronchoalveolar lavage macrophages acquired from healthy volunteers, and exposed to PM ex vivo, and examined for changes in immune cell phenotype and function. The role of PM-induced changes in bioenergetics will also be examined. The in vitro studies in SA1 and SA2 will be linked to human in vivo studies proposed in SA3. In SA3, one hundred volunteers from Xinxiang Medical University will be personal air samplers and undergo collection of nasal mucosal samples and induced sputum samples during high and low air pollution periods. Innate immune endpoints as described in SA1 and SA2 will be measured on the collected nasal and sputum samples in SA3.The data derived from these studies will yield important mechanistic information on PM-induced health effects to support current epidemiological associations. Furthermore, these data will address a clinical knowledge gap regarding global health implications for highly polluted and populated countries around the world.

项目摘要 众所周知，急性和长期暴露于PM都会显着影响人类健康，造成700万 全球过早死亡。 PM越来越明显地改变了呼吸道宿主防御反应，这 会影响各个年龄段的群体，并可能对患有免疫系统的儿童或 易感的人患有呼吸系统疾病。呼吸道的宿主防御反应包括 先天驻留的免疫细胞，例如单核细胞/巨噬细胞和上皮细胞，它们提供了第一道防线 在反对入侵污染物或病原体的气道中。污染物诱导的任何一个或两者的修改 呼吸宿主防御的组成部分将对宿主气道抗击感染的能力产生重大影响。 尽管流行病学研究表明环境PM暴露与增强之间的关联 对感染的敏感性，存在有关PM诱导的免疫之间的机械联系的关键知识差距 上皮细胞和气道免疫细胞功能障碍以及呼吸免疫健康作用的体内证据。这 该提案的目的是解决PM如何修饰细胞机制，这些机制是保持呼吸系统不可或缺的 免疫功能稳态，并将其与体内人类进行的观察联系起来。我们假设PM样品 在中国的高空气污染期（vs vs vs vs Low）期间收集1）在测试中抑制呼吸免疫功能 体外（UNC）和2）在中国暴露的个体（中国）在体内检查时显示出类似的有害影响 合作者）。 SA 1将确定来自中国对上皮细胞免疫和抗病毒宿主防御的影响 功能并确定介导这些反应的机制。这些研究将使用我们良好的系统 分化的人类鼻皮细胞将暴露于中国收集的PM，并检查 主机防御功能和生物能修改。 SA 2将确定PM引起的先天免疫的修饰 细胞表型和功能以及介导这些反应的机制。这些研究将使用痰液， 从健康志愿者那里获得的支气管肺泡灌洗巨噬细胞，并暴露于PM Ex Vivo，并检查了 免疫细胞表型和功能的变化。还将检查PM诱导的生物能量变化的作用。 SA1和SA2的体外研究将与SA3中提出的人体体内研究有关。在SA3中，一百个志愿者 来自Xinxiang医科大学将是个人空中抽样器，并收集鼻粘膜样品和 在高空气污染期间诱导的痰液样品。 SA1和SA2中所述的先天免疫端点 将根据SA的鼻和痰样品进行测量。从这些研究中得出的数据将产生重要 有关PM引起的健康效应的机械信息，以支持当前的流行病学关联。此外，这些 数据将解决有关高度污染和人口的全球健康影响的临床知识差距 世界各地。