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: 10113618
• 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/10113618
• 关键词: Acute; Address; Adverse effects; Affect; Age; Air Pollutants; Air Pollution; Antiviral Agents; Area; Biochemical; Bioenergetics; Biological; Biological Response Modifiers; Bronchoalveolar Lavage; Cell physiology; Cells; Cessation of life; Child; China; Chinese People; 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 response; 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; 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，急性和长期接触PM都会严重影响人类健康，造成700万人 全球范围内的过早死亡。越来越明显的是，PM改变了呼吸道宿主的防御反应，这 会影响所有年龄段的群体，并可能对免疫系统发育中的儿童或 既往有呼吸道疾病的易感人群。呼吸道的宿主防御反应包括 天然常驻免疫细胞，如单核/巨噬细胞和上皮细胞，提供了第一道防线 在呼吸道中抵抗入侵的污染物或病原体。污染物引起的其中一个或两个的修改 呼吸道宿主防御的组成部分将对宿主呼吸道抵抗感染的能力产生重大影响。 虽然流行病学研究表明暴露在环境中的PM与增强的 对于感染的易感性，关于PM诱导的免疫之间的机制联系存在着关键的知识缺口 上皮细胞和呼吸道免疫细胞功能障碍和呼吸道免疫健康影响的活体证据。这个 这项提案的目的是解决PM如何修改维持呼吸不可或缺的细胞机制 免疫功能动态平衡，并将这些与人体活体观察联系起来。我们假设PM样本 中国在高(低)空气污染期间收集的数据将1)在测试中抑制呼吸道免疫功能 体外(UNC)，以及2)在中国(中国)暴露的个人体内检测时显示出类似的有害效应 合作者)。SA-1将确定中国颗粒剂对上皮细胞免疫和抗病毒宿主防御的影响 发挥作用，并确定调解这些反应的机制。这些研究将使用我们完善的系统 分化的人鼻上皮细胞，暴露于中国采集的PM并观察其变化 宿主防御功能和生物能量修饰。SA 2将确定PM诱导的天然免疫修饰 细胞的表型和功能以及调节这些反应的机制。这些研究将使用痰和 从健康志愿者获得的支气管肺泡灌洗巨噬细胞，体外暴露于PM，并检查 免疫细胞表型和功能的变化。还将研究PM引起的生物能量学变化的作用。 SA1和SA2的体外研究将与SA3中提出的人体体内研究联系起来。在SA3,100名志愿者 来自新乡医科大学的将是个人空气采样器，接受鼻黏膜样本的采集和 空气污染高峰和低峰期的诱导痰样本。SA1和SA2中描述的先天免疫终点 将在SA3收集的鼻腔和痰样本上进行测量。来自这些研究的数据将产生重要的 关于PM引起的健康影响的机械性信息，以支持当前的流行病学关联。此外，这些 数据将解决有关高污染和人口稠密国家的全球健康影响的临床知识差距 环游世界。