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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要众所周知，急性和慢性接触 PM 都会严重影响人类健康，导致 700 万人死亡全球过早死亡。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儿童产生重大影响患有呼吸道疾病的易感人群。呼吸道的宿主防御反应包括先天常驻免疫细胞，例如单核细胞/巨噬细胞和上皮细胞，提供第一道防线在呼吸道中抵抗污染物或病原体的入侵。污染物引起的其中一个或两个的改变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。虽然流行病学研究已经证明环境 PM 暴露与增强感染易感性，关于 PM 诱导的免疫之间的机制联系存在一个关键的知识差距上皮细胞和气道免疫细胞的功能障碍以及呼吸道免疫健康影响的体内证据。这该提案的目的是解决 PM 如何改变维持呼吸系统不可或缺的细胞机制免疫功能稳态并将其与人体体内的观察结果联系起来。我们假设 PM 采样在中国空气污染严重（与低度）期间收集的病毒将 1）在测试中抑制呼吸道免疫功能体外（UNC）和2）在对中国暴露个体进行体内检查时显示出类似的有害影响（中国合作者）。 SA 1将确定来自中国的PM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介导这些反应的机制。这些研究将使用我们完善的系统分化的人鼻上皮细胞，将其暴露于在中国收集的PM并检查其变化宿主防御功能和生物能修饰。 SA 2 将确定 PM 诱导的先天免疫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和从健康志愿者处获得支气管肺泡灌洗巨噬细胞，并离体暴露于 PM，并检查免疫细胞表型和功能的变化。还将研究 PM 引起的生物能学变化的作用。 SA1和SA2中的体外研究将与SA3中提出的人体体内研究相关联。在 SA3 中，一百名志愿者新乡医科大学的个人空气采样器将进行鼻粘膜样本的采集和在空气污染高和低的时期诱导痰样本。 SA1 和 SA2 中描述的先天免疫终点将在 SA3 中对收集的鼻腔和痰液样本进行测量。从这些研究中得出的数据将产生重要的结果有关 PM 引起的健康影响的机制信息，以支持当前的流行病学关联。此外，这些数据将解决对高污染和人口稠密国家的全球健康影响的临床知识差距世界各地。