PM exposure and changes in respiratory host defense responses

项目摘要 众所周知，急性和慢性暴露于PM都会显著影响人类健康， 全球过早死亡越来越明显的是，PM改变呼吸道宿主的防御反应， 会影响所有年龄段的人群，并可能对免疫系统发育的儿童产生重大影响， 有呼吸系统疾病的易感个体。呼吸道的宿主防御反应包括 提供第一道防线的先天驻留免疫细胞，如单核细胞/巨噬细胞和上皮细胞 在呼吸道中对抗入侵的污染物或病原体。污染物引起的这两者之一或两者的变化 呼吸道宿主防御的组分将对宿主气道抵抗感染的能力具有显著影响。 虽然流行病学研究已经证明了环境PM暴露与增强的 由于对感染的易感性，关于PM诱导的免疫与细胞免疫之间的机制联系存在着一个关键的知识缺口。 上皮细胞和气道免疫细胞的功能障碍以及呼吸免疫健康效应的体内证据。的 这项提案的目的是解决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，并将这些与人体内观察结果联系起来。我们假设PM样品 在中国的高（与低）空气污染时期收集的样本将1）抑制呼吸道免疫功能， 体外（10）和2）在中国（中国）暴露个体体内检查时显示出相似的有害作用 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 功能，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，将暴露于在中国收集的PM，并检查其 宿主防御功能和生物能量修饰。SA 2将决定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， 从健康志愿者获得的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。PM引起的生物能量学变化的作用也将被检查。 SA 1和SA 2的体外研究将与SA 3中拟定的人体体内研究相关联。在SA 3中，一百名志愿者 来自新乡医学院的将是个人空气采样器，并接受鼻粘膜样本的收集， 在高、低空气污染期间采集诱导痰样本。先天免疫终点如SA 1和SA 2所述 将在SA 3中采集鼻和痰样本进行测量。从这些研究中获得的数据将产生重要的 关于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。而且这些 数据将填补高度污染和人口密集国家在全球健康影响方面的临床知识空白 世界各地

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.