Innate immune cell contribution in wood smoke induced effects to pulmonary function

先天免疫细胞在木烟中的作用对肺功能产生影响

• 批准号: 10195519
• 负责人: CHRISTOPHER Todd MIGLIACCIO
• 金额: $ 22.15万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195519
• 关键词: Acute; Address; Affect; Age; Alveolar; Alveolar Macrophages; Animals; Asthma; Breathing; Cells; Child; Chronic Obstructive Airway Disease; Communities; Complement; Complex Mixtures; Core Facility; Data; Diabetes Mellitus; Diesel Exhaust; Dose; Elderly; Environment; Environmental Pollutants; Event; Exhibits; Exposure to; Fire - disasters; Future; Gases; Health; Heart Diseases; Histologic; Immune; Immunobiology; Individual; Inflammation Mediators; Inflammatory Response; Inhalation; Laboratory Study; Link; Lung; Lung diseases; Lymphoid Cell; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Montana; Morbidity - disease rate; Mus; Natural Immunity; Particulate; Particulate Matter; Pathology; Physiology; Population; Populations at Risk; Production; Public Health; Pulmonary Inflammation; Risk; Risk Assessment; Risk Factors; Signal Transduction; Smoke; System; Testing; Therapeutic; Time; Tissues; Universities; Wildfire; Work; aged; airway hyperresponsiveness; cigarette smoke; climate change; cohort; cytokine; design; experimental study; field study; fine particles; immunotoxicity; interstitial; longitudinal human study; macrophage; mortality; mouse model; novel; pulmonary function; respiratory; respiratory health; response; sex; wood smoke

Innate immune cell contribution in wood smoke induced effects to pulmonary function Wildfires are a growing global issue, and a significant concern for public health. Each year, wildfires continue to make headlines as tens of thousands of fires and millions of acres burn around the world. Due to the effects of climate change, these wildfires have become more intense and longer burning. Although wildfires threaten lives directly, and wildfire smoke affects us all—particularly as the intensity and duration of wildfires escalates globally. exciting new preliminary data shows that individuals from a community inundated with hazardous levels of wildfire smoke (daily average: 220.9 µg/m3 of PM2.5) for 49 days exhibited a significant decrease in lung function at least two years after the wildfire event, with a greater effect observed in the older (>65 years) fraction of the cohort. Moreover, we demonstrate pulmonary inflammation and airway hyperreactivity, facilitated by cytokine mediators in our mouse model of acute wood smoke exposure. The objective of this proposal is to determine how wildfire smoke affects components of innate immunity, macrophage subsets and innate lymphoid cells, into generating alarmins and inflammatory mediators that result in tissue remodeling and decreased lung function. We propose the central hypothesis that ILC2 activities are initiated by IL-33 and macrophages in response to wood smoke exposure, resulting in the production and release of inflammatory mediators which trigger pathology. To effectively test this hypothesis, the following specific aims will be addressed: Aim 1: Exposure to WS will result in time-, dose-, age-, and sex-dependent adverse pulmonary effects. Aim 2: Exposure to high levels of wildfire smoke will result in alterations to innate immune components that will promote tissue remodeling in the lungs. The proposed studies will utilize the state-of-the- art Inhalation and Pulmonary Physiology Core facility at the University of Montana to develop a mouse model of the community exposures. Impact Together, the proposed cutting-edge murine studies complementing the ongoing unique longitudinal human studies will have a sustained and powerful impact on wildfire smoke-induced health effects and macrophage immunobiology. The successful completion of the project will provide a significant missing link into a novel mechanism by which the environment adversely affects respiratory health, and also provide a link to how other environmental pollutants (e.g. cigarette smoke, diesel exhaust, particulate matter) may serve as risk factors for diminished lung function. Lastly by understanding how macrophage subsets influence inflammatory responses in ILC2s, therapeutic approaches can be developed with greater precision and efficacy, thereby significantly advancing treatment options for this growing public health concern.

木烟诱导肺功能的先天免疫物贡献 野火是日益增长的全球问题，也是公共卫生的重大关注点。每年，野火继续 成为世界上成千上万的大火和数百万英亩燃烧的头条新闻。由于影响 气候变化，这些野火变得更加激烈，燃烧更长。虽然野火威胁着 直接生活，野火烟雾会影响我们所有人 - 尤其是随着野火的强度和持续时间升级 全球。令人兴奋的新初步数据表明，来自一个被危险的社区的个人 野火烟的水平（每天：220.9 µg/m3的PM2.5）持续49天，暴露了显着下降 野火事件至少两年后的肺功能，在较旧的情况下观察到更大的影响（> 65年） 队列的一部分。此外，我们证明了肺部感染和气道高反应性， 在我们的急性木烟雾暴露的小鼠模型中，由细胞因子介质促进。这个目的 提案是确定野火烟如何影响先天免疫，巨噬细胞子集和 先天淋巴样细胞，产生警报蛋白和炎症介质，导致组织重塑和 肺功能降低。我们提出了一个中心假设，即ILC2活性是由IL-33发起的 巨噬细胞响应木烟暴露，导致生产和释放 引发病理的炎症介质。为了有效检验这一假设，以下特定 目标将被解决：目标1：接触WS将导致时间，剂量，年龄和与性别有关的广告 肺作用。目标2：暴露于高水平的野火烟雾将导致先天免疫的改变 将促进肺部组织重塑的成分。拟议的研究将利用最先进的 蒙大拿州大学的艺术吸入和肺动物核心设施开发老鼠模型 社区暴露。 影响 一起，提出的尖端鼠研究完成了正在进行的独特纵向人类 研究将对野火烟雾引起的健康影响和巨噬细胞产生持续和强大的影响 免疫生物学。该项目的成功完成将为小说提供大量的缺失链接 环境对呼吸健康的不利影响机制，也提供了与其他方式的联系 环境污染物（例如香烟烟，柴油排气，颗粒物）可能是风险因素 肺功能降低。最后，通过了解巨噬细胞子集如何影响炎症反应 在ILC2中，可以更加精确和有效性开发治疗方法，从而显着 为这种日益增长的公共卫生关注而推进治疗方案。