Role of Splenic Pro-Resolving Mediators During Exposure to Particulate Air Pollution

暴露于颗粒空气污染期间脾促分解介质的作用

• 批准号: 10658099
• 负责人: Brian Edward Sansbury
• 金额: $ 56.64万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658099
• 关键词: Acceleration; Address; Adoptive Transfer; Affect; Air Pollution; Apolipoprotein E; Applied Research; Arachidonate 15-Lipoxygenase; Atherosclerosis; Biological; Cardiovascular Diseases; Cells; Chronic; Complex; Contracts; Coronary Arteriosclerosis; Development; Disease; Disease Progression; Engraftment; Enzymes; Erythrocytes; Erythrophagocytosis; Event; Excision; Exposure to; FPR2 gene; Genetic Transcription; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heme; Homeostasis; Homing; Immune response; Immunity; Impairment; Individual; Infection; Inflammation; Inflammation Process; Inflammatory; Interruption; Investigation; Iron; Knockout Mice; Lead; Leukocytes; Life; Link; Longevity; Macrophage; Maintenance; Maps; Measures; Mediating; Mediator; Metabolism; Mus; Myelogenous; Myelopoiesis; Organ; Particulate; Particulate Matter; Pathology; Pathway interactions; Patients; Phase; Play; Population; Premature aging syndrome; Process; Production; Property; Resolution; Risk; Role; Scheme; Signal Transduction; Site; Spleen; Splenectomy; Splenic Red Pulp; Stimulus; Systemic disease; Testing; Tissues; Up-Regulation; Work; cardiovascular disorder risk; cardiovascular risk factor; cell type; cytokine; exhaustion; fine particles; fundamental research; immune function; immunoregulation; in vivo; interest; lipid mediator; monocyte; multiorgan injury; oxidative damage; prevent; programs; receptor; response; senescence; single-cell RNA sequencing; spleen transplantation; uptake; vascular inflammation

Exposure to ambient particulate matter (PM) is a risk factor for cardiovascular disease. Although the mechanisms by which PM induces pervasive multi-organ injury are still under investigation, evidence strongly implicates chronic inflammation as a primary driver of pathology. Whether exposure to fine PM (PM2.5) specifically impairs the endogenous pathways that promote the resolution of inflammation is not known. Therefore, the long-term goal of this project is to determine how exposure to PM impacts the resolution of inflammation and whether this contributes to PM exposure-exacerbated atherosclerosis. In work in progress, we discovered that in mice exposed to concentrated PM (PM2.5) for 30 days circulating erythrocytes expressed markers of premature aging and oxidative damage. In the spleens of these mice there was an expansion of the population of cells responsible for erythrocyte disposal, red pulp macrophages, while pathways related to erythrocyte turnover, heme metabolism, and iron cycling were upregulated. Additionally, we found that several factors related to hematopoiesis were induced in the tissue. These alterations were accompanied by a marked decrease in the abundance of specialized lipid mediators that promote resolution (SPMs) and their receptors. The changes in spleen are particularly critical because the spleen plays a central role in regulating immune response dynamics. It houses an important and distinct reservoir of monocytes, which can be rapidly mobilized and deployed in response to various insults. In addition to coordinating immune function, the spleen acts as a filter to remove senescent and damaged erythrocytes. Though patients survive following splenectomy, they are more likely to contract serious and life-threatening infections and have heightened risk of developing hematological malignancies and coronary artery disease among other disorders. Our preliminary studies suggest that exposure to PM2.5 may disrupt splenic homeostasis with targeted impacts on red pulp macrophages. As macrophages are the critical facilitators of erythrophagocytosis, maintenance of the splenic hematopoietic niche, and SPM actions, our central hypothesis is that PM2.5 exposure increases splenic macrophage erythrophagocytosis, which suppresses SPM production and permits local myelopoiesis, thereby enhancing monocyte egress and exacerbating vascular inflammation. To test this hypothesis, we will examine the effects of PM2.5 exposure on splenic macrophages, determine the impact of PM2.5 exposure on the splenic hematopoietic niche and delineate the contribution of splenic myelopoiesis to PM2.5-exacerbated atherosclerosis. This project will elucidate the effects of PM on the resolution of inflammation and will provide a new mechanism by which exposure to PM establishes a state of chronic, non-resolving inflammation that affects multiple organs and processes.

暴露在环境颗粒物(PM)中是心血管疾病的危险因素。尽管这些机制 PM导致弥漫性多器官损伤的原因仍在调查中，证据有力地表明 慢性炎症是病理的主要驱动力。暴露在细颗粒物(PM2.5)中是否会特别损害 促进炎症消退的内源性途径尚不清楚。因此，从长远来看， 该项目的目标是确定暴露在PM中如何影响炎症的消退，以及这是否 导致PM暴露-加剧动脉粥样硬化。在进行中的研究中，我们发现在老鼠身上 暴露于高浓度可吸入颗粒物(PM2.5)30天的循环红细胞表达早衰的标志 和氧化损伤。在这些小鼠的脾中，负责细胞的数量扩大了。 对于红细胞处置，红髓巨噬细胞，而与红细胞周转有关的途径，血红素 新陈代谢和铁循环上调。此外，我们发现有几个因素与 在组织中诱导了造血。这些变化伴随着显著的减少 丰富的促进分解的专门化脂质介体(SPM)及其受体。中的变化 脾尤其关键，因为脾在调节免疫反应动态中起着核心作用。 它拥有一个重要而独特的单核细胞储存库，可以快速动员和部署在 对各种侮辱的回应。除了协调免疫功能外，脾还起着滤网的作用 衰老和受损的红细胞。尽管患者在脾切除后存活下来，但他们更有可能 感染严重和危及生命的感染，并增加发展为血液病的风险 除其他疾病外，还有恶性肿瘤和冠状动脉疾病。我们的初步研究表明，暴露于 PM2.5可能通过对红髓巨噬细胞的靶向影响来破坏脾的动态平衡。因为巨噬细胞 红细胞吞噬、维持脾造血生态位和SPM活动的关键促进剂， 我们的中心假设是，PM2.5暴露增加了脾巨噬细胞的红细胞吞噬功能，这 抑制SPM的产生，允许局部骨髓生成，从而促进单核细胞外流和 加重血管炎症。为了验证这一假设，我们将检验PM2.5暴露对 脾巨噬细胞，测定PM2.5暴露对脾造血生态位的影响 脾造血在PM2.5加重动脉粥样硬化中的作用。这个项目将阐明 PM对炎症消退的影响，并将提供一种新的暴露于PM的机制 建立一种影响多个器官和过程的慢性、未消退的炎症状态。