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.

暴露于环境颗粒物（PM）是心血管疾病的危险因素。虽然是机制 PM诱导普遍的多器官损伤仍在研究中，证据很大暗示 慢性炎症是病理的主要驱动力。暴露于罚款PM（PM2.5）是否特别损害 尚不清楚促进炎症分辨率的内源性途径。因此，长期 该项目的目标是确定暴露于PM如何影响炎症的分辨率以及是否影响 有助于PM暴露的动脉粥样硬化。在进行的工作中，我们发现在老鼠中 暴露于浓缩的PM（PM2.5）30天循环红细胞表达早熟的标记 和氧化损伤。在这些小鼠的脾脏中，负责的细胞种群扩大了 对于红细胞处置，红色果肉巨噬细胞，而与红细胞更新有关的途径，血红素 代谢和铁循环上调。此外，我们发现与 在组织中诱导造血。这些改变伴随着明显下降的 促进分辨率（SPM）及其受体的大量专门脂质介质。变化 脾脏特别重要，因为脾脏在调节免疫反应动力学方面起着核心作用。 它容纳了一个重要而独特的单核细胞储层，可以快速动员和部署 对各种侮辱的反应。除了协调免疫功能外，脾脏还充当过滤器去除 衰老和损害的红细胞。尽管患者在脾切除术后幸存，但他们更有可能 严重和威胁生命的感染，并增加了血液学的风险 恶性肿瘤和冠状动脉疾病以及其他疾病。我们的初步研究表明暴露 到PM2.5可能会破坏具有针对红纸浆巨噬细胞的目标影响的脾稳态。如巨噬细胞 红细胞增多的关键促进因子，脾造血生态位维持和SPM作用， 我们的中心假设是，PM2.5暴露会增加脾巨噬细胞红细胞增多，这会增加 抑制SPM的生产并允许局部骨髓卵子，从而增强单核细胞的出口和 加剧血管炎症。为了检验这一假设，我们将检查PM2.5暴露对 脾巨噬细胞，确定PM2.5暴露对脾脏造血生态位的影响 脾脊髓病的贡献对PM2.5的效力表达了动脉粥样硬化。这个项目将阐明 PM对炎症分辨率的影响，并将提供一种新机制 建立一种影响多个器官和过程的慢性，非分辨炎症状态。