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。虽然机制 PM引起广泛的多器官损伤仍在调查中，证据强烈暗示 慢性炎症作为病理学的主要驱动因素。暴露于细颗粒物（PM2.5）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，长期 该项目的目标是确定暴露于PM如何影响炎症的解决，以及这是否 有助于PM的发生-加剧动脉粥样硬化。在进行中的工作中，我们发现在小鼠中， 暴露于浓缩PM（PM2.5）30天，循环红细胞表达过早老化的标志物 和氧化损伤。在这些小鼠的脾脏中， 红细胞处置，红髓巨噬细胞，而红细胞周转，血红素相关的途径， 代谢和铁循环上调。此外，我们还发现， 组织中诱导了造血。这些变化伴随着一个显着下降， 丰富的专门脂质介质，促进决议（SPM）及其受体。的变化 脾是特别关键的，因为脾在调节免疫应答动力学中起着中心作用。 它容纳了一个重要的和独特的单核细胞库，可以快速动员和部署， 回应各种侮辱。除了协调免疫功能外，脾脏还充当过滤器， 衰老和受损的红细胞。虽然患者在脾切除术后存活，但他们更有可能 感染严重和危及生命的感染，并有更高的风险发展血液学 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 PM2.5可能会破坏脾脏的稳态，并对红髓巨噬细胞产生靶向影响。由于巨噬细胞 红细胞吞噬作用、脾造血生态位维持和SPM作用的关键促进剂， 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作用， 抑制SPM产生并允许局部骨髓生成，从而增强单核细胞排出， 加剧了血管炎症为了验证这一假设，我们将研究PM2.5暴露对 脾巨噬细胞，确定PM2.5暴露对脾造血生态位的影响，并描绘 脾骨髓生成对PM2.5加重动脉粥样硬化的贡献。该项目将阐明 PM对炎症消退的影响，并将提供一种新的机制， 建立一种影响多个器官和过程的慢性、非消退性炎症状态。