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

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 引起广泛性多器官损伤的原因仍在调查中，证据强烈表明 慢性炎症是病理学的主要驱动因素。接触细颗粒物 (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，从长远来看 该项目的目标是确定接触 PM 如何影响炎症的消退，以及这是否会影响炎症的消退。 导致 PM 暴露加剧动脉粥样硬化。在正在进行的工作中，我们发现在小鼠中 暴露于浓缩 PM (PM2.5) 30 天，循环红细胞表达早衰标志物 和氧化损伤。在这些小鼠的脾脏中，负责的细胞数量有所增加。 对于红细胞处理，红髓巨噬细胞，而与红细胞周转相关的途径，血红素 新陈代谢和铁循环上调。此外，我们还发现与以下几个因素相关： 在组织中诱导造血。这些变化伴随着显着下降 大量促进分辨率的特殊脂质介质（SPM）及其受体。的变化 脾脏尤其重要，因为脾脏在调节免疫反应动态中起着核心作用。 它拥有一个重要且独特的单核细胞库，可以快速动员并部署在 对各种侮辱的回应。脾脏除了协调免疫功能外，还充当过滤器的作用，清除体内的毒素。 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 感染严重且危及生命的感染，并增加患血液病的风险 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 PM2.5 可能会破坏脾脏稳态，并对红髓巨噬细胞产生有针对性的影响。由于巨噬细胞是 吞噬红细胞作用、维持脾脏造血生态位和 SPM 作用的关键促进因子， 我们的中心假设是 PM2.5 暴露会增加脾脏巨噬细胞的红细胞吞噬作用，从而 抑制 SPM 产生并允许局部骨髓细胞生成，从而增强单核细胞排出和 加剧血管炎症。为了检验这一假设，我们将研究 PM2.5 暴露对 脾脏巨噬细胞，确定 PM2.5 暴露对脾脏造血生态位的影响并描绘 脾脏骨髓细胞生成对 PM2.5 加剧的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，通过该机制暴露于 PM 建立一种影响多个器官和过程的慢性、无法解决的炎症状态。

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.