Nanoparticle Targeting of Neutrophil Subpopulations in Inflammatory Lung Injury

纳米颗粒靶向炎症性肺损伤中性粒细胞亚群

• 批准号: 10186803
• 负责人: Asrar B. Malik
• 金额: $ 59.92万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186803
• 关键词: Address; Adhesions; Adult Respiratory Distress Syndrome; Albumins; Antibiotics; Bacterial Infections; Blood Circulation; Body Fluids; Bone Marrow; Cell Cycle Kinetics; Cells; Cessation of life; Complication; Data; Development; Disease; Disease Progression; Drug Targeting; Edema; Endotoxemia; Femur; Fluorochrome; Heterogeneity; Host Defense; Human; Immune; Immune response; Immune system; Infection; Inflammatory; Inflammatory Response; Injury; Integrins; Label; Lead; Lung; Mediating; Mus; Nature; Neutrophil Activation; Organ; Oxygen; Patients; Pharmaceutical Preparations; Phenotype; Piceatannol; Play; Population; Property; Protein Tyrosine Kinase; Proteins; Reporter; Research; Role; Sepsis; Signal Pathway; Signal Transduction; Spleen; Stimulus; Testing; Time; Tissues; chemokine receptor; design; immune activation; inhibitor/antagonist; lung injury; lung vascular injury; mouse model; nanoparticle; nanoparticle delivery; neutrophil; new therapeutic target; peripheral blood; polymicrobial sepsis; prevent; response; septic patients; targeted treatment; transcriptome sequencing; transcriptomics; two photon microscopy; uptake; vascular injury

PROJECT SUMMARY / ABSTRACT ARDS results from a severely dysregulated immune response that leads to lung vascular injury and protein-rich edema. Excessive activation of neutrophils (PMNs) is a primary cause of the lung damage. In experimental sepsis and septic patients, some PMNs are intensely activated and sequestered in lungs while others pass through the lung microvasculature unimpeded and function as essential host-defense cells. Previous findings suggest that PMNs might exist as various subsets and in different stages of activation. The concept of heterogeneity of PMNs raises the possibility that a subset of activated PMNs may contribute to a maladaptive inflammatory response and be responsible for lung injury. We found that a subset of PMNs specifically internalized 100 nm albumin nanoparticles (ANPs). As our Supporting Data show this population of PMNs increased significantly in experimental sepsis in mice and they were shown to be essential for the development of inflammatory lung injury. We also conjugated drugs to ANP for their precise delivery into these PMNs. These results raise several fundamental questions: What is the nature of this PMN population? Is there a related population in humans? What is their function and what is their origin? What is the mechanism of ANP internalization? Do these cells mediate lung injury and can ANP deliver drugs into this PMN population to reverse the course of the disease? We will address these PMNs by characterizing the function of CD11bhighCD16+CD45highANPhigh PMN subset as opposed to control CD11bhighCD16+CD45highANPlow PMNs in mediating inflammatory lung injury (Aim 1). Here we will test the hypothesis that ANPhigh PMNs are functionally distinct from ANPlow PMNs and that the former are crucial in mediating lung injury. Next, we will determine differential β2 integrin signaling in the distinct PMN sub-populations and their role in mediating lung injury (Aim 2). Here we will test the hypothesis that β2 integrins and downstream signaling pathway are hyper-activated in ANPhigh PMNs compared to ANPlow PMNs and differential PMN signaling is required inflammatory lung injury. Finally, we will define the origin, fate, and phenotypic heterogeneity of PMNs mediating lung injury (Aim 3). Here, RNA-Seq profiling has thus far revealed distinct chemokine receptors as markers of ANPhigh PMNs in lungs, and we will use this information to isolate this subset to further characterize them and assess their functional role in mediating lung injury. We will also define the time- dependent transcriptomic profiles and networks of ANPhigh vs. ANPlow PMNs during inflammatory activation to assess their differential properties. Thus, together studies will not only define a population toxic injury-promoting population of PMN but also hopefully identify new therapeutic targets to reverse the course of inflammatory lung injury.

项目摘要 /摘要 ARDS是由于严重失调的免疫激素导致肺血管损伤和富含蛋白质 浮肿。中性粒细胞过度激活（PMN）是肺损伤的主要原因。在实验中 败血症和化粪池患者，一些PMN被强烈激活并在肺部隔离，而另一些则通过 通过肺微血管统一并充当基本宿主防御细胞。以前的发现 表明PMN可能作为各种子集存在，并且处于激活的不同阶段。概念 PMN的异质性增加了激活PMN的子集可能导致适应不良的可能性 炎症反应并负责肺损伤。我们发现PMN的一部分特别 内部化100 nm白蛋白纳米颗粒（ANP）。正如我们的支持数据显示的PMN人群 小鼠实验性败血症的显着增加，证明它们对于发育至关重要 炎症性肺损伤。我们还将药物与ANP结合在一起，以便将其精确输送到这些PMN中。这些 结果提出了几个基本问​​题：PMN人群的性质是什么？有相关吗 人口在人类中？它们的功能是什么，它们的起源是什么？ ANP的机制是什么 内部化？这些细胞是否培养肺损伤，并且ANP可以将药物输送到该PMN种群中以逆转 疾病的病程？我们将通过表征的功能来解决这些PMN CD11BHIGHCD16+CD45HIGHANPHIGHPMN子集，而不是控制CD11BHIGHCD16+CD45HIGHANPLOW PMNS 在介导炎症性肺损伤中（AIM 1）。在这里，我们将测试以下假设： 在功能上与Anplow PMN不同，前者对于介导肺损伤至关重要。接下来，我们会的 确定不同PMN亚种群中的差异β2整合素信号传导及其在 介导肺损伤（AIM 2）。在这里，我们将测试β2整合素和下游信号传导的假设 与Anplow PMN相比 需要炎症性肺损伤。最后，我们将定义起源，命运和表型异质性 PMN介导肺损伤（AIM 3）。在这里，RNA-Seq分析迄今已揭示了不同的趋化因子 接收器是肺中抗肺部PMN的标记，我们将使用此信息来隔离此子集以进一步 表征它们并评估其在介导肺损伤中的功能作用。我们还将定义时间 - 在炎症激活期间，Anphigh与Anplow PMN的相关转录组和网络 评估其差异特性。这不仅将定义人口毒性造成损害的研究 PMN的人群，但也希望确定新的治疗靶标，以扭转炎症肺的进程 受伤。