Cellular Lipids and Leukocyte Function

细胞脂质和白细胞功能

基本信息

批准号：
9313269
负责人：
G M ANANTHARAMAIAH
金额：
$ 29.03万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313269
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Acute-Phase Reaction Adhesions Adoptive Transfer Affect Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apolipoprotein A-I Apolipoprotein E Area Attenuated Bacterial Infections Binding Blood specimen Bone Marrow Bone Marrow Transplantation Cause of Death Cell physiology Cell surface Cells Characteristics Cholesterol Coagulation Process Data Development Endothelial Cells Endothelium Endotoxemia Enzymes Functional disorder Gram-Negative Bacteria Gram-Positive Bacteria Hematopoietic Hepatocyte High Density Lipoproteins Human Immune response In Vitro Inflammatory Inflammatory Response Injury Intensive Care Units Lead Leukocytes Leukocytosis Ligation Link Lipids Lipopolysaccharides Lipoproteins Lung Mediating Membrane Monocytosis Multiple Organ Failure Mus Neutrophil Infiltration Neutrophilia Pathologic Patients Pharmacology Phenotype Plasma Play Predisposition Process Property Proteins Proteoglycan Puncture procedure Respiratory Failure Rodent Model Role Sepsis Septic Shock Stem cells Testing Tissues Toll-like receptors Toxin Vascular Endothelium antioxidant enzyme aryldialkylphosphatase cell injury chemokine cytokine cytotoxic functional mimics heparin proteoglycan immunoregulation improved leukocyte activation leukocyte proliferation macrophage mimetics monocyte mortality mouse model neutrophil novel particle pathogen peptidomimetics prevent protective effect public health relevance pulmonary function repaired response reverse cholesterol transport septic stem success synthetic peptide tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Sepsis is characterized by the release of bacterial structural components and toxins that activate inflammatory cascades in target cells. The recruitment of neutrophils and their binding to the vascular endothelium is an important, early response to sepsis. Neutrophils and resident macrophages initiate repair processes via the secretion of cytokines, chemokines and digestive enzymes. Dysregulation of the immune response, however, can lead to widespread and uncontrolled inflammatory injury characterized by leukocytosis (neutrophilia/monocytosis). This dysregulation results in multiple organ dysfunction syndrome (MODS) with the transition to overt septic shock. Respiratory failure progresses rapidly and is associated with approximately 40- 50% mortality. HDL serves as a carrier for diverse proteins, including apolipoprotein (apo) A-I and apoE, that play a role in mediating reverse cholesterol transport. Several studies suggest that apoE exerts anti-inflammatory effects, including the modulation of immune cell function, that are independent of its ability to lower plasma cholesterol levels. In this regard, apoE was recently shown to limit th expansion of hematopoietic stem and multipotential progenitor cells (HSPCs), resulting in a decrease in neutrophil and monocyte proliferation. The inhibitory effect of apoE on leukocyte activation was linked to a reduction in cellular cholesterol content per se. It is proposed that HDL-associated apoE plays a critical role in reducing inflammatory cell injury in the context of sepsis. This protective effect of apoE, however, may be limited by reduced levels of HDL that characterize sepsis. Preliminary data presented in the application show that a synthetic peptide (Ac-hE18A-NH2) that mimics effects of native apoE prevents the activation of leukocytes and improves survival in a rodent model of sepsis. Ac-hE18A-NH2 also induces the release of preß-HDL particles containing the antioxidant paraoxonase and apoE itself. Our data also show that apoE mimetics bind to cell surface proteoglycans and mediate cholesterol efflux from leukocytes, a response that is associated with a reduction in lipopolysaccharide-induced cytokine/chemokine release. In this application, we will test the novel hypothesis that Ac-hE18A-NH2 and related apoE mimetic peptides attenuate sepsis-induced inflammatory injury by inhibiting HSPC expansion and leukocyte proliferation/activation by a mechanism involving a reduction in cellular cholesterol content. Additional studies will test whether in vitro treatment with apoE mimetic peptides alters the phenotype/function of leukocytes isolated from septic patients.

描述（由申请人提供）：脓毒症的特征是释放细菌结构成分和毒素，激活靶细胞中的炎症级联反应。中性粒细胞的募集及其与血管内皮的结合是对中性粒细胞和驻留细胞的重要早期反应。巨噬细胞通过分泌细胞因子、趋化因子和消化酶启动修复过程，然而，免疫反应的失调可能导致广泛且不受控制的炎症损伤。以白细胞增多（中性粒细胞增多/单核细胞增多）为特征，这种失调会导致多器官功能障碍综合征 (MODS)，并迅速进展为明显的感染性休克，并与约 40-50% 的死亡率相关。蛋白质，包括载脂蛋白 (apo) A-I 和 apoE，在介导胆固醇反向转运中发挥作用。多项研究表明，apoE 具有抗炎作用。包括免疫细胞功能的调节，这与其降低血浆胆固醇水平的能力无关。在这方面，apoE 最近被证明可以限制造血干细胞和多能祖细胞 (HSPC) 的扩增，从而导致中性粒细胞和多能祖细胞的减少。 apoE 对白细胞活化的抑制作用与细胞胆固醇含量本身的降低有关，有人提出 HDL 相关的 apoE 在减少炎症细胞损伤方面发挥着关键作用。然而，在脓毒症的情况下，apoE 的这种保护作用可能会受到脓毒症特征的 HDL 水平降低的限制，该申请中提供的初步数据表明，合成肽 (Ac-hE18A-NH2) 可以模拟天然 apoE 的作用。在败血症啮齿动物模型中，Ac-hE18A-NH2 可以防止白细胞活化并提高存活率，还可以诱导含有抗氧化剂对氧磷酶的 preß-HDL 颗粒的释放。我们的数据还表明，apoE 模拟物与细胞表面蛋白聚糖结合并介导白细胞中的胆固醇流出，这种反应与脂多糖诱导的细胞因子/趋化因子释放的减少有关。 Ac-hE18A-NH2 和相关的 apoE 模拟肽通过抑制 HSPC 扩张来减轻脓毒症诱导的炎症损伤通过涉及细胞胆固醇含量降低的机制来促进白细胞增殖/激活。另外的研究将测试 apoE 模拟肽的体外治疗是否会改变从脓毒症患者中分离出的白细胞的表型/功能。