Cellular Lipids and Leukocyte Function

细胞脂质和白细胞功能

• 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
• 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

 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（由适用提供）：败血症的特征是细菌结构成分和毒素激活靶细胞中的炎症性级联反应。中性粒细胞的募集及其与血管内皮的结合是对败血症的重要反应。中性粒细胞和居民巨噬细胞通过细胞因子，趋化因子和消化酶的分泌开始修复过程。然而，免疫反应的失调可能导致白细胞增多（中性粒细胞增多/单核细胞增多）为特征的宽度和不受控制的炎症损伤。这种失调导致多个器官功能障碍综合征（MOD），并过渡到明显的败血性休克。呼吸衰竭迅速发展，大约40-50％的死亡率有关。 HDL充当潜水蛋白的载体，包括载脂蛋白（APO）A-I和APOE，它们在介导反向胆固醇转运中发挥作用。几项研究表明，APOE发挥抗炎作用，包括免疫细胞功能的调节，这些作用与降低血浆胆固醇水平的能力无关。在这方面，最近显示APOE限制了造血茎和多能祖细胞（HSPC）的TH膨胀，从而导致中性粒细胞和单核细胞增殖的降低。 APOE对白细胞激活的抑制作用与细胞胆固醇含量的降低有关。有人提出，与HDL相关的APOE在败血症的背景下减少炎症细胞损伤方面起着关键作用。但是，APOE的这种保护作用可能受到败血症的HDL水平降低的限制。申请中提供的初步数据表明，合成肽（AC-HE18A-NH2）模仿天然APOE的效果可防止白细胞的激活并改善啮齿动物AC AC-HE18A-NH2的生存率，还诱导了含有抗​​氧化剂氧化二氧化碳酶和ApoE本身的Preß-HDL颗粒的释放。我们的数据还表明，ApoE Mimetics与细胞表面蛋白聚糖结合并介导白细胞的胆固醇外排，这一反应与脂多糖诱导的细胞因子/趋化因子释放有关。在此应用中，我们将测试新的假设，即AC-HE18A-NH2和相关的APOE模拟肽通过抑制HSPC的扩张和白细胞增殖/激活，通过涉及涉及细胞胆固醇含量减少的机制来减轻败血症诱导的炎症性损伤。其他研究将测试用APOE模拟肽的体外治疗是否改变了从化粪池患者分离的白细胞的表型/功能。