Chlorinated lipids in sepsis

败血症中的氯化脂质

基本信息

批准号：
9132272
负责人：
DAVID A. FORD
金额：
$ 45.99万
依托单位：
SAINT LOUIS UNIVERSITY
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：
2015-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9132272
关键词：
Acids Adherence Admission activity Adult Aldehydes Atherosclerosis Biochemical Biochemistry Biological Assay Biological Markers Biology Blood Blood Cells Blood Circulation Blood Platelets Blood Vessels Cell Adhesion Molecules Cell Communication Cell physiology Cells Child Clinical Clinical Microbiology Collaborations Complex Data Dilatation - action Discipline Disease Endothelial Cells Environment Functional disorder Health Hospitals Human Hydrogen Peroxide Hypochlorous Acid Immune response In Vitro Infection Inflammation Inflammation Mediators Investigation Leukocytes Ligation Lipids Lipopolysaccharides Measures Mediating Mediator of activation protein Mesentery Microbe Microcirculation Modeling Molecular Biology Molecular Target Morbidity - disease rate Multiple Organ Failure Myocardial Infarction Organ Organ failure Outcome Oxidants Oxygen Pathology Pathway interactions Patients Peritonitis Peroxidases Phagocytosis Physiological Pilot Projects Plasma Plasmalogens Positioning Attribute Production Proteins Puncture procedure Rattus Receptor Signaling Research Design Research Personnel Robin bird Rodent Rodent Model Role Saints Sampling Sendai virus Sepsis Severities Severity of illness Shock Splanchnic Circulation Surface System Testing Tissues United States Universities University Hospitals Vascular Permeabilities Virus Virus Diseases Washington antimicrobial cytokine endothelial dysfunction follow-up human data improved outcome in vivo inflammatory marker inhibitor/antagonist innovation insight interdisciplinary approach intravital microscopy killings leukocyte activation mast cell microbial host microbicide mortality multidisciplinary neutrophil new therapeutic target novel novel diagnostics novel therapeutics response septic therapeutic effectiveness vascular endothelial dysfunction vinyl ether

项目摘要

DESCRIPTION (provided by applicant): Sepsis is a major cause of morbidity and mortality in both adults and children with an estimated 750,000 cases per year in the United States. To improve outcomes in these patients, it is vital to increase our understanding of the pathophysiology of the disease and identify new therapeutic targets. Sepsis occurs when the tightly controlled host response to infection extends beyond the local environment and into the systemic circulation. This results in complex interactions involving microbes, blood cells, and the endothelial barrier in the microcirculation that can progress to vascular collapse and organ failure. Neutrophils are key early responders to infection. Neutrophils kill microbes by phagocytosis and by oxidant-mediated microbe killing in the surrounding environment. Myeloperoxidase (MPO) is a major mediator of oxygen-dependent microbicidal activity. MPO catalyzes the conversion of H2O2 to the potent oxidant, hypochlorous acid (HOCl), which reacts with both microbial and host molecular targets including proteins and lipids. The Ford group at Saint Louis University (SLU) has used physiological, biochemical and bio-organic approaches to demonstrate that the vinyl ether bond at the sn-1 position of plasmalogen lipids is targeted by HOCl, resulting in the production of 2-chlorofatty aldehyde, which is metabolized to 2-chlorofatty acid under physiological and pathophysiological conditions. These chlorinated lipids are elevated in activated neutrophils as well as in in vivo inflammation models including LPS treatment, Sindai virus exposure and peritonitis. Pilot studies show elevated levels of chlorinated lipids in a rat model of sepsis, and in human plasma of sepsis patients compared to controls. Additional preliminary data provide strong evidence that chlorinated lipids modulate leukocyte, platelet and endothelial cell function in the microcirculation and in isolated cell systems. Accordingly, we have assembled a multidisciplinary group with three PIs to test our hypothesis that chlorinated lipids produced by activated leukocytes during sepsis are mediators of severe endothelial dysfunction resulting in multiple organ failure. This hypothesis will be tested by three specific aims. Specific Aim 1 will test the hypothesis that chlorinated lipids produced by neutrophils are key mediators of endothelial dysfunction and organ damage during sepsis. Specific Aim 2 will test the hypothesis that chlorinated lipids mediate dysfunction in human endothelial cells. Specific Aim 3 will test the hypothesis that plasma 2-ClFA levels indicate both severity and therapeutic effectiveness in sepsis patients. Overall, a multi-disciplinary approach will examine the role of chlorinated lipids produced as a result of leukocyte activation during sepsis as indicators of the severity of human sepsis, and mediators of vascular endothelial dysfunction examined both in vivo in the rat microcirculation and in vitro for mechanistic insights. The project is innovative and significant. These studies are designed to discover new paradigms for the role of neutrophils in eliciting endothelial dysfunction providing new targets for therapeutics to treat septic patients.

描述（由申请人提供）：脓毒症是成人和儿童发病和死亡的主要原因，在美国每年估计有 750,000 例脓毒症病例。为了改善这些患者的治疗结果，增加我们对病理生理学的了解至关重要。当严格控制的宿主对感染的反应超出涉及局部环境并进入全身循环时，脓毒症就会发生，这会导致微生物、血细胞和血液的复杂相互作用。微循环中的内皮屏障可导致血管塌陷和器官衰竭，中性粒细胞是感染的关键早期反应者，其通过吞噬作用和周围环境中氧化剂介导的微生物杀伤作用来杀死微生物。 MPO 催化 H2O2 转化为强效氧化剂次氯酸。（HOCl），它与微生物和宿主分子靶标（包括蛋白质和脂质）发生反应，圣路易斯大学（SLU）的福特小组使用生理学、生化和生物有机方法来证明 sn-1 上的乙烯基醚键。 HOCl 靶向缩醛磷脂脂质的位置，导致产生 2-氯脂肪醛，在生理和病理生理条件下代谢为 2-氯脂肪酸。在活化的中性粒细胞以及体内炎症模型（包括 LPS 治疗、Sindai 病毒暴露和腹膜炎）中，氯化脂质水平升高。初步数据提供了强有力的证据，表明氯化脂质可调节微循环和分离细胞系统中的白细胞、血小板和内皮细胞功能。因此，我们组建了一个由三位 PI 组成的多学科小组。检验我们的假设，即败血症期间活化的白细胞产生的氯化脂质是导致多器官衰竭的严重内皮功能障碍的介质。具体目标 1 将检验中性粒细胞产生的氯化脂质是关键的假设。脓毒症期间内皮功能障碍和器官损伤的介质将检验氯化脂质介导人内皮细胞功能障碍的假设。将检验血浆 2-ClFA 水平表明脓毒症患者的严重程度和治疗效果的假设。总体而言，多学科方法将检查白细胞产生的氯化脂质的作用。脓毒症期间的激活作为人类脓毒症严重程度的指标，并在大鼠体内和体外检查血管内皮细胞的功能障碍，以获取机制见解。这些研究旨在发现新的范例。中性粒细胞在引起内皮功能障碍中的作用为脓毒症患者的治疗提供了新的靶点。