Chlorinated lipids in sepsis

败血症中的氯化脂质

• 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
• 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

 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（由适用提供）：败血症是成年人和儿童发病率和死亡率的主要原因，在美国估计每年750,000例。为了改善这些患者的预后，至关重要的是，我们对疾病的病理生理学的理解并确定新的治疗靶标至关重要。当受到严格控制的宿主对感染的反应延伸到局部环境并进入系统循环时，败血症就会发生。这导致涉及微生物，血细胞和 微循环中的内皮屏障可以发展为血管塌陷和器官衰竭。中性粒细胞是对感染的主要早期反应者。中性粒细胞通过吞噬作用和氧化剂介导的微生物在周围环境中杀死微生物。脊髓过氧化物酶（MPO）是氧依赖性杀菌活性的主要介体。 MPO催化H2O2向有效的氧化物，次氯酸酸（HOCL）催化，该转化与包括蛋白质和脂质在内的微生物和宿主分子靶标反应。圣路易斯大学（SLU）的福特小组使用了生理，生化和生物有机方法来证明，HOCL的Sn-1位置的乙烯基键是由HOCL靶向的，这是由2-氯反应型alddehyde的产生，这是2-氯氟化的，这是酸性的，且酸不足。这些氯化脂质在活化的中性粒细胞以及体内注射模型中升高，包括LPS治疗，Sindai病毒暴露和腹膜炎。试验研究表明，与对照组相比，败血症大鼠模型中的氯化脂质水平升高，败血症患者的人血浆中的水平升高。其他初步数据提供了有力的证据表明，在微循环和分离的细胞系统中，氯化脂质调节白细胞，血小板和内皮细胞功能。彼此之间，我们已经组装了一个多学科基团的三个PI，以测试我们的假设，即败血症期间活性白细胞产生的氯化脂质是严重内皮功能障碍的介体导致多器官衰竭。该假设将通过三个特定目标检验。具体目标1将检验以下假设：中性粒细胞产生的氯化脂质是脓毒症期间内皮功能障碍和器官损伤的关键介体。具体目标2将检验以下假设：人内皮细胞中氯化脂质中位功能障碍。具体目标3将检验以下假设：等离子体2-CLFA水平表明败血症患者的严重程度和治疗有效性。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 败血症期间的激活是人类败血症的严重程度的指标，以及血管内皮功能障碍的介体在大鼠微循环中的体内和体外进行了机械洞察力检查。该项目具有创新性和重要意义。这些研究旨在发现中性粒细胞在引发内皮功能障碍中的作用的新范式，从而为治疗败血症患者提供了新的靶标。