Chlorinated lipids in sepsis

败血症中的氯化脂质

• 批准号: 10378863
• 负责人: DAVID A. FORD
• 金额: $ 5.94万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378863
• 关键词: Acids; Acute Renal Failure with Renal Papillary Necrosis; Address; Adherence; Admission activity; Adult; Adult Respiratory Distress Syndrome; Aldehydes; Blood Platelets; Cessation of life; Child; Data; Endothelial Cells; Endothelium; Family; Functional disorder; Grant; Human; Hypochlorous Acid; Infection; Intensive Care Units; Intervention; Investigation; Knowledge; Leukocytes; Lipids; Measures; Mediating; Mediator of activation protein; Microbe; Molecular Target; Morbidity - disease rate; Multiple Organ Failure; Organ; Organ failure; Oxidants; Pathway interactions; Patients; Peroxidases; Phagocytosis; Pharmacology; Plasma; Plasmalogens; Production; Proteins; Role; Sepsis; Testing; United States; endothelial dysfunction; inhibitor/antagonist; interdisciplinary approach; leukocyte activation; member; microbial host; mortality; multiorgan injury; neutrophil; novel diagnostics; novel therapeutics; oxidation; response; vinyl ether; Acids; Acute Renal Failure with Renal Papillary Necrosis; Address; Adherence; Admission activity; Adult; Adult Respiratory Distress Syndrome; Aldehydes; Blood Platelets; Cessation of life; Child; Data; Endothelial Cells; Endothelium; Family; Functional disorder; Grant; Human; Hypochlorous Acid; Infection; Intensive Care Units; Intervention; Investigation; Knowledge; Leukocytes; Lipids; Measures; Mediating; Mediator of activation protein; Microbe; Molecular Target; Morbidity - disease rate; Multiple Organ Failure; Organ; Organ failure; Oxidants; Pathway interactions; Patients; Peroxidases; Phagocytosis; Pharmacology; Plasma; Plasmalogens; Production; Proteins; Role; Sepsis; Testing; United States; endothelial dysfunction; inhibitor/antagonist; interdisciplinary approach; leukocyte activation; member; microbial host; mortality; multiorgan injury; neutrophil; novel diagnostics; novel therapeutics; oxidation; response; vinyl ether

Sepsis is a major cause of morbidity and mortality in both adults and children with >1.6 million cases per year in the United States. Neutrophils are key early responders to infection. Neutrophils eliminate microbes by phagocytosis and by oxidant-mediated killing. Neutrophil myeloperoxidase (MPO) produces the potent oxidant, hypochlorous acid (HOCl), which reacts with both microbial and host molecular targets including lipids. PI Dr. David Ford has shown HOCl targets the vinyl ether bond of plasmalogen lipids, resulting in the production of 2- chlorofatty aldehyde (2-ClFALD) and other chlorolipids, including 2-chlorofatty acid (2-ClFA), in response to leukocyte activation. This led our multi-PI team during the previous grant interval to determine chlorolipids elicit endothelial activation leading to leukocyte and platelet adherence, and to demonstrate chlorolipids associate with ARDS and 30-day mortality in human sepsis. Our multi-PI group has accrued new preliminary data showing that: 1) 2-ClFA modifies specific endothelial cell proteins, which may represent a new paradigm to target for intervention of 2-ClFA-caused endothelial activation; 2) plasma levels of w-oxidation products of 2- ClFA, 2-chlorodicarboxylic acids (2-ClDCAs), measured on admission to the intensive care unit (ICU) with sepsis are elevated in patients that develop acute kidney injury (AKI); and 3) 2-ClDCA causes endothelial dysfunction. The role of chlorolipids in sepsis is expanding, and these preliminary data indicate there are knowledge gaps that need to be addressed in the proposed studies, which will test our overall hypothesis that chlorolipids produced by activated neutrophils during sepsis are mediators of severe endothelial dysfunction resulting in multiple organ failure. There are two specific aims. Specific Aim 1 will test the hypothesis that chlorolipid-mediated dysfunction in human endothelial cells can be pharmacologically targeted. Specific Aim 2 will test the hypothesis that plasma 2-ClDCA levels associate with specific organ dysfunctions and death in human sepsis. Overall, a multi-disciplinary approach with our multi-PI team and Co-Is will examine chlorolipids produced by activated neutrophils during sepsis as critical mediators of microcirculatory dysfunction leading to organ failure, and test inhibitors of, and pathways activated by, chlorolipid-elicited endothelial dysfunction as intervention points. This collaborative investigation has the potential to provide new therapeutic and diagnostic targets for patients with sepsis.

败血症是成人和儿童每年160万例的发病率和死亡率的主要原因 在美国。中性粒细胞是对感染的主要早期反应者。中性粒细胞消除微生物 吞噬作用和氧化剂介导的杀伤。嗜中性粒细胞髓过氧化物酶（MPO）产生有效的氧化剂， 次氯酸酸（HOCL）与包括脂质在内的微生物和宿主分子靶标反应。 PI Dr. 大卫·福特（David Ford）表明，HOCL靶向血质脂质的乙烯基醚键，从而产生2-- 氯氟法醛醛（2-clfald）和其他氯脂脂，包括2-氯脂蛋白酸（2-Clfa），响应于 白细胞激活。这导致了我们在上一个赠款间隔期间的多P-PI团队，以确定叶绿素引起的 内皮激活导致白细胞和血小板粘附，并展示叶绿素助理 人类败血症中的ARD和30天死亡率。我们的Multi-Pi组获得了新的初步数据 表明：1）2-CLFA修饰特定的内皮细胞蛋白，这可能代表新的范式 2-CLFA引起的内皮激活的干预目标； 2）2-的W-氧化产物的血浆水平 CLFA，2-氯二羧酸（2-CLCA），在接受重症监护室（ICU）时测量 急性肾损伤（AKI）的患者败血症升高； 3）2-CLDCA会导致内皮 功能障碍。叶绿素在败血症中的作用正在扩大，这些初步数据表明存在 在拟议的研究中需要解决的知识差距，这将检验我们的整体假设 败血症期间激活的嗜中性粒细胞产生的叶绿素是严重内皮的介体 功能障碍导致多器官衰竭。有两个具体的目标。特定目标1将测试 假设可以将叶绿素介导的人内皮细胞中的功能障碍靶向。 特定目标2将检验以下假设：等离子体2-CLDCA水平与特定器官功能障碍相关 和人类败血症的死亡。总体而言，我们的多PIC团队和Co-IS将采用多学科的方法 检查败血症期间活化中性粒细胞产生的叶绿素作为微循环的关键介体 功能障碍导致器官衰竭，并测试由叶绿素引起的激活的抑制剂和途径 内皮功能障碍作为干预点。这项协作调查有可能提供新的 败血症患者的治疗和诊断靶标。