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Chlorinated lipids in sepsis

败血症中的氯化脂质

基本信息

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
项目类别：
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

项目摘要

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.

脓毒症是成人和儿童发病和死亡的主要原因，每年有超过 160 万例病例在美国。中性粒细胞是感染的关键早期反应者。中性粒细胞通过以下方式消灭微生物吞噬作用和氧化剂介导的杀伤作用。中性粒细胞髓过氧化物酶 (MPO) 产生强效氧化剂，次氯酸 (HOCl)，与微生物和宿主分子靶标（包括脂质）发生反应。 PI博士 David Ford 证明 HOCl 靶向缩醛磷脂脂质的乙烯基醚键，从而产生 2- 氯脂肪醛 (2-ClFALD) 和其他氯脂，包括 2-氯脂肪酸 (2-ClFA)，响应白细胞活化。这导致我们的多 PI 团队在之前的资助间隔期间确定了氯脂引起的内皮激活导致白细胞和血小板粘附，并证明氯脂相关 ARDS 和人类脓毒症 30 天死亡率。我们的多 PI 小组已经积累了新的初步数据结果表明：1) 2-ClFA 修饰特定的内皮细胞蛋白，这可能代表了一种新的范例干预 2-ClFA 引起的内皮激活的目标； 2) 2-的w-氧化产物的血浆水平 ClFA，2-氯二羧酸 (2-ClDCA)，在进入重症监护病房 (ICU) 时进行测量发生急性肾损伤 (AKI) 的患者脓毒症发病率升高； 3) 2-ClDCA 导致内皮细胞功能障碍。氯脂在脓毒症中的作用正在扩大，这些初步数据表明拟议研究中需要解决的知识差距，这将检验我们的总体假设败血症期间由活化的中性粒细胞产生的氯脂是严重内皮细胞损伤的介质功能障碍导致多器官衰竭。有两个具体目标。具体目标 1 将测试假设氯脂介导的人内皮细胞功能障碍可以通过药物靶向。具体目标 2 将检验血浆 2-ClDCA 水平与特定器官功能障碍相关的假设和人类败血症死亡。总体而言，我们的多 PI 团队和 Co-Is 的多学科方法将检查败血症期间活化的中性粒细胞产生的氯脂作为微循环的关键介质导致器官衰竭的功能障碍，并测试氯脂引起的抑制剂和激活的途径内皮功能障碍作为干预点。这项合作研究有可能提供新的脓毒症患者的治疗和诊断目标。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Platelet-Activating Factor Quantification Using Reversed Phase Liquid Chromatography and Selected Reaction Monitoring in Negative Ion Mode.

使用反相液相色谱和负离子模式下的选择反应监测进行血小板激活因子定量。

DOI：
10.1007/s11745-016-4204-3
发表时间：
2016
期刊：
Lipids
影响因子：
1.9
作者：
Pike,DanielP;Hartman,CelineL;Weissler,GregoryJ;Palladino,ElisaND;Albert,CarolynJ;Ford,DavidA
通讯作者：
Ford,DavidA

E. coli strain-dependent lipid alterations in cocultures with endothelial cells and neutrophils modeling sepsis.