Chlorinated lipids in sepsis

败血症中的氯化脂质

基本信息

批准号：
10210265
负责人：
DAVID A. FORD
金额：
$ 32.12万
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/10210265
关键词：
Acids Acute Renal Failure with Renal Papillary Necrosis Address Adherence Admission activity Adult Adult Respiratory Distress Syndrome Aldehydes Bacterial Translocation Biology Blood Cells Blood Circulation Blood Platelets Blood Vessels CD36 gene Cell Communication Cell Culture Techniques Cell Degranulation Cessation of life Chemistry Child Clinical Complex Data Dilatation - action Discipline Endothelial Cells Endothelium Environment Epithelial Cells Failure Family Functional disorder Glutathione S-Transferase Grant Human Hypochlorous Acid Immune response Infection Injury Intensive Care Units Intervention Investigation Knowledge Leukocytes Lipids Measures Mediating Mediator of activation protein Mesentery Microbe Microcirculation Molecular Target Morbidity - disease rate Multiple Organ Failure Organ Organ failure Oxidants P-Selectin Panthera leo Pathology Pathway interactions Patients Pennsylvania Peroxidases Phagocytosis Pharmacology Phenotype Plasma Plasmalogens Post-Translational Protein Processing Production Prospective cohort study Proteins Rattus Research Personnel Role Scientist Sepsis Signal Transduction Surface TLR4 gene Testing Therapeutic Intervention Tissues United States Universities Vascular Permeabilities analog cecal ligation puncture drug testing endothelial dysfunction gastrointestinal epithelium in vivo indexing inflammatory marker inhibitor/antagonist interdisciplinary approach intestinal barrier intestinal epithelium intravital microscopy leukocyte activation mast cell member microbial host mortality multiorgan injury neutrophil novel diagnostics novel therapeutics oxidation response septic patients small molecule libraries targeted treatment uptake 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. To further investigate the role of chlorolipids in sepsis pathophysiology, our multi-PI group has accrued new preliminary data showing that: 1) inhibitors of TLR4, CD36 and glutathione S-transferase (GST) decrease 2-ClFA-elicited endothelial dysfunction; 2) the TLR4 inhibitor, TAK-242, reduces 2-ClFA-elicited and cecal ligation and puncture (CLP) sepsis-elicited mesenteric microcirculatory dysfunction using in vivo intravital microscopy; 3) 2-ClFA modifies specific endothelial cell proteins, which may represent a new paradigm to target for intervention of 2-ClFA-caused endothelial activation; 4) chlorolipids cause gut epithelial barrier leakiness, including in vivo gut bacterial translocation; 5) plasma levels of ω-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 6) 2-ClDCA causes endothelial cell 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 three specific aims. Specific Aim 1 will test the hypothesis that chlorolipid-mediated dysfunction in human endo- thelial and epithelial cells can be pharmacologically targeted. Specific Aim 2 will test the hypothesis that in vivo chlorolipid- and sepsis-elicited microcirculatory dysfunction and gut barrier dysfunction can be pharmacologically inhibited. Specific Aim 3 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。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）产生有效的氧化剂，次氯酸 (HOCl)，与微生物和宿主分子靶标（包括脂质）发生反应。 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的诱导。内皮激活导致白细胞和血小板粘附，并证明氯脂相关与 ARDS 和人类脓毒症 30 天死亡率的关系进一步研究氯脂在脓毒症中的作用。病理生理学方面，我们的多 PI 小组已经积累了新的初步数据，表明：1）TLR4 抑制剂， CD36 和谷胱甘肽 S-转移酶 (GST) 减少 2-ClFA 引起的内皮功能障碍 2) TLR4；抑制剂 TAK-242 可减少 2-ClFA 引起的和盲肠结扎穿刺 (CLP) 引起的肠系膜脓毒症使用活体活体显微镜观察微循环功能障碍；3) 2-ClFA 修饰特定的内皮细胞蛋白质，这可能代表了一种针对 2-ClFA 引起的内皮细胞干预的新范例激活；4) 氯脂导致肠道上皮屏障渗漏，包括体内肠道细菌易位； 2-ClFA、2-氯二羧酸 (2-ClDCA) 的 ω-氧化产物的血浆水平，在发生急性肾损伤的患者因脓毒症入住重症监护病房 (ICU) 的比例较高 (AKI)；和 6) 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，并且这些初步数据表明拟议研究中存在需要解决的知识差距，这将检验我们的总体假设，即败血症期间由活化的中性粒细胞产生的氯脂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 将检验以下假设：叶绿素介导的人体内分泌功能障碍。皮细胞和上皮细胞可以被药理学靶向。具体目标 2 将检验这一假设。体内氯脂和脓毒症引起的微循环功能障碍和肠道屏障功能障碍可能是具体目标 3 将检验血浆 2-ClDCA 水平与相关的假设。总体而言，我们的多PI的多学科方法。研究小组和 Co-Is 将检查败血症期间活化的中性粒细胞产生的氯脂作为关键介质微循环功能障碍导致器官衰竭的研究，并测试其抑制剂和激活的途径，氯脂引起的内皮功能障碍作为干预点。为脓毒症患者提供新的治疗和诊断靶点的潜力。