The Role of Plasmalogen Mitochondrial and Endothelial Antioxidant Properties in Sepsis

缩醛磷脂线粒体和内皮抗氧化特性在脓毒症中的作用

基本信息

批准号：
10751627
负责人：
Reagan McGuffee
金额：
$ 5.27万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2027-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751627
关键词：
Admission activity Angiopoietins Antibiotic Resistance Antibiotics Antioxidants Bacteria Bacterial Infections Biochemical Blood Cell Adhesion Molecules Cell Compartmentation Cell Respiration Cell membrane Cells Cellular Membrane Cessation of life Characteristics Choline Cohort Studies Collaborations Complex Correlation Studies Coupled Data Disease Electron Transport Electrons Endothelium Endotoxins Enzymes Ethanolamines Extravasation Functional disorder Glycerol Health Heart Homeostasis Hospital Costs Hospital Mortality Human Immune response Impairment Infection Inflammation Inflammatory Injury Kidney Kinetics Knock-out Link Lipids Lipopolysaccharides Liquid substance Liver Lung Mass Spectrum Analysis Mediating Membrane Mentors Microvascular Dysfunction Mitochondria Mitochondrial DNA Modeling Molecular Epidemiology Multiple Organ Failure Mus Mycoses Nature Organ Organ failure Outcome Oxidants Oxidation-Reduction Oxidative Stress Patient-Focused Outcomes Pennsylvania Permeability Phospholipids Physicians Pilot Projects Plasma Plasma Cells Plasmalogens Positioning Attribute Process Production Property Publications Reactive Oxygen Species Replacement Therapy Reporting Research Role Scientist Sepsis Signal Transduction Supplementation TLR2 gene TLR4 gene Testing Therapeutic Tissues Training Programs Universities Vascular Permeabilities Vertebral column Virus Diseases Visualization Washington cecal ligation puncture diacetyldichlorofluorescein electric impedance endothelial dysfunction experimental study extracellular fatty acid metabolism fluorophore improved improved outcome interdisciplinary approach lipid disorder lipid metabolism lung microvascular endothelial cells mitochondrial dysfunction mortality mouse model organ injury outcome prediction oxidative damage pathogenic Escherichia coli pathogenic bacteria prevent septic septic patients therapeutic target tool uptake vinyl ether

项目摘要

ABSTRACT Sepsis is triggered by bacterial, viral, or fungal infection, and it is characterized by multi-organ failure following an impaired host response. Sepsis ranks highly in both national in-hospital mortality and cost burden in comparison to all diseases. Sepsis treatment over the years has been limited to antibiotics, fluids, and organ support. New treatments are needed, which could potentially target sepsis cellular pathophysiology including excessive oxidative stress, inflammatory overactivation at the blood-endothelium interface, declines in mitochondrial health, and disordered lipid homeostasis. Plasmalogens are a unique class of phospholipids containing a characteristic vinyl ether bond at the sn-1 position, which links the glycerol backbone to the aliphatic chain. The vinyl ether bond is a target of reactive oxygen species (ROS), and thus plasmalogens are antioxidants. My recent studies have shown plasma plasmalogen levels are reduced in human sepsis, which likely reflects sepsis endothelial oxidative stress derived from redox enzymes and electron leakage from the mitochondrial electron transport chain (ETC). Mitochondrial damage by ROS impacts cellular respiration and lipid metabolism which is detrimental to overall cell health. This suggests a protective role for plasmalogens which reside in cell and organellar membranes, including the mitochondria. Lysoplasmalogen (lysoPls), a plasmalogen class lacking an acyl chain at the sn-2 position, is a useful plasmalogen precursor that displays more rapid cell uptake than plasmalogen and still contains the ROS-scavenging vinyl ether bond. Pilot data show that supplementation of lysoPls to human lung microvascular endothelial cells (HLMVECs) reduces cellular oxidative stress and maintains plasmalogen pools in the presence of pathogenic bacteria, and lysoPls supplementation protects HLMVEC barrier integrity in the presence lipopolysaccharide. Taken together, this suggests lysoPls have an ROS-scavenging role and provide critical endothelial protection during septic oxidative stress. Therefore, we hypothesize plasmalogen loss reflects injurious endothelial oxidative stress during sepsis, and plasmalogen replacement may limit oxidative stress, improving outcomes via mitochondrial and endothelial effects. Studies in Aim 1 will include: 1) examining human sepsis plasma plasmalogen levels as outcome predictors in collaboration with Dr. Nuala Meyer (University of Pennsylvania) and 2) testing plasmalogen replacement therapy in the mouse cecal ligation and puncture model of sepsis for protection against mortality and organ failure in collaboration with Dr. Richard Hotchkiss (Washington University). Physician-scientists Drs. Meyer and Hotchkiss will also serve as co-mentors for this training program. Studies in Aim 2 will test mechanisms that plasmalogen augmentation reduces inflammation and oxidative stress in the endothelium, improving endothelial function. Overall, these studies open new research avenues to distinguish sepsis targets and therapeutics and to ultimately improve sepsis patient outcomes, especially given the rise of antibiotic resistance in recent decades.

抽象的败血症是由细菌，病毒或真菌感染触发的，其特征是多器官衰竭之后宿主反应受损。败血症在国家医院死亡率和成本负担中的排名很高与所有疾病进行比较。多年来，败血症的治疗仅限于抗生素，液体和器官支持。需要新的治疗方法，这可能靶向脓毒症细胞病理生理学过度的氧化应激，血细胞皮界面处的炎症过度活化，下降线粒体健康和无序脂质稳态。血浆元是一类独特的磷脂在SN-1位置包含特征性的乙烯基醚键，该键将甘油主链连接到脂肪族链。乙烯基醚键是活性氧（ROS）的靶标，因此浆元为抗氧化剂。我最近的研究表明，人败血症的血浆血浆水平降低了，这可能反映了从氧化还原酶衍生出的败血症内皮氧化应激和从线粒体电子传输链（ETC）。线粒体损害ROS会影响细胞呼吸和脂质代谢不利于整体细胞健康。这表明浆元具有保护作用驻留在细胞和细胞器膜中，包括线粒体。溶质膜（溶血），a 在SN-2位置缺乏酰基链的血浆原类是一个有用的血浆原始前体，显示比浆质基因更快的细胞摄取，并且仍然包含ROS扫除的乙烯基醚键。试点数据表明将溶酶体补充对人肺微血管内皮细胞（HLMVEC）减少细胞氧化应激并在病原细菌存在下保持静脉池和溶酶体补充可保护在存在脂多糖的情况下HLMVEC屏障完整性。总的来说，这个表明溶血具有ROS扫除作用，并在化粪池期间提供关键的内皮保护氧化应激。因此，我们假设血浆原质损失反映了有害的内皮氧化性。败血症期间的胁迫和血质原替代可能会限制氧化应激，从而改善预后通过线粒体和内皮作用。 AIM 1的研究将包括：1）检查人类败血症等离子体血浆原水平作为结果预测因子与Nuala Meyer博士（宾夕法尼亚大学）合作 2）在小鼠盲肠结扎和败血症的小鼠结扎和穿刺模型中测试血浆原替代疗法与理查德·霍奇基斯（Richard Hotchkiss）博士合作，防止死亡率和器官衰竭（华盛顿）大学）。医师科学家Drs。 Meyer和Hotchkiss也将担任此培训程序。 AIM 2中的研究将测试血浆基因增强的机制可减少炎症和内皮中的氧化应激，改善内皮功能。总体而言，这些研究开放了新的研究区分败血症靶标和治疗剂并最终改善败血症患者预后的途径，特别是考虑到近几十年来抗生素抗性的兴起。