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

• 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
• 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

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.

摘要 脓毒症是由细菌、病毒或真菌感染引起的，其特征是多器官功能衰竭， 宿主反应受损脓毒症在全国住院死亡率和费用负担中排名很高， 与所有疾病相比。脓毒症治疗多年来一直限于抗生素，液体和器官 支持.需要新的治疗方法，这些方法可能靶向脓毒症细胞病理生理学，包括 过度的氧化应激，血液-内皮界面的炎症过度活化， 线粒体健康和脂质稳态紊乱。缩醛磷脂是一类独特的磷脂 在sn-1位含有特征性乙烯基醚键，其将甘油主链连接到 脂肪链乙烯基醚键是活性氧物质（ROS）的靶标，因此缩醛磷脂是 抗氧化剂我最近的研究表明，人败血症时血浆酶原水平降低， 可能反映了败血症内皮细胞氧化应激来源于氧化还原酶和电子泄漏， 线粒体电子传递链（ETC）。ROS引起的线粒体损伤影响细胞呼吸， 脂质代谢对整体细胞健康有害。这表明缩醛磷脂具有保护作用 其存在于细胞和细胞器膜中，包括线粒体。溶浆菌原（lysoPls），a 在sn-2位缺少酰基链的缩醛磷脂类是有用的缩醛磷脂前体， 比缩醛磷脂更快的细胞摄取，并且仍然含有清除ROS的乙烯基醚键。导频数据 显示向人肺微血管内皮细胞（HLMVEC）补充lysoPls降低了 细胞氧化应激，并在病原菌存在下维持缩醛磷脂池， 补充保护脂多糖存在下HLMVEC屏障完整性。总的来说，这 提示lysoPls具有ROS清除作用，并在脓毒症期间提供关键的内皮保护。 氧化应激因此，我们假设血浆酶原丢失反映了损伤性内皮氧化损伤， 脓毒症期间的应激和血浆酶原替代可能限制氧化应激，改善预后 通过线粒体和内皮作用。目标1中的研究将包括：1）检查人脓毒症血浆 与Nuala Meyer博士（宾夕法尼亚大学）合作，将血浆酶原水平作为结果预测因子 和2）在脓毒症的小鼠盲肠结扎和穿刺模型中测试缩醛磷脂替代疗法， 与Richard霍奇基斯博士（华盛顿）合作，预防死亡和器官衰竭 大学）。物理学家兼科学家Meyer博士和霍奇基斯博士也将担任此次培训的共同导师 程序.目标2中的研究将测试缩醛原增加减少炎症的机制， 内皮细胞的氧化应激，改善内皮功能。总的来说，这些研究开辟了新的研究领域。 区分脓毒症靶标和治疗剂以及最终改善脓毒症患者结果的途径， 特别是考虑到近几十年来抗生素耐药性的上升。