Plasmalogen-Derived Chlorinated Lipids: Mediators of Acute Lung Injury in Sepsis

缩醛磷脂衍生的氯化脂质：脓毒症急性肺损伤的介质

• 批准号: 10207749
• 负责人: Daniel Pike
• 金额: $ 5.1万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207749
• 关键词: 16S ribosomal RNA sequencing; Acids; Acute Lung Injury; Adherence; Adult Respiratory Distress Syndrome; Aldehydes; Animal Model; Antibiotics; Back; Basic Science; Blood Platelets; Cecum; Cell Culture Techniques; Cells; Cessation of life; Chemistry; Coagulation Process; Data; Defect; Development; Diagnosis; Diagnostic; Disease; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Extravasation; Functional disorder; Genomics; Glycerol; Glycerophospholipids; Goals; Human; Hydrogen Peroxide; Hypochlorous Acid; Immune response; Immune system; Immunohistochemistry; Infection; Inflammatory; Innate Immune Response; Innate Immune System; Intestinal permeability; Lead; Leukocytes; Lip structure; Lipids; Lung; Manuscripts; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Membrane; Microbe; Microvascular Dysfunction; Modeling; Molecular Target; Morbidity - disease rate; Multiple Organ Failure; Neutrophil Activation; Organ; Organ failure; Outcome; Oxidants; Oxides; Patients; Permeability; Peroxidases; Pharmacology; Physicians; Physiological; Plasma; Plasmalogens; Play; Positioning Attribute; Production; Proteins; Pulmonary Pathology; Rattus; Research Project Grants; Respiratory Burst; Role; Scheme; Scientist; Sepsis; Supportive care; Techniques; Testing; Tight Junctions; Training; Training Programs; Treatment Protocols; United States; Vertebral column; Weibel-Palade Bodies; analog; career; design; efficacious treatment; endothelial dysfunction; experimental study; in vivo; lipid mediator; lung injury; mortality; neutrophil; new therapeutic target; organ injury; prevent; septic; skills; vinyl ether

ABSTRACT This proposal will determine the relationships between lung injury and mortality in sepsis and plasmalogen- derived chlorinated lipids, which are produced during the innate immune response. A significant cause of morbidity and mortality in patients worldwide, sepsis is the systemic dysregulation of the immune response to an initial infection and often leads to acute lung injury (ALI), other organ damage, and death. Host neutrophils are a component of the innate immune system and are systemically activated during sepsis. Neutrophil myeloperoxidase (MPO) is important in bacterial killing during sepsis. MPO catalyzes the production of hypochlorous acid (HOCl) from hydrogen peroxide produced during the respiratory burst. HOCl, in turn, is a powerful oxidant that targets microbes. However, HOCl may also react with host molecules, including the vinyl ether bond of membrane plasmalogens. Plasmalogens are a class of glycerophospholipids with an aliphatic chain connected to the glycerol backbone through a vinyl ether bond. When attacked by HOCl, the aliphatic chain is liberated as chlorofatty aldehyde (2-ClFALD). 2-ClFALD can be oxidized to chlorofatty acid (2-ClFA) under physiologic conditions. These compounds, designated as plasmalogen-derived chlorinated lipids, are elevated in a variety of inflammatory conditions. A Ford lab manuscript in review demonstrates plasma 2-ClFA predicts acute respiratory distress syndrome-associated mortality in sepsis. Other projects suggest plasmalogen-derived chlorinated lipids elicit endothelial dysfunction, a major causative factor of ALI. We hypothesize that plasmalogen-derived chlorinated lipids are critical mediators of acute lung injury and mortality in sepsis through their role in eliciting endothelial dysfunction. Aim 1 of this proposal will use a cecal slurry (CS) model of sepsis in rats to determine if plasmalogen-derived chlorinated lipid production predicts sepsis outcomes, such as mortality, endothelial dysfunction, and lung injury. Mechanistic studies will be employed to demonstrate causative roles of MPO and 2-ClFA in CS elicited mortality, endothelial dysfunction, and lung injury. Aim 2 will determine that plasmalogen-derived chlorinated lipids cause endothelial dysfunction and lung injury in the absence of sepsis by giving rats exogenous 2-ClFA. A click chemistry analog of 2-ClFA will visualize the localization of the lipid to lung endothelium. Additional experiments will examine 2-ClFA-elicited gut permeability. The mechanisms through which 2-ClFA elicits endothelial dysfunction will also be explored using human lung endothelial cells. Current treatment regimens for sepsis and sepsis-related ALI consist of antibiotics and supportive care, with a noticeable paucity in treatments targeting the dysregulated host response. Further understanding of the mechanisms mediating lung damage and pathology in sepsis is vital for the development of more efficacious treatments and diagnostic strategies. A comprehensive training plan is proposed that includes these exciting studies to develop needed skills for my career goal to become a clinician-scientist.

抽象的 该提议将确定败血症和血浆原成的肺损伤与死亡率之间的关系 衍生的氯化脂质，是在先天免疫反应期间产生的。一个重要原因 败血症是全球患者的发病率和死亡率，是免疫反应的系统性失调 最初的感染并经常导致急性肺损伤（ALI），其他器官损伤和死亡。宿主中性粒细胞 是先天免疫系统的组成部分，并在败血症期间被系统地激活。中性粒细胞 髓过氧化物酶（MPO）在脓毒症期间细菌杀死很重要。 MPO催化生产 来自呼吸道爆发过程中产生的过氧化氢的次氯酸（HOCL）。霍克又是 靶向微生物的强大氧化剂。但是，HOCL也可能与宿主分子反应，包括乙烯基 膜质基因的醚键。浆元是一类具有脂肪族的甘油磷脂 链通过乙烯基醚键连接到甘油主链。当被HOCL攻击时，脂肪族 链被解放为氯氟醛醛（2-clfald）。 2-clfald可以被氧化为氯脂粉酸（2-CLFA） 在生理条件下。这些化合物，被指定为血浆原源性的氯化脂质，是 在各种炎症条件下升高。评论中的福特实验室手稿演示了等离子体2-CLFA 预测脓毒症中与急性呼吸窘迫综合症相关的死亡率。其他项目建议 血浆原源性的氯化脂质会引起内皮功能障碍，这是ALI的主要病因。我们 假设血质原衍生的氯化脂质是急性肺损伤的关键介质和 败血症中的死亡率通过引起内皮功能障碍的作用。该提案的目标1将使用 大鼠败血症的盲肠浆（CS）模型，以确定纤溶酶衍生的氯化脂质的产生 预测败血症的结局，例如死亡率，内皮功能障碍和肺损伤。机械研究将 被用来证明MPO和2-CLFA在CS引起的死亡率，内皮的原因 功能障碍和肺损伤。 AIM 2将确定血浆原衍生的氯化脂质引起 在没有败血症的情况下，内皮功能障碍和肺部损伤通过给大鼠外源性2-CLFA。单击 2-CLFA的化学类似物将可视化脂质对肺内皮的定位。额外的 实验将检查2-CLFA引诱的肠渗透性。 2-CLFA引起的机制 还将使用人肺内皮细胞探索内皮功能障碍。当前的治疗方案 对于败血症和败血症相关的ALI，由抗生素和支持性护理组成，明显缺乏 针对失调宿主反应的治疗方法。进一步了解介导的机制 败血症中的肺损伤和病理学对于开发更有效的治疗和 诊断策略。提出了一个全面的培训计划，其中包括这些令人兴奋的研究 为我的职业目标发展所需的技能，成为一名临床医生科学家。