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.

摘要 该提案将确定脓毒症肺损伤和死亡率之间的关系和血浆- 衍生的氯化脂质，这是在先天免疫反应过程中产生的。的重要原因 脓毒症是一种全身性免疫应答失调， 初始感染，通常导致急性肺损伤（ALI）、其他器官损伤和死亡。宿主中性粒细胞 是先天免疫系统的一个组成部分，在脓毒症期间被全身激活。中性粒 髓过氧化物酶（MPO）在脓毒症期间的细菌杀灭中是重要的。MPO催化产生 次氯酸（HOCl）来自呼吸爆发期间产生的过氧化氢。反过来，HOCl是一个 针对微生物的强大氧化剂。然而，HOCl也可以与主体分子反应，包括乙烯基单体。 膜缩醛磷脂的醚键。缩醛磷脂是一类甘油磷脂，具有脂族结构， 链通过乙烯基醚键连接到甘油主链。当被HOCl攻击时， 链以氯代脂肪醛（2-ClOFA D）的形式释放。2-ClO 2 D可被氧化成氯脂肪酸（2-ClFA） 在生理条件下。这些化合物被称为缩醛磷脂衍生的氯化脂质， 在各种炎症条件下升高。一份正在审查的福特实验室手稿证明了血浆2-ClFA 预测脓毒症中急性呼吸窘迫综合征相关的死亡率。其他项目建议 缩醛磷脂衍生的氯化脂质引起内皮功能障碍，这是ALI的主要致病因素。我们 假设血浆醇衍生的氯化脂质是急性肺损伤的关键介质， 通过其在诱发内皮功能障碍中的作用而导致败血症的死亡率。本提案的目标1将使用 在大鼠中建立脓毒症的盲肠浆液（CS）模型，以确定是否由缩醛磷脂衍生的氯化脂质产生 预测败血症的结局，如死亡率、内皮功能障碍和肺损伤。机械研究将 用于证明MPO和2-ClFA在CS引起的死亡率、内皮细胞 功能障碍和肺损伤。目的2将确定缩醛磷脂衍生的氯化脂质导致 内皮功能障碍和肺损伤在没有脓毒症的大鼠给予外源性2-ClFA。点击 2-ClFA的化学类似物将使脂质在肺内皮上的定位可视化。额外 实验将检测2-ClFA引起的肠道渗透性。2-ClFA的作用机制 还将使用人肺内皮细胞探索内皮功能障碍。目前的治疗方案 对于脓毒症和脓毒症相关的ALI，抗生素和支持性护理组成， 针对失调的宿主反应的治疗。进一步了解调解机制 脓毒症中的肺损伤和病理学对于开发更有效的治疗是至关重要的， 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， 发展我的职业目标所需的技能，成为一名临床科学家。