Neutrophil-dependent mediators of sepsis

脓毒症的中性粒细胞依赖性介质

• 批准号: 9578653
• 负责人: DAVID A. FORD
• 金额: $ 29.53万
• 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: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9578653
• 关键词: Acids; Acute Renal Failure with Renal Papillary Necrosis; Adult Respiratory Distress Syndrome; Aldehydes; Bacteria; Biological Markers; Biology; Blood; Blood Circulation; Blood Platelets; Blood Vessels; Cecum; Cell Communication; Ceramides; Cessation of life; Clinical; Coculture Techniques; Complex; Data; Endothelial Cells; Endothelium; Escherichia coli; Failure; Family; Functional disorder; Glutathione; Goals; Human; Hydrogen Peroxide; Hypochlorous Acid; Immune response; In Vitro; Infection; Injury; Intervention; Leukocytes; Lipids; Lung; Mediating; Mediator of activation protein; Metabolic; Microbe; Modeling; Molecular Profiling; Molecular Target; NADPH Oxidase; Neutrophil Activation; Organ; Organ failure; Outcome; Oxidants; Oxides; Oxygen; Pathology; Pennsylvania; Peroxidases; Phagocytosis; Pharmacology; Phenotype; Pilot Projects; Plasma; Plasmalogens; Production; Rattus; Research Personnel; Respiratory Burst; Role; Saints; Scientist; Sepsis; Site; Specimen; Superoxides; Technology; Testing; Therapeutic Intervention; Universities; adduct; arm; candidate marker; design; endothelial dysfunction; extracellular; in vivo; indexing; innovation; interdisciplinary approach; metabolomics; microbial host; microbicide; mortality; neutrophil; new therapeutic target; novel; outcome prediction; oxidation; oxidized lipid; response; sample collection; septic patients; targeted treatment; vascular endothelial dysfunction

Sepsis strikes over one million in the US per year, with a mortality rate of 28-50%. Sepsis occurs when the host response to microbes extends beyond the site of infection and into the systemic circulation. This results in complex interactions involving microbes, blood components, and the endothelium that can progress to vascular collapse and organ failure. Neutrophils are key early responders to infection. Neutrophil myeloperoxidase (MPO) is a major mediator of oxygen-dependent microbicidal activity. MPO catalyzes the conversion of hydro- gen peroxide to hypochlorous acid, which reacts with both microbial and host molecular targets to produce a diverse array of oxidized lipids and metabolites. While neutrophil-derived oxidants promote microbe killing, they also have a critical role in host injury. For the proposed studies the complexity of host and polymicrobial mo- lecular targeting by neutrophil-derived oxidants will be investigated using both targeted and untargeted omics to identify new biomarkers, mediators and mechanisms of sepsis-associated multi-organ failure. Thus, we will test the hypothesis that neutrophil activation during sepsis leads to an oxidant-derived family of mole- cules that mediate sepsis-associated multi-organ failure and are candidate biomarkers of human sep- sis outcomes. This hypothesis will be tested with three specific aims. Specific Aim 1 will test the hypothesis that lipid and metabolic molecular signatures of neutrophil activation mediate endothelial dysfunction in human endothelial cells. There is a discovery arm to this aim to identify new molecular signatures of neutrophil activa- tion. Discovered molecular signatures as well as those revealed in our pilot studies will be tested as mediators of endothelial dysfunction and altered microbe killing. Specific Aim 2 will test the hypothesis that lipid and metabolic molecular signatures of neutrophil activation are biomarkers and mediators of multi-organ failure in rat sepsis. Pharmacological intervention will be used to examine the role of molecular signatures in outcomes of rat sepsis as determined by survival, endothelial dysfunction and multi-organ failure. Specific Aim 3 will test the hypothesis that novel molecular signatures of neutrophil activation associate with organ dysfunction and death in human sepsis. A multi-PI group has been assembled for the proposed studies with each PI having unique expertise. These PIs include the pioneer in the identification and biology of neutrophil-derived chlorin- ated lipids, Dr. Ford; an established clinician scientist with expertise in clinical sepsis studies, Dr. Nuala Meyer; and an expert in platelet, leukocyte, endothelial cell interactions and pathology, Dr. Jane McHowat. Overall, a multi-disciplinary approach will examine the role of oxidized lipids and metabolites produced as a result of neutrophil activation during sepsis as predictors of organ failure and mortality in human sepsis, and as media- tors of vascular endothelial dysfunction examined both in vivo in the rat and in vitro to test mechanisms of dysfunction. These innovative studies are designed to discover new paradigms for the role of neutrophils in eliciting endothelial dysfunction providing new targets for therapeutics to treat septic patients.

美国每年有超过一百万人患脓毒症，死亡率为 28-50%。脓毒症发生时 宿主对微生物的反应超出了感染部位并进入了体循环。这导致 涉及微生物、血液成分和内皮细胞的复杂相互作用，可进展为血管 崩溃和器官衰竭。中性粒细胞是感染的关键早期反应者。中性粒细胞髓过氧化物酶 (MPO) 是氧依赖性杀菌活性的主要介质。 MPO 催化氢转化 过氧化氢生成次氯酸，次氯酸与微生物和宿主分子靶标发生反应，产生 多种氧化脂质和代谢物。虽然中性粒细胞衍生的氧化剂促进微生物杀灭，但它们 在宿主损伤中也发挥着关键作用。对于拟议的研究，宿主和多种微生物的复杂性 将使用靶向组学和非靶向组学研究中性粒细胞衍生的氧化剂的分子靶向 确定脓毒症相关多器官衰竭的新生物标志物、介质和机制。这样，我们将 检验脓毒症期间中性粒细胞活化导致氧化剂衍生的摩尔家族的假设 介导脓毒症相关多器官衰竭的细胞，是人类脓毒症的候选生物标志物 SIS 结果。该假设将通过三个具体目标进行检验。具体目标 1 将检验假设 中性粒细胞激活的脂质和代谢分子特征介导人类内皮功能障碍 内皮细胞。这个目标有一个发现部门，旨在识别中性粒细胞激活的新分子特征。 。发现的分子特征以及我们试点研究中揭示的分子特征将作为介质进行测试 内皮功能障碍和微生物杀灭能力改变。具体目标 2 将检验脂质和 中性粒细胞激活的代谢分子特征是多器官衰竭的生物标志物和介质 大鼠败血症。药理学干预将用于检查分子特征在结果中的作用 通过存活、内皮功能障碍和多器官衰竭来确定大鼠脓毒症的发生率。具体目标3将测试 中性粒细胞激活的新分子特征与器官功能障碍相关的假设 人类败血症死亡。为拟议的研究组建了一个多 PI 小组，每个 PI 都有 独特的专业知识。这些 PI 包括中性粒细胞来源的二氢卟酚的鉴定和生物学领域的先驱。 吃过的脂质，福特博士； Nuala Meyer 博士是一位在临床脓毒症研究方面具有专业知识的知名临床科学家； 以及血小板、白细胞、内皮细胞相互作用和病理学方面的专家 Jane McHowat 博士。总体而言，一个 多学科方法将检查氧化脂质和代谢物的作用 脓毒症期间的中性粒细胞活化作为人类脓毒症器官衰竭和死亡率的预测因子，并作为介质 血管内皮功能障碍的因素在大鼠体内和体外进行了检查，以测试其机制 功能障碍。这些创新研究旨在发现中性粒细胞在 引起内皮功能障碍，为脓毒症患者的治疗提供新靶点。