Neutrophil-dependent mediators of sepsis

脓毒症在美国每年侵袭100多万人，死亡率为28-50%。脓毒症发生在以下情况 宿主对微生物的反应超越了感染部位，进入了体循环。这将导致 涉及微生物、血液成分和可进展为血管的内皮的复杂相互作用 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 髓过氧化物酶(MPO)是氧依赖杀菌活性的主要介体。MPO催化氢化-2，4-二苯基-2，4-二苯基-2，4-三甲基-4 Gen过氧化氢转化为次氯酸，次氯酸与微生物和宿主分子靶标反应产生 各种氧化脂质和代谢物的阵列。虽然中性粒细胞衍生的氧化剂促进微生物杀灭，但它们 在宿主损伤中也起着关键作用。对于拟议的研究，宿主和多菌体分子的复杂性 将使用靶向和非靶向组学研究中性粒细胞衍生氧化剂的凝集性靶向 寻找新的脓毒症相关多器官衰竭的生物标志物、介体和机制。因此，我们将 测试脓毒症期间中性粒细胞激活导致氧化剂衍生的鼹鼠家族的假设- 介导脓毒症相关的多器官衰竭的CRE是人类SEP-2的候选生物标志物。 SIS结果。这一假设将通过三个具体目标进行检验。具体目标1将检验这一假设 中性粒细胞激活的脂质和代谢分子特征介导人的内皮功能障碍 内皮细胞。有一个发现臂的目的，以确定新的中性粒细胞激活的分子特征- 提顿。已发现的分子签名以及在我们的初步研究中揭示的分子签名将作为中介进行测试 内皮功能障碍和改变的微生物杀伤力。特指目标2将检验这样的假设：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体 老鼠败血症。药物干预将被用来检查分子签名在结果中的作用 由存活、内皮功能障碍和多器官衰竭决定的大鼠脓毒症。《特定目标3》将进行测试 假设中性粒细胞激活的新分子特征与器官功能障碍和 死于人类败血症。已经为拟议的研究组装了一个多PI小组，每个PI具有 独特的专业知识。这些PI包括中性粒细胞来源的氯的鉴定和生物学方面的先驱-- 福特博士；在临床脓毒症研究方面拥有专业知识的知名临床科学家Nuala Meyer博士； 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简·麦考瓦特博士。总体而言， 多学科方法将检查氧化脂质和代谢物的作用，其结果是 脓毒症期间中性粒细胞的激活可作为人类败血症器官衰竭和死亡率的预测指标，并可作为介质- 在大鼠体内和体外检测血管内皮细胞功能障碍的TORS，以测试其机制 功能障碍。这些创新的研究旨在发现中性粒细胞在脑内的作用的新范例 引发内皮功能障碍为治疗败血症患者提供了新的靶点。

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.