The Role of Plasmalogen Mitochondrial and Endothelial Antioxidant Properties in Sepsis

摘要 脓毒症是由细菌、病毒或真菌感染引发的，其特征是随后出现多器官衰竭 宿主反应受损。年，脓毒症在全国住院死亡率和费用负担中都位居榜首 与所有疾病相比。多年来，脓毒症的治疗仅限于抗生素、液体和器官。 支持。需要新的治疗方法，可能针对脓毒症的细胞病理生理学包括 过度的氧化应激，血液-内皮界面的炎性过度激活，在 线粒体健康，脂类动态平衡失调。血浆原是一类独特的磷脂 在sn-1位含有特征的乙烯基醚键，它将甘油主链连接到 脂肪链。乙烯基醚键是活性氧物种(ROS)的靶标，因此血浆原是 抗氧化剂。我最近的研究表明，在人类脓毒症中，血浆纤溶酶原水平降低， 可能反映了脓毒症由氧化还原酶产生的内皮氧化应激和电子泄漏 线粒体电子传递链(ETC)。ROS对线粒体的损伤影响细胞呼吸和 不利于细胞整体健康的脂类代谢。这表明了血浆原细菌的保护作用。 它们存在于细胞和细胞器的膜中，包括线粒体。溶血纤溶蛋白原(Lysopls)，a 在sn-2位缺少酰基链的血浆蛋白原类是一种有用的血浆蛋白原前体 细胞比纤溶酶原摄取更快，并且仍然含有清除ROS的乙烯基醚键。试点数据 研究表明，补充人肺微血管内皮细胞(HLMVECs)的LysoPls可减少 在病原菌和溶血素存在的情况下，细胞氧化应激和维持血浆蛋白原池 补充内毒素可保护HLMVEC屏障的完整性。总而言之，这是 提示LysoPls具有清除ROS的作用，并在脓毒症期间提供关键的内皮保护 氧化应激。因此，我们假设血浆蛋白原丢失反映了损伤性的内皮氧化。 脓毒症期间的应激，和纤溶酶原替代可能限制氧化应激，改善预后 通过线粒体和内皮细胞的作用。目标1的研究将包括：1)检测人类脓毒症血浆 血浆蛋白原水平作为预后预测因子与Nuala Meyer博士(宾夕法尼亚大学)合作 2)在小鼠盲肠结扎和穿孔脓毒症模型上测试血浆蛋白原替代疗法 与理查德·霍奇基斯博士(华盛顿州)合作，预防死亡和器官衰竭 大学)。内科科学家迈耶博士和霍奇基斯博士也将担任此次培训的共同导师 程序。AIM 2的研究将测试纤溶酶原增强减少炎症和 内皮细胞中的氧化应激，改善内皮功能。总体而言，这些研究开启了新的研究 区分脓毒症靶点和治疗方法并最终改善脓毒症患者预后的途径 尤其是考虑到近几十年来抗生素耐药性的上升。

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.