Chlorinated lipids in sepsis

败血症中的氯化脂质

• 批准号: 10210265
• 负责人: DAVID A. FORD
• 金额: $ 32.12万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210265
• 关键词: Acids; Acute Renal Failure with Renal Papillary Necrosis; Address; Adherence; Admission activity; Adult; Adult Respiratory Distress Syndrome; Aldehydes; Bacterial Translocation; Biology; Blood Cells; Blood Circulation; Blood Platelets; Blood Vessels; CD36 gene; Cell Communication; Cell Culture Techniques; Cell Degranulation; Cessation of life; Chemistry; Child; Clinical; Complex; Data; Dilatation - action; Discipline; Endothelial Cells; Endothelium; Environment; Epithelial Cells; Failure; Family; Functional disorder; Glutathione S-Transferase; Grant; Human; Hypochlorous Acid; Immune response; Infection; Injury; Intensive Care Units; Intervention; Investigation; Knowledge; Leukocytes; Lipids; Measures; Mediating; Mediator of activation protein; Mesentery; Microbe; Microcirculation; Molecular Target; Morbidity - disease rate; Multiple Organ Failure; Organ; Organ failure; Oxidants; P-Selectin; Panthera leo; Pathology; Pathway interactions; Patients; Pennsylvania; Peroxidases; Phagocytosis; Pharmacology; Phenotype; Plasma; Plasmalogens; Post-Translational Protein Processing; Production; Prospective cohort study; Proteins; Rattus; Research Personnel; Role; Scientist; Sepsis; Signal Transduction; Surface; TLR4 gene; Testing; Therapeutic Intervention; Tissues; United States; Universities; Vascular Permeabilities; analog; cecal ligation puncture; drug testing; endothelial dysfunction; gastrointestinal epithelium; in vivo; indexing; inflammatory marker; inhibitor/antagonist; interdisciplinary approach; intestinal barrier; intestinal epithelium; intravital microscopy; leukocyte activation; mast cell; member; microbial host; mortality; multiorgan injury; neutrophil; novel diagnostics; novel therapeutics; oxidation; response; septic patients; small molecule libraries; targeted treatment; uptake; vinyl ether

Sepsis!is a major cause of morbidity and mortality in both adults and children with >1.6 million cases per year in the United States. Neutrophils are key early responders to infection. Neutrophils eliminate microbes by phagocytosis and by oxidant-mediated killing. Neutrophil myeloperoxidase (MPO) produces the potent oxidant, hypochlorous acid (HOCl), which reacts with both microbial and host molecular targets including lipids. PI Dr. David Ford has shown HOCl targets the vinyl ether bond of plasmalogen lipids, resulting in the production of 2- chlorofatty aldehyde (2-ClFALD) and other chlorolipids, including 2-chlorofatty acid (2-ClFA), in response to leukocyte activation. This led our multi-PI team during the previous grant interval to determine chlorolipids elicit endothelial activation leading to leukocyte and platelet adherence, and to demonstrate chlorolipids associate with ARDS and 30-day mortality in human sepsis. To further investigate the role of chlorolipids in sepsis pathophysiology, our multi-PI group has accrued new preliminary data showing that: 1) inhibitors of TLR4, CD36 and glutathione S-transferase (GST) decrease 2-ClFA-elicited endothelial dysfunction; 2) the TLR4 inhibitor, TAK-242, reduces 2-ClFA-elicited and cecal ligation and puncture (CLP) sepsis-elicited mesenteric microcirculatory dysfunction using in vivo intravital microscopy; 3) 2-ClFA modifies specific endothelial cell proteins, which may represent a new paradigm to target for intervention of 2-ClFA-caused endothelial activation; 4) chlorolipids cause gut epithelial barrier leakiness, including in vivo gut bacterial translocation; 5) plasma levels of ω-oxidation products of 2-ClFA, 2-chlorodicarboxylic acids (2-ClDCAs), measured on admission to the intensive care unit (ICU) with sepsis are elevated in patients that develop acute kidney injury (AKI); and 6) 2-ClDCA causes endothelial cell dysfunction. The role of chlorolipids in sepsis is expanding, and these preliminary data indicate there are knowledge gaps that need to be addressed in the proposed studies, which will test our overall hypothesis that chlorolipids produced by activated neutrophils during sepsis are mediators of severe endothelial dysfunction resulting in multiple organ failure. There are three specific aims. Specific Aim 1 will test the hypothesis that chlorolipid-mediated dysfunction in human endo- thelial and epithelial cells can be pharmacologically targeted. Specific Aim 2 will test the hypothesis that in vivo chlorolipid- and sepsis-elicited microcirculatory dysfunction and gut barrier dysfunction can be pharmacologically inhibited. Specific Aim 3 will test the hypothesis that plasma 2-ClDCA levels associate with specific organ dysfunctions and death in human sepsis. Overall, a multi-disciplinary approach with our multi-PI team and Co-Is will examine chlorolipids produced by activated neutrophils during sepsis as critical mediators of microcirculatory dysfunction leading to organ failure, and test inhibitors of, and pathways activated by, chlorolipid-elicited endothelial dysfunction as intervention points. This collaborative investigation has the potential to provide new therapeutic and diagnostic targets for patients with sepsis.

败血症！是成人和儿童发病和死亡的主要原因，每年有超过160万例病例 在美国中性粒细胞是感染的关键早期反应者。中性粒细胞通过以下方式清除微生物： 吞噬作用和氧化剂介导的杀伤作用。中性粒细胞髓过氧化物酶（MPO）产生强氧化剂， 次氯酸（HOCl），其与微生物和宿主分子靶标（包括脂质）反应。PI医生 大卫福特已经表明HOCl靶向缩醛磷脂的乙烯基醚键，导致产生2- 氯脂肪醛（2-ClOFA D）和其他氯脂，包括2-氯脂肪酸（2-ClFA）， 白细胞活化这导致我们的多PI团队在上一次拨款期间确定氯脂引起的 内皮激活导致白细胞和血小板粘附，并证明氯脂相关 急性呼吸窘迫综合征和30天的死亡率。进一步探讨氯脂在脓毒症中的作用 病理生理学，我们的多PI组已经积累了新的初步数据，显示：1）TLR 4的抑制剂， CD 36和谷胱甘肽S-转移酶（GST）减少2-ClFA引起的内皮功能障碍; 2）TLR 4 抑制剂TAK-242可减少2-ClFA引起的和盲肠结扎穿孔（CLP）引起的肠系膜脓毒症 使用活体显微镜观察微循环功能障碍; 3）2-ClFA修饰特异性内皮细胞 蛋白质，这可能代表了一种新的范式，以干预2-ClFA引起的内皮细胞 激活; 4）氯脂类引起肠上皮屏障渗漏，包括体内肠细菌移位; 5） 2-ClFA、2-氯二羧酸（2-ClDCA）的ω-氧化产物的血浆水平， 急性肾损伤患者因败血症进入重症监护室（ICU）的几率增加 (AKI)6）2-ClDCA引起内皮细胞功能障碍。氯脂类在脓毒症中的作用正在扩大， 这些初步数据表明，在拟议的研究中存在需要解决的知识差距， 这将检验我们的假设，即脓毒症时活化的中性粒细胞产生的氯脂 是导致多器官衰竭的严重内皮功能障碍的介质。有三 具体目标。具体目标1将检验以下假设： 上皮细胞和上皮细胞可以是靶向的。具体目标2将检验假设， 体内氯脂质和脓毒症引起的微循环功能障碍和肠屏障功能障碍可以 很压抑。具体目标3将检验血浆2-ClDCA水平与以下相关的假设： 特定器官功能障碍和人败血症死亡。总的来说，我们的多PI采用多学科方法 研究小组和Co-Is将检查脓毒症期间活化的中性粒细胞产生的氯脂质作为关键介质 导致器官衰竭的微循环功能障碍，以及测试抑制剂和激活途径， 氯脂质引起的内皮功能障碍作为干预点。这次合作调查 有可能为脓毒症患者提供新的治疗和诊断靶点。