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.

脓毒症！是成人和儿童每年160万例的发病率和死亡率的主要原因 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消除微生物 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)产生强有力的氧化剂， 次氯酸(HOCl)，可与微生物和宿主分子靶标(包括脂质)反应。少年派博士。 大卫·福特已经证明，HOCI针对的是血浆蛋白原脂质的乙烯基醚键，从而产生2- 氯代脂肪醛(2-ClFALD)和其他氯脂，包括2-氯代脂肪酸(2-ClFA)，以响应 白细胞被激活。这使得我们的多PI团队在之前的授予间隔期间确定了氯脂类化合物的诱导性 内皮激活导致白细胞和血小板黏附，并证明氯脂相关 与人类败血症的ARDS和30天死亡率有关。进一步研究氯脂在脓毒症中的作用 病理生理学方面，我们的多PI小组已经积累了新的初步数据，表明：1)TLR4的抑制剂， CD36和谷胱甘肽S转移酶减轻2-ClFA诱导的内皮功能障碍；2)TLR4 抑制剂TAK-242可降低2-ClFA和盲肠结扎穿孔(CLP)诱导的肠系膜损伤 活体显微镜下的微循环功能障碍；3)2-ClFA修饰特异性内皮细胞 蛋白质，这可能是一种新的靶向干预2-ClFA引起的内皮细胞的范例 激活；4)氯脂导致肠道上皮屏障渗漏，包括体内肠道细菌易位；5) 血浆中2-ω-2-ClFA，2-ClDCA氧化产物的水平 发生急性肾损伤的重症监护病房(ICU)合并脓毒症的患者入院率增加 (Aki)；6)2-ClDCA导致内皮细胞功能障碍。氯脂在脓毒症中的作用正在扩大，并且 这些初步数据表明，拟议的研究中存在需要解决的知识差距， 这将检验我们的总体假设，即败血症期间激活的中性粒细胞产生氯磷脂 是导致多器官衰竭的严重内皮功能障碍的介质。一共有三个 明确的目标。特定目标1将检验以下假设：氯脂介导的人体内皮细胞功能障碍。 内皮细胞和上皮细胞可以作为药理靶点。《特定目标2》将检验这一假设： 体内氯脂和脓毒症引起的微循环功能障碍和肠屏障功能障碍 被药物抑制了。特指目标3将检验如下假设：血浆2-ClDCA水平与 人类脓毒症的特定器官功能障碍和死亡。总体而言，我们的多PI采用多学科方法 团队和Co-IS将检查脓毒症期间激活的中性粒细胞产生的氯脂作为关键介质 导致器官衰竭的微循环障碍，以及试验抑制物和激活的途径， 以氯脂诱导的内皮功能障碍为干预点。这项合作调查具有 有可能为脓毒症患者提供新的治疗和诊断靶点。