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。中性粒细胞是对感染的主要早期反应者。中性粒细胞消除微生物 吞噬作用和氧化剂介导的杀伤。嗜中性粒细胞髓过氧化物酶（MPO）产生潜在的氧化剂， 次氯酸酸（HOCL）与包括脂质在内的微生物和宿主分子靶标反应。 PI Dr. 大卫·福特（David Ford）表明，HOCL靶向血质脂质的乙烯基醚键，从而产生2-- 氯氟法醛醛（2-clfald）和其他氯脂脂，包括2-氯脂蛋白酸（2-Clfa），响应于 白细胞激活。这导致了我们在上一个赠款间隔期间的多P-PI团队，以确定叶绿素引起的 内皮激活导致白细胞和血小板粘附，并展示叶绿素助理 人类败血症中的ARD和30天死亡率。进一步研究叶绿素在败血症中的作用 病理生理学，我们的多PI组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（GST）降低了2-CLFA的内皮功能障碍； 2）TLR4 抑制剂TAK-242，减少了2-CLFA的结扎和穿刺（CLP）败血症肠系膜 使用体内插入式显微镜的微循环功能障碍； 3）2-CLFA修饰特定的内皮细胞 蛋白质，这可能代表一个新的范式，以靶向2-CLFA引起的内皮干预 激活; 4）叶绿素引起肠道上皮屏障泄漏，包括体内肠道细菌； 5） 2-CLFA，2-氯二碳苯甲酸（2-CLCAS）的ω氧化产物的血浆水平，在 患有急性肾脏损伤的患者接受重症监护病房（ICU）的入院率升高 （aki）; 6）2-CLDCA会导致内皮细胞功能障碍。叶绿素在败血症中的作用正在扩大，并且 这些初步数据表明，在拟议的研究中需要解决知识差距， 这将检验我们的总体假设，即脓毒症期间活化中性粒细胞产生的叶绿素 是严重内皮功能障碍的介体导致多器官衰竭。有三个 具体目标。特定的目标1将检验以下假设：叶绿素介导的人类内部功能障碍 可以针对苯细胞和上皮细胞。具体目标2将检验以下假设。 体内叶绿素和败血症的微循环功能障碍和肠道屏障功能障碍可能是 药理抑制。具体目标3将检验以下假设：等离子体2-CLDCA水平与 人类败血症的特定器官功能障碍和死亡。总体而言，我们的Multi-Pi是一种多学科的方法 团队和共同IS将检查败血症期间活化中性粒细胞产生的叶绿素作为关键介体 导致器官衰竭的微循环功能障碍，并测试由 叶绿素引起的内皮功能障碍作为干预点。这项协作调查具有 为败血症患者提供新的治疗和诊断靶标的潜力。