Phospholipidomics and inflammation in sepsis

脓毒症中的磷脂组学和炎症

• 批准号: 9287400
• 负责人: Konstantin Birukov
• 金额: $ 29.36万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9287400
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Anticoagulants; Blood Circulation; Blood Vessels; Cell membrane; Cell model; Cells; Choline; Clinical; Coagulation Process; Combating Antibiotic Resistant Bacteria; Complication; Data; Development; Disease; Down-Regulation; Endothelial Cells; Event; Exhibits; Extravasation; Frequencies; Functional disorder; Generations; Human; Impairment; Infection; Infiltration; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Lead; Length; Link; Lipid Peroxidation; Lipid Peroxides; Lung; Lung Inflammation; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Methicillin Resistance; Modeling; Molecular; Mono-S; Morbidity - disease rate; Multiple Organ Failure; Mus; Organ; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Pathologic; Pathway interactions; Permeability; Phospholipids; Phosphotransferases; Pilot Projects; Pneumonia; Pre-Clinical Model; Process; Property; Role; Sepsis; Severities; Signal Transduction; Staphylococcus aureus; Sterility; Stress; Syndrome; TFPI; TLR3 gene; TXNIP gene; Testing; Time; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelium; Vascular Permeabilities; base; combat; cytokine; effective therapy; killings; lung injury; methicillin resistant Staphylococcus aureus; microbial; mortality; novel; novel strategies; oxidant stress; oxidation; particle; pathogen; septic; therapeutic evaluation; translational study; vascular inflammation

Project Summary/Abstract Sepsis remains a major cause of morbidity and mortality. Typically, 50% of all sepsis cases start as an infection in the lungs. Sepsis is accompanied by multiple organ dysfunction, cytokine storm, and disseminated coagulation syndrome. These processes directly involve vascular endothelial cells. Although inflammation, dysregulated coagulation, and alterations in endothelial permeability are recognized factors of septic acute lung injury (ALI), the endogenous mediators and cellular mechanisms orchestrating processes of endothelial inflammatory activation and coagulation in septic conditions remain poorly understood. In pilot studies we identified truncated oxidized phospholipids (TR-OxPLs) in the inflamed lungs using Mass Spectrometry-based phospholipidomics approach. Our exciting preliminary data show that TR-OxPLs markedly exacerbated lung dysfunction and impaired vascular endothelial barrier in cell and animal models of septic ALI. Using pneumonia-related models of ALI induced by live Staphylococcus aureus (S. au, USA300 CA-MRSA clinical strain 923) or heat-killed S. au (HKSA) this translational study will employ for the first time the quantitative phospholipidomics approach to identify specific TR-OxPLs elevated during ALI and elucidate their role as factors exacerbating inflammation and dysregulating coagulation cascade. We hypothesize that increased generation of TR-OxPLs during sepsis augments lung injury by inducing expression of NLRP3 inflammasome activator, thioredoxin interacting protein (TXNIP); and by suppressing the expression of vascular anticoagulant, Tissue Factor Pathway Inhibitor (TFPI). Altogether, these events lead to activation of inflammatory signaling, dysregulated coagulation, inflammatory cell infiltration in the lung, and organ damage. Aim-1 will determine the spectrum of TR-OxPL generated in the lungs of S. au-challenged animals. Aim-2 will study the impact of TR- OxPL generated in S. au-induced septic conditions on the severity of lung injury. Aim-3 will study molecular mechanisms of TR-OxPL-induced exacerbation of septic inflammation and coagulation. Aim-4 will test new mechanism-based strategies to alleviate TR-OxPLs generation and their pathologic consequences in S. au- induced septic ALI.

项目总结/摘要 脓毒症仍然是发病率和死亡率的主要原因。通常情况下，50%的败血症病例开始于 肺部感染脓毒症伴有多器官功能障碍、细胞因子风暴和播散性 凝血综合征这些过程直接涉及血管内皮细胞。虽然炎症， 凝血功能失调和内皮通透性改变是公认的脓毒症急性发作的因素。 肺损伤（ALI），内源性介质和细胞机制协调过程的内皮细胞 脓毒症中的炎性活化和凝血仍然知之甚少。在试点研究中， 使用基于质谱的方法在发炎的肺中鉴定了截短的氧化磷脂（TR-OxPL）。 磷脂组学方法。我们令人兴奋的初步数据显示，TR-OxPL显著加重了肺 在脓毒性ALI的细胞和动物模型中的功能障碍和血管内皮屏障受损。使用 肺炎相关模型由活金黄色葡萄球菌（S. Au，USA 300 CA-MRSA临床 菌株923）或热灭活的S. Au（香港会计师公会）这项翻译研究将首次采用定量 磷脂组学方法来鉴定ALI期间升高的特异性TR-OxPL，并阐明其作为 加重炎症和凝血级联失调的因素。我们假设 脓毒症期间TR-OxPL的产生通过诱导NLRP 3炎性体的表达而加重肺损伤 激活剂，硫氧还蛋白相互作用蛋白（TXNIP）;并通过抑制血管抗凝剂的表达， 组织因子途径抑制剂（TFPI）。总之，这些事件导致炎症信号的激活， 凝血失调、肺中的炎性细胞浸润和器官损伤。Aim-1将确定 S.挑战动物Aim-2将研究TR的影响- OxPL在S. au-induced脓毒症条件对肺损伤的严重程度。Aim-3将研究分子 TR-OxPL诱导的脓毒性炎症和凝血恶化的机制。Aim-4将测试新的 基于机制的策略，以减轻TR-OxPL的产生和它们在S. Au- 引起脓毒性ALI。