Phospholipidomics and inflammation in sepsis

脓毒症中的磷脂组学和炎症

• 批准号: 9920760
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920760
• 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; Endothelium; Event; Exhibits; Extravasation; Frequencies; Functional disorder; Generations; Human; Impairment; Infection; Infiltration; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Lead; Length; Link; Lipid Peroxidation; Lung; Lung Inflammation; Lung infections; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mus; Organ; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Pathologic; Pathway interactions; Permeability; Phospholipids; Pilot Projects; Pneumonia; Pre-Clinical Model; Process; Property; Role; Sepsis; Severities; Signal Transduction; Staphylococcus aureus; Staphylococcus aureus infection; Sterility; Syndrome; TFPI; TLR3 gene; TXNIP gene; Testing; Time; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelium; Vascular Permeabilities; antibiotic resistant infections; base; combat; cytokine release syndrome; effective therapy; lung injury; methicillin resistant Staphylococcus aureus; microbial; mortality; novel; novel strategies; oxidant stress; oxidation; particle; pathogen; pathogenic bacteria; septic; stress kinase; 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.

项目摘要/摘要 败血症仍然是发病率和死亡率的主要原因。通常，所有败血症病例中有50％以 肺部感染。败血症伴随着多个器官功能障碍，细胞因子风暴和散布 凝血综合征。这些过程直接涉及血管内皮细胞。虽然发炎，但 凝血失调和内皮渗透性的改变是败血性急性的公认因素 肺损伤（ALI），内源性介体和细胞机制，策划了内皮的过程 败血症条件下的炎症激活和凝结尚未理解。在试点研究中 使用基于质谱的肺部鉴定出截短的氧化磷脂（TR-OXPLS） 磷脂学方法。我们令人兴奋的初步数据表明，Tr-Oxpls明显恶化的肺 化粪池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 活体金黄色葡萄球菌诱导的ALI的肺炎模型（S. au，USA300 CA-MRSA临床 菌株923）或热杀死的S. au（HKSA）该翻译研究将首次使用定量 鉴定在ALI期间升高的特定TR-OXPL的磷脂方法方法，并阐明其作用为 因素加剧炎症和失调的凝血级联反应。我们假设增加了 通过诱导NLRP3炎性体的表达，败血症期间的Tr-Oxpls产生增强肺损伤 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传导激活， 凝血失调，肺部炎性细胞浸润和器官损伤。 AIM-1将确定 在Au挑战的动物的肺中产生的Tr-oxpl光谱。 AIM-2将研究Tr-的影响 在Au S.诱导的败血性条件下产生的OXPL对肺损伤的严重程度。 AIM-3将研究分子 TR-OXPL诱导的化粪池炎症和凝结的加剧机制。 AIM-4将测试新 基于机制的策略来减轻TR-OXPLS的产生及其在S. au-中的病理后果 诱导化粪池Ali。

项目成果

S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis.

• DOI: 10.1186/s40659-023-00461-2
• 发表时间: 2023-09-29
• 期刊: Biological research
• 影响因子: 6.7
• 作者: Koning T;Cordova F;Aguilar G;Sarmiento J;Mardones GA;Boric M;Varas-Godoy M;Lladser A;Duran WN;Ehrenfeld P;Sanchez FA
• 通讯作者: Sanchez FA