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.

项目总结/文摘

项目成果

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

内皮细胞中的S-亚硝基化有助于乳腺癌转移期间肿瘤细胞粘附和渗出。

• 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