Cell-free hemoglobin-oxidized LDL-LOX-1 axis and microvascular hyperpermeability during sepsis

脓毒症期间无细胞血红蛋白氧化的 LDL-LOX-1 轴和微血管通透性过高

• 批准号: 10739620
• 负责人: Jamie E Meegan
• 金额: $ 14.02万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739620
• 关键词: Abbreviations; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adherens Junction; Antibodies; Apoptotic; Atherosclerosis; Automobile Driving; Binding; Blood Vessels; CREB1 gene; Cardiovascular Diseases; Cell Separation; Cells; Cessation of life; Clinical; Cyclic AMP-Responsive DNA-Binding Protein; Data; Edema; Endothelial Cells; Endothelium; Erythrocytes; Filtration; Functional disorder; Generations; Goals; Haptoglobins; Hemoglobin; Human; Immune response; Infection; Inflammation Mediators; Inflammatory; Injections; Injury; Laboratories; Lectin; Lectin Receptors; Link; Lipoproteins; Low Density Lipoprotein oxidation; Lung; MAP Kinase Gene; Matrix Metalloproteinases; Measures; Mediating; Membrane Proteins; Mentors; Metalloproteases; Microvascular Dysfunction; Mitogens; Molecular; Morbidity - disease rate; Mus; Organ; Oxidants; Pathogenesis; Pathologic; Pathway interactions; Patients; Peer Review; Peptide Hydrolases; Permeability; Phase; Phosphotransferases; Physiological; Plasma; Plasma Cells; Positioning Attribute; Preparation; Prevention strategy; Proteins; Receptor Signaling; Regulation; Research; Resolution; Role; Sepsis; Signal Pathway; Signal Transduction; Small Interfering RNA; Technical Expertise; Testing; Tight Junctions; Tissues; Training; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelium; Writing; career; cell injury; clinically relevant; endothelial dysfunction; ex vivo perfusion; inhibitor; lung injury; lung microvascular endothelial cells; model development; mortality; mouse model; new therapeutic target; novel; oxidation; oxidized LDL receptors; oxidized low density lipoprotein; p38 Mitogen Activated Protein Kinase; polymicrobial sepsis; programs; receptor; septic patients; skills; systemic inflammatory response; targeted treatment; translational study; treatment strategy

PROJECT SUMMARY/ABSTRACT Sepsis, a dysregulated host response to infection with high morbidity and mortality, is characterized by a systemic inflammatory response and widespread vascular hyperpermeability leading to edema, organ dysfunction, and death. Lung vascular hyperpermeability in sepsis contributes to acute respiratory distress syndrome (ARDS), with no specific prevention or treatment strategies. Disruption of the microvascular endothelial cell (MVEC) barrier is a critical pathological feature of sepsis-induced lung injury driven by circulating inflammatory mediators, oxidants, and proteolytic enzymes. Our group has shown that plasma cell- free hemoglobin (CFH), released during sepsis due to red blood cell fragility, is a mechanistic driver of acute lung injury through induction of lung MVEC hyperpermeability. However, the cellular and molecular mechanisms are unknown. One potential mechanism by which CFH may disrupt the MVEC barrier is through its known ability to oxidize low-density lipoprotein (oxLDL). OxLDL binds and signals through its major endothelial receptor lectin-like oxidized LDL receptor 1 (LOX-1) to cause endothelial dysfunction. LOX-1 activation has been implicated in cardiovascular diseases such as atherosclerosis but its involvement in MVEC hyperpermeability during sepsis is unknown. Our preliminary data from patients with sepsis show that circulating CFH and oxLDL are tightly correlated with each other, MVEC injury markers, and mortality. However, little is known regarding LOX-1 receptor signaling leading to hyperpermeability, especially in the context of sepsis-induced injury to the lung microvasculature. This proposal aims to test the central hypothesis that MVEC hyperpermeability and lung injury during sepsis are mediated through oxidation of LDL by CFH to induce LOX-1 receptor signaling and ectodomain shedding. My career and long-term research goals are to establish an independent academic research program to identify novel signaling mechanisms regulating microvascular endothelial hyperpermeability during sepsis that can be targeted therapeutically for treatment of sepsis-induced organ dysfunction. During the mentored phase of this proposal, I will develop new physiologically relevant and translationally significant technical skills like ex vivo perfused human lung, lung filtration coefficient, endothelial cell isolation, and tissue-specific mouse model development, as well as gain expertise in lipoprotein and membrane protein pathophysiology. I will also enhance my proficiency in laboratory management, mentoring, peer review and writing. I have assembled a superb mentoring team to help me achieve these new skills and my career goals. The proposed research and training in this application will be crucial preparation for my transition to an independent academic research career and position me well to achieve my goal of becoming a leader in mechanistic and translational studies of microvascular dysfunction in sepsis.

项目总结/文摘