Haptoglobin 2 variant and endothelial glycocalyx shedding in sepsis-induced ARDS

脓毒症诱导的 ARDS 中结合珠蛋白 2 变异和内皮糖萼脱落

基本信息

批准号：
10473750
负责人：
Lorraine B Ware
金额：
$ 56.67万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10473750
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Acute respiratory failure Address Adhesions African African ancestry Alleles Ascorbic Acid Bacteria Blood Circulation Blood Vessels Cells Cessation of life Chronic Disease Clinical Clinical Trials Critical Illness Data Development Diabetes Mellitus Dose Early treatment Endothelium Enzymes European Exposure to Functional disorder Future Genes Genetic Genetic Variation Genotype Glycocalyx Glycosaminoglycans Goals HP gene Haptoglobins Hemoglobin Hemoglobin concentration result Homeostasis Human Infection Injury Lead Leukocytes Life Link Lung Mass Spectrum Analysis Mediating Mediator of activation protein Microvascular Permeability Modeling Morbidity - disease rate Mouse Strains Mus Organ Orthologous Gene Outcome Oxidants Oxidative Stress Pathologic Pathway interactions Patients Pattern Permeability Persons Pharmacology Phenotype Plasma Population Preparation Prevention Proteins Publishing Reporting Research Risk Sepsis Severities Testing Translating Translations Up-Regulation Variant antimicrobial antioxidant therapy genetic manipulation genetic variant heparanase insight lung injury macrovascular disease mortality mouse model new therapeutic target novel novel strategies novel therapeutics oxidation oxidative damage polymicrobial sepsis preservation prevent response sepsis induced ARDS septic patients severe injury therapeutic evaluation trait

Acute Acute Lung Injury Acute Respiratory Distress Syndrome Acute respiratory failure Address Adhesions African African ancestry Alleles Ascorbic Acid Bacteria Blood Circulation Blood Vessels Cells Cessation of life Chronic Disease Clinical Clinical Trials Critical Illness Data Development Diabetes Mellitus Dose Early treatment Endothelium Enzymes European Exposure to Functional disorder Future Genes Genetic Genetic Variation Genotype Glycocalyx Glycosaminoglycans Goals HP gene Haptoglobins Hemoglobin Hemoglobin concentration result Homeostasis Human Infection Injury Lead Leukocytes Life Link Lung Mass Spectrum Analysis Mediating Mediator of activation protein Microvascular Permeability Modeling Morbidity - disease rate Mouse Strains Mus Organ Orthologous Gene Outcome Oxidants Oxidative Stress Pathologic Pathway interactions Patients Pattern Permeability Persons Pharmacology Phenotype Plasma Population Preparation Prevention Proteins Publishing Reporting Research Risk Sepsis Severities Testing Translating Translations Up-Regulation Variant antimicrobial antioxidant therapy genetic manipulation genetic variant heparanase insight lung injury macrovascular disease mortality mouse model new therapeutic target novel novel strategies novel therapeutics oxidation oxidative damage polymicrobial sepsis preservation prevent response sepsis induced ARDS septic patients severe injury therapeutic evaluation trait

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项目摘要

ABSTRACT Sepsis-induced acute respiratory distress syndrome (ARDS) is a leading cause of acute respiratory failure in critical illness. Morbidity and mortality are high and there are no proven pharmacologic therapies other than antimicrobials. Sepsis-associated ARDS is characterized by pathologic degradation of the pulmonary endothelial glycocalyx—a glycosaminoglycan-enriched endovascular layer necessary for pulmonary vascular homeostasis. There is a vital need to identify early triggers of endothelial glycocalyx degradation in sepsis, both to enhance our understanding of pathophysiology, and critically, to identify new therapeutic targets for prevention and early treatment of sepsis-induced ARDS. Our published and preliminary data suggest that (1) cell-free hemoglobin (CFH) is released into the circulation in sepsis and contributes to oxidant-mediated organ dysfunction and death; (2) CFH can directly injure the lung endothelial glycocalyx, causing degradation and shedding; (3) haptoglobin, an endogenous scavenger for cell-free hemoglobin that limits its ability to cause oxidative injury has a common genetic variant, HP-2, that increases the risk of ARDS in both humans and mice with sepsis; and (4) patients and mice with sepsis and the HP-2 variant have increased degradation of the endothelial glycocalyx and evidence of increased oxidative stress. The studies in this proposal will build on these preliminary findings to characterize the mechanisms by which CFH-mediated endothelial glycocalyx degradation is modified by the HP-2 genotype. Our primary goal is to translate these findings to new targeted therapies that will be tested in our novel isolated human lung model as preparation for rapid translation to targeted clinical trials in sepsis. In Aim 1, we will use state-of-the-art mass spectrometry analyses of circulating glycosaminoglycan fragments to determine the extent and signature of endothelial glycocalyx shedding in patients with the HP-2 variant, study the association with ARDS and determine downstream mechanisms of endothelial injury. In Aim 2 we will use genetically manipulated mouse models to determine the contribution of heparanase and oxidative injury to glycocalyx degradation in mice with the HP-2 genotype. In Aim 3, we will test the therapeutic potential of targeting oxidant mediated injury in the HP-2 genotype to preserve the endothelial glycocalyx in the isolated perfused human lung as a translational bridge to future patient studies. The studies proposed in these aims have the potential for major and sustained scientific impact. Since HP-2 is the most common allele of the HP gene and over 40% of people of European or African ancestry are homozygous for this allele, targeting patients with the HP2 genotype with therapies to prevent endothelial glycocalyx degradation is a new approach that could have a major impact on clinical outcomes.

抽象的败血症引起的急性呼吸窘迫综合征（ARDS）是导致急性呼吸衰竭的主要原因重症病。发病率和死亡率很高，没有证明的药物结肠疗法抗菌剂。败血症相关的ARD的特征是肺的病理降解内皮糖脂 - 富含糖胺聚糖的内血管内血管内层，是肺血管稳态。至关重要的是鉴定败血症中内皮糖脂降解的早期触发因素，既以增强我们对病理生理学的理解，又是批判性的，以确定新的治疗靶点败血症引起的ARD的预防和早期治疗。我们发布的初步数据表明（1）无细胞的血红蛋白（CFH）在败血症中释放到循环中，并有助于氧化剂介导的器官功能障碍和死亡；（2）CFH可以直接损伤肺内皮糖囊肿，从而导致降解和脱落；（3）Haptoglobin，一种无细胞血红蛋白的内源性清除剂，可限制其引起的能力氧化损伤具有常见的遗传变异HP-2，可增加人类和小鼠的ARDS风险败血症；（4）患有败血症和HP-2变体的患者和小鼠的降解增加内皮糖脂和氧化应激增加的证据。该提议中的研究将基于这些初步发现，以表征CFH介导的内皮糖蛋白的机制降解通过HP-2基因型修饰。我们的主要目标是将这些发现转化为新的目标将在我们新颖的孤立人肺模型中测试的疗法，以准备快速翻译为败血症的靶向临床试验。在AIM 1中，我们将使用循环的最新质谱分析糖胺聚糖片段，以确定内皮糖脂脱落的程度和特征具有HP-2变体的患者，研究与ARDS的关联并确定下游机制内皮损伤。在AIM 2中，我们将使用一般操纵的鼠标模型来确定 HP-2基因型的小鼠糖蛋白降解的肝酶和氧化损伤。在AIM 3中，我们将测试靶向HP-2基因型中氧化物介导的损伤以保留的治疗潜力孤立的灌注人类肺中的内皮糖卵果糖是未来患者研究的翻译桥梁。这些目标中提出的研究可能会产生重大和持续的科学影响。由于HP-2是 HP基因最常见的等位基因和40％以上的欧洲或非洲血统是该等位基因的纯合子，针对具有疗法的HP2基因型患者，以防止内皮糖脂降解是一种新方法，可能会对临床结果产生重大影响。