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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：
10686129
负责人：
Lorraine B Ware
金额：
$ 56.09万
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/10686129
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Acute respiratory failure Address Adhesions African African ancestry Alleles Ascorbic Acid Bacteria Blood Vessels Cells Cessation of life Chronic Disease Circulation Clinical Clinical Trials Critical Illness Data Development Diabetes Mellitus Dose Early identification Early treatment Endothelium Enzymes European European ancestry 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 Microvascular Permeability Modeling Morbidity - disease rate Mouse Strains Mus Organ Orthologous Gene Outcome Oxidants Oxidative Stress Pathologic Pathway interactions Patients Pattern Permeability Persons Phenotype Plasma Population Preparation Prevention Proteins Publishing Regional Perfusion Reporting Research Risk Sepsis Severities Testing Translating Translations Up-Regulation Variant Vascular Endothelium antimicrobial antioxidant therapy ex vivo perfusion genetic manipulation genetic variant heparanase insight lung injury macrovascular disease mortality mouse model new therapeutic target novel novel strategies novel therapeutics oxidation oxidative damage pharmacologic polymicrobial sepsis preservation prevent response sepsis induced ARDS septic patients severe injury therapeutic evaluation trait

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.

抽象的脓毒症引起的急性呼吸窘迫综合征（ARDS）是急性呼吸衰竭的主要原因危重疾病。发病率和死亡率很高，除此之外没有经过验证的药物治疗方法抗菌剂。脓毒症相关 ARDS 的特点是肺动脉病理性退化。内皮糖萼——肺血管必需的富含糖胺聚糖的血管内层体内平衡。迫切需要确定败血症中内皮糖萼降解的早期触发因素，既可以增强我们对病理生理学的理解，更重要的是，可以确定新的治疗靶点脓毒症引起的 ARDS 的预防和早期治疗。我们发布的初步数据表明 (1) 无细胞血红蛋白 (CFH) 在脓毒症中释放到循环系统中，有助于氧化介导的器官功能障碍和死亡； (2)CFH可直接损伤肺内皮糖萼，导致其降解和降解。脱落； (3)触珠蛋白，一种无细胞血红蛋白的内源性清除剂，限制了其引起的能力氧化损伤有一个常见的遗传变异 HP-2，它会增加人类和小鼠患 ARDS 的风险患有败血症； (4) 脓毒症患者和小鼠以及 HP-2 变异体的降解增加内皮糖萼和氧化应激增加的证据。本提案中的研究将建立在这些初步发现表征了 CFH 介导的内皮糖萼的机制降解由 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这些疗法将在我们的新型分离人肺模型中进行测试，为快速转化为败血症的靶向临床试验。在目标 1 中，我们将使用最先进的质谱分析法对循环糖胺聚糖片段以确定内皮糖萼脱落的程度和特征患有 HP-2 变异的患者，研究与 ARDS 的关联并确定下游机制内皮损伤。在目标 2 中，我们将使用基因操纵的小鼠模型来确定 HP-2 基因型小鼠中乙酰肝素酶和糖萼降解的氧化损伤。在目标 3 中，我们将测试针对 HP-2 基因型中氧化剂介导的损伤的治疗潜力，以保护分离的灌注人肺中的内皮糖萼作为未来患者研究的转化桥梁。这些目标中提出的研究有可能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，超过 40% 的欧洲或非洲血统的人是该等位基因纯合，针对 HP2 基因型患者进行治疗以预防内皮细胞损伤糖萼降解是一种可能对临床结果产生重大影响的新方法。