An ABO Blood Type Defined ARDS Endotype in Sepsis

ABO 血型定义的脓毒症 ARDS 内型

• 批准号: 10297790
• 负责人: John Patrick Reilly
• 金额: $ 56.3万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297790
• 关键词: Address; Admission activity; Adult Respiratory Distress Syndrome; Airway Resistance; Alveolar; Antigens; Attenuated; Biological; Biology; Blood; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Blood capillaries; Carbohydrates; Cells; Clinical; Clinical Data; Clinical Trials; Coagulation Process; Collaborations; Critical Care; Critical Illness; Data; Diagnostic tests; Disease; Disseminated Intravascular Coagulation; Dose; Endothelial Cells; Endothelium; Enrollment; Epidemiologist; Erythrocytes; Exhibits; Extravascular Lung Water; Failure; Family; Functional disorder; Future; Genes; Genetic Variation; Genotype; Glycoproteins; Goals; Heterogeneity; Human; Hypoxia; Injury; Knowledge; Lung; Lung Inflammation; Measures; Mediating; Modeling; Modification; Molecular; Morbidity - disease rate; Myocardial Infarction; Patients; Pattern; Perfusion; Permeability; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Plasma; Polysaccharides; Population; Precision therapeutics; Prior Therapy; Prospective cohort study; Proteins; Publishing; Pulmonary Vascular Resistance; Recombinants; Recording of previous events; Reproducibility; Research; Research Personnel; Resources; Respiratory Failure; Risk; Risk Estimate; Sepsis; Subgroup; Syndrome; System; Testing; Thrombomodulin; Thrombosis; Transferase; Translating; Transplantation; Validation; Work; base; cohort; endothelial dysfunction; glycosyltransferase; high risk; improved outcome; injured; injury recovery; innovation; lung injury; mortality; multidisciplinary; new therapeutic target; patient population; patient subsets; predictive modeling; predictive tools; prevent; prospective; response; septic; septic patients; targeted treatment; tool; trait; translational genetics; translational scientist; venous thromboembolism; von Willebrand Factor

ABSTRACT Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome of lung inflammation, alveolar capillary barrier dysfunction, and micro-thrombosis that is common in sepsis. Mortality is above 30% and no pharmacotherapies exist for ARDS. We previously identified a reproducible association between ABO blood type A and an approximately 14% higher absolute risk of ARDS compared to blood type O in sepsis. ABO blood type is genetically determined by the ABO gene, which encodes a family of glycosyltransferases responsible for catalyzing specific carbohydrate modifications on glycans and glycoproteins on erythrocytes, endothelial cells, and platelets. The genetic variation that determines blood type is associated with risk to multiple coagulopathic diseases, including myocardial infarction and venous thromboembolism, as well as plasma levels of multiple endothelial-derived glycoproteins. Our published preliminary data, demonstrate an association between the genetically determined A1 subtype of blood type A, distinguished by 30-50 fold higher “A” transferase activity relative to the A2 subtype, and highest ARDS risk. Additionally, we identified an association of blood type with plasma levels of two proteins measured early in sepsis and important in endothelial activation and coagulation, von Willebrand factor (vWF) and soluble thrombomodulin (sTM), as well as with risk of disseminated intravascular coagulation (DIC). These same proteins have been implicated in ARDS. On vWF, A antigens reduce degradation by ADAMTS13, resulting in a pro-coagulant effect, suggesting septic blood type A patients may require higher ADAMTS13 levels. Therefore, we hypothesize that there is an endotype of ARDS influenced by ABO blood type that can be identified and targeted clinically. The goals of the research proposed in this application is to obtain critical information necessary to identify a population most likely to benefit from therapies targeting ABO-influenced vascular biology and to understand the effect of ABO glycans on injured lungs. We will accomplish this through the following Aims; Aim 1 will determine the association of genetically determined ABO blood type A1 and mortality in sepsis and sepsis-associated ARDS, in two large cohorts of critically ill sepsis patients. Aim 2 will derive and validate a predictive tool that includes ABO genotype, plasma levels of vWF and sTM, and components of the DIC score to identify a population at high risk for an ABO-defined coagulopathic endotype of ARDS in sepsis. Aim 3 will determine the longitudinal physiologic effects of ABO blood type on lung injury recovery in an ex vivo lung perfusion (EVLP) model and test if these effects are modified by the administration of recombinant ADAMTS13. The multidisciplinary team of investigators includes a translational scientist and genetics expert (Meyer), two molecular epidemiologist with expertise in ARDS and predictive modeling (Christie, Ware), an EVLP expert (Cantu), a bio-statistician with a history of collaboration in critical care research (Feng), and the PI (Reilly), a translational epidemiologist who first identified an association between ABO blood type and ARDS risk.

摘要 急性呼吸窘迫综合征（ARDS）是一种异质性的肺部炎症、肺泡炎、呼吸道感染和呼吸道感染综合征。 毛细血管屏障功能障碍和败血症中常见的微血栓形成。死亡率超过30%， 药物疗法存在于ARDS中。我们以前发现ABO血型与 与O型血相比，A型血在脓毒症中发生ARDS的绝对风险高出约14%。Abo 血型是由ABO基因决定的，该基因编码一个糖基转移酶家族 负责催化红细胞上聚糖和糖蛋白的特异性碳水化合物修饰， 内皮细胞和血小板。决定血型的遗传变异与以下风险有关： 多种凝血病，包括心肌梗死和静脉血栓栓塞，以及 多种内皮衍生糖蛋白的血浆水平。我们公布的初步数据表明， A型血的基因决定的A1亚型之间的关联，以高30-50倍区分 “A”转移酶活性相对于A2亚型，和最高的ARDS风险。此外，我们还发现了一个 血型与脓毒症早期测量的两种蛋白质血浆水平的相关性， 血管性血友病因子（vWF）和可溶性血栓调节蛋白（sTM），以及 与弥散性血管内凝血（DIC）的风险一样。这些相同的蛋白质与 ARDS。在vWF上，A抗原减少ADAMTS 13的降解，导致促凝血作用，表明 A型败血症患者可能需要更高的ADAMTS 13水平。因此，我们假设有一个 受ABO血型影响的ARDS的内源型，可以在临床上识别和靶向。的目标 在本申请中提出的研究是获得识别群体所必需的关键信息， 可能受益于针对ABO影响的血管生物学的治疗，并了解ABO的影响 受损肺部的聚糖。我们将通过以下目标实现这一目标：目标1将决定 ABO血型A1基因与败血症和败血症相关ARDS死亡率的相关性， 在两个大的重症脓毒症患者队列中。目标2将推导并验证一个预测工具，包括 ABO基因型、血浆vWF和sTM水平以及DIC评分的组成部分，以确定 脓毒症中ABO定义的ARDS凝血病内型的高风险。目标3将确定纵向 在离体肺灌注（EVLP）模型中ABO血型对肺损伤恢复的生理作用， 测试这些作用是否通过施用重组ADAMTS 13而改变。多学科小组 研究人员包括一名翻译科学家和遗传学专家（迈耶），两名分子流行病学家 具有ARDS和预测建模专业知识（Christie，Ware），EVLP专家（Cantu），生物统计学家 在重症监护研究（冯）和PI（赖利），一个翻译流行病学家合作的历史 他首先发现了ABO血型和ARDS风险之间的联系。