The role of damage-associated molecular patterns in perioperative morbidities and mortalities of pediatric congenital heart diseases

损伤相关分子模式在小儿先天性心脏病围手术期发病率和死亡率中的作用

基本信息

批准号：
10669290
负责人：
Koichi Yuki
金额：
$ 22.13万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10669290
关键词：
Adult Age Biological Biological Assay Birth Blood Blood Platelets Blood Transfusion Body Size Brain Cardiac Surgery procedures Cardiopulmonary Bypass Cells Cessation of life Child Childhood Circulation Clinical Clinical Management Coagulation Process Complex Data Databases Failure Flow Cytometry Functional disorder Goals Heart Heart Arrest Histones Hospital Mortality Human Immune Immunologics In Vitro Incidence Incubated Infant Inflammatory Inpatients Intervention Ligands Live Birth Logistics Lung Mediating Medical Mitochondria Molecular Morbidity - disease rate Mus Neonatal Nuclear Operative Surgical Procedures Organ Outcome Pathway interactions Patients Pattern Pattern Recognition Pattern recognition receptor Perfusion Perioperative Physiological Platelet Activation Population Postoperative Period Production Regional Perfusion Reperfusion Injury Reporter Reporting Research Risk Factors Rodent Role Sepsis Signal Pathway Signal Transduction Source Stream TLR2 gene TLR4 gene Testing Therapeutic Intervention Thrombelastography Thrombophilia Thrombosis Time Toll-Like Receptor Pathway Toll-like receptors Trauma age group age related cell injury clinical care congenital heart disorder cytokine experience extracellular high risk histological specimens immune activation improved in vivo mRNA sequencing mechanical circulatory support mortality mouse model neonate neutrophil novel therapeutic intervention organ injury perioperative morbidity perioperative mortality receptor repaired response surgery outcome systemic inflammatory response therapeutic target tissue injury tissue repair transcriptome sequencing

项目摘要

Project Summary Although the mortality of congenital heart disease (CHD) has been reduced significantly, neonates and infants undergoing cardiac surgery are still at a high risk of morbidity and mortality due to multiple organ injury/failure. In the Kids’ Inpatient Database, neonates and infants occupied about 57% of all the pediatric population undergoing congenital heart surgery and carried significantly higher in-hospital mortality rate (6.9%) compared to other age groups. Delineation of the cause and mechanism of their organ injury/dysfunction would provide an opportunity to modify our clinical approach and develop therapeutic intervention. Damage-associated molecular patterns (DAMPs) are endogenous nuclear, mitochondrial, or cytosolic molecules that have physiological functions inside the cell. However, upon tissue injury, DAMPs are released into the blood stream by injured cells, and recognized by pattern recognition receptors (PRRs) on neutrophils and platelets. DAMPs can cause organ injury by inducing systemic inflammatory responses (SIRS) and hypercoagulable state resulting in thrombosis. The circulating levels of DAMPs correlated to the SIRS and multiple organ injury in patients with trauma and sepsis. Ischemia-reperfusion injury associated with cardiopulmonary bypass (CPB) and subsequent organ injury/dysfunction has been well described. In the majority of cardiac surgical cases for older children and adults, organs other than heart and lung are continuously perfused during CPB, but in complex neonatal and infant surgery, it is not rare to have surgical repair done under complete circulatory arrest or regional perfusion only to the brain, suggesting that multiple organs may be subjected to ischemia- reperfusion injury. Blood transfusion can induce organ injury and is almost always required in neonates and infants due to their small body size relative to the volume of CPB circuit. Our preliminary study showed that the circulating levels of DAMPs interacting with Toll-like receptor (TLR)2/4/9 were elevated after CPB separation in infants and neonates. We hypothesize that 1) in congenital cardiac surgery in neonates and infants, higher DAMP levels are associated with hypercoagulability (thrombosis) as well as greater organ injury/ dysfunction, and 2) DAMPs induce more NETs-mediated thrombosis and organ injury in infants via TLRs that in adults. In Aim 1, we will examine the 1st hypothesis by performing profiling of DAMPs specific to Toll-like receptor (TLR)2, TLR4 and TLR9 and DAMPs for an aggregate of PRRs, and examine the relationship between DAMPs and systemic inflammation, neutrophil signature, coagulation, as well as postoperative outcomes of neonates and infants undergoing surgical repair. In Aim 2, we will test the 2nd hypothesis using human blood in vitro as well as in vivo mouse model. The goals of this proposal are to 1) establish the correlation between the type and levels of DAMPs and postoperative organ dysfunction/ outcomes, and 2) to determine responses to DAMPs including TLR2/4/9 functions in young age. Once we establish the correlation, we will plan to apply an intervention to reduce DAMP loads or therapeutically target responsible PRRs to mitigate organ injury.

项目概要虽然先天性心脏病（CHD）的死亡率已显着降低，但新生儿和婴儿由于多器官损伤/衰竭，接受心脏手术的患者仍然面临很高的发病和死亡风险。在儿童住院数据库中，新生儿和婴儿约占所有儿科人群的 57% 接受先天性心脏病手术的院内死亡率（6.9%）明显较高对其他年龄组的器官损伤/功能障碍的原因和机制的描述将提供帮助。一个修改我们的临床方法和开发治疗干预的机会。分子模式 (DAMP) 是内源性核、线粒体或胞质分子，具有然而，在组织损伤时，DAMP 会释放到血流中。由受损细胞识别，并被中性粒细胞和血小板上的模式识别受体 (PRR) 识别。可通过诱导全身炎症反应 (SIRS) 和高凝状态导致器官损伤导致血栓形成的 DAMP 循环水平与 SIRS 和多器官损伤相关。与体外循环（CPB）相关的创伤和脓毒症患者。在大多数心脏手术病例中，已经详细描述了随后的器官损伤/功能障碍。年龄较大的儿童和成人，在 CPB 期间，除心脏和肺外的器官会持续灌注，但在新生儿及婴儿手术复杂，在全循环下进行手术修复并不罕见仅大脑停止或局部灌注，表明多个器官可能遭受缺血。再灌注损伤可引起器官损伤，新生儿和新生儿几乎总是需要输血。婴儿由于其身体尺寸相对于体外循环回路的体积较小，我们的初步研究表明， CPB 分离后，与 Toll 样受体 (TLR)2/4/9 相互作用的 DAMP 循环水平升高我们发现，1) 在新生儿和婴儿的先天性心脏手术中，死亡率较高。 DAMP 水平与高凝状态（血栓形成）以及更大的器官损伤/功能障碍有关， 2) 与成人相比，DAMP 通过 TLR 在婴儿中诱导更多 NET 介导的血栓形成和器官损伤。目标 1，我们将通过对 Toll 样受体特异性的 DAMP 进行分析来检验第一个假设 (TLR)2、TLR4 和 TLR9 以及 PRR 聚合的 DAMP，并检查 DAMP 之间的关系和新生儿的全身炎症、中性粒细胞特征、凝血以及术后结果在目标 2 中，我们将使用体外人体血液来检验第二个假设。该提案的目标是 1) 建立类型之间的相关性。以及 DAMP 水平和术后器官功能障碍/结果，以及 2) 确定对一旦我们建立了相关性，我们将计划应用一个包含 TLR2/4/9 功能的 DAMP。干预以减少 DAMP 负荷或治疗性靶向负责任的 PRR 以减轻器官损伤。