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

• 批准号: 10492851
• 负责人: Koichi Yuki
• 金额: $ 26.55万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/10492851
• 关键词: Adult; Age; Biological; Biological Assay; Birth; Blood; Blood Circulation; Blood Platelets; Blood Transfusion; Body Size; Brain; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cells; Cessation of life; Child; Childhood; 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 receptor; 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

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.

项目摘要 尽管先天性心脏病(CHD)的死亡率已显著降低，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有很高的发病率和死亡率。 在儿童住院数据库中，新生儿和婴儿约占所有儿科人口的57% 接受先天性心脏病手术，住院死亡率(6.9%)显著高于 给其他年龄段的人。对他们器官损伤/功能障碍的原因和机制的描述将提供 这是一个修改我们的临床方法和开发治疗干预的机会。与损害相关 分子模式(DAMP)是内源性的核、线粒体或胞质分子，具有 细胞内的生理功能。然而，一旦组织损伤，湿气就会释放到血液中。 由受损细胞识别，并由中性粒细胞和血小板上的模式识别受体(PRRs)识别。湿气 可通过诱导全身炎症反应(SIRS)和高凝状态而导致器官损伤 导致血栓形成。湿气循环水平与全身炎症反应综合征及多脏器损伤的关系 有创伤和脓毒症的病人。体外循环(CPB)相关的缺血再灌注损伤 随后的器官损伤/功能障碍已经被很好地描述了。在大多数心脏外科手术病例中 在CPB期间，年龄较大的儿童和成人，心和肺以外的器官持续灌流，但在 复杂的新生儿和婴儿手术，在全循环下进行手术修复并不少见 停滞或仅对大脑进行区域灌流，表明多个器官可能受到缺血- 再灌注损伤。输血会导致器官损伤，几乎总是需要新生儿和 婴幼儿由于体型较小，CPB电路体积相对较小。我们的初步研究表明， 体外循环后循环中与Toll样受体(TLR)2/4/9相互作用的DAMP水平升高 婴儿和新生儿。我们假设1)在新生儿和婴儿的先天性心脏手术中， 潮湿水平与高凝状态(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，潮湿可通过TLRs在婴儿体内诱导更多的Nets介导的血栓形成和器官损伤。在……里面 目标1，我们将通过对Toll样受体特异的DAMP进行分析来检验第一种假设 (TLR)2、TLR4和TLR9和阻尼值，并检查阻尼值之间的关系 以及全身炎症、中性粒细胞特征、凝血和新生儿的术后结局 以及正在接受手术修复的婴儿。在目标2中，我们将使用体外人类血液作为测试第二个假设 以及活体小鼠模型。这项建议的目标是1)建立类型之间的关联 以及湿气水平和术后器官功能障碍/结果，以及2)确定对 包括TLR2/4/9在内的阻尼剂在年轻时起作用。一旦我们建立了关联，我们将计划应用 减少湿负荷的干预或以负责任的PRR为治疗靶点以减轻器官损伤。