Effects of glycemic control on immunity

描述（由申请人提供）： 心脏搭桥术（CPB）是复杂先天性心脏病（CHD）修复的必要手段，但也是手术修复后存活儿童的发病率和死亡率的原因之一。CPB后，应激相关激素和促炎细胞因子的释放通过介导内皮细胞-白细胞粘附和血管炎症而导致术后器官功能障碍。此外，促炎细胞因子和应激激素可能介导胰岛素抵抗，并导致CPB后儿童高血糖发生率升高。越来越多的证据表明，高血糖症对器官功能、院内感染、重症监护室（ICU）住院时间和各种危重患者人群的死亡率产生负面影响，尤其是在术后心血管患者中。正在进行一项针对接受CPB治疗CHD的婴儿的协作随机对照试验（RCT），以确定术后时间范围内的严格血糖控制是否可以改变这些有害结果。高血糖和胰岛素已被证明会影响人类和动物重症模型中细胞因子的产生;然而，严格的血糖控制影响这种宿主免疫反应的机制仍然未知。值得注意的是，循环树突状细胞（DC）在连接先天性和适应性免疫应答中起关键作用，并且通过炎症损伤而显著减少。DC的这种损失归因于促炎细胞因子的增加和细胞能量学的改变，并且已显示增加宿主的感染风险。此外，我们已经观察到CPB后循环单核细胞的促炎细胞因子表达的显著减弱，我们认为这是由于典型的1型和2型细胞因子的启动子区的表观遗传介导的变化。目前在儿科心脏手术患者中进行的严格血糖控制RCT为探索减少促炎症、器官功能障碍和感染发展的潜在免疫生物学机制提供了机会。在本试验的背景下，我们的目标是测试以下假设：在术后期间严格的血糖控制将改变婴儿的免疫应答，从而导致促炎症减少、循环DC增加和表观遗传特征改变，从而减少器官功能障碍和术后感染。公共卫生相关性：使用一种机器，使血液绕过心脏和肺，所谓的，心肺转流术（CPB），需要停止心脏，并保持它仍然在手术过程中，以修复复杂的解剖异常婴儿往往患有所谓的“先天性心脏病”（CHD），这种策略使挽救生命的手术，而且还导致器官损伤或衰竭，有时导致在这种最初的外科修复中存活的儿童死亡。体外循环后，机体释放的应激相关激素和炎症分子导致血管炎症和术后器官功能障碍。此外，这些分子和激素可能介导胰岛素抵抗，并导致CPB后儿童中常见的高血糖（称为“高血糖症”）的高发生率。我们认为，高血糖症会对器官功能产生负面影响，增加医院恢复期间感染的风险，延长重症监护室的时间，特别是在心脏手术后的患者中。一项由美国国立卫生研究院（NIH）赞助的对接受CPB治疗CHD的婴儿进行的合作试验正在进行中，以确定在术后时间范围内严格控制血糖是否可以改变这些结果。高血压及其主要疗法胰岛素已被证明会影响这些有问题的分子在人类和危重动物中的产生;然而，这种方法影响免疫反应的机制仍然未知。值得注意的是，在血流中循环的特定细胞类型称为树突状细胞（DC），在优化免疫系统功能方面发挥着重要作用，这些细胞在感染后发生炎症时会显着减少，可能是CPB。DC的这种损失归因于促炎分子的增加和细胞能量状态的改变，最重要的是已被证明会增加感染的风险。此外，我们已经观察到CPB后循环细胞中促炎细胞因子表达的显著降低，我们认为这可能是由于DNA部分的独特变化决定了分子的产生方式。目前在儿科心脏手术患者中进行的严格血糖控制试验为探索减少促炎症、器官功能障碍和感染发展的潜在方法提供了机会。(End摘要）

DESCRIPTION (provided by applicant): Cardiopulmonary bypass (CPB) is necessary to repair complex congenital heart disease (CHD), but also contributes to the morbidity and mortality in children surviving surgical repair. Following CPB, release of both stress-related hormones and pro-inflammatory cytokines contribute to post-operative organ dysfunction by mediating endothelial cell-leukocyte adhesion and vascular inflammation. Furthermore, pro inflammatory cytokines and stress hormones may mediate insulin resistance and contribute to the high rate of hyperglycemia in children after CPB. Increasingly, there is evidence to suggest that hyperglycemia negatively impacts organ function, acquisition of nosocomial infections, intensive care unit (ICU) length of stay, and mortality in various critically ill patient populations-but particularly in post-operative cardiovascular patients. A collaborative, randomized controlled trial (RCT) of infants undergoing CPB for CHD is being conducted to determine whether tight glycemic control in the post-operative time frame can alter these detrimental outcomes. Hyperglycemia and insulin have been shown to impact the production of cytokines in human and animal models of critical illnesses; however, the mechanism(s) by which tight glycemic control affects this host immune response remains unknown. Notably, circulating dendritic cells (DCs) play a key role in linking the innate and adaptive immune responses and are significantly decreased by inflammatory insults. This loss of DCs has been attributed to increased pro inflammatory cytokines and altered cellular energetics and has been shown to increase the host's risk of infection. Furthermore, we've observed significant attenuation of pro inflammatory cytokine expression from circulating monocytes post- CPB that we propose is due to epigenetically-mediated changes on the promoter regions of canonical type 1 and type 2 cytokines. The current RCT of tight glycemic control in pediatric cardiac surgical patients provides the opportunity to explore potential immunobiologic mechanisms that reduce pro inflammation, organ dysfunction and development of infection. In the context of this trial, we aim to test the hypothesis that tight glycemic control during the post-operative period will modify the infant's immune response resulting in decreased pro-inflammation, increased circulating DCs and modified epigenetic signature thereby decreasing organ dysfunction and post-operative infections. PUBLIC HEALTH RELEVANCE: Using a machine that enables blood to bypass the heart and lungs, so called, cardiopulmonary bypass (CPB), is needed stop the heart and keep it still during operations to repair complicated anatomic abnormalities babies are often borne with termed "congenital heart disease" (CHD), This strategy enables life saving surgeries, but also contributes to organ injury or failure and at times the death experienced by children surviving this initial surgical repair. After CPB, release of both stress-related hormones and inflammatory molecules the body makes contribute to blood vessel inflammation and post-operative organ dysfunction. Furthermore, these molecules and hormones may mediate insulin resistance and contribute to the high rate of high blood sugars (called "hyperglycemia") often seen in children after CPB. We believe that hyperglycemia negatively impacts organ function, increases the risk of getting an infection during the recovery period in the hospital, prolongs the time in the intensive care unit in very sick patients, but especially in patients following heart surgery. A collaborative, NIH-sponsored trial of infants undergoing CPB for CHD is being performed to determine whether tightly controlling the blood sugar in the post- operative time frame can alter these outcomes. Hyperglycemia and its main therapy, insulin, have been shown to impact the production of these problematic molecules in both humans and animals who are critically ill; however, the mechanism by which this approach affects the immune response remains unknown. Notably, a particular cell type that circulates in the blood stream called dendritic cell (DCs) play an important role in optimizing the function of the immune system and these cells are significantly decreased by inflammation as occurs after infections and probably CPB. This loss of DCs has been attributed to increased pro inflammatory molecules and altered cellular energy states and most importantly has been shown to increase the risk of getting an infection. Furthermore, we've already observed a significant lowering of pro inflammatory cytokine expression from circulating cells after CPB that we think may be due to unique changes on the parts of the DNA that determines how a molecule will be made or not. The current trial of tight glycemic control in pediatric cardiac surgical patients provides the opportunity to explore potential ways to reduce pro inflammation, organ dysfunction and development of infection. (End of Abstract)