Effects of glycemic control on immunity

描述(由申请人提供)： 体外循环(CPB)对于修复复杂的先天性心脏病(CHD)是必要的，但也会导致手术修复后存活的儿童的发病率和死亡率。体外循环后，应激相关激素和促炎细胞因子的释放通过介导内皮细胞-白细胞黏附和血管炎症而导致术后器官功能障碍。此外，促炎性细胞因子和应激激素可能介导胰岛素抵抗，并导致儿童CPB后高血糖发生率。越来越多的证据表明，在各种危重患者中，高血糖对器官功能、医院感染的获得性、重症监护病房(ICU)的住院时间和死亡率都有负面影响，尤其是在手术后的心血管患者中。一项协作性随机对照试验(RCT)正在对接受CPB治疗CHD的婴儿进行，以确定术后严格的血糖控制是否可以改变这些有害的结果。在危重疾病的人类和动物模型中，高血糖和胰岛素已被证明影响细胞因子的产生；然而，严格控制血糖影响宿主免疫反应的机制(S)仍不清楚。值得注意的是，循环树突状细胞(DC)在连接先天免疫反应和获得性免疫反应中起着关键作用，并且在炎性侮辱中显著减少。这种树突状细胞的丢失被归因于致炎细胞因子的增加和细胞能量的改变，并被证明增加了宿主感染的风险。此外，我们观察到CPB后循环单核细胞促炎性细胞因子的表达显著减弱，我们认为这是由于表观遗传介导的规范1型和2型细胞因子启动子区域的变化。目前在儿童心脏手术患者中严格控制血糖的RCT为探索潜在的免疫生物学机制提供了机会，这些机制可以减少促炎症、器官功能障碍和感染的发生。在这项试验的背景下，我们的目标是检验这一假设，即术后严格的血糖控制将改变婴儿的免疫反应，从而减少促炎反应，增加循环中的DC，并改变表观遗传学特征，从而减少器官功能障碍和术后感染。与公共卫生相关：使用一种使血液能够绕过心脏和肺的机器，即所谓的体外循环(CPB)，需要在手术期间停止心脏并保持其静止以修复复杂的解剖异常婴儿通常被称为“先天性心脏病”(CHD)，这一策略使挽救生命的手术成为可能，但也会导致器官损伤或衰竭，有时还会导致儿童在最初的手术修复中幸存下来。体外循环后，应激相关激素和机体产生的炎症分子的释放都会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后儿童常出现的高血糖(称为“高血糖”)。我们认为，高血糖对器官功能有负面影响，增加了在医院恢复期感染的风险，延长了重症患者在重症监护室的时间，尤其是在心脏手术后的患者。一项由美国国立卫生研究院赞助的合作试验正在对接受体外循环治疗冠心病的婴儿进行，以确定在术后时间框架内严格控制血糖是否可以改变这些结果。高血糖及其主要治疗方法胰岛素已被证明会影响危重患者和动物体内这些问题分子的产生；然而，这种方法影响免疫反应的机制尚不清楚。值得注意的是，在血流中循环的一种特殊类型的细胞称为树突状细胞(DC)，它在优化免疫系统的功能方面发挥着重要作用，这些细胞因炎症而显著减少，就像感染后发生的那样，可能还有体外循环。这种树突状细胞的丧失被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，已被证明增加了感染的风险。此外，我们已经观察到CPB后循环细胞的促炎细胞因子表达显著降低，我们认为这可能是由于DNA决定分子形成或不形成的部分发生了独特的变化。目前在儿科心脏手术患者中严格控制血糖的试验为探索减少促炎、器官功能障碍和感染发展的潜在方法提供了机会。(摘要结束)

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)