The Role and Mechanisms of Lipid and Lipoprotein Dysregulation in Sepsis

方案主任/首席调查员：吉尔吉斯，法希姆·瓦吉德 败血症是一种对感染的失调反应，既有致命的也有非致命的病态后果。 不幸的是，最初的存活期并不能缓解大多数败血症幸存者的并发症。初期临床 轨迹包括快速恢复、早期住院死亡和进展为慢性危重疾病(ICU Stay≥ 14天有器官功能障碍)。晚期并发症包括败血症再入院和晚期死亡，两者都 90天和6个月的利率分别约为40%。循环中的血脂起着重要的作用 高密度脂蛋白和低密度脂蛋白在脓毒症和胆固醇水平中的作用 (低密度脂蛋白-C)在脓毒症中动态调节。高密度脂蛋白和低密度脂蛋白都被认为在脓毒症中起到保护作用 通过几种机制(抗氧化/抗炎功能、细菌毒素清除、类固醇合成)， 但高密度脂蛋白和低密度脂蛋白预防脓毒症的确切机制尚不清楚。 脂类和脂蛋白的失调发生在脓毒症的早期，导致对脓毒症的预防失败。我们 已有研究表明：1)脓毒症早期高密度脂蛋白功能紊乱(促氧化和促炎)； 2)Dys-高密度脂蛋白水平升高与器官衰竭严重程度呈正相关，并可预测器官衰竭的严重程度 不良结局，包括28天的死亡率；3)老年脓毒症患者的高密度脂蛋白表现出胆固醇外流受损 能力(毒素清除和类固醇生成所需)；4)高密度脂蛋白和低密度脂蛋白水平在 脓毒症，下降的严重程度预示着死亡；5)低基线低密度脂蛋白水平与 社区获得性败血症的长期风险增加。具有高度生物活性的脂类代谢物也 在脓毒症期间存在于循环中，可能会传播和促进炎症消退并有助于 到胆固醇功能障碍。我们的数据有力地表明，脓毒症患者存在脂类和脂蛋白失调。 并导致功能改变、氧化和水平降低，这可能会影响临床结果。我们 假设脂类和脂蛋白代谢发生特定的功能、脂类和基因组变化 在早期脓毒症中，并与相关的临床轨迹有关(快速恢复、早期死亡和慢性危重疾病 和脓毒症累犯)。为了验证我们的假设，我们将利用已有的和经验丰富的脓毒症 研究团队和现有样本库提供的机会，这些样本来自80个不同的队列 来自两个中心的社区获得性(CA)和医院获得性(HA)败血症患者85例。这种方法具有 几个优点：1)使用具有分离的mRNA的现有样本节省成本，2)最近的一组 败血症患者(2016-2018年)持续接受机构循证管理捆绑治疗，3) 连续样本随时间的变化(登记、48小时、28天和90天)、败血症再入院样本，以及 CA队列的mRNA，4)年龄/性别匹配的对照样本，5)可用的临床和结果数据。我们 还建议在两个地点进行一小部分脓毒症再入院患者的前瞻性研究 新的和重要的成果。该项目满足了NIGMS研究生物机制的任务 这为脓毒症等疾病的治疗进展奠定了基础。 OMB编号0925-0001/0002(01/18修订版批准至2020年3月31日)页面续格式页面

Program Director/Principal Investigator : Guirgis, Faheem Wagid Sepsis is a dysregulated response to infection that has both fatal and non-fatal morbid consequences. Unfortunately, initial survival does not provide relief from morbidity for most sepsis survivors. Initial clinical trajectories include rapid recovery, early in-hospital death, and progression to chronic critical illness (ICU stay ≥ 14 days with organ dysfunction). Late complications include sepsis readmission and late death, both of which have rates of approximately 40% at 90 days and 6 months, respectively. Circulating lipids play an important role in sepsis and cholesterol levels of both high density lipoproteins (HDL-C) and low density lipoproteins (LDL-C) are dynamically regulated in sepsis. HDL and LDL are both thought to play protective roles in sepsis via several mechanisms (antioxidant/anti-inflammatory function, bacterial toxin clearance, steroid synthesis), but the exact mechanisms by which HDL and LDL protects against sepsis are not known. Lipid and lipoprotein dysregulation occurs in early sepsis, leading to failure to protect against sepsis. We have shown that: 1) HDL becomes dysfunctional (pro-oxidant and pro-inflammatory) in early sepsis (Dys-HDL); 2) elevated Dys-HDL levels positively correlate with and predict organ failure severity and are associated with poor outcomes including 28-day mortality; 3) HDL from older septic patients exhibits impaired cholesterol efflux capacity (required for toxin clearance and steroidogenesis); 4) HDL and LDL levels drop precipitously during sepsis, and the severity of the drop is predictive of death; and 5) low baseline LDL levels are associated with increased long-term community-acquired sepsis risk. Highly biologically active lipid metabolites are also present in the circulation during sepsis that may propagate and promote inflammation resolution and contribute to cholesterol dysfunction. Our data strongly suggest that lipid and lipoprotein dysregulation occurs in sepsis and leads to altered function, oxidation, and reduced levels that may influence clinical outcomes. We hypothesize that specific functional, lipidomic, and genomic changes in lipid and lipoprotein metabolism occur in early sepsis and relate to relevant clinical trajectories (rapid recovery, early death, and chronic critical illness and sepsis recidivism). To test our hypothesis, we will capitalize on an established and experienced sepsis research team and the opportunity provided by an existing bank of samples from a diverse cohort of 80 community-acquired (CA) and 85 hospital-acquired (HA) sepsis patients from two-centers. This approach has several advantages: 1) cost-savings from use of existing samples with isolated mRNA, 2) a recent cohort of sepsis patients (2016-2018) consistently treated with institutional evidence-based management bundles, 3) availability of serial samples over time (enrollment, 48h, 28d, and 90d), sepsis readmission samples, and mRNA for the CA cohort, 4) age/gender matched control samples, 5) available clinical and outcomes data. We also propose two-site prospective enrollment of a small cohort of sepsis readmission patients to study this novel and important outcome. This project satisfies the NIGMS mission of researching biological mechanisms that underlay the foundation for advances in treatment of diseases such as sepsis. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page