The Role and Mechanisms of Lipid and Lipoprotein Dysregulation in Sepsis

脓毒症中脂质和脂蛋白失调的作用和机制

• 批准号: 10382511
• 负责人: Faheem W Guirgis
• 金额: $ 5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382511
• 关键词: Anti-Inflammatory Agents; Antioxidants; Bacterial Toxins; Biological; Blood Circulation; Cessation of life; Cholesterol; Chronic; Clinical; Communities; Cost Savings; Critical Illness; Data; Disease; Drops; Enrollment; Exhibits; Failure; Foundations; Functional disorder; Gender; Gene Expression; Genomics; High Density Lipoproteins; Homeostasis; Hospitals; Impairment; Infection; Inflammation; Inflammatory; Lipids; Lipoproteins; Low-Density Lipoproteins; Messenger RNA; Metabolism; Mission; Morbidity - disease rate; National Institute of General Medical Sciences; Organ; Organ failure; Outcome; Patient Readmission; Patients; Play; Principal Investigator; Publishing; Reactive Oxygen Species; Recovery; Research; Resolution; Risk; Role; Sampling; Sepsis; Severities; Site; Steroid biosynthesis; Steroids; Survivors; Testing; Time; Toxin; biological research; clinically relevant; cohort; evidence base; experience; hospital readmission; lipidomics; lipoprotein cholesterol; mortality; novel; oxidation; programs; prospective; recidivism; response; septic patients

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

项目主任/主要研究者：Guirgis，Faheem Wagid 脓毒症是一种对感染的失调反应，具有致命和非致命的病态后果。 不幸的是，最初的生存并不能减轻大多数脓毒症幸存者的发病率。初始临床 轨迹包括快速恢复、早期住院死亡和进展为慢性危重病（ICU住院时间≥ 器官功能障碍14天）。晚期并发症包括脓毒症再入院和晚期死亡，这两种并发症都是 90天和6个月时的发生率分别约为40%。循环脂质在 高密度脂蛋白（HDL-C）和低密度脂蛋白在脓毒症和胆固醇水平中的作用 （LDL-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HDL和LDL对抗脓毒症的确切机制尚不清楚。 脂质和脂蛋白失调发生在早期脓毒症中，导致不能防止脓毒症。我们 已经表明：1）HDL在早期脓毒症（Dys-HDL）中变得功能失调（促氧化剂和促炎剂）; 2)升高的Dys-HDL水平与器官衰竭的严重程度呈正相关，并可预测器官衰竭的严重程度， 不良结局，包括28天死亡率; 3）老年脓毒症患者的HDL表现出胆固醇流出受损 能力（毒素清除和类固醇生成所需）; 4）HDL和LDL水平急剧下降， 败血症，并且下降的严重程度是死亡的预测;和5）低基线LDL水平与 增加长期社区获得性败血症风险。高生物活性的脂质代谢物也是 存在于脓毒症期间的循环中，可能传播并促进炎症消退， 胆固醇功能紊乱我们的数据有力地表明，脂质和脂蛋白失调发生在败血症 并导致功能改变、氧化和水平降低，从而可能影响临床结果。我们 假设脂质和脂蛋白代谢发生特定功能、脂质组学和基因组学变化 在早期脓毒症和相关的临床轨迹（快速恢复，早期死亡，慢性危重病 和败血症复发）。为了验证我们的假设，我们将利用一个既定的和经验丰富的败血症 研究团队和现有样本库提供的机会， 社区获得性（CA）和85例医院获得性（HA）脓毒症患者。这种方法有 几个优点：1）使用具有分离的mRNA的现有样品节省了成本，2）最近的一组 脓毒症患者（2016-2018年）持续接受机构循证管理包治疗，3） 随时间推移（入组、48 h、28 d和90 d）连续样本的可用性，脓毒症再入院样本，以及 CA组群的mRNA，4）年龄/性别匹配的对照样品，5）可用的临床和结果数据。我们 我还建议在两个研究中心前瞻性招募一小群脓毒症再入院患者来研究这一点。 新颖而重要的成果。该项目满足了NIGMS研究生物机制的使命 这为败血症等疾病的治疗进展奠定了基础。 OMB编号0925-0001/0002（2018年1月批准至2020年3月31日修订版）页码续页格式页码