Oxygen and perioperative organ injury

氧气与围术期器官损伤

• 批准号: 10799354
• 负责人: Frederic Tremaine Billings
• 金额: $ 12.66万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10799354
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Arteries; Blood Vessels; Brain Injuries; Cells; Cessation of life; Clinical Trials; Collaborations; Complement; Functional disorder; Genetic Transcription; Genetically Engineered Mouse; Heart Atrium; Heart Injuries; Heme; Heme Group; Hemoglobin; High Prevalence; Hyperoxia; Hypoxia; Hypoxia Inducible Factor; Injury to Kidney; Investigation; Laboratories; Lead; Measurement; Measures; Mediating; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myocardium; National Institute of General Medical Sciences; Operative Surgical Procedures; Organ; Oxygen; Oxygen Therapy Care; Pathway interactions; Patient-Focused Outcomes; Patients; Perioperative; Perioperative complication; Plasma Cells; Postoperative Period; Pre-Clinical Model; Prospective, cohort study; Proteins; Research; Sampling; Signal Transduction; Soluble Guanylate Cyclase; Tissue Model; Tissues; Transcript; Vascular Smooth Muscle; arteriole; biobank; circulating biomarkers; experience; experimental study; human tissue; improved; laboratory experiment; lung injury; multimodality; normoxia; novel; novel therapeutics; organ injury; oxidation; oxidative damage; oxidized lipid; programs; response; therapeutic target; therapy development; transcriptome; translational approach

Project Summary/Abstract More than 20% of patients undergoing major surgery experience acute kidney, brain, and heart injury, and these perioperative complications lead to persistent organ dysfunction, long-term morbidity, and death. My research program is investigating and manipulating mechanisms of perioperative organ injury in order to identify therapeutic targets and develop novel therapies. We are currently focused on the critical impact of oxygen tension on organ injury, because perioperative oxygen administration is inconsistent, unguided, often excessive, and potentially harmful. Both hypoxia and hyperoxia can be harmful to surgical patients, yet both occur frequently, despite the ease with which the fraction of inspired oxygen (FiO2) can be manipulated in the perioperative period. Our laboratory is focused on identifying and investigating molecular pathways and therapeutic targets that a) impact oxygen tension in tissues during surgery and b) impact hypoxia- and hyperoxia-mediated organ injury. We target these molecular pathways to reduce organ injury. We have recently demonstrated that: 1) perioperative oxidative damage increases acute kidney, brain, and heart injury; 2) intraoperative normoxia improves vascular reactivity compared to hyperoxia possibly by reducing intraoperative oxidation of the heme moiety of vascular smooth muscle soluble guanylyl cyclase; 3) normoxia upregulates hypoxia inducible factor (HIF)-regulated transcription and reduces circulating markers of oxidative damage; and 4) increased circulating cell-free hemoglobin (Hb) oxidizes lipids and is independently associated with postoperative kidney, lung, and brain injury. In the next 5 years we will investigate the effects of oxygen tension on mechanisms of organ injury, including oxidative damage, vascular function, HIF signaling, and cell free Hb-mediated organ injury, using a multifaceted translational approach. Our program combines laboratory experiments in human tissues and preclinical models with prospective cohort studies and mechanistic trials in patients having major surgery. We perform experiments on arterioles and arteries isolated from patients during surgery to study the effects of hypoxic, normoxic, and hyperoxic treatments on vascular function. We investigate the impact of oxygen treatments during preclinical models of acute kidney injury in genetically engineered mice in collaboration with oxygen biologist nephrologist Volker Haase, and we are measuring the effect of intraoperative hyperoxia vs. normoxia treatment in samples biobanked from the NIGMS-supported ROCS clinical trial. Examples of these experiments include the measurement of HIF- regulated transcripts in atrial myocardium and the oxidation state of the heme group in plasma cell-free Hb. We will complement these hypothesis-driven experiments with unbiased approaches to measure the transcriptome and protein responses in vascular and murine tissues to identify and support new paths of investigation. This rigorous multimodal strategy provides the framework to advance the understanding of perioperative organ injury and guide the development of therapies for hundreds of thousands of surgical patients.

项目概要/摘要 超过 20% 接受大手术的患者会经历急性肾、脑和心脏损伤， 这些围手术期并发症会导致持续的器官功能障碍、长期发病和死亡。我的 研究计划正在调查和操纵围手术期器官损伤的机制，以便 确定治疗靶点并开发新疗法。我们目前关注的重点是 氧压对器官损伤的影响，因为围手术期的供氧不一致、缺乏指导，通常 过量且有潜在危害。缺氧和高氧都会对手术患者造成伤害，但两者都 尽管吸入氧 (FiO2) 的分数可以很容易地在 围手术期。我们的实验室专注于识别和研究分子途径和 治疗目标 a) 影响手术期间组织中的氧张力 b) 影响缺氧和 高氧介导的器官损伤。我们针对这些分子途径来减少器官损伤。 我们最近证明：1）围术期氧化损伤会增加急性肾、脑、 和心脏损伤； 2）与高氧相比，术中常氧可改善血管反应性，可能是通过 减少血管平滑肌可溶性鸟苷酸环化酶血红素部分的术中氧化； 3） 含氧量正常会上调缺氧诱导因子（HIF）调节的转录并减少循环标记物 氧化损伤； 4) 增加的循环游离血红蛋白 (Hb) 氧化脂质并且独立地 与术后肾、肺和脑损伤有关。未来5年我们将研究其影响 氧张力对器官损伤机制的影响，包括氧化损伤、血管功能、HIF 信号传导、 和无细胞 Hb 介导的器官损伤，使用多方面的转化方法。我们的计划结合了 人体组织和临床前模型的实验室实验以及前瞻性队列研究和 在接受大手术的患者中进行机械试验。我们对小动脉和分离的动脉进行实验 从手术期间的患者身上收集数据，研究低氧、常氧和高氧治疗对血管的影响 功能。我们研究了氧气治疗对急性肾损伤临床前模型的影响 与氧生物学家肾病学家 Volker Haase 合作开发基因工程小鼠，我们正在 测量术中高氧与常氧治疗对来自生物样本库的样本的影响 NIGMS 支持的 ROCS 临床试验。这些实验的例子包括 HIF- 的测量 心房肌中调节的转录物和血浆游离血红蛋白中血红素基团的氧化态。我们 将用公正的方法来补充这些假设驱动的实验来测量转录组 以及血管和鼠组织中的蛋白质反应，以确定和支持新的研究途径。 这种严格的多模式策略提供了促进围手术期理解的框架 器官损伤并指导数十万外科患者的治疗方法的开发。