Oxygen and perioperative organ injury

项目摘要/摘要 超过20%的大手术患者经历了急性肾、脑和心脏损伤， 这些围术期并发症会导致持续的器官功能障碍、长期的发病率和死亡。我的 研究项目正在调查和处理围手术期器官损伤的机制，以期 确定治疗目标并开发新的治疗方法。我们目前关注的是 氧分压对器官损伤的影响，因为围手术期给氧不一致，无指导，经常 过量的，可能有害的。低氧和高氧都会对外科病人有害，但两者 经常发生，尽管吸入氧的分数(FiO2)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)在手术中影响组织中的氧分压，b)影响缺氧-以及 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)围手术期氧化损伤增加急性肾、脑、 和心脏损伤；2)与高氧相比，术中常氧改善血管反应性可能通过 减少术中血管平滑肌可溶性鸟苷酸环化酶血红素部分的氧化；3) 常氧上调缺氧诱导因子(HIF)调节的转录并减少循环中的标志物 氧化损伤；以及4)循环中的游离血红蛋白(Hb)增加，氧化脂质，并独立 与术后肾、肺和脑损伤有关。在接下来的5年里，我们将调查这些影响 氧张力对器官损伤机制的影响，包括氧化损伤，血管功能，缺氧诱导因子信号转导， 和无细胞Hb介导的器官损伤，使用多方面的翻译方法。我们的节目结合了 人体组织和临床前模型的实验室实验，具有前瞻性的队列研究和 对接受大手术的患者进行机械学试验。我们在分离的小动脉和动脉上进行实验。 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在急性肾损伤临床前模型中的影响。 基因工程小鼠与氧气生物学家肾病学家Volker Haase合作，我们 比较术中高氧治疗与常氧治疗的效果 NIGMS支持的ROCS临床试验。这些实验的例子包括测量HIF- 血浆中无细胞血红蛋白中血红素组的氧化状态和心房心肌的调节转录本。我们 将用无偏见的方法来测量转录组来补充这些假设驱动的实验 以及血管和小鼠组织中的蛋白质反应，以确定和支持新的研究途径。 这一严格的多模式策略提供了框架，以促进对围手术期的理解 此外，该中心还为器官损伤提供了技术支持，并指导为数十万外科患者开发治疗方法。

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.