Oxygen and perioperative organ injury

项目总结/摘要 超过20%的接受大手术的患者经历急性肾、脑和心脏损伤， 并且这些围手术期并发症导致持续的器官功能障碍、长期发病和死亡。我 研究计划是调查和操纵围手术期器官损伤的机制， 确定治疗靶点并开发新疗法。我们目前关注的是 氧张力对器官损伤的影响，由于围手术期给氧不一致，无指导， 过量的，并且可能有害的。缺氧和高氧都可能对手术患者有害，但两者都 经常发生，尽管吸入氧气的分数（FiO2）可以在 围手术期我们的实验室专注于识别和研究分子途径， a）在手术期间影响组织中的氧张力和B）影响缺氧的治疗靶点-和 高氧介导的器官损伤。我们靶向这些分子途径以减少器官损伤。 我们最近已经证明：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，术中常氧可能通过以下方式改善血管反应性： 减少血管平滑肌可溶性鸟苷酸环化酶的血红素部分的术中氧化; 3） 常氧上调缺氧诱导因子（HIF）调节的转录，并减少循环标志物 氧化损伤;和4）增加的循环无细胞血红蛋白（Hb）氧化脂质，并独立地 与术后肾、肺和脑损伤相关。在接下来的5年里，我们将研究 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。我们的计划结合了 在人体组织和临床前模型中进行的实验室实验，以及前瞻性队列研究， 在接受大手术的患者中进行的机械试验。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， 基因工程小鼠与氧生物学家肾脏学家Volker Haase合作，我们正在 测量术中高氧与常氧治疗对来自生物库的样本的影响 NIGMS支持的ROCS临床试验。这些实验的实例包括测量HIF-1 α。 调节转录在心房心肌和血红素组的氧化状态在血浆中的无细胞血红蛋白。我们 将补充这些假设驱动的实验与公正的方法来衡量转录组 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一个框架，以促进围手术期的理解 器官损伤，并指导数十万外科患者的治疗方法的发展。

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.