Exosomes in aging and operative hypothermic circulatory arrest

摘要 老年患者容易发生与手术相关的细胞应激事件。Exosome代表了一种新的 细胞应激反应的范例，直到最近才开始在外科手术中解决 人口。胞外体是细胞对多种刺激的反应而释放的，包括细胞应激和携带一种 生物活性分子货物，包括DNA、RNA、蛋白质、脂类、细胞因子、生长因子和 代谢物。外周小体在老年外科人群中的作用尚不清楚，并可能对 围手术期护理。深低温停循环是一种严重的围手术期应激事件 包括通过体外循环隔离全身血管系统和停止对主要 器官系统。目前还没有关于外切体因压力而释放的信息。 深低温心脏停搏后的全身缺血和再灌流，最重要的是与年龄有关。在 加州大学圣地亚哥分校在肺血栓内膜剥脱术的同时进行深低温心脏停搏 (PTE)手术。我们每年的临床量为200例PTE手术，适用于不同年龄的患者(18- 80岁)接受深低温心脏直视手术。我们将检验这一新的假设，即手术诱导的深低温停搏会增加 外切体的释放，改变了外切体的特征，并改变了外切体的能力 以年龄依赖的方式影响细胞新陈代谢和功能。在提案中，我们将：1)确定 深低温心脏直视手术前后患者外周血中外切体的特征和含量 患者年龄对外切体释放和含量的潜在作用，以及2)评估外切体的潜力 不同年龄段对深低温停循环的反应对人体代谢和功能的影响 内皮细胞。这项工作将结合麻醉、外科、医学和基础科学的专业知识 学科，并促进未来对创新假说和新疗法的研究 老年患者对缺血再灌注损伤的机体反应。

ABSTRACT Aged patients are susceptible to cellular stress events associated with surgery. Exosomes represent a new paradigm in the cellular stress response that has only recently begun to be addressed in the surgical population. Exosomes are released by cells in response to numerous stimuli including cell stress and carry a cargo of biologically active molecules including DNA, RNA, proteins, lipids, cytokines, growth factors and metabolites. The role of exosomes in the aging surgical population is unknown and may have major impact on perioperative care. Deep hypothermic circulatory arrest (DHCA) is a profound perioperative stress event involving isolation of the systemic vasculature via cardiopulmonary bypass and arrest of the circulation to major organ systems. There is no information available regarding the release of exosomes as a result of the stress of whole body ischemia and reperfusion after DHCA in patients and most importantly as a function of age. At the University of California, San Diego we perform DHCA in conjunction with pulmonary thromboendarterectomy (PTE) surgery. Our clinical volume of 200 PTE surgeries per year results in patients with a range of ages (18- 80 years old) undergoing DHCA. We will test the novel hypothesis that surgically induced DHCA increases the release of exosomes, alters the characteristics of the exosome profile, and alters the ability of exosomes to affect cellular metabolism and function in an age dependent manner. In the proposal we will: 1) Determine the characteristics and content of exosomes released from patients before and after DHCA and address the potential role of patient age on the release and content of exosomes, and 2) Assess the potential of exosomes released from different age groups in response to DHCA to affect metabolism and function in human endothelial cells. The work will combine expertise from anesthesia, surgery, medicine and basic science disciplines and promote the future investigation of innovative hypotheses and novel therapies for the organismal response to ischemia-reperfusion injury in aged patients.