PMN ACTIVATION AND OXIDATIVE STRESS IN HEMODIALYSIS

心血管疾病和细菌感染是终末期肾病（ESRD）血液透析（HD）患者死亡的主要原因。除了高发病率的已知危险因素外，这些患者还处于氧化应激升高的状态，其特征是自由基产生过多和/或抗氧化防御能力低下。该建议的主要假设是，多形核细胞暴露于体外回路，触发活性氧（ROS）的产生，导致白细胞功能障碍，以及氧化内皮细胞损伤。此外，在这些患者中，越来越多的常规使用肠外铁，一种有毒自由基生成的有效促进剂，可能会增强氧化应激诱导的细胞损伤和功能障碍。本研究将利用体外模型来评估透析器生物相容性和各种铁制剂对氧化应激和细胞损伤指标的影响。这些模型将涉及PMN（健康vs尿毒症）的激活，通过暴露于不同成分的透析膜片段铁或ROS抑制剂，以及通过体外透析循环。此外，共培养模型将用于评估透析膜活化PMN对培养内皮细胞报告单层（过量铁）在静态和流动条件下生长的影响。这一建议的结果有望增强我们对ros诱导的细胞损伤和功能障碍的发病机制的理解，并为开发对抗动脉粥样硬化、血管通路和免疫功能障碍的新策略奠定基础。

Cardiovascular disease and bacterial infections are the leading causes of death in patients with end-stage renal disease (ESRD) on hemodialysis (HD). Besides the high prevalence of well established risk factors, these patients are in a state of heightened oxidative stress, characterized by excessive free radical production and/or low antioxidant defenses. The principal hypothesis of this proposal is that exposure of polymorphonuclear cells to the extracorporeal circuit, triggers production of reactive oxygen species (ROS) leading to leukocyte dysfunction, as well as oxidative endothelial cell injury. Furthermore, the increasingly routine use of parenteral iron, a potent promoter of toxic free radical generation, in these patients may enhance oxidative stress-induced cell injury and dysfunction. This proposal will address these concerns using in vitro models to evaluate the impact of dialyzer biocompatibility and various iron preparations on indices of oxidative stress, and cell injury. These models will involve PMN (healthy vs uremic) activation by exposure to dialysis membrane fragments of varying composition t iron or ROS inhibitors, as well as during circulation through an in vitro dialysis circuit. In addition, a coculture model will be utilized to assess the effects of dialyzer membrane-activated PMN on reporter monolayers of cultured endothelial cells (t excess iron) grown under static and flow conditions. The results of this proposal are expected to enhance our understanding of the pathogenesis of ROS-induced cell injury and dysfunction and lay the foundation for the development of novel strategies to combat atherogenesis, vascular access and immune dysfunction in this vulnerable population.