PMN ACTIVATION AND OXIDATIVE STRESS IN HEMODIALYSIS

心血管疾病和细菌感染是血液透析(HD)中终末期肾病(ESRD)患者的主要死亡原因。除了公认的危险因素的高流行率外，这些患者还处于氧化应激加剧的状态，特征是过度产生自由基和/或抗氧化剂防御能力低下。这一建议的主要假设是，多形核细胞暴露在体外循环中，触发活性氧物种(ROS)的产生，导致白细胞功能障碍，以及氧化性内皮细胞损伤。此外，在这些患者中越来越常规地使用肠外铁，这是一种有效的有毒自由基产生的促进剂，可能会加强氧化应激诱导的细胞损伤和功能障碍。这项建议将解决这些问题，使用体外模型来评估透析剂的生物相容性和各种铁制剂对氧化应激指标和细胞损伤的影响。这些模型将涉及通过暴露于不同组成的铁或ROS抑制剂的透析膜片段以及通过体外透析回路的循环来激活PMN(健康与尿毒症)。此外，还将利用共培养模型来评估透析膜激活的PMN对静态和流动条件下培养的内皮细胞报告单层(t过量铁)的影响。这一建议的结果有望加深我们对ROS诱导的细胞损伤和功能障碍的发病机制的理解，并为开发新的策略来对抗这一脆弱人群的动脉粥样硬化、血管通路和免疫功能障碍奠定基础。

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.