PMN ACTIVATION AND OXIDATIVE STRESS IN HEMODIALYSIS

血液透析中的 PMN 激活和氧化应激

• 批准号: 6294729
• 负责人: SUSIE I HU
• 金额: $ 4.95万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6294729
• 关键词: artificial membranes; biomaterial compatibility; chronic renal failure; clinical research; cytotoxicity; free radical oxygen; hemodialysis; human subject; iron; leukocyte activation /transformation; mixed tissue /cell culture; neutrophil; oxidative stress; postdoctoral investigator; vascular endothelium

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.

心血管疾病和细菌感染是终末期肾病（ESRD）血液透析（HD）患者的主要死亡原因。除了高患病率的已确立的风险因素，这些患者是在一个高度氧化应激状态，其特征是过度的自由基产生和/或低抗氧化剂防御。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，以及氧化性内皮细胞损伤。此外，在这些患者中，越来越多地常规使用肠外铁（毒性自由基产生的有效促进剂）可能会增强氧化应激诱导的细胞损伤和功能障碍。本提案将使用体外模型来解决这些问题，以评价透析器生物相容性和各种铁制剂对氧化应激指数和细胞损伤的影响。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在通过体外透析回路的循环期间的PMN（健康vs尿毒症）活化。此外，将使用共培养模型评估透析器膜激活的PMN对静态和流动条件下生长的培养内皮细胞（过量铁）报告细胞单层的影响。该提案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，并为开发新的策略以对抗该脆弱人群中的动脉粥样硬化，血管通路和免疫功能障碍奠定基础。