Cardiomyopathy:Pro-Oxidant Role of Zidovudine (AZT)

描述（由申请方提供）：在接受齐多夫定（AZT）长期治疗的HIV患者中观察到的毒性可能在多种风险因素的背景下发生：异常组织铁状态、营养性镁缺乏（MgD）、炎症和氧化应激。该提案将评估长期AZT治疗是否与共存的MgD协同作用，以增强体内铁失衡和由此产生的氧化应激。 我们实验室的最新数据也表明AZT介导的肠道损伤可能促进随后的心脏和肝脏组织的内毒素损伤。这使我们提出了以下具体目标：（1）确定AZT是否会导致慢性治疗大鼠和炎症细胞模型中的全身氧化应激、组织炎症和组织铁状态改变。(2)评估螯合或抗生素治疗是否减轻内毒素血症，组织和细胞氧化应激指数，以及慢性AZT治疗动物的组织炎症。(3)评价AZT治疗是否与MgD协同作用，以增强体内由于铁干扰增加而引起的组织损伤;并评估螯合和抗生素治疗的保护效果。(4)确定AZT治疗是否与MgD协同作用，以增强心肌对体外I/R应激的敏感性;并评估体内螯合治疗的保护效果。敏感的免疫细胞化学和分子生物学技术将被用来定位和量化心肌细胞因子，粘附分子和细胞凋亡。将通过测量组织谷胱甘肽和蛋白硫醇状态、脂质过氧化产物、一氧化氮和过氧亚硝酸盐标记物以及离体缺血/再灌注心脏中的自由基产生（ESR自旋捕获）和功能障碍来确定氧化应激。主要目的是评估AZT与MgD结合是否会进一步改变铁状态，导致心脏、肝脏和肠组织对氧化应激的敏感性增强。建议的铁螯合和抗生素干预策略可能会导致旨在减少AZT相关的心血管毒性的辅助治疗。

DESCRIPTION (Provided by applicant): Cardiotoxicity seen in HIV patients receiving long-term treatment with zidovudine (AZT) may occur against a background of multiple risk factors: abnormal tissue iron status, nutritional Mg-deficiency (MgD), inflammation and oxidative stress. This proposal will evaluate if chronic AZT treatment synergizes with co-existing MgD to enhance iron imbalance, and resultant oxidative stress in vivo. Recent data from our lab also suggest that AZT-mediated gut injury may promote subsequent endotoxic injury to cardiac and hepatic tissue. This led us to propose the following Specific Aims: (1) Determine if AZT causes systemic oxidative stress, tissue inflammation, and altered tissue iron status in chronically-treated rats and in inflammatory cell models. (2) Assess whether chelation or antibiotic therapy attenuates endotoxemia, indices of tissue and cell oxidative stress, and tissue inflammation in chronic AZT-treated animals. (3) Evaluate if AZT treatment synergizes with MgD to enhance tissue injury in vivo due to increased iron disturbances; and assess the protective efficacy of chelation and antibiotic therapy. (4) Determine if AZT treatment synergizes with MgD to enhance myocardial susceptibility to imposed I/R stress ex vivo; and assess the protective efficacy of in vivo chelation therapy. Sensitive immunocytochemical and molecular biology techniques will be used to localize and quantify cytokines, adhesion molecules, and apoptosis in the myocardium. Oxidative stress will be determined by measuring tissue glutathione and protein-thiol status, lipid peroxidation products, nitric oxide and peroxynitrite marker, as well as free radical production (ESR spin-trapping) and dysfunction in isolated ischemia/reperfused hearts. The main goal is to assess whether AZT, in conjunction with MgD, will further alter iron status, leading to enhanced sensitivity of cardiac, hepatic and intestinal tissue to oxidative stress. The proposed iron chelation and antibiotic intervention strategies may lead to adjunct therapies aimed at lessen AZT-related cardiovascular toxicity.