Cardiomyopathy: Pro-Oxidant Role of Zidovudine (AZT)

描述(申请人提供)：接受齐多夫定(AZT)长期治疗的艾滋病毒患者的心脏毒性可能发生在多种危险因素的背景下：组织铁状态异常、营养性镁缺乏(MGD)、炎症和氧化应激。这项建议将评估慢性AZT治疗是否与共存的MGD协同作用，以增强体内的铁失衡和由此产生的氧化应激。我们实验室最近的数据也表明，AZT介导的肠道损伤可能会促进随后对心脏和肝脏组织的内毒素损伤。为此，我们提出了以下具体目标：(1)确定AZT是否会在长期治疗的大鼠和炎症细胞模型中导致全身氧化应激、组织炎症和组织铁状态改变。(2)评价螯合或抗生素治疗是否能减轻慢性AZT动物的内毒素血症、组织和细胞氧化应激指数以及组织炎症。(3)评估AZT治疗与MGD是否有协同作用，以加强体内由于铁紊乱增加而造成的组织损伤；并评估螯合治疗和抗生素治疗的保护效果。(4)确定AZT治疗与MGD是否有协同作用，以增强心肌对外加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定量心肌中的细胞因子、黏附分子和细胞凋亡。氧化应激将通过测量组织谷胱甘肽和蛋白质-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，以及自由基产生(ESR自旋捕获)和功能障碍来确定。主要目标是评估AZT与MGD联合使用是否会进一步改变铁的状态，导致心脏、肝脏和肠道组织对氧化应激的敏感性增强。建议的铁络合和抗生素干预策略可能导致旨在减轻AZT相关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.