NITRIC OXIDE PRODUCTION IN CARDIAC ALLOGRAFT REJECTION

心脏同种异体移植排斥反应中一氧化氮的产生

• 批准号: 2633024
• 负责人: T B FERGUSON
• 金额: $ 21.09万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-29 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2633024
• 关键词: apoptosis; calcium channel; electron spin resonance spectroscopy; electrophysiology; enzyme induction /repression; enzyme inhibitors; free radical scavengers; heart cell; heart contraction; heart transplantation; homologous transplantation; laboratory mouse; laboratory rat; muscle cells; nitric oxide; nitric oxide synthase; oxidative stress; superoxides; transplant rejection

Nitric oxide (NO) is produced during acute cardiac allograft rejection by the expression of inducible nitric oxide synthase (iNOS). This three-year proposal will examine the significance of this pathophysiological production of NO. The primary hypothesis is that NO, alone or in combination with oxygen free-radicals, is a principal effector mechanism for: 1) the myocyte functional impairment seen in early rejection, and 2) the myocyte necrosis that develops as the rejection process progresses unabated. The corollary to this hypothesis is that specific iNOS inhibitors, alone or in combination with new oxygen free-radical scavengers, are potentially novel and non-immunosuppressive therapeutic options for acute allograft rejection. Two processes that occur during cardiac allograft rejection will be examined to test this hypothesis: 1) the necrosis of myocytes that occurs relatively late in rejection, and 2) the reversible contractile dysfunction that occurs earlier in rejection. The site(s) of INOS expression, and role of NO in cell necrosis and apoptosis will be studied. The role of superoxide and peroxynitrite in conjunction with NO will be examined. Interaction of NO with the L-type calcium channel as a cause of reversible contractile/electrophysiologic dysfunction will be examined. Application of novel iNOS inhibitors to ameliorate these pathophysiologic sequelae during acute allograft rejection is fundamental to these investigations. The experiments outlined in this proposal will apply functional, electrophysiological, histological, biochemical, immunohistochemical and molecular biological techniques to 1) isolated myocyte and papillary muscle preparations, and 2) vascularized rat allograft models. The coupling of available electrophysiologic and EPR techniques with direct NO quantitation using bioelectroanalytical techniques is unique. It is anticipated that this proposal will generate considerable insight into the effector role of NO in the setting of early cardiac allograft rejection, and will demonstrate the efficacy of iNOS inhibitors as potent and novel therapeutic options in preventing the sequelae of acute rejection.

一氧化氮（NO）是在急性同种异体心脏移植排斥过程中产生的 诱导型一氧化氮合酶（iNOS）的表达。这三年 该提案将研究这种病理生理学的意义 生产NO。主要假设是 NO，单独或在 与氧自由基结合，是主要的效应机制 原因：1) 早期排斥反应中出现的肌细胞功能损伤，以及 2) 随着排斥过程的进展而发生的肌细胞坏死 有增无减。这一假设的推论是特定的 iNOS 抑制剂，单独或与新氧自由基组合 清道夫，是潜在的新型非免疫抑制治疗药物 急性同种异体移植排斥的选择。期间发生的两个过程 将检查心脏同种异体移植排斥反应以检验这一假设：1) 排斥反应相对较晚发生的肌细胞坏死，2) 排斥反应早期发生的可逆性收缩功能障碍。 INOS 表达位点以及 NO 在细胞坏死和死亡中的作用 将研究细胞凋亡。超氧化物和过氧亚硝酸盐的作用 将检查与 NO 的结合。 NO 与 L 型的相互作用 钙通道作为可逆收缩/电生理的原因 将检查功能障碍。新型iNOS抑制剂的应用 改善急性同种异体移植期间的这些病理生理后遗症 拒绝是这些调查的基础。实验概述 在本提案中将应用功能性、电生理学、 组织学、生物化学、免疫组织化学和分子生物学 1) 分离的肌细胞和乳头肌制剂的技术，以及 2）血管化大鼠同种异体移植模型。可用的耦合 电生理学和 EPR 技术，使用直接 NO 定量 生物电分析技术是独一无二的。预计这 该提案将对 NO 的效应子作用产生深入的了解 在早期心脏同种异体移植排斥的情况下，并将证明 iNOS 抑制剂作为有效且新颖的治疗选择的功效 预防急性排斥反应的后遗症。