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）在急性心脏同种异体移植时产生 诱导型一氧化氮合酶（iNOS）的表达。这三年 提案将检查该病理生理学的重要性 否。主要假设是，不，一个人或 与氧自由基的结合是主要效应器机制 对于：1）在早期排斥中看到的心肌功能障碍，以及2） 随着拒绝过程的进展而发展的心肌细胞坏死 没有减弱。该假设的推论是特定的iNOS 抑制剂，单独或与新的氧自由基结合 清道夫，是潜在的新颖和非免疫抑制治疗的 急性同种异体拒绝的选择。在 将检查心脏同种异体移植排斥以检验以下假设：1） 在排斥反应中相对较晚的肌细胞的坏死和2） 拒绝早期发生的可逆收缩功能障碍。 iNOS表达的部位以及NO在细胞坏死中的作用 将研究凋亡。超氧化物和过氧亚硝酸盐在 将检查与NO的连词。与L型的NO相互作用 钙通道是可逆收缩/电生理的原因 将检查功能障碍。新型iNOS抑制剂的应用 在急性同种异体移植期间改善这些病理生理后遗症 拒绝对这些调查至关重要。实验概述了 在此提案中，将采用功能性，电生理学， 组织学，生化，免疫组织化学和分子生物学 1）孤立的心肌和乳头状肌肉制剂，以及 2）血管化大鼠同种异体移植模型。可用的耦合 具有直接无定量的电生理和EPR技术 生物电分析技术是独一无二的。预计这是 提案将对NO的效应子作用产生大量的了解 在早期心脏同种异体拒绝的情况下，将证明 iNOS抑制剂作为有效和新颖的治疗选择的功效 防止急性排斥的后遗症。