NITROGEN AND OXYGEN RADICAL INTERACTIONS IN SURGERY

描述：（改编自研究者摘要）最近， 表明自由基一氧化氮（NO）是一种以前未被认识到的 在许多病理生理条件相关的关键球员， 手术、休克和许多其他临床上重要的现象。许多（如果 不是大多数）这些病症涉及细胞和组织损伤， 活性氧化物质（ROS）如超氧化物，过氧化氢， 和羟基自由基。不同学科的大量研究表明， NO可以导致显著的保护或增强 损伤本提案所述工作的总体目的是 利用一个完善的和定义明确的系统，隔离大鼠 肝细胞，以揭示决定NO是否会 保护或破坏氧化损伤。这其中的主要假设 研究表明，NO/ROS的结果（保护性与破坏性） 细胞中的相互作用取决于（1）在许多可能的 细胞中的化学/生物化学NO/ROS相互作用在 具体条件和（2）生物防御反应安装 当细胞预先暴露于少量无毒的这些反应性 物种基于这一假设的两个具体目标是：1）识别 细胞内特定的化学/生物化学相互作用决定了 NO对氧化损伤的保护作用与损伤作用。通过 利用氧化损伤中特定生化步骤的效应物， 将完成那些被调制的步骤的识别 一氧化氮，从而导致其保护和破坏作用， 分离的肝细胞。2)识别由以下因素诱导的保护性反应： 预先暴露于少量的NO/ROS，这会导致对 随后的氧化损伤的破坏作用。的预暴露 分离的肝细胞对少量的NO或ROS诱导抗性 第二种毒性治疗，包括上调 新蛋白质合成。通过测定表型和基因型 这种预暴露引起的细胞变化， 在这种防御反应中上调的机制将被确定， D.

DESCRIPTION: (Adapted from investigator's abstract) It has recently been shown that the radical nitric oxide (NO) is a previously unrecognized key player in many pathophysiological conditions of relevance to surgery, shock, and many other clinically important phenomena. Many (if not most) of these conditions involve cell and tissue injury from reactive oxidative species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radical. Numerous studies in diverse disciplines have shown that NO can result in either dramatic protection or enhancement of injury. The overall purpose of the work described in this proposal is to utilize one well-developed and well-defined system, the isolated rat hepatocyte, to uncover the factors which determine whether NO will be protective or damaging in oxidative injury. The major hypothesis in this work is that the outcome (protective vs. damaging) of NO/ROS interactions in cells is determined by (1) which of the many possible chemical/biochemical NO/ROS interactions in the cell predominate under specific conditions and (2) the biological defensive responses mounted by cells when pre-exposed to small nontoxic amounts of these reactive species. The two Specific Aims based on this hypothesis are: 1) Identify which specific chemical/biochemical interactions within cells determine the protective vs. damaging effects of NO on oxidative injury. By utilizing effectors of specific biochemical steps in oxidative injury, identification will be accomplished of those steps which are modulated by NO and thus result in its protective and also damaging actions in isolated hepatocytes. 2) Identify the protective responses induced by pre-exposure to small amounts of NO/ROS which cause resistance to the damaging effects of a subsequent oxidative injury. Pre-exposure of isolated hepatocytes to a small amount of NO or ROS induces resistance to a second otherwise toxic treatment, which involves upregulation of new protein(s) synthesis. By determining the phenotypic and genotypic changes in cells induced by this pre-exposure, the specific protective mechanisms which are upregulated in this defensive response will be identif d.