NITROGEN AND OXYGEN RADICAL INTERACTIONS IN SURGERY

描述：(改编自调查人员摘要)最近 表明自由基一氧化氮(NO)是一种以前未被认识到的 在许多与以下疾病相关的病理生理状况中扮演重要角色 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)这些情况涉及细胞和组织损伤 活性氧化物种(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可以导致戏剧性的保护或增强 受伤。本提案所述工作的总体目的是 要利用一个发展良好且定义良好的系统，隔离的大鼠 肝细胞，以揭示决定NO是否会 在氧化损伤中具有保护性或破坏性。其中的主要假设是 工作是，NO/ROS的结果(保护性与破坏性) 细胞内的相互作用取决于(1)多种可能的 细胞内的化学/生化NO/ROS相互作用在 特定条件和(2)生物防御反应 当细胞预先暴露于少量无毒的这些活性物质时 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/生化相互作用决定了 一氧化氮对氧化损伤的保护作用与损伤作用。通过 在氧化损伤中利用特定生化步骤的效应器， 将完成对被调制的那些步骤的识别 从而导致其保护性和破坏性的行为 分离的肝细胞。2)确定由以下因素引起的保护反应 预先暴露在少量的NO/ROS中，导致对 随后的氧化损伤的破坏性影响。预曝光 分离的肝细胞对少量NO或ROS诱导的抵抗 进行第二次毒性治疗，这涉及到上调 新蛋白质(S)合成。通过测定表型和遗传型 这种预暴露诱导的细胞变化，具有特定的保护作用 在这种防御反应中上调的机制将被识别 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.