Granger D Neil, Kvietys Peter R
Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, United States.
Department of Physiological Sciences, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Redox Biol. 2015 Dec;6:524-551. doi: 10.1016/j.redox.2015.08.020. Epub 2015 Oct 8.
Reperfusion injury, the paradoxical tissue response that is manifested by blood flow-deprived and oxygen-starved organs following the restoration of blood flow and tissue oxygenation, has been a focus of basic and clinical research for over 4-decades. While a variety of molecular mechanisms have been proposed to explain this phenomenon, excess production of reactive oxygen species (ROS) continues to receive much attention as a critical factor in the genesis of reperfusion injury. As a consequence, considerable effort has been devoted to identifying the dominant cellular and enzymatic sources of excess ROS production following ischemia-reperfusion (I/R). Of the potential ROS sources described to date, xanthine oxidase, NADPH oxidase (Nox), mitochondria, and uncoupled nitric oxide synthase have gained a status as the most likely contributors to reperfusion-induced oxidative stress and represent priority targets for therapeutic intervention against reperfusion-induced organ dysfunction and tissue damage. Although all four enzymatic sources are present in most tissues and are likely to play some role in reperfusion injury, priority and emphasis has been given to specific ROS sources that are enriched in certain tissues, such as xanthine oxidase in the gastrointestinal tract and mitochondria in the metabolically active heart and brain. The possibility that multiple ROS sources contribute to reperfusion injury in most tissues is supported by evidence demonstrating that redox-signaling enables ROS produced by one enzymatic source (e.g., Nox) to activate and enhance ROS production by a second source (e.g., mitochondria). This review provides a synopsis of the evidence implicating ROS in reperfusion injury, the clinical implications of this phenomenon, and summarizes current understanding of the four most frequently invoked enzymatic sources of ROS production in post-ischemic tissue.
再灌注损伤是一种自相矛盾的组织反应，表现为在血流和组织氧合恢复后，原本缺血缺氧的器官所出现的反应。在过去四十多年里，它一直是基础研究和临床研究的重点。虽然已经提出了多种分子机制来解释这一现象，但活性氧（ROS）的过量产生作为再灌注损伤发生的关键因素，仍然备受关注。因此，人们投入了大量精力来确定缺血再灌注（I/R）后过量ROS产生的主要细胞和酶来源。在迄今为止描述的潜在ROS来源中，黄嘌呤氧化酶、NADPH氧化酶（Nox）、线粒体和非偶联型一氧化氮合酶已成为再灌注诱导的氧化应激最可能的促成因素，并代表了针对再灌注诱导的器官功能障碍和组织损伤进行治疗干预的优先靶点。尽管所有这四种酶来源都存在于大多数组织中，并且可能在再灌注损伤中发挥一定作用，但人们已将重点放在某些组织中富集的特定ROS来源上，例如胃肠道中的黄嘌呤氧化酶以及代谢活跃的心脏和大脑中的线粒体。有证据表明氧化还原信号传导可使一种酶来源（如Nox）产生的ROS激活并增强另一种来源（如线粒体）产生的ROS，这支持了多种ROS来源导致大多数组织再灌注损伤的可能性。本综述概述了与再灌注损伤相关的ROS证据、这一现象的临床意义，并总结了目前对缺血后组织中四种最常提及的ROS产生酶来源的理解。
