Wu Jian, Hecker James G, Chiamvimonvat Nipavan
Department of Internal Medicine, Transplant Research Program, University of California, Davis Medical Center, Sacramento, CA 95817, USA.
Adv Drug Deliv Rev. 2009 Apr 28;61(4):351-63. doi: 10.1016/j.addr.2009.01.005. Epub 2009 Feb 20.
The balance of redox is pivotal for normal function and integrity of tissues. Ischemic insults occur as results of a variety of conditions, leading to an accumulation of reactive oxygen species (ROS) and an imbalanced redox status in the tissues. The oxidant stress may activate signaling mechanisms provoking more toxic events, and eventually cause tissue damage. Therefore, treatments with antioxidants, free radical scavengers and their mimetics, as well as gene transfer approaches to overexpress antioxidant genes represent potential therapeutic options to correct the redox imbalance. Among them, antioxidant gene transfer may enhance the production of antioxidant scavengers, and has been employed to experimentally prevent or treat ischemic injury in cardiovascular, pulmonary, hepatic, intestinal, central nervous or other systems in animal models. With improvements in vector systems and delivery approaches, innovative antioxidant gene therapy has conferred better outcomes for myocardial infarction, reduced restenosis after coronary angioplasty, improved the quality and function of liver grafts, as well as outcome of intestinal and cerebral ischemic attacks. However, it is crucial to be mindful that like other therapeutic armentarium, the efficacy of antioxidant gene transfer requires extensive preclinical investigation before it can be used in patients, and that it may have unanticipated short- or long-term adverse effects. Thus, it is critical to balance between the therapeutic benefits and potential risks, to develop disease-specific antioxidant gene transfer strategies, to deliver the therapy with an optimal time window and in a safe manner. This review attempts to provide the rationale, the most effective approaches and the potential hurdles of available antioxidant gene transfer approaches for ischemic injury in various organs, as well as the possible directions of future preclinical and clinical investigations of this highly promising therapeutic modality.
氧化还原平衡对于组织的正常功能和完整性至关重要。缺血性损伤是由多种情况导致的，会致使活性氧（ROS）积累以及组织中氧化还原状态失衡。氧化应激可能激活引发更多毒性事件的信号传导机制，并最终导致组织损伤。因此，使用抗氧化剂、自由基清除剂及其模拟物进行治疗，以及通过基因转移方法过表达抗氧化基因，都代表了纠正氧化还原失衡的潜在治疗选择。其中，抗氧化基因转移可增强抗氧化清除剂的产生，并已被用于在动物模型中实验性预防或治疗心血管、肺、肝、肠、中枢神经或其他系统的缺血性损伤。随着载体系统和递送方法的改进，创新的抗氧化基因疗法在心肌梗死方面取得了更好的效果，减少了冠状动脉成形术后的再狭窄，改善了肝移植的质量和功能，以及肠和脑缺血发作的预后。然而，必须注意的是，与其他治疗手段一样，抗氧化基因转移的疗效在用于患者之前需要进行广泛的临床前研究，并且它可能会产生意想不到的短期或长期不良反应。因此，在治疗益处和潜在风险之间取得平衡、制定针对特定疾病的抗氧化基因转移策略、在最佳时间窗口并以安全的方式进行治疗至关重要。本综述试图提供针对各种器官缺血性损伤的现有抗氧化基因转移方法的原理、最有效的方法和潜在障碍，以及这种极具前景的治疗方式未来临床前和临床研究的可能方向。
