Christofidou-Solomidou Melpo, Muzykantov Vladimir R
Institute of Environmental Medicine and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Treat Respir Med. 2006;5(1):47-78. doi: 10.2165/00151829-200605010-00004.
Pulmonary oxidant stress plays an important pathogenetic role in disease conditions including acute lung injury/adult respiratory distress syndrome (ALI/ARDS), hyperoxia, ischemia-reperfusion, sepsis, radiation injury, lung transplantation, COPD, and inflammation. Reactive oxygen species (ROS), released from activated macrophages and leukocytes or formed in the pulmonary epithelial and endothelial cells, damage the lungs and initiate cascades of pro-inflammatory reactions propagating pulmonary and systemic stress. Diverse molecules including small organic compounds (e.g. gluthatione, tocopherol (vitamin E), flavonoids) serve as natural antioxidants that reduce oxidized cellular components, decompose ROS and detoxify toxic oxidation products. Antioxidant enzymes can either facilitate these antioxidant reactions (e.g. peroxidases using glutathione as a reducing agent) or directly decompose ROS (e.g. superoxide dismutases [SOD] and catalase). Many antioxidant agents are being tested for treatment of pulmonary oxidant stress. The administration of small antioxidants via the oral, intratracheal and vascular routes for the treatment of short- and long-term oxidant stress showed rather modest protective effects in animal and human studies. Intratracheal and intravascular administration of antioxidant enzymes are being currently tested for the treatment of acute oxidant stress. For example, intratracheal administration of recombinant human SOD is protective in premature infants exposed to hyperoxia. However, animal and human studies show that more effective delivery of drugs to cells experiencing oxidant stress is needed to improve protection. Diverse delivery systems for antioxidants including liposomes, chemical modifications (e.g. attachment of masking pegylated [PEG]-groups) and coupling to affinity carriers (e.g. antibodies against cellular adhesion molecules) are being employed and currently tested, mostly in animal and, to a limited extent, in humans, for the treatment of oxidant stress. Further studies are needed, however, in order to develop and establish effective applications of pulmonary antioxidant interventions useful in clinical practice. Although beyond the scope of this review, antioxidant gene therapies may eventually provide a strategy for the management of subacute and chronic pulmonary oxidant stress.
肺氧化应激在多种疾病状态中发挥重要的致病作用，这些疾病包括急性肺损伤/成人呼吸窘迫综合征（ALI/ARDS）、高氧、缺血再灌注、脓毒症、辐射损伤、肺移植、慢性阻塞性肺疾病（COPD）以及炎症。活性氧（ROS）由活化的巨噬细胞和白细胞释放，或在肺上皮细胞和内皮细胞中形成，会损害肺部并引发促炎反应级联，从而加剧肺部和全身应激。多种分子，包括小有机化合物（如谷胱甘肽、生育酚（维生素E）、类黄酮），作为天然抗氧化剂，可还原氧化的细胞成分、分解ROS并使有毒氧化产物解毒。抗氧化酶可促进这些抗氧化反应（如以谷胱甘肽为还原剂的过氧化物酶）或直接分解ROS（如超氧化物歧化酶[SOD]和过氧化氢酶）。许多抗氧化剂正在进行治疗肺氧化应激的测试。在动物和人体研究中，通过口服、气管内和血管途径给予小抗氧化剂治疗短期和长期氧化应激，显示出的保护作用相当有限。目前正在测试气管内和血管内给予抗氧化酶治疗急性氧化应激。例如，气管内给予重组人SOD对暴露于高氧的早产儿具有保护作用。然而，动物和人体研究表明，需要更有效地将药物递送至经历氧化应激的细胞以改善保护效果。正在采用并测试多种抗氧化剂递送系统，包括脂质体、化学修饰（如连接掩蔽聚乙二醇化[PEG]基团）以及与亲和载体偶联（如针对细胞粘附分子的抗体），主要在动物中进行测试，在人体中的测试范围有限，用于治疗氧化应激。然而，为了开发并确立在临床实践中有用的肺抗氧化干预的有效应用，还需要进一步研究。尽管超出了本综述的范围，但抗氧化基因疗法最终可能为亚急性和慢性肺氧化应激的管理提供一种策略。
