Víctor Víctor M, Espulgues Juan V, Hernández-Mijares Antonio, Rocha Milagros
Fundación Hospital Universitario Doctor Peset, Avda Gaspar Aguilar 90, 46017, Valencia, Spain.
Infect Disord Drug Targets. 2009 Aug;9(4):376-89. doi: 10.2174/187152609788922519.
Sepsis and septic shock are the major causes of death in intensive care units. The prevalent hypothesis regarding the mechanisms of sepsis and septic shock indicates that this syndrome is caused by an excessive defensive and inflammatory response characterised by massive increases in reactive oxygen species (ROS), nitric oxide (NO) and inflammatory cytokines. The consequences of these syndromes are systemic damage to the vascular endothelium, impaired tissue and a compromised whole body respiration, glutathione depletion and mitochondrial respiratory dysfunction with diminished levels of ATP and O(2) consumption. In general, ROS are essential to the functions of cells and particularly immune cells, but adequate levels of antioxidant defenses are required to protect against the harmful effects of excessive ROS production. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves in a range of conditions, including sepsis. This review considers the process of sepsis from a mitochondrial perspective, discussing strategies for the targeted delivery of antioxidants to mitochondria currently under development. We will provide a summary of the following areas: the cellular metabolism of ROS and its role in pathophysiological processes such as sepsis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in antioxidants that target the matrix-facing surface of the inner mitochondrial membrane in order to protect against mitochondrial oxidative damage, and their therapeutic potential as a treatment for sepsis.
脓毒症和脓毒性休克是重症监护病房患者死亡的主要原因。关于脓毒症和脓毒性休克发病机制的普遍假说表明，该综合征是由过度的防御性和炎症反应引起的，其特征是活性氧（ROS）、一氧化氮（NO）和炎症细胞因子大量增加。这些综合征的后果是对血管内皮的系统性损伤、组织受损以及全身呼吸功能受损、谷胱甘肽耗竭和线粒体呼吸功能障碍，同时ATP水平降低和氧气消耗减少。一般来说，ROS对细胞尤其是免疫细胞的功能至关重要，但需要足够水平的抗氧化防御来抵御过量ROS产生的有害影响。线粒体氧化应激损伤和功能障碍会导致多种细胞病变，这些病变在包括脓毒症在内的一系列病症中表现出来。本综述从线粒体的角度探讨脓毒症的发病过程，讨论目前正在开发的将抗氧化剂靶向递送至线粒体的策略。我们将总结以下几个方面：ROS的细胞代谢及其在脓毒症等病理生理过程中的作用；目前可用的抗氧化剂及其在改善氧化应激介导疾病方面有效和无效的可能原因；以及靶向线粒体内膜面向基质表面以防止线粒体氧化损伤的抗氧化剂的最新进展及其作为脓毒症治疗方法的治疗潜力。
