Ischemia/Reperfusion.

Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease.

缺血性疾病，如心肌梗死、中风和外周血管疾病，是西方文化中导致衰弱性疾病和死亡的最常见原因。组织损伤的程度直接与血流减少的程度以及缺血期的长短有关，这会影响细胞内三磷酸腺苷（ATP）和细胞内pH值降低的水平。由于缺血损害了依赖ATP酶的离子转运，导致细胞内和线粒体钙水平升高（钙超载）。细胞体积调节机制也因ATP缺乏而被破坏，这可能导致细胞器和质膜的裂解。再灌注虽然是挽救缺氧组织所必需的，但会产生矛盾的组织反应，促进活性氧物质的产生（氧反常）、促炎性免疫细胞在缺血组织中的滞留、内质网应激以及缺血后毛细血管无复流的发展，从而加重组织损伤。这些病理事件最终导致线粒体通透性转换孔开放，这是缺血/再灌注（I/R）诱导的细胞裂解和死亡的一个常见的最终效应器。新出现的概念包括肠道微生物组、胎儿编程、表观遗传变化和微粒在I/R发病机制中的影响。本综述的总体目标是描述这些以及其他导致I/R损伤的机制。由于有如此多不同的有害事件参与I/R，很明显只有针对多种病理过程的治疗方法才会有效。此外，通过更广泛地使用纳入心血管疾病危险因素复杂影响的动物模型，将提高I/R研究的转化意义。