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Pathophysiology of Ischemia-Reperfusion Injury and Hemorrhagic Transformation in the Brain
Introduction
Restoration of blood supply, referred to as “reperfusion,” is a desired goal for acute stroke treatment. Spontaneous reperfusion occurs commonly after stroke, in about 50–70% of patients with ischemic stroke. Reperfusion can also be achieved either by thrombolytic therapy using tissue plasminogen activator (tPA) or endovascular therapy, including embolectomy surgery using retrieval devices and thrombus disruption using stents. Since the publication of the first edition of Primer on Cerebrovascular Diseases in 1997, there has been considerable progress in the mechanisms study and treatment development for reperfusion injury in stroke. The time window of thrombolysis using tPA has been extended up to 4.5 h after stroke onset; meanwhile the embolectomy surgery using stent retrievers has undergone multiple clinical trials in the United States in the past 10 years with significantly beneficial outcomes and is expected to be widely practiced in the near future. However, despite the beneficial effect of oxygen supply brought by reperfusion, rapid reperfusion also has detrimental impact on brain function, the so-called reperfusion injury. This has been documented by both experimental studies using animal stroke models and clinical evidence, such as rat stroke models showing significantly increased infarct volume after reperfusion compared with permanent occlusion. In addition, MRI studies using fluid-attenuated inversion recovery and perfusion-weighted images for human stroke showed that reperfusion could be linked to an early opening of the blood–brain barrier (BBB) and consequently to secondary reperfusion injury and poor outcome . In this chapter, we briefly discuss the pathophysiology and cellular and molecular mechanisms of reperfusion injury and hemorrhagic transformation (HT), and potential therapeutic strategies against these injuries.
Cellular and Molecular Mechanisms of Ischemia-Reperfusion Injury and Hemorrhagic Transformation
To date the deleterious effect of reperfusion in brain function after stroke has been widely recognized and the underlying cellular and molecular mechanisms are being clarified, part of which are learnt from ischemia-reperfusion injuries in other organs such as heart and liver. The mechanisms of reperfusion injury include oxidative stress, leukocyte infiltration, platelet activation, complement activation, and disruption of the BBB, which ultimately lead to edema or HT. HT significantly contributes to the neurological dysfunction and mortality after acute ischemic stroke, and is further worsened by reperfusion caused by either tPA recanalization or embolectomy surgery. In the past few years, the concept of neurovascular unit (NVU) has been widely accepted, in which multiple cell types including endothelial cells, astrocytes, pericytes, oligodendrocytes, microglia, and neurons functionally interact with each other to maintain brain function. As a consequence, in addition to vascular damage, ischemia-reperfusion also causes deleterious effects on these NVU components. Due to the space limit of this chapter, we mainly focus on endovascular damage caused by ischemia-reperfusion.
Oxidative Stress
Oxidative stress results from an imbalance in which the manifestation of reactive oxygen species overwhelms the antioxidant capacity of the cells. The overproduction of reactive oxygen species, mainly peroxides and free radicals, causes damages to all components of the cells, including proteins, DNA, and lipids. Oxidative stress has emerged as one of the mechanisms implicated in the pathogenesis and disease progression of many diseases including stroke. Increased ROS production has been demonstrated in ischemic stroke, both during ischemia and reperfusion . The cerebral ischemia-reperfusion model revealed that oxidative stress mediates BBB dysfunction in mice with superoxide dismutase deficiency. Furthermore, free radical generation and oxidative damage in BBB are main triggers of HT after transient focal cerebral ischemia, which is supported by experimental evidence that free radical scavenger can significantly decrease tPA-induced HT in embolic focal ischemia.
Although a large array of experimental studies have established that oxidative stress is an important mechanism of reperfusion-injury and HT, supportive clinical evidence is scant. A clinical investigation for patients with stroke after tPA thrombolysis showed that the oxidative stress markers including malondialdehyde and myeloperoxidase were already increased at baseline of stroke, whereas no further increases were found for these markers after tPA recanalization, suggesting no relationship between free radical–induced oxidative damage to lipids/proteins and reperfusion injury. However, there exists much limitation in clinical studies; for instance, the peak of oxidative stress might have been missed. The contribution of oxidative stress in reperfusion injury cannot be denied, which warrants further investigation in the future.
Leukocyte Infiltration
Leukocytes play important roles in cerebral reperfusion injury. During reperfusion, activated leukocytes attach to endothelial cells through chemotactic signals, and matrix metalloproteinase and neutrophil-derived oxidants are subsequently produced to break down the BBB. The leukocytes then extravasate from capillaries and infiltrate into brain tissue, releasing proinflammatory cytokines, which eventually result in deterioration of the penumbra .
The destructive effect caused by leucocyte infiltration has been validated by numerous animal studies. It was revealed that in rat stroke models neutrophil accumulation at the neuronal injury site occurred earlier and to a greater extent in reperfusion tissue than in tissue with permanent occlusion. In addition, the contribution of leukocyte infiltration in reperfusion injury is also supported by the beneficial effects of neutrophil depletion, in which the animals after transient ischemia showed smaller infarct size when administered with either antineutrophil antiserum or monoclonal antibodies. Furthermore, leukocyte infiltration is also involved in HT, supported by increased white blood cell count in patients with HT than in those without. The subsequent enhanced leukocyte infiltration may damage microvascular endothelial cells, causing BBB dysfunction and HT.
Leukocyte infiltration is a cascade of processes including leukocyte migration and adhesion to the microvascular endothelial surface, matrix metalloproteinase production for BBB breakdown, leukocyte extravasation into brain tissue, and finally the release of cytokines to brain tissue triggering an inflammatory response. One important regulator of leukocyte adherence to endothelium is endothelial P-selectin, which is upregulated by superoxide free radicals produced during ischemia and reperfusion. P-selectin interacts with its receptor on leukocyte, P-selectin glycoprotein ligand-1, which facilitates the low-affinity “rolling” of leukocytes on the endothelium. Firm adherence of leucocytes to endothelium is mediated by the interaction of leukocyte β 2 integrins CD11a/CD18 and CD11b/CD18 with endothelial intercellular adhesion molecule 1. The subsequent transmigration of leukocytes is regulated by platelet-endothelial cell adhesion molecule-1 along the endothelial cell junction.
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