Pathophysiology of Ischemia-reperfusion Injury

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 fluidattenuated 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 [1]. 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.