Mizuma Atsushi, Yenari Midori A
Department of Neurology, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, CA, United States.
Front Neurol. 2017 Sep 7;8:467. doi: 10.3389/fneur.2017.00467. eCollection 2017.
While the mainstay of acute stroke treatment includes revascularization via recombinant tissue plasminogen activator or mechanical thrombectomy, only a minority of stroke patients are eligible for treatment, as delayed treatment can lead to worsened outcome. This worsened outcome at the experimental level has been attributed to an entity known as reperfusion injury (R/I). R/I is occurred when revascularization is delayed after critical brain and vascular injury has occurred, so that when oxygenated blood is restored, ischemic damage is increased, rather than decreased. R/I can increase lesion size and also worsen blood barrier breakdown and lead to brain edema and hemorrhage. A major mechanism underlying R/I is that of poststroke inflammation. The poststroke immune response consists of the aberrant activation of glial cell, infiltration of peripheral leukocytes, and the release of damage-associated molecular pattern (DAMP) molecules elaborated by ischemic cells of the brain. Inflammatory mediators involved in this response include cytokines, chemokines, adhesion molecules, and several immune molecule effectors such as matrix metalloproteinases-9, inducible nitric oxide synthase, nitric oxide, and reactive oxygen species. Several experimental studies over the years have characterized these molecules and have shown that their inhibition improves neurological outcome. Yet, numerous clinical studies failed to demonstrate any positive outcomes in stroke patients. However, many of these clinical trials were carried out before the routine use of revascularization therapies. In this review, we cover mechanisms of inflammation involved in R/I, therapeutic targets, and relevant experimental and clinical studies, which might stimulate renewed interest in designing clinical trials to specifically target R/I. We propose that by targeting anti-inflammatory targets in R/I as a combined therapy, it may be possible to further improve outcomes from pharmacological thrombolysis or mechanical thrombectomy.
虽然急性中风治疗的主要手段包括通过重组组织型纤溶酶原激活剂或机械取栓术进行血管再通，但只有少数中风患者适合接受治疗，因为延迟治疗会导致预后恶化。在实验层面，这种预后恶化归因于一种称为再灌注损伤（R/I）的情况。当关键的脑和血管损伤发生后血管再通延迟时，就会发生R/I，以至于当恢复含氧血液时，缺血性损伤会增加，而不是减少。R/I会增加病变大小，还会加重血脑屏障破坏，并导致脑水肿和出血。R/I的一个主要潜在机制是中风后炎症。中风后的免疫反应包括胶质细胞的异常激活、外周白细胞的浸润以及脑缺血细胞释放的损伤相关分子模式（DAMP）分子。参与这种反应的炎症介质包括细胞因子、趋化因子、黏附分子以及几种免疫分子效应物，如基质金属蛋白酶-9、诱导型一氧化氮合酶、一氧化氮和活性氧。多年来的几项实验研究对这些分子进行了表征，并表明对它们的抑制可改善神经功能预后。然而，众多临床研究未能在中风患者中证明任何积极结果。不过，这些临床试验中的许多是在常规使用血管再通疗法之前进行的。在本综述中，我们涵盖了R/I中涉及的炎症机制、治疗靶点以及相关的实验和临床研究，这可能会激发人们对设计专门针对R/I的临床试验重新产生兴趣。我们提出，通过将R/I中的抗炎靶点作为联合疗法，有可能进一步改善药物溶栓或机械取栓的效果。
