贫血与脑损伤：问题多，答案少

大量临床研究显示围手术期患者的脑损伤与急性贫血有关。这种损伤发生在接近于我们普遍认同的输血指征[血红蛋白（Hb）浓度7～8g/dl]，但高于脑组织缺氧的血红蛋白浓度（Hb3～4g／dl）的情况下。但是，贫血引起脑损伤的缺氧和非缺氧机制仍不清楚。此外，能最大程度降低急性贫血所致脑损伤的保护性机制仍未阐明。包括一氧化氮（NO）在内的血管扩张机制，在贫血时有助于维持大脑氧供，在各种急性稀释性缺血试验模型中，3种NO合成酶（NOS）（神经型、内皮型及可诱导型NOS）都有上调。近来的实验也证实了在相当于临床缺氧Hb浓度（Hb6—7g/dl）的啮齿类动物的大脑皮质中，重要的转录因子如缺氧诱导因子（HIF）-1α有所增加。这说明急性贫血对脑氧的供需平衡可能造成威胁，在缺氧的情况下，细胞浆中的HIF-1α降解被抑制，HIF-1α积聚成二聚体，移位到细胞核中并增加许多低氧分子的转录。这些低氧分子在贫血的脑组织中的表达也被发现上调，包括红细胞生成素，血管内皮生长因子，可诱导型NOS。此外，非低氧介质，包括细胞因子和血管激素，可以增加HIF-1α的转录。而且，源于NOS的NO也可以在没有组织缺氧时稳定HIF—1α。因此，在贫血时，HIF-1α在低氧和常氧情况下能对脑细胞进行调节。实验研究发现，针对不同类型的细胞，上调的HIF-1α可以表现为神经保护作用或神经毒性作用。在本综述中，我们描述了这些细胞作用过程，对贫血引起的脑损伤和保护机制有了更清晰的认识。贫血引起损伤的可能机制包括脑栓塞、组织缺氧、炎症、活性氧和兴奋性毒性。可能的细胞保护机制包括NOS／NO依赖的细胞氧供增强和包括HIF-1α、红细胞生成素及血管内皮生长因子在内的细胞保护机制。这些激活的细胞机制的总体平衡决定着它们在贫血时的上调是起细胞保护作用还是细胞损伤作用。深入了解这些机制有助于明确什么样的治疗措施可以降低围手术期贫血性脑损伤。

A number of clinical studies have associated acute anemia with cerebral injury in perioperative patients. Evidence of such injury has been observed near the currently accepted transfusion threshold （hemoglobin [Hb] concentration, 7 -8 g/dl）, and well above the threshold for cerebral tissue hypoxia （Hb 3 -4 g/dl）. However, hypoxic and nonhypoxic mechanisms of anemia-induced cerebral injury have not been clearly elucidated. In addition, protective mechanisms which may minimize cerebral injury during acute anemia have not been well defined. Vasodilatory mechanisms, including nitric oxide （NO）, may help to maintain cerebral oxygen delivery during anemia as all three NO synthase （NOS） isoforms （neuronal, endothelial, and inducible （NOS） have been shown to be up-regulated in different experimental models of acute hemodilutional anemia. Recent experimental evidence has also demonstrated an increase in an important transcription factor, hypoxia inducible factor （HIF）-1α, in the cerebral cortex of anemic rodents at clinically relevant Hb concentrations （Hb 6 - 7 g/dl）. This suggests that cerebral oxygen homeostasis may be in jeopardy during acute anemia. Under hypoxic conditions, cytoplasmic HIF-1α degradation is inhibited, thereby allowing it to accumulate, dimerize, and translocate into the nucleus to promote transcription of a number of hypoxic molecules. Many of these molecules, including erythropoietin, vascular endothelial growth factor, and inducible NOS have also been shown to be up-regulated in the anemic brain. In addition, HIF-1α transcription can be increased by nonhypoxic mediators including cytokines and vascular hormones. Furthermore,NOS-derived NO may also stabilize HIF-1α in the absence of tissue hypoxia. Thus, during anemia, HIF-1α has the potential to regulate cerebral cellular responses under both hypoxic and normoxic conditions. Experimental studies have demonstrated that HIF-1α may have either neuroproteetive or neurotoxic capacity depending on the cell type in which it is upregulated. In the current review, we characterize these cellular processes to promote a clearer understanding of anemia-induced cerebral injury and protection. Potential mechanisms of anemia-induced injury include cerebral emboli, tissue hypoxia, inflammation, reactive oxygen species generation, and excitotoxicity. Potential mechanisms of cerebral protection include NOS/NO-dependent optimization of cerebral oxygen delivery and cytoprotective mechanisms including HIF-1α, erythropoietin, and vascular endothelial growth factor. The overall balance of these activated cellular mechanisms may dictate whether or not their up-regulation leads to cytoprotection or cellular injury during anemia. A clearer understanding of these mechanisms may help us target therapies that will minimize anemia-induced cerebral injury in perioperative patients.