Norenberg M D
Neurochem Pathol. 1987 Feb-Apr;6(1-2):13-33. doi: 10.1007/BF02833599.
The Alzheimer type II astrocyte change is the distinctive morphologic alteration in brain of humans and experimental animals succumbing to hepatic encephalopathy (HE). Whether this change is a primary event in the pathogenesis of HE or whether it is secondary to injury of some other component(s) of the CNS has not been clarified. Studies in a rat model of HE have revealed early reactive changes in astrocytes characterized by cytoplasmic hypertrophy. During the later phases, degenerative changes ensue corresponding to the Alzheimer type II change observed by light microscopy. In view of the role of astrocytes in ammonia detoxification and the importance of ammonia in the pathogenesis of HE, we have suggested that the initial astrocytic changes are the morphological correlates of ammonia detoxification. We have speculated that the later degenerative alterations could lead to failure by astrocytes to carry out key functions (e.g., neurotransmitter uptake, ion regulation, and the like) and contribute the development of the encephalopathy. Recently, the potential involvement of astrocytes in HE has been further investigated, using primary astrocyte cultures. Exposure of cultures to ammonia at clinically relevant concentrations has shown morphologic changes closely resembling those observed in experimental HE in vivo. These deleterious effects can partly be prevented by raising cyclic AMP levels in cells. Other potential toxins (octanoic acid, phenol) have shown pathologic changes as well. Although some alterations were common to all three, they each possessed distinctive pathological effects. A synergistic interaction has also been demonstrated with these toxins. Functional studies of ammonia-treated astrocytes have shown the following: With low doses or short-term exposure, the uptakes of K+, glutamate, and GABA remained unchanged or slightly increased, whereas with higher doses or longer treatment, those activities diminished. A fall in ATP values occurred with prolonged ammonia treatment. Preliminary findings have shown no significant derangements in the beta-adrenergic receptor, except for a slight decrease in receptor affinity. However, cyclic AMP production was diminished following stimulation with isoproterenol. A slight rise in the number of benzodiazepine receptors was found. These studies indicate that profound changes occur in astrocytes following exposure to ammonia and other putative toxins. It is proposed that toxins and factors involved in the precipitation of HE do so by affecting astroglial properties. Derangements in such properties may lead to glial dysfunction (primary gliopathy), resulting in an encephalopathic state.
阿尔茨海默II型星形胶质细胞变化是人类和实验动物因肝性脑病（HE）而死亡时大脑中独特的形态学改变。这种变化是HE发病机制中的原发性事件，还是继发于中枢神经系统其他某些成分的损伤，目前尚不清楚。对HE大鼠模型的研究揭示了星形胶质细胞早期的反应性变化，其特征为细胞质肥大。在后期阶段，会出现与光镜下观察到的阿尔茨海默II型变化相对应的退行性变化。鉴于星形胶质细胞在氨解毒中的作用以及氨在HE发病机制中的重要性，我们认为最初的星形胶质细胞变化是氨解毒的形态学相关表现。我们推测后期的退行性改变可能导致星形胶质细胞无法执行关键功能（如神经递质摄取、离子调节等），并促使脑病的发展。最近，利用原代星形胶质细胞培养进一步研究了星形胶质细胞在HE中的潜在作用。将培养物暴露于临床相关浓度的氨中，已显示出形态学变化，与体内实验性HE中观察到的变化非常相似。通过提高细胞内的环磷酸腺苷（cAMP）水平，可部分预防这些有害影响。其他潜在毒素（辛酸、苯酚）也显示出病理变化。虽然这三种毒素都有一些共同的改变，但它们各自具有独特的病理作用。还证明了这些毒素之间存在协同相互作用。对氨处理的星形胶质细胞的功能研究表明：低剂量或短期暴露时钾离子、谷氨酸和γ-氨基丁酸的摄取保持不变或略有增加，而高剂量或长时间处理时，这些活性会降低。长时间氨处理会导致三磷酸腺苷（ATP）值下降。初步研究结果表明，除了受体亲和力略有下降外，β-肾上腺素能受体没有明显紊乱。然而，用异丙肾上腺素刺激后，环磷酸腺苷的产生减少。发现苯二氮䓬受体数量略有增加。这些研究表明，星形胶质细胞在暴露于氨和其他假定毒素后会发生深刻变化。有人提出，参与HE诱发的毒素和因素是通过影响星形胶质细胞的特性来起作用的。这些特性的紊乱可能导致胶质细胞功能障碍（原发性胶质病），从而导致脑病状态。
