Hypoxia and Oxidative Stress in the Causation of Diabetic Retinopathy
Hypoxia and Oxidative Stress in the Causation of Diabetic Retinopathy
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DOI：
10.2174/157339911797415620
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发表时间：
2011-01-01
影响因子：
3.3
通讯作者：
Sivaprasad, Sobha
中科院分区：
文献类型：
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作者：
Arden, Geoffrey B.;Sivaprasad, Sobha
糖尿病视网膜病变与高血糖症相关，并且有令人信服的证据表明，在患者中间接测量的氧化应激（活性氧（ROS）的过度产生）与糖尿病并发症的严重程度有关。此外，通过各种手段减少这种压力，包括药物和降低高血糖症，降低糖尿病视网膜病变（DR）的发展速度。因此，推测氧化应激导致DR，以及糖尿病动物（和人类制剂）视网膜中ROS引起的损伤。但是在DR的小动物模型中首先受到影响的细胞在整个视网膜内层被发现，并且直到后来在视网膜病变的发展中才与小血管特异性相关。我们提出问题A：为什么在人类疾病中，视网膜小血管受到如此选择性的影响B：什么过程会诱导视网膜的氧化损伤。在解释实验结果方面存在困难，因为在临床或动物实验中没有将损伤程度与ROS水平联系起来的度量，并且用于证明组织实验中氧化损伤的不同方法的相对灵敏度是不可量化的。同样重要的是要注意，除了氧化应激外，高血糖症还诱导几种变化，包括白细胞停滞、血管收缩和促炎状态，这也会导致视网膜缺氧。最早的视网膜病理学和最早的生物化学变化似乎在动物变成糖尿病并由高血糖引起的时间的1周内开始。这些变化包括小胶质细胞外观的改变、晚期糖基化终产物（AGEs）的形成、血管内皮生长因子（VEGF）及其mRNA的过量产生以及随后的毛细血管内皮细胞渗漏。这些早期促炎性变化可直接引起视网膜缺氧，而不一定通过ROS。对分离细胞的实验表明，视网膜毛细血管比其他视网膜细胞更不易受高血糖症的影响，但在体内可能通过旁分泌变化而选择性受损。这提出了一个新的概念：尽管血管中的变化可能是氧化应激的逐渐和累积发展的结果，但是导致氧化应激发展的先前旁分泌和其它变化对于DR的理解和治疗是非常重要的。临床重要性在于，大约在氧化应激变得容易证实的时候，DR的进展已经是不可逆的。DR的许多治疗方法取决于视网膜缺氧的缓解。如果氧化应激被认为是DR的“决定因素”，那么仅用氧化应激来解释这些发现就需要额外的假设。
Diabetic retinopathy is associated with hyperglycemia, and there is convincing evidence that oxidative stress (the overproduction of reactive oxygen species (ROS)) measured indirectly in patients, is related to the severity of diabetic complications. Also, reducing such stress by various means, including drugs and reducing hyperglycemia, decreases the rate of development of diabetic retinopathy (DR). It is therefore supposed that oxidative stress causes DR, and the injuries caused by ROS in retinas of diabetic animals (and in human preparations). But the cells first affected in small animal models of DR are found throughout the inner retina, and not specifically associated with small blood vessels until later in the development of retinopathy. We raise the questions A: why in human disease the small retinal blood vessels are so selectively affected B: what are the processes that induce oxidative damage in the retina. There are difficulties in interpretation of experimental results, because there is no metric which relates the degree of damage to the level of ROS, either in clinical or animal experiments and the relative sensitivity of the different methods employed to demonstrate oxidative damage in experiments on tissues is unquantified. It is also important to note that in addition to oxidative stress, hyperglycemia induces several changes including leucostasis, vasoconstriction and a pro-inflammatory state that also causes hypoxia in the retina. The earliest retinal pathology and the earliest biochemical changes appear to begin within 1 week of the time when the animals become diabetic and are provoked by hyperglycemia. These changes include alterations to the appearance of microglia, the formation of Advanced Glycation Endproducts (AGEs), the overproduction of Vascular Endothelial Growth Factor (VEGF) and its mRNA and consequent leakage of capillary endothelial cells. These early pro-inflammatory changes can directly cause hypoxia in the retina and not necessarily via ROS. Experiments on isolated cells indicate that retinal capillaries are less susceptible to hyperglycemia than other retinal cells, but in vivo are selectively damaged, possibly via paracrine changes. This suggests a new concept: although the changes in blood vessels may be a consequence of gradual and cumulative development of oxidative stress, the preceding paracrine and other changes that cause the development of oxidative stress are highly significant to the understanding and treatment of DR. The clinical importance is that about the time that oxidative stress becomes easily demonstrable, the progress of DR is already irreversible. A number of methods of treatment of DR depend upon the relief of retinal hypoxia. If oxidative stress is considered 'the' determinant of DR, explanation of such findings solely in terms of oxidative stress would require additional hypotheses.