高压氧诱导低氧耐受的分子机制

发布时间：2019-06-19 14:10

【摘要】：低氧是指机体生命活动所需的氧不能得到充足的供给,通常是由于吸入气氧分压过低、氧运输障碍或组织不能充分利用氧所引起。低氧可诱发机体各系统功能改变,威胁人体健康。它是多种疾病如心、肺疾病、中风及肿瘤的主要病理生理反应。另外,剧烈运动及高原居住的人群均面临着低氧的问题。经典的诱导低氧耐受方法为低氧预适应,不论是人还是动物,通过低氧预适应均可获得对低氧一定程度的耐受,但低氧预适应具体处理措施也存在不足。低氧预适应诱导低氧耐受的机制,一直是低氧研究领域的热点之一,尽管取得了许多进展,但具体机制尚未完全明了。低氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)在低氧预适应诱导低氧耐受的机制中发挥极其重要的作用。HIF-1蛋白是由a亚单位(HIF-1a)与β亚单位(HIF-1β)组成的二聚体,是氧平衡调控的管家调节因子。低氧环境下它可通过调节其下游基因的转录来促进机体血管及红细胞的生成、增强糖酵解及葡萄糖转运,使机体产生低氧耐受。HIF-1与DNA结合首先要求HIF-1a与HIF-1β形成二聚体,HIF-1a蛋白水平是HIF-1 DNA结合活性的主要决定因素。HIF-1a蛋白水平主要受氧分压调节,同时也受过渡金属、一氧化氮(nitric oxide,NO)、活性氧(reactive oxygenspecies,ROS)、细胞因子及机械应力等因素影响。表面上看,高压氧(hyperbaric oxygen,HBO)和低氧对机体的影响截然相反,前者可提高体内氧和二氧化碳含量,后者则会降低体内氧和二氧化碳含量。实际上,HBO和低氧对机体的影响有许多相似之处。比如,两者都可抑制能量代谢,降低脑内ATP含量,增加体内自由基(free radical,FR)和H~+含量,并对机体产生损害,甚至导致个体死亡。HBO和低氧适应性暴露都可增强机体抗氧化损伤的能力,预防动物慢性氧中毒,减轻中枢神经系统(central nervous system,CNS)缺血性损伤,提高CNS对HBO的敏感性。这些现象提示,HBO适应性暴露可能具有提高机体耐受低氧损伤的能力,可能是一种低氧预适应的替代方案。根据上述现象,我们推测HBO暴露可能具有诱导机体低氧耐受的效应。作为一种治疗手段,HBO已广泛应用于临床上缺血性疾病、休克、一氧化碳中毒、气栓症及减压病等疾病的治疗。由于HBO治疗方法比低氧预适应时间短、安全性高,如果这一方法确实有效,必将为临床医学、高原医学、运动医学及军事医学中低氧问题提供一个新的解决途径。
[Abstract]:Hypoxia refers to the fact that the oxygen needed for life activities of the body can not be adequately supplied, which is usually caused by the low partial pressure of oxygen in inhaled gas, the obstacle of oxygen transport or the inability of tissues to make full use of oxygen. Hypoxia can induce changes in the functions of various systems and threaten human health. It is the main pathophysiological reaction of many diseases such as heart, lung disease, stroke and tumor. In addition, strenuous exercise and people living at high altitude are facing the problem of hypoxia. The classical method of inducing hypoxia tolerance is hypoxia pretreatment, which can be used to obtain a certain degree of tolerance to hypoxia in both human and animals, but there are also some shortcomings in the specific treatment measures of hypoxia tolerance. The mechanism of hypoxia tolerance induced by hypoxia pretreatment has always been one of the hotspots in the field of hypoxia research. although a lot of progress has been made, the specific mechanism has not been fully understood. Hypoxia inducible factor-1 (hypoxia-inducible factor-1,HIF-1) plays an important role in the mechanism of hypoxia tolerance induced by hypoxia pretreatment. HIF-1 protein is a dimer composed of a subunit (HIF-1a) and 尾 subunit (HIF-1 尾), which is a housekeeper regulator of oxygen balance regulation. In hypoxia environment, it can promote the production of blood vessels and red blood cells by regulating the transcription of its downstream genes, enhance glycolysis and glucose transport, and make the body produce hypoxia tolerance. The binding of HIF-1a-1 to DNA first requires the formation of dimer between HIF-1 and HIF-1 尾, and HIF-1a protein level is the main determinant of HIF-1 DNA binding activity. HIF-1a protein level is mainly regulated by oxygen partial pressure, but also by transition metal. Nitric oxide (nitric oxide,NO), reactive oxygen species (reactive oxygenspecies,ROS), cytokines and mechanical stress. On the surface, hyperbaric oxygen (hyperbaric oxygen,HBO) and hypoxia have the opposite effect on the body. The former can increase the content of oxygen and carbon dioxide in the body, while the latter can reduce the content of oxygen and carbon dioxide in the body. In fact, there are many similarities between the effects of HBO and hypoxia on the body. For example, both of them can inhibit energy metabolism, decrease the content of ATP in the brain, increase the content of free radicals (free radical,FR) and H ~, and cause damage to the body, and even lead to individual death. Free radical,FR and hypoxia adaptive exposure can enhance the ability of antioxidant damage, prevent chronic oxygen poisoning in animals, reduce (central nervous system,CNS ischemic damage in central nervous system, and increase the sensitivity of CNS to HBO. These phenomena suggest that HBO adaptive exposure may improve the ability of the body to withstand hypoxia injury, and may be an alternative to hypoxia pretreatment. According to the above phenomena, we speculate that HBO exposure may have the effect of inducing hypoxia tolerance. As a treatment, HBO has been widely used in the treatment of ischemic diseases, shock, carbon monoxide poisoning, air embolism and decompression sickness. Because the treatment time of HBO is shorter and the safety is higher than that of hypoxia, if this method is really effective, it will provide a new way to solve the problem of hypoxia in clinical medicine, altitude medicine, sports medicine and military medicine.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2005
【分类号】：R363

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