氢气治疗脓毒症相关性脑病的新机制：Nrf2/HO-1调控神经元与星形胶质细胞间线粒体动力学平衡

Sepsis-associated encephalopathy (SAE) contributes significantly to the death and long-term prognosis of septic patients. However, there is still no effective treatment. My published results prove that 2% hydrogen gas can effectively improve the survival and organ function in septic mice, which is closely correlated with the activation of Nrf2/HO-1 pathway and the balance of mitochondrial dynamics. A recent report has shown that astrocytes can receive the damaged mitochondria released by neurons, and transfer normal mitochondria to neurons to repair the neurons. Therefore, we hypothesized that hydrogen gas could protect against SAE through Nrf2/HO-1 pathway-induced the balance of mitochondrial dynamics between astrocytes and neurons. Based on our previous researches, using Nrf2 knockout mice, we will firstly investigate the events of mitochondrial fusion/fission, mitophagy and biogenesis, as well as mitochondrial morphology and function in astrocytes and neurons of septic mice. Furthermore, we will investigate mitochondrial transfer between astrocytes and neurons, and the mechanisms how astrocytes repair the damaged mitochondria in neurons. Finally, we will prove that hydrogen gas can protect against SAE through Nrf2/HO-1 pathway activation-induced the balance of mitochondrial dynamics between astrocytes and neurons, which can lay a foundation for its clinical application in septic patients.

脓毒症相关性脑病（SAE）与脓毒症患者远期死亡和预后密切相关，目前无有效治疗方法。申请人已发表的结果证实2%氢气可显著改善脓毒症小鼠的存活率和器官功能，机制与激活Nrf2/HO-1通路和调控线粒体动力学平衡有关。新近报道，星形胶质细胞能吞噬神经元释放的受损线粒体，分泌并传递正常线粒体给神经元，促进神经元修复。因此，本课题假设：氢气通过Nrf2/HO-1通路调控神经元与星形胶质细胞间线粒体动力学平衡发挥对SAE的防治作用。本项目拟在前期研究基础上，利用Nrf2基因敲除型小鼠，采用形态、功能、分子生物学和神经电生理等方法，在动物和细胞水平通过检测神经元和星形胶质细胞的线粒体形态、功能、融合/分裂、自噬和生物合成等指标，观察细胞间线粒体传递情况，探讨星形胶质细胞修复神经元线粒体的机制，阐明Nrf2/HO-1通路在此过程中具体作用，明确氢气治疗SAE的重要机制，为氢气治疗脓毒症的临床应用奠定基础。

脓毒症相关性脑病（SAE）与脓毒症患者远期死亡和预后密切相关，目前无有效治疗方法。课题负责人已发表的结果证实2%氢气可显著改善脓毒症小鼠的存活率和器官功能，机制与激活Nrf2/HO-1通路和调控线粒体动力学平衡有关。研究报道，星形胶质细胞能吞噬神经元释放的受损线粒体，分泌并传递正常线粒体给神经元，促进神经元修复。因此，本课题假设：氢气通过Nrf2/HO-1通路调控神经元与星形胶质细胞间线粒体动力学平衡发挥对SAE的防治作用。通过研究我们发现：1)通过在体实验证实氢气对脓毒症相关性脑病(SAE)具有保护作用；2)证实神经元和星形胶质细胞之间存在线粒体传递，并且传递功能性线粒体，对线粒体动力学(线粒体融合/分裂、生物合成、自噬和细胞间传递)存在积极作用；3)明确氢气治疗促进脓毒症时神经元和星形胶质细胞之间线粒体动力学(线粒体融合/分裂、生物合成、自噬和细胞间传递)，阐明氢气通过调控神经元和星形胶质细胞之间线粒体动力学平衡发挥对SAE的治疗作用；4)明确Nrf2/HO-1通路促进脓毒症神经元和星形胶质细胞之间线粒体动力学(线粒体融合/分裂、生物合成、自噬和细胞间传递)；5)证明氢气通过激活Nrf2/HO-1通路促进脓毒症时神经元和星形胶质细胞之间线粒体的融合，减少分裂，促进其生物合成和自噬，促进在细胞间的传递；6)观察氢气对正常动物脑组织和细胞中Nrf2/HO-1通路和线粒体动力学(线粒体融合/分裂、生物合成、自噬和细胞间传递)的影响，证明氢气无明显副作用。7)证明氢气通过激活Nrf2/YY1通路调控脓毒症时神经元和星形胶质细胞之间线粒体动力学(线粒体融合/分裂、生物合成、自噬和细胞间传递)平衡。综上所述，氢气通过调控神经元与星形胶质细胞间线粒体传递和线粒体动力学平衡发挥对SAE的防护作用，其机制可能与氢气激活Nrf2/HO-1信号通路有关。上述研究结果为氢气治疗脓毒症提供理论依据，为氢气的临床应用奠定基础，为脓毒症的治疗提供新的分子靶点。氢气具有无毒、渗透性强、相对安全、无残留、价格便宜等诸多优点，具有很强的临床应用前景。