甲烷通过选择性抗氧化治疗脑缺血再灌注损伤

Ischemia-reperfusion triggers a complex series of biochemical and molecular mechanisms that damage the neurologic functions through numerous ways such as accumulation of reactive oxygen species, calcium overload, strengthen of inflammation, increase of endothelial cell damage or apoptosis.Reactive oxygen species is an vital and crucial initiating factor leading to inactivation of biological macromolecules, or death of tissue cells undergo apoptosis during the development of ischemia-reperfusion injury. Methane is a simple organic gas molecule, Interestingly, recent studies demonstrate a protective effect on intestinal ischemia-reperfusion injury. With intestine ischemia-reperfusion injury model, some foreign researchers found that ischemic intestinal tissue can release methane, and methane inhalation could decrease oxidative stress, improve the canine intestinal ischemia-reperfusion injury. We speculate that cerebral ischemia-reperfusion injury may also promote the release of methane, and methane in cerebral ischemia-reperfusion injury also may have protective role. To test this hypothesis, we will use cellular and whole animal experiments, by detecting the level of reactive oxygen species, oxidative stress, and the degree of tissue and cell damage, apoptosis and inflammation factors detection, to prove 1) cerebral ischemia-reperfusion injury to brain tissue can promote the release of methane, 2) exogenous methane has a therapeutic effect on cerebral ischemia-reperfusion injury, 3) initially undetstand anti-oxidation effect of methane, part of the molecular mechanism of anti-neuronal apoptosis and anti-inflammatory effect. This project will lay the technical and theoretical foundation for the research and application of methane in clinical disease.

缺血性脑血管病的典型病理过程脑缺血再灌注损伤发生机制较复杂，活性氧增多、炎症反应、钙超载、细胞凋亡等都是重要参与因素，其中活性氧增多可导致生物大分子失活、细胞凋亡甚至死亡，是缺血再灌注损伤的关键途径。甲烷是结构最简单的有机气体分子，国外学者采用犬肠缺血再灌注损伤模型，证明缺血可促进小肠组织释放甲烷，少量甲烷能降低肠缺血再灌注后氧化应激，改善炎症损伤，保护肠功能。我们预实验发现甲烷对脑缺血再灌注损伤有显著治疗作用。我们推测脑缺血再灌注损伤可促进神经组织释放甲烷，甲烷可通过选择性抗氧化作用保护脑缺血再灌注损伤。本项目采用化学溶液、细胞和整体动物等实验，通过检测活性氧和氧化应激水平、细胞调亡和炎症分子水平，确定脑缺血再灌注损伤促进脑组织释放甲烷，分析甲烷产生的细胞类型和代谢途径，探讨外源性甲烷通过选择性抗氧化、抑制细胞凋亡和减少炎症反应等治疗缺血再灌注损伤的机制，奠定甲烷生物学效应研究基础。

本课题主要研究外源性甲烷在缺血再灌注模型中的保护作用以及发挥作用的机制。本课题组具有长期研究气体的生物学效应，针对甲烷的生物学研究，课题组探索了一套甲烷生理盐水制备和探测的方法。结合前期研究我们通过组织学验证了甲烷对于脏器的缺血再灌注损伤具有显著的保护作用。甲烷的保护作用不仅在脑缺血再灌注的模型中得到验证，同时在肝缺血和心肌缺血模型中同样得到了很好的效果。在进一步的研究当中，我们发挥甲烷具有显著的抗炎、抗氧化和抗凋亡的效果，在脏器缺血再灌注模型当中也得到了很好的证明。本研究的发现为甲烷应用于临床，作为一个潜在手段治疗和预防缺血再灌注损伤具有重要意义。