腺苷与一氧化氮相互作用在高压氧致中枢神经系统氧中毒中的意义研究

Hyperbaric oxygen (HBO) has been widely used in diving operations, submarine escape and illness therapies. But prolonged inhalation can result in convulsion, which is a severe threat to the life safty of exposed people, and also limit the increase of diving operation efficiency. By now its pathogenesis remains unclear, and the preventative measures are passive. Studies indicated both adenosine and nitric oxide (NO), two inherent metabolites in the body and all closely realting oxygen metabolism, having great influences to oxygen convulsion, but being opposite. As both adenosine and NO having high activities, there exist great interactions between them in various physiological and pathological processes. However, effects of these interactions on oxygen convulsion occurrence have not been reported. In this project, some advanced technologies, such as simultaneously monitoring electroencephalogram (EEG) and cerebral blood flow (CBF) under hyperbaric condition, microdialysis, gene knockout will be employed to probe the interactions in generating, releasing and functioning between adenosine and NO, as well as the significance of such interactions in oxygen convulsion. Different from previous studies, which focused on the effects of single substance, this project will more synthetically elucidate the mechanism of HBO-induced convulsion from a new point of view that the interactions between two molecules which are all with great influences to the occurrence of oxygen convulsion. The studies are important for finding new targets and preventive measures to HBO-induced convulsion, further to the safety and efficiency of diving operations, and to promoting the therapeutic effects of HBO.

高压氧在潜水作业、潜艇脱险和疾病治疗中有广泛用途，但持续吸入可引发惊厥，严重威胁吸氧人员的安全，制约了潜水作业的效率。目前尚不完全清楚其发病机制，只能采取被动预防措施。研究显示两种体内固有、且与氧代谢密切相关的物质-腺苷和NO对氧惊厥发作都有显著影响，但作用相反。由于都具有高活性，二者在多种生理、病理过程中存在相互作用，但对氧惊厥发作的影响未见报道。本研究采用高压下脑电与脑血流量联合监测，微透析取样，动物基因敲除等方法，在整体动物，离体组织和细胞等水平，探讨高压氧暴露时脑组织中腺苷和NO在产生、释放和功能发挥等方面存在的相互作用，及其在氧惊厥发生中的意义。与以往研究多局限于单一成分的作用不同，本研究从与氧惊厥有密切联系的两种分子间的相互作用对疾病的影响这一新角度全面综合地探讨该病的发病机制，对于寻找新的干预靶点，发展新的预防措施，提高潜水作业的安全性和效率，提升高压氧的疗效等都有重要意义。

高压氧在水下、高气压作业和疾病治疗中有着广泛的用途。但机体吸入氧分压过高的气体超过一定时间后，会出现毒性反应，即氧中毒。当氧分压大于3 ATA时，氧中毒以中枢神经系统功能紊乱为主要表现，称为中枢神经系统氧中毒。它严重威胁着受暴露人员的安全，制约了潜水作业的效率。目前有关其发病的确切机制还不完全清楚，所能采取的防治措施也非常有限，在很大程度上限制了高压氧的应用和作业效率的提升。.脑组织中腺苷与一氧化氮（NO）的代谢均与氧含量的变化密切相关。研究表明，它们在中枢神经系统氧中毒发作中具有相反的作用，腺苷可抑制发作，NO则可促进。它们的作用途径并不相同。本项目中，我们同时应用腺苷效应放大和NO抑制两种措施，探讨多途径同时干预对中枢神经系统氧中毒的防治作用。.综合项目的研究结果，我们在国内外首次发现并报道了：① 在中枢神经系统氧中毒发生过程中，腺苷和NO两个对发作具有完全相反作用的物质之间，具有强烈的相互作用。增强腺苷的作用可以显著抑制NO及其代谢产物过氧亚硝酸盐的产生；增加NO或其代谢产物过氧亚硝酸盐的含量，则可以显著影响与腺苷代谢密切相关的酶的活性，进而影响腺苷的含量及其对中枢的抑制作用。两者间的相互作用对中枢神经系统氧中毒的最终发作具有重要影响。 ② 基于两者之间的相互作用，通过联合应用腺苷效应放大和NO抑制两种措施，可以收到非常好的预防中枢神经系统氧中毒的效果，防护作用远优于其中任何一种组成措施。此外，联合应用可以显著减小单种措施的干预强度（用药剂量），这样可以有效减小单种措施因用药剂量过高而产生的副作用，从而提高了联合预防的安全性。.本项目的研究成果为中枢神经系统氧中毒的发病机制和预防措施研究开辟了新的方向，也为寻找预防药物奠定了基础。