Chan Julie Y H, Chang Alice Y W, Chan Samuel H H
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81346, Taiwan, ROC.
Prog Neurobiol. 2005 Dec;77(6):396-425. doi: 10.1016/j.pneurobio.2005.11.004. Epub 2005 Dec 22.
As much as brain stem death is currently the clinical definition of death in many countries and is a phenomenon of paramount medical importance, there is a dearth of information on its mechanistic underpinnings. A majority of the clinical studies are concerned only with methods to determine brain stem death. Whereas a vast amount of information is available on the cellular and molecular mechanisms of cell death, rarely are these studies directed specifically towards the understanding of brain stem death. This review presents a framework for translational research on brain stem death that is based on systematically coordinated clinical and laboratory efforts that center on this phenomenon. It begins with the identification of a novel clinical marker from patients that is related specifically to brain stem death. After realizing that this "life-and-death" signal is related to the functional integrity of the brain stem, its origin is traced to the rostral ventrolateral medulla (RVLM). Subsequent laboratory studies on this neural substrate in animal models of brain stem death provide credence to the notion that both "pro-life" and "pro-death" programs are at work during the progression towards death. Those programs (mitochondrial functions, nitric oxide, peroxynitrite, superoxide anion, coenzyme Q10, heat shock proteins and ubiquitin-proteasome system) hitherto identified from the RVLM are presented, along with their cellular and molecular mechanisms. It is proposed that outcome of the interplay between the "pro-life" and "pro-death" programs (dying) in this neural substrate determines the final fate of the individual (being dead). Thus, identification of additional programs in the RVLM and delineation of their regulatory mechanisms should shed new lights on future directions for clinical management of life-and-death.
尽管脑干死亡目前是许多国家临床意义上的死亡定义，且是极为重要的医学现象，但关于其机制基础的信息却十分匮乏。大多数临床研究仅关注确定脑干死亡的方法。虽然关于细胞死亡的细胞和分子机制已有大量信息，但这些研究很少专门针对理解脑干死亡。本综述提出了一个关于脑干死亡转化研究的框架，该框架基于围绕这一现象系统协调的临床和实验室工作。它始于从患者中识别出一种与脑干死亡特别相关的新型临床标志物。在认识到这种“生死”信号与脑干的功能完整性相关后，将其起源追溯到延髓头端腹外侧区（RVLM）。随后在脑干死亡动物模型中对该神经基质进行的实验室研究证实了这样一种观点，即在死亡进程中“促生存”和“促死亡”程序都在起作用。本文介绍了迄今从RVLM中确定的那些程序（线粒体功能、一氧化氮、过氧亚硝酸盐、超氧阴离子、辅酶Q10、热休克蛋白和泛素 - 蛋白酶体系统）及其细胞和分子机制。有人提出，在这个神经基质中“促生存”和“促死亡”程序之间相互作用的结果（濒死）决定了个体的最终命运（死亡）。因此，识别RVLM中的其他程序并阐明其调节机制，应为生死临床管理的未来方向提供新的思路。
