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辐射可以通过引起造血干细胞(hematopoietic stem cell,HSC)内活性氧(reactive oxygen species,ROS)系统水平升高导致HSC损伤。HSC损伤患者出现难治性血液系统疾病,严重影响患者生存质量,甚至威胁患者生命。ROS可以通过多种机制引起组织、器官和细胞损伤。ROS的来源包括:线粒体、NOX(NADPH oxidases)、细胞色素P450酶、黄嘌呤氧化酶、非偶联NO合酶。已证实HSC内ROS来源于NOX。ROS升高后影响HSC在成骨细胞微环境定位,导致HSC与微环境相互作用减弱,从而影响HSC功能。此外,ROS升高后通过激活P38MAPK-P16Ink4途径,损伤HSC自我更新能力,并且使HSC定向分化产生更多的髓系克隆而不是红细胞系克隆;PI3K-Akt-mTOR途径可能也是ROS诱导HSC损伤途径。ROS对细胞周期影响为:促使HSC离开G0期进入细胞周期,导致干细胞池的耗尽。基于NOX在氧化还原信号传递过程中的重要作用,证实辐射通过NOX产生的ROS以及鉴定产生ROS的NOX亚型,这一工作会为临床靶向治疗辐射诱发的血液系统疾病提供重要的价值。
Radiation can cause HSC injury by raising the level of reactive oxygen species (ROS) system in hematopoietic stem cells (HSC). HSC injury patients with refractory hematological diseases, seriously affecting the quality of life of patients, and even threaten the lives of patients. ROS can cause tissue, organ and cell damage through a variety of mechanisms. Sources of ROS include mitochondria, NOX (NADPH oxidases), cytochrome P450 enzymes, xanthine oxidase, and unconjugated NO synthase. It has been demonstrated that ROS in HSC is derived from NOX. ROS increased HSC affect the localization of osteoblasts in the microenvironment, leading to the interaction of HSC with the microenvironment weakened, thus affecting HSC function. In addition, elevated ROS could impair HSC self-renewal by activating the P38MAPK-P16Ink4 pathway and direct HSCs to differentiate to produce more myeloid clones than erythroid clones. The PI3K-Akt-mTOR pathway may also be a ROS-induced pathway of HSC injury . The effect of ROS on the cell cycle is that the HSC is forced to leave the G0 phase and enter the cell cycle leading to depletion of the stem cell pool. Based on the important role of NOX in redox signaling, confirming the ROS emitted by NOX and identifying the NOX subtype that produces ROS, this work will provide important clinical value for targeted therapy of radiation-induced hematologic disorders.