Gelsolin减轻辐射继发病理损伤作用和机制研究

The patients with severe bone marrow form of acute radiation sickness still died of multiple organ failure after successive treatment of hematopoietic reconstruction. No methods control for its occurrence righ now. Inflammation,infection and circulatory obstruction are important factor-induced MOF. Ionizing radiation induced release of the actin protein by cell death and damage can lead to secondary pathological effects like circulatory disorders,cytotoxity and inflammation which are associated with multiple organ failure. Recently gelsolin was found that could promote blood circulation by removing stasis caused by circulation actin and could also function as multi functions including antioxidant,antiinfectious and limiting inflammation spread.But less researches were done about functions and behaviours plaied by gelsolin in prevention and control of radiation induced secondary pathylogical damage.Based on early discoveries of anti-oxidation damage of radiation and promoting damaged animal survival in this project the relationship between radiation induced injuries and fluctuation value of gelsolin and actin in irradiated cell and animal will be systematically observed; radiation sensitivity in the levels of cells and mice with different gelsolin expression will be well compared; by observing of the indexes including tissue and cell damage,microcirculatory disorders,infection and inflammation associated with changes of gelsolin quantity during different pathological stages of acute radiation sickness animal model when damage animal was supplied with gelsolin after exposure; the linkage and pathyway of gelsolin action will be determined; the role and mechanism of gelsolin in anti secondary radiation pathological damage will be deeply studied. Results will be great significance to understand impact factors of radiation injury and look for new control methods for radiation induced MOF.

重度以上骨髓型急性放射病治疗，造血重建后患者仍死于继发多器官功能衰竭（MOF），目前尚无很好防治方法。炎症、感染和循环障碍是多器官功能衰竭发生的重要病因。辐射致组织细胞死亡和损伤释放的actin可致循环障碍、炎症和细胞毒等与MOF发生相关的病理效应。gelsolin具有清除actin疏通微循环，抗感染及限制炎症传播等多种功能，但能否在防治MOF中发挥作用尚缺乏系统研究。本课题在前期gelsolin辐射防护作用研究的基础上，进一步在细胞和整体动物水平明确循环gelsolina和actin消长与辐射损伤的关系；比较gelsolin表达量不同细胞和动物的辐射敏感性；观察补充外源性gelsolin对受照动物微循环、炎症和感染方面的影响，确定主要影响环节和途径，研究其在减轻辐射继发病理损伤中的主要作用机理。结果对于深入了解放射损伤病理发展规律，寻找防治辐射继发多器官功能衰竭的新方法有理论和实践意义。

多器官功能衰竭 （MOF）是重度以上骨髓型急性放射病患者的严重继发效应，目前尚无很好防治方法。炎症、感染、循环障碍以及组织细胞死亡是MOF发生的重要病因。鉴于辐射致组织细胞死亡和损伤释放的Actin可致循环障碍、炎症和细胞毒等病理效应，Gelsolin具有清除Actin疏通微循环、抗感染及限制炎症传播等多种功能和效应，本课题围绕Gelsolin能否减轻辐射继发病理损伤作用及其机制在以下方面展开研究 1.Gelsolin、Actin在基因和蛋白水平的变化与放射损伤严重程度和损伤进展的关系。2.观察不同Gelsolin表达量细胞和动物的辐射敏感性。3.Gelsolin 在急性放射损伤中作用、作用环节和作用机制。. 研究发现，小鼠受大剂量照射后血浆Gelsolin和Actin量的改变程度与辐射剂量、病理损伤进展不同阶段和时间有关，二者之间存在明显消长关系；外源性Gelsolin可以显著提高受照小鼠生存率，延长其平均存活时间，提高受照小鼠外周血白细胞和骨髓细胞计数；通过构建KD小鼠和KO小鼠发现Gelsolin KD和Gelsolin KO小鼠较野生型小鼠辐射敏感性增加，同等剂量照射下KD与KO小鼠损伤更加严重。机制研究发现Gelsolin既可以通过清除循环血中过量actin造成的循环堵塞,也可以通过调节体内抗凝系统改善微循环和抗出血; 既可通过抗氧化发挥保护作用,也可以通过LPS-TLR4信号通路抑制LPS诱导的炎症因子IL-6，TNF-α和NO水平发挥保护作用; 既可以通过降低DC刺激T细胞增殖的能力进而抑制LPS诱导的炎性细胞因子, 还可以通过诱导MDSCs上调经由其他免疫调节发挥减轻感染和炎性的作用。此外，本课题还尝试进行了部分Gelsolin与细胞凋亡、与小鼠造血干细胞分化发育等相关实验研究。研究表明，Gelsolin能在减轻辐射继发病理损伤中发挥重要功能和作用，十分具有预防和治疗继发辐射损伤效应的应用潜能。上述研究对于深入了解放射损伤病理的发生发展规律，寻找防治辐射继发多器官功能衰竭的新手段和新方法有理论和实践意义。本项目基本按照原计划（No. 81372932）进行，执行情况良好。研究结果已发表SCI论文2篇，SCI收录杂志接收和修回文章各1篇，成文待投稿1篇，正在撰写中的1篇。参加国内会议6次。培养和协助培养硕博研究生5名。