中文摘要
热射病发病率逐年升高,死亡率60%以上。过度激活炎症反应是其重要的发病机制,调节性T细胞(Tregs)在炎症性疾病中发挥了重要作用,白介素2(IL-2)可通过抑制Tregs凋亡治疗炎症性疾病。但Tregs参与热射病及IL-2在治疗热射病中的作用及机制无人研究。前期工作发现IL-2下降、脾脏Tregs凋亡增加、数量减少。本项目建立热射病小鼠模型,将肝肾功、病理、死亡率及炎症反应作为评价疾病严重程度的参数。分别研究过继性转移Tregs或条件性敲除Tregs对疾病严重程度的影响,明确Tregs在热射病中的作用。采用多色荧光标记的流式细胞技术、免疫荧光技术等阐明IL-2通过何种机制减轻热射病,并优化IL-2的治疗方案。从而提出并验证IL-2通过抑制Fas介导的Tregs凋亡减轻热射病的科学假说。本项目的完成不仅使热射病发病机制研究获得新的突破,而且为临床应用IL-2治疗热射病奠定了坚实的理论基础。
英文摘要
Heatstroke morbidity is growing higher and mortality is more than 60%. Overwhelming systemic inflammatory response is one of the important pathogenesis. Regulatory T cells (Tregs) was proved to play an important role in inflammatory related diseases. Interleukin-2 could attenuate inflammatory related diseases via inhibiting Tregs apoptosis.However, whether Tregs is involved in heatstroke and IL-2 could protect against heatstorke and its potential mechanism were unknown. Our group has found decrease of serum IL-2 and splenic Tregs and increase of Treg apoptosis. In this research,we firstly established heatsroke mouse model and define illness severity as hepatic and renal function,pathology,mortality and inflammatory response; secondly, we verified whether Tregs were invovled in heatstroke via detection of illness severity in the situation of adoptive transfer or conventional depletion of Tregs; thirdly, we clarified the the attenuation of IL-2 in heatstroke and its potential mechanism by the way of multiple color flow cytometry, single photon fluorescence imaging,and etc.; at last, we optimized theraputic protocal of IL-2. With all the problems solved,our research could for the first time reveal that Tregs was involved in heatstroke and IL-2 could attenuate heatstroke via inhibiting Fas-mediated Treg apoptosis,which might provide new clue to research on mechanisms of heatstroke and IL-2 therapy in heatstroke and highlight its application in clinical practice.
