基于Warburg效应和炎症微环境探索砷在多器官损伤中作用及其机制

Coal-burning type arsenism is a particular complex systemic injurious disease in our country. It characterize by multiple organ damage with high risk of cancer. Because of current studies are focus on the mechanism of a certain organ damage caused by arsenic, there is no theory to fully explain the toxic mechanism of multiple organ damage and no effective prevention strategy to multiple organ and even systemic damage caused by arsenic. It has been reported that Warburg effect and inflammatory microenvironment are the basis and crucial inducer to chronic inflammation, fibrosis and malignant transformation of organs. Therefore, this project is based on the long-term research of arsenism pathogenesis and intervention of our research group, taking Warburg effect and inflammatory microenvironment as the cutting point combined with concerning the characteristic of multiple organ damage caused by arsenic, to further study the function and mechanism of PKM2 pathway on Warburg effect, HMGB1 release and inflammatory microenvironment formation on the basis of our new findings and new progress at home and abroad on population, animal and cellular experiments. The aim of this study is to illuminate the specific molecular mechanism of Warburg effect and inflammatory microenvironment on arsenic-induced multiple organ damage, and to looking for early sensitive and specific biomarkers and intervention targets, providing scientific evidence for optimizing prevention strategy that aim at arsenic-induced vital organ and even systemic damage. The results of this study can provide reference and comparison to other types of arsenic poisoning.

燃煤型砷中毒是我国独有的、以多脏器损害乃至癌症高发的全身性损害疾病，目前研究多集中在砷致某单一器官损害机制方面，至今尚无一种机制可完整解释其多器官损害的毒性机制，亦无针对多器官乃至全身性损害的有效防治策略。基于Warburg效应和炎症微环境可能是各器官慢性炎症、纤维化甚至癌变的基础和促发关键，本项目在长期从事砷致病机制及其干预研究基础上，以Warburg效应和炎症微环境为切入点，通盘考虑砷致多器官乃至全身性损害特点，结合近期研究新发现及国内外新进展，从人群、动物、细胞三个层面深入研究PKM2通路在Warburg效应、HMGB1释放以及炎症微环境形成中作用及机制，揭示Warburg效应和炎症微环境在砷致多器官损害中的具体分子过程，寻找早期敏感特异生物标志及干预靶点，为针对性优化地砷病重要靶器官乃至全身性损害的防治策略提供科学依据。结果尚可为其他类型砷中毒提供借鉴与比较。

燃煤型砷中毒是我国独有且以多脏器损害乃至癌症高发的全身性损害疾病，目前研究多集中在砷致某单一器官损害方面，多器官损害的毒性机制及其针对性防治措施欠缺。本项目在动态追踪地砷病病区人群疾病流行特征基础上，以Warburg效应和炎症微环境为切入点，从人群-动物-细胞三个层面，探讨了砷致肺、肝、肾、胰岛、心血管系统乃至全身性代谢改变作用及其机制。经四年项目实施，获得下列研究成果：.（1）追踪调研了燃煤型砷中毒多器官损伤的疾病分布现况。发现该地区居民近3年就诊前五位疾病类型顺次为呼吸、循环、消化、肌肉骨骼和泌尿系统疾病，尤其是地砷病病区居民的呼吸和循环系统疾病门诊构成比明显高于非病区；探讨了地砷病病区居民肺、肝、肾损伤现况以及高血压与心血管疾病、糖尿病同源性疾病互为因果、相互影响的特点；提出肺部疾患、高血压与心血管疾病和糖尿病以及继续关注肝肾损害慢性病应成为当地今后防治工作重点。.（2）通过非靶向代谢组学和机器学习算法，识别与砷中毒相关的生物标志物并建立风险评估预测模型。揭示了甘氨酸、丝氨酸和苏氨酸代谢3个代谢途径的改变与砷中毒密切相关；基于L-carnosine的单一生物标志物建立的模型可准确识别砷中毒患者与健康人群。.（3）明确了Warburg效应和炎症反应参与了砷致多器官损伤的发生发展；发现燃煤砷暴露可造成机体持续性难可逆代谢和免疫功能损伤：NLRP3炎性小体活化以及炎症微环境形成是多器官慢性炎症、纤维化乃至癌变的基础和促发关键。.（4）揭示了代谢重编程和炎症微环境在砷致多器官损害中的具体分子过程及防治的关键毒作用分子靶点；控制NLRP3炎性小体活化以及炎症微环境形成以及靶向干预HIF-1α有望在分子水平上为其防治提供新方向。.（5）综合分析人群、动物和细胞研究结果，侧重从代谢重编程和炎症微环境角度阐释了砷致多器官损伤的主要效应及其机制，其系列研究成果对进一步明确砷致多器官损伤的早期生物学标志和治疗靶点以及新形势下针对性优化防治措施提供了科学依据。