Nrf2对血细胞促凝活性的调控在TiO2NP暴露致静脉血栓形成中的作用

纳米二氧化钛（TiO2NP）因其良好杀菌和光催化等功能广泛应用于食品包装、涂料、航空和医疗等领域，但其潜在健康风险尚缺少系统研究。血栓性疾病是全球死亡率占比最大的疾病，严重威胁人类生命和健康。血细胞作为TiO2NP进入机体内最主要靶细胞之一，其促凝活性变化与静脉血栓形成(VT)密切相关，但TiO2NP是否通过影响血细胞促凝活性引发VT及相关机制尚不清楚。本研究拟通过动物血栓模型和体外人血细胞的促凝活性和相关指标的检测，阐明TiO2NP对以红细胞为主，血小板和白细胞参与的相关凝血通路和对VT形成的影响；应用全身、髓红系细胞特异性Nrf2基因敲除小鼠模型，结合Nrf2调节剂，厘清以Nrf2为核心调控因子的适应性抗氧化反应在TiO2NP致VT中细胞特异性作用及相关分子机制，明确Nrf2信号通路作为防治关键分子靶点的病理生理学基础，为TiO2NP致VT的风险评估和科学防治提供实验依据。

Nano titanium dioxide (TiO2NP) is widely used in food packaging, coatings, aerospace and medical fields owing to its good bactericidal and photocatalytic properties, however, its potential health risks still lack systematic research. Thrombotic disease, as a contributor to the largest proportion of deaths worldwide, seriously threatens human life and health. Blood cells, as one of the most important target cells when TiO2NP enters the body, alterations of pro-coagulant activity of which are closely related to venous thrombosis (VT). However, whether and how TiO2NP triggers VT by affecting the procoagulant activity of blood cells are still unclear. In this study, we aims to elucidate the effects of TiO2NP mainly on red blood cells-associated coagulation pathways, with other blood cells as participants, eventually leading to VT. Here, thrombosis animal model is performed for observation of thrombosis in vivo, in addition, freshly isolated human blood cells are applied to evaluate pro-coagulant activity as well as other related indicators. To further investigate the underlying mechanism, global Nrf2 gene knockout mouse models and myeloid (mainly erythroid) cell-specific Nrf2 gene knockout mouse models are used, in the presence or absence of Nrf2 regulator. Upon these experiments, we aim to clarify the cell-specific roles and related molecular mechanisms of adaptive antioxidant responses with Nrf2 as the core regulatory factor in VT induced by TiO2NP. Of note, our study attempts to figure it out that the Nrf2 signaling pathway serves as a pathophysiological basis for key molecular targets for prevention and treatment, providing an experimental basis for the risk assessment and scientific prevention of VT caused by TiO2NP exposure.