空气颗粒物暴露致肺部和骨关节炎性反应的作用机理

Most studies have focused on the direct health effects upon air particulate matter exposure, such as respiratory and cardiovascular diseases. However, little attention has been paid to other organs including bone joints, with little insight into the corresponding mechanisms. Our previous study recognized a correlation between the exposure of air pollution and the occurrence of bone joint inflammation in patients. Meanwhile, animal experiments also indicated that carbon materials can induce local (including lung and bone joints) and systematic inflammation. Together, previous studies suggested that inflammation in bone joints may be greatly attributed to air particulate matter exposure. However, many questions remain unanswered thus far. First, is there an association between air particulate matter exposure and bone joint diseases? Second, what’s the underlying mechanism responsible for bone joint diseases under air pollution? To be specific, is the damage to bone joints directly or indirectly linked to exposure of air pollution? In other words, what is the contribution of lung inflammation to joint diseases under air pollution? To address these questions, on one hand, we will conduct in-depth epidemiological study by enlarging our sample size to confirm the relationship between air particulate matter exposure and the occurrence of lung inflammation and bone joint diseases. On the other hand, black carbon particles and the complexes of black carbon with heavy metals or organic pollutants will be made. Thereafter, their tissue distribution and toxicological features related to inflammation in lung and bone joints will be thoroughly investigated. Furthermore, great efforts will be made to illustrate the underlying molecular mechanisms for lung and joint inflammation upon exposure to black carbon particles and black carbon complexes.

空气颗粒物暴露致呼吸和心血管等系统健康危害已有诸多研究，然而其诱发其它组织器官损伤(如远端骨关节）的研究却较少，对机制的探究几乎为零。我们初步的流行病学调查显示：颗粒物暴露与骨关节炎症发生之间存在一定的相关性；实验研究表明，碳纳米颗粒物暴露可诱发小鼠肺部、骨关节及系统性炎症反应。然而，目前仍有诸多亟待解决的科学问题：⑴空气颗粒物暴露与肺部炎症及骨关节疾病发生或恶化的相关性？⑵空气颗粒物继发或加剧骨关节炎性反应的作用途径：是直接还是间接效应（如通过呼吸系统炎性反应继发）？其主要信号通路是什么？针对这些问题，本项目一方面将扩大样本量开展流行病学调查，明确颗粒物与肺部炎症反应和骨关节疾病的相关性。另一方面，制备黑碳样品及其与重金属或有机污染物复合体，通过建立动物暴露模型阐明颗粒物的组织分布和诱发肺部与骨关节炎性反应的毒性特征，进一步通过细胞研究揭示其导致肺部和骨关节炎性反应的作用途径和分子机制。

目前，对由空气细颗粒物暴露引发的骨与关节损伤研究和报道很少。本项目通过人群流行病学研究，明确颗粒物的暴露与骨关节炎性疾病的关系，并通过动物和分子生物学实验揭示其诱发或加剧骨关节炎性疾病的相关机制。.流行病学数据显示：空气颗粒物暴露与骨关节炎性疾病的发生发展具有统计相关性。实验动物模拟人群暴露颗粒物的毒性效应，发现：颗粒物是通过间接途径诱发或加剧骨关节炎性反应。选择碳黑颗粒（CB）作为空气颗粒物模拟物，发现其与碳纳米管颗粒物有类似空气动力学特性，并均能直接活化炎性细胞、促进炎症因子表达，引起周身炎症反应级联放大，进一步间接引发滑膜细胞和软骨细胞活化，导致基质金属蛋白酶和环加氧酶等与关节软骨退变相关酶的活性增加，诱发滑膜炎症反应、滑膜增厚及软骨细胞损伤，导致骨关节疾病风险增加。相关成果发表于Nanoscale.8(42)。颗粒物通过激活肺部巨噬细胞刺激促炎作用，我们发现:CB的细胞毒性强弱与其含氧量高低成反向相关性，氧含量越低，CB在体内和体外的聚集度越高，诱发的肺损伤和炎症反应越强烈。本研究为阐明超细空气颗粒物导致肺损伤的理化学决定因素开辟了一条新的思路。相关成果发表于journal of hazardous materials. 2018 Jul 5。我们还发现：CB暴露存在影响成骨细胞分化的风险，表现为：低浓度CB能显著降低成骨分化相关基因的表达来抑制成骨细胞分化。我们证实：颗粒物暴露骨关节相关细胞后可产生大量的活性氧，ROS累积导致的氧化损伤是颗粒物导致细胞毒性的直接原因，并且不同含氧量的黑炭对细胞毒性具有显著的毒性差异（相关工作正在投稿中）。.骨关节炎性疾病患病率高，极大影响中老年人群的健康和生活质量。本项目以空气颗粒物-呼吸系统疾病-骨关节疾病三者之间关系的流行病学调查研究为切入点，通过碳纳米管和黑碳样品两种碳颗粒物体内外暴露实验，阐明空气颗粒物的毒性效应及其二次毒性效应，并进一步明确其与骨关节炎性疾病的相关性途径和分子机制。对于骨关节炎性疾病的发生机制和预防增添了新的认知。