There is growing public awareness regarding the health effects of indoor nanoscale particulate matter (INPM) since people spend the majority of their time indoors. INPM could have a direct entry route into the brain via the axons of the olfactory nerve and migrating across the blood-brain barrier (BBB). Using animals to explore this possibility is not a reliable method to fully demonstrate human physiological responses. We, therefore, set out to develop a human 3D functional blood-brain barrier model to examine the potential effects of INPM on the cerebral nervous system. Human astrocytes were co-cultured and human umbilical vein endothelial cells in 3D within a microfluidic chip to simulate the micro-complex physiological structure of the human BBB. This 3D human organotypic model has then been made to investigate any INPM-induced BBB dysfunction linked to potential cellular responses. A 3D human functional blood-brain barrier was constructed in this study. We observed the translocation of INPM across the blood-brain barrier. The 3D human organotypic chip initially reflected damage to the nervous system with abnormal astrocyte proliferation and a decline in cell viability. We also looked at the behavior of oxidative stress-related biomarkers (ROS, GSH-Px, and MDA). INPM was implicated in aggravating inflammation via reactive oxygen species (ROS). The Keap1-Nrf2-ARE pathway is a key mechanism in cellular resistance to oxidative stress by mediating and activating a variety of antioxidant and detoxification enzymes. Following ROS accumulation, INPM induced abnormal expression of nuclear transcription factor Nrf2. This behavior disturbed the expression of, γ-glutamate synthase (γ-GCS) and heme oxygenase (HO-1), which further exacerbated the imbalance of the antioxidant system. This functional 3D human organotypic chip effectively mimics the physiological response of the human BBB. The chip provides a micro-complex structure to simulate the internal environment of the human blood-brain barrier, and partially simulates the physiological responses of the BBB to INPM exposure. Based on this model, INPM was shown to affect the blood-brain barrier biofunction by disrupting the Keap1-Nrf2-ARE pathways.

中文翻译：

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基于3D人体血脑屏障芯片的室内空气纳米粒子神经毒性研究

由于人们大部分时间都在室内度过，公众越来越意识到室内纳米级颗粒物 (INPM) 对健康的影响。 INPM 可以通过嗅神经轴突直接进入大脑并穿过血脑屏障 (BBB)。用动物来探索这种可能性并不是充分展示人类生理反应的可靠方法。因此，我们着手开发人体 3D 功能性血脑屏障模型，以检查 INPM 对脑神经系统的潜在影响。将人星形胶质细胞与人脐静脉内皮细胞在微流控芯片内进行 3D 共培养，以模拟人血脑屏障的微观复杂生理结构。然后建立这个 3D 人体器官模型来研究与潜在细胞反应相关的任何 INPM 诱导的 BBB 功能障碍。本研究构建了 3D 人体功能血脑屏障。我们观察到 INPM 穿过血脑屏障的易位。 3D人体器官芯片最初反映了神经系统受损，星形胶质细胞增殖异常和细胞活力下降。我们还研究了氧化应激相关生物标志物（ROS、GSH-Px 和 MDA）的行为。 INPM 可能通过活性氧 (ROS) 加剧炎症。 Keap1-Nrf2-ARE 通路是细胞通过介导和激活多种抗氧化和解毒酶抵抗氧化应激的关键机制。 ROS 积累后，INPM 诱导核转录因子 Nrf2 的异常表达。这种行为扰乱了γ-谷氨酸合酶（γ-GCS）和血红素加氧酶（HO-1）的表达，进一步加剧了抗氧化系统的失衡。这种功能性 3D 人体器官芯片有效模仿了人类血脑屏障的生理反应。该芯片提供了微观复杂的结构来模拟人体血脑屏障的内部环境，并部分模拟了BBB对INPM暴露的生理反应。基于该模型，INPM 通过破坏 Keap1-Nrf2-ARE 通路来影响血脑屏障生物功能。