Yan Li1, Yan Liu1, Chuanlin Hu2, Qing Chang3, Qihong Deng4, Xu Yang5, Yang Wu6. 1. Key Laboratory for Deep Processing of Major Grain and Oil (The Chinese Ministry of Education), College of Food Science and Engineering, Wuhan Polytechnic University, Wuhan 430023, PR China. 2. State Key Laboratory of Silicate Materials for Architectures, Wuhan University of Technology, Wuhan 430070, PR China. 3. Department of Chemical and Biomolecular Engineering, Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong, China. 4. XiangYa School of Public Health, Central South University, Changsha 410083, PR China. 5. XiangYa School of Public Health, Central South University, Changsha 410083, PR China; Lab of Environmental Biomedicine, School of Life Sciences, Central China Normal University, Wuhan 430079, PR China. Electronic address: yangxu@mail.ccnu.edu.cn. 6. Key Laboratory for Deep Processing of Major Grain and Oil (The Chinese Ministry of Education), College of Food Science and Engineering, Wuhan Polytechnic University, Wuhan 430023, PR China; Hubei Key Laboratory for Processing and Transformation of Agricultural Products, College of Food Science and Engineering, Wuhan Polytechnic University, Wuhan, 430023, PR China. Electronic address: wuyangwhpu@163.com.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.