研究發炎刺激物(TNF-α和空氣懸浮微粒)對肺上皮細胞的影響及相關機制

Abstract

Inflammation is considered to be a key factor in lung injury leading to respiratory system failure. Therefore, there is an urgent need for new research related to lung injury to generate new insights into the potential treatment of lung injury. A growing evidence showed that vitamin D3 deficiency is closely related to inflammatory diseases. However, the anti-inflammatory effects of vitamin D3 and their underlying mechanisms remained to be determined. In the part I study, we aimed to examine the effects and mechanisms of vitamin D3 (Vit. D) on the expression of intercellular adhesion molecule-1 (ICAM-1) in vitro and in vivo with or without tumor necrosis factor α (TNF-α) treatment. After TNF-α stimulation, ICAM-1 expression, mitochondrial ROS (mtROS), mitochondrial fission and mitophagy were significantly increased in A549 cells. In this study, Vit. D prevents TNF-α-induced pulmonary inflammation by the regulation of mitochondrial function. Vit. D inhibits TNF-α-induced mitochondrial fission and mitophagy by the inhibition of the expression of DRP1, Mff and Bnip3 in A549 cells. This effect is mediated through the AKT/NF-κB pathway. Due to these findings, Vit. D should be considered as a new and novel therapeutic agent for the targeting epithelial activation in lung inflammation. In addition, we use particulate matter in air pollutants as an inflammatory stimulant to study the damage and mechanism of lung epithelial cells. Particulate matters (PMs) can easily enter the human circulatory system through the respiratory tract, causing systemic inflammation and immune response. However, the role of PMs in epithelial-mesenchymal transition (EMT) and pulmonary fibrosis needs to be clarified. In the part II study, we aimed to investigate the effect of PMs on the formation of EMT, the development of pulmonary fibrosis and the related mechanisms in pulmonary epithelial cells by in vitro and in vivo studies. In this study, we found that EMT, fibronectin, cell migration and EMT-related transcription factors (NF-κB p65 and ETS-1) were increased in A549 cells treated with PMs. In addition, the EMT formation and the expression of fibronectin and ETS-1 were increased in lung tissues of mice for 7 and 14 days after PMs exposure. The results of human lung fibrosis tissue microarray showed that ETS-1 expression was closely related to the fibronectin expression. Therefore, PMs induced EMT and pulmonary fibrosis via the activation of ETS-1. Based on the above findings, these data provide a mechanism for the damage of respiratory diseases caused by inflammatory stimulants. In addition, we also provide a new and practical treatment for this injury.