Different exposure modes of PM induces bronchial asthma and fibrosis in male rats through macrophage activation and immune imbalance induced by TIPE2 methylation.

Exposure to PM can aggravate the occurrence and development of bronchial asthma and fibrosis. Here, we investigated the differences in bronchial injury caused by different exposure modes of PM (high concentration intermittent exposure and low concentration continuous exposure), and the mechanism of macrophage activation and respiratory immune imbalance induced by PM, leading to bronchial asthma and airway fibrosis using animal and cell models. A "PM real-time online concentrated animal whole-body exposure system" was used to conduct PM respiratory exposure of Wistar rats for 12 weeks, which can enhance oxidative stress in rat bronchus, activate epithelial cells and macrophages, release chemokines, recruit inflammatory cells, release inflammatory factors and extracellular matrix, promote bronchial mucus hypersecretion, inhibit the expression of epithelial cytoskeletal proteins, destroy airway barrier, and induce asthma. Furthermore, PM induced M2 polarization in lung bronchial macrophages through JAK/STAT and PI3K/Akt signaling pathways, and compared with low concentration continuous exposure, high concentration intermittent exposure of PM could regulate significantly higher expression of TIPE2 protein through promoter methylation of TIPE2 DNA, thereby activating PI3K/Akt signaling pathway and more effectively inducing M2 polarization of macrophages. Additionally, activated macrophages release IL-23, and activated epithelial cells and macrophages released TGF-β1, which promoted the differentiation of Th17 cells, triggered the Th17 dominant immune response, and activated the TGF-β1/Smad2 signaling pathway, finally causing bronchial fibrosis. Moreover, when the total amount of PM exposure was equal, high concentration-intermittent exposure was more serious than low concentration-continuous exposure. In vitro experiments, the co-culture models of PM with BEAS-2B, WL-38 and rat primary alveolar macrophages further confirmed that PM could induce the macrophage activation through oxidative stress and TIPE2 DNA methylation, and activate the TGF-β1/Smad2 signaling pathway, leading to the occurrence of bronchial fibrosis.