PPARγ/LXRα axis mediated phenotypic plasticity of lung fibroblasts in silica-induced experimental silicosis

Silicosis is a disease mainly caused by pulmonary interstitial fibrosis caused by long-term inhalation of dust with excessively high content of free SiO2. Transdifferentiation of lung fibroblasts into myofibroblasts is an important cellular basis for silicosis, but the key transcription factors (TFs) involved in this process are still unclear. In order to explore the biological regulation of transcription factor PPAR gamma/LXR alpha in silica-induced pulmonary fibrosis, this study explored the molecular mechanism of PPAR gamma/LXR alpha involved in regulating transcription factors related to SiO2-induced lung injury at the cellular level and in animal models. ChIP-qPCR detected that PPAR gamma directly regulated the transcriptional activity of the LXR alpha gene promoter, while the PPAR gamma agonist RSG increased the expression of LXR alpha. In addition, we demonstrated in the cell model that upregulation of LXR alpha can inhibit silicamediated fibroblast transdifferentiation, accompanied by an increase in the expression of SREBF1, PLTP and ABCA1. The results of LXR alpha silencing experiment matched those of overexpression experiment. These studies explored the role of LXR alpha in plasticity and phenotypic transformation between lung fibroblasts and myofibroblasts. Therefore, inhibiting or reversing the transdifferentiation of lung fibroblasts to myofibroblasts by intervening PPAR gamma/LXR alpha may provide a new therapeutic target for the treatment of silicosis.

Automated summary

Silicosis is a disease caused by long-term inhalation of dust with excessively high content of free SiO2. This study investigated the role of PPAR gamma/LXR alpha in the biological regulation and potential therapeutic target for silicosis by inhibiting the transdifferentiation of lung fibroblasts into myofibroblasts.