Transcriptome analysis reveals a protective role of liver X receptor alpha against silica particle-induced experimental silicosis.

Silicosis, a severe and irreversible form of pulmonary fibrosis (PF) caused by long-termexposure to dust particles in production environments, is the biggest occupational health concern in China and most low-income countries. The transdifferentiation of pulmonary fibroblasts is the terminal event in silicosis, and specific transcription factors (TFs) play a crucial role in this condition. However, the relationship between TF-mediated regulation and silicosis remains unknown. We performed a transcriptomic analysis to elucidate this relationship, and our results revealed that two TFs, EGR2 and BHLHE40, were upregulated and five, i.e., TBX2, NR1H3 (LXR alpha), NR2F1, PPARG (PPAR gamma), and EPAS1, were downregulated in activated fibroblasts. Notably, PPAR gamma and LXR alpha expression was also decreased in an experimental mouse model of silicosis. The mechanism underlying these changes may involve TGF-beta 1 secretion from silica-exposed alveolar macrophages, causing PPAR gamma and LXR alpha downregulation, which in turn would result in aberrant alpha-SMA transcription. Our results suggest that LXR alpha is a potential target for the prevention of silicosis and PF. (C) 2020 Elsevier B.V. All rights reserved.