Insights into Silica-Induced Lung Fibrosis: Fibrotic Gene Signatures, Pathways, and Therapeutic Opportunities

Silica exposure is a significant environmental hazard linked to lung inflammation and fibrosis. Despite general protective measures, there remains a critical need for pharmacological interventions targeting the molecular mechanisms of silica-induced lung injury and fibrosis.

In silico reanalysis of publicly available transcriptomic datasets (GSE250537, GSE142446) from silica-exposed Fischer-344 rats was conducted to investigate molecular pathways and therapeutic targets. Rats were exposed to crystalline silica via inhalation, and lung/blood transcriptomes were analyzed at 1 day, 3, 6, and 9 months post-exposure. Differential expression, gene set enrichment analysis (GSEA), protein-protein interaction (PPI) clustering, and drug-gene matching (Open TG-GATEs) were performed, followed by in vivo validation of simvastatin in a murine silica fibrosis model.

GSEA revealed activation of fibro-inflammatory and aging pathways in lung tissue, including TGF-beta, NOD-like receptor protein 3, and TNF-α signaling, with limited effects in blood. Differential expression identified 12 fibrotic markers consistently upregulated in lung tissue, such as Cxcl6, Mmp12, and S100a9, implicated in inflammation, tissue remodeling, and fibrosis. Temporal analysis showed prolonged upregulation up to 9 months post-exposure. Protein-protein interaction networks highlighted clusters related to chemokine signaling, tissue remodeling, and matrix metalloproteinases. Using the Open TG-GATEs database, 179 pharmacological agents were identified, with 37 targeting five or more fibrotic genes. Notable candidates included non-steroidal anti-inflammatory drugs, captopril, and simvastatin. In vivo validation in a silica-induced murine fibrosis model showed that simvastatin significantly reduced key fibro-inflammatory genes and attenuated increases in fibrotic markers in lung tissue.

These findings provide insights into silica immunopathology and potential drug repurposing strategies; however, further studies are warranted to elucidate mechanisms and evaluate therapeutic efficacy in clinical settings.