Inhalation of crystalline silica (CS) is linked to pulmonary silicosis, fibrosis, and cancer in exposed workers, but the underlying molecular mechanisms are obscure. We obtained publicly available datasets in the NCBI Gene Expression Omnibus for CS-induced gene expression changes in the rat lung. Seven datasets were identified via a PRISMA-guided systematic search using predefined databases, search terms, and eligibility criteria. Data from seven datasets, in total 194 rats and 5726 genes were classified for responses after equivalent to acute (≤2 days), sub-acute (3 days to 1 month), and sub-chronic exposures (1 to 6 months). Following normalization and batch correction, transcriptomic datasets were subjected to temporal clustering, pathway-level gene set enrichment analysis, immune cell deconvolution, and machine-learning-based feature selection to identify key molecular signatures associated with crystalline silica exposure. The temporal clustering revealed eight distinct gene clusters. Acute responses were marked by macrophage-driven proinflammatory cytokines (TNF/NF-κB, Il1b signaling) and neutrophil-recruiting chemokines (Cxcl2). The sub-acute responses showed transient suppression of interferon signaling, while later responses were dominated by persistent inflammatory and fibrosis-related programs reflected by Spp1, TGF-β signaling, and glycolytic metabolic reprogramming. Immune cell deconvolution indicated a neutrophil influx in the sub-acute time points, followed by progressive macrophage accumulation throughout exposure. ML analyses highlighted Chi3l1, Mt1, Phka1, and Sod2 as top predictive biomarkers, which were consistently changed across all time points, enriched in immune and fibrotic pathways, and strongly correlated with macrophage subtypes. Verification using transcriptomic profiles from chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis lungs further supported their predictive value. This integrative approach revealed temporal gene expression patterns and indicated both known and novel mechanisms and lung cell dynamics underlying CS-lung pathogenesis.
Lei et al. (Sun,) studied this question.