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Abstract Background Fibroblasts have important roles in the synthesis and remodeling of extracellular matrix (ECM) proteins during pulmonary fibrosis. However, the spatiotemporal distribution of heterogeneous fibroblasts during disease progression remains unknown. Results In the current study, silica was used to generate a mouse model of pathological changes in the lung, and single-cell sequencing, spatial transcriptome sequencing and an analysis of markers of cell subtypes were performed to identify fibroblast subtypes. A group of heterogeneous fibroblasts that play an important role at the early pathological stage were identified, characterized based on the expression of inflammatory and proliferation genes (termed inflammatory-proliferative fibroblasts) and found to be concentrated in the lesion area. The expression of GREM1/protein phosphatase 2 regulatory subunit B''alpha (PPP2R3A) in inflammatory-proliferative fibroblasts was found to initiate early pulmonary pathological changes by increasing the viability, proliferation and migration of cells. Conclusions Inflammatory-proliferative fibroblasts play a key role in the early pathological changes that occur in silicosis, and during this process, GREM1 is the driving factor that targets PPP2R3A and initiates the inflammatory response, which is followed by irreversible fibrosis induced by SiO2. The GREM1/PPP2R3A pathway may be a potential target in the early treatment of silicosis.