Short-term silica inhalation triggers sustaining pulmonary fibrosis in a rat recovery model

Late-onset silicosis is characterized by the progression of pulmonary fibrosis long after cessation of silica exposure, yet its underlying mechanisms remain poorly understood. This study aimed to determine whether a brief silica exposure could initiate a sustaining fibrotic process and to characterize the associated pathological and molecular alterations. A rat model of silicosis was established by short-term silica inhalation for two weeks, followed by a recovery period of up to 46 weeks. Histopathological and micro-CT analyses demonstrated progressive fibrotic development even after exposure cessation. Notably, fibrotic pulmonary dust foci (fPDFs) emerged as a predominant lesion, characterized by alveolar remodeling and diffuse collagen deposition distinct from classical silicotic nodules. These lesions were associated with alveolar type II (AT2) cell dysfunction, evidenced by aberrant differentiation, loss of homeostatic markers such as ATP-binding cassette subfamily A member 3 (ABCA3), lysophosphatidylcholine acyltransferase 1 (LPCAT1), and fatty acid synthase (FAS), and gain of transitional markers keratin 8 (KRT8) and stratifin (SFN). Integrated proteomic and lipidomic analyses revealed profound metabolic reprogramming, with significant dysregulation of lipid metabolism pathways. Key enzymes involved in lipid synthesis and remodeling were identified in AT2 cells and downregulated in fPDF regions. Our findings establish that short-term silica exposure initiates a sustaining fibrotic cascade, highlight fPDFs as a critical pathological entity, and suggest that AT2 cell dysfunction and metabolic reprogramming are closely associated with the progression of silicosis, highlighting them as potential key correlates of the sustaining fibrotic cascade. These insights provide a novel framework for understanding disease progression and identifying therapeutic targets.