From perinodular to nodular tissues: aberrant accumulation of ornithine accelerates pulmonary fibrosis in silicosis

Silicosis is one of the most serious and prevalent occupational diseases globally, characterized by typical silicotic nodules and fibrosis. Recent studies suggest that the perinodular zone of the lung shares certain characteristics with the nodules themselves. In this study, a silicotic rat model was established via a single intratracheal instillation of a 50 mg/mL silica suspension. Pulmonary anatomical and pathological examinations revealed that silica deposition induced severe alterations in both the nodular and perinodular tissues. Subsequently, pseudotargeted metabolomics analysis revealed that abnormally elevated ornithine levels were closely associated with the progression of silicosis, from normal to perinodular and finally to nodular tissues. Immunofluorescent staining demonstrated that, in addition to M2 macrophages, silica exposure increased the protein levels of ARG1 in epithelial cells, a finding further confirmed by in vitro experiments using A549 and BEAS-2B cells. Moreover, accumulated ornithine induced epithelial-mesenchymal transition in vitro, increased extracellular matrix expression in NIH 3T3 fibroblasts, and enhanced TGF-β1 levels in RAW264.7 cells. Co-exposure to ornithine and silica significantly induced the aberrant expression of fibrosis-associated proteins compared to silica exposure alone, characterized by increased levels of FN and α-SMA, as well as decreased E-cad expression. These findings suggest that silica exposure up-regulates ARG1 in various cells, leading to ornithine accumulation, which in turn accelerates the progression of fibrosis.