Pulmonary microbiota affects silica-induced pulmonary fibrosis through activation of the PI3K/AKT-mediated senescence in alveolar epithelial cells

The rise of new industries has led to the increased manufacture and use of silica, posing a significant threat to public health. Lung microbiota is closely associated with chronic respiratory diseases, particularly pulmonary fibrosis. However, the role of lung microbiota in the progression of silicosis remains inadequately explored. This study established a model of C57BL/6 J mice exposed to silica via inhalation through intratracheal drip, while the lung microbiota was modified using antibiotics via intratracheal drip. Silica exposure induced dysbiosis of the lung microbiota and the triggered cellular senescence. Transcriptomic analysis of lung tissue revealed enrichment of the PI3K/AKT pathway. Mechanistically, lipopolysaccharide (LPS) produced by lung microbiota drives cellular senescence, which plays a key role in pulmonary fibrosis, as demonstrated by LPS stimulation and indirect co-culture experiments. In conclusion, silica affects the progression of pulmonary fibrosis by altering the composition of lung microbiota, leading to increased LPS production, which promotes senescence of type Ⅱ alveolar epithelial cells (ATⅡ) through activation of the PI3K/AKT pathway. This study provides novel insights and rationale for targeted intervention aimed at mitigating ATⅡ senescence to counteract silica-induced pulmonary fibrosis.