Pirfenidone reduces fine particulate matter-induced epithelial to mesenchymal transition in lung epithelial cells through regulating mitochondrial fission and autophagy

Epidemiological studies have shown that fine particulate matter (PM) is closely associated with increased morbidity and mortality from lung diseases. However, the mechanisms by which PM affects alveolar epithelial-mesenchymal transition (EMT), such as mitochondrial dysfunction, remain unclear, and therapy options require further investigation. Human type II alveolar epithelial cells (A549 cells) were exposed to 100 µg/mL PM to investigate EMT induction. In an animal model, mice were exposed to PM via intratracheal injection to simulate air pollution exposure. PM exposure reduced the expression of the epithelial marker E-cadherin while increasing the expression of mesenchymal markers vimentin, α-smooth muscle actin (α-SMA), and transforming growth factor β1 (TGF-β1). Furthermore, the expression of EMT-related transcription factors Snail and Slug was upregulated, accompanied by a morphological shift in A549 cells from cubic to spindle shapes and enhanced cell migration. PM also promoted mitochondrial fission and induced the accumulation of LC3B and p62 proteins. Treatment with the antifibrotic drug pirfenidone (PFD) effectively reduced PM-induced EMT-related protein expression and cell migration. These effects are achieved by reducing mitochondrial fission, increasing autophagosome accumulation, and related autophagic degradation. The lungs of PM-treated mice showed increased expression of EMT-related proteins, significant blood cell infiltration, and alveolar wall thickening. PFD treatment significantly improved these conditions and reduced collagen deposition. PM induces increased mitochondrial fission and incomplete autophagy (characterized by autophagosome accumulation and impaired flux), leading to EMT. PFD treatment can also effectively reduce PM-induced EMT formation by modulating these pathways.