Abstract
BackgroundPirfenidone (PFD) is effective for pulmonary fibrosis (PF), but its action mechanism has not been fully explained. This study explored the signaling pathways involved in anti-fibrosis role of PFD, thus laying a foundation for clinical application.MethodsPulmonary fibrosis mice models were constructed by bleomycin (BLM), and TGF-β1 was used to treat human fetal lung fibroblasts (HLFs). Then, PFD was added into treated mice and cells alone or in combination with β-catenin vector. The pathological changes, inflammatory factors levels, and Collagen I levels in mice lung tissues were assessed, as well as the activity of HLFs was measured. Levels of indices related to extracellular matrix, epithelial-mesenchymal transition (EMT), Wnt/GSK-3β/β-catenin and TGF-β1/Smad2/3 signaling pathways were determined in tissues or cells.ResultsAfter treatment with BLM, the inflammatory reaction and extracellular matrix deposition in mice lung tissues were serious, which were alleviated by PFD and aggravated by the addition of β-catenin. In HLFs, PFD reduced the activity of HLFs induced by TGF-β1, inhibited levels of vimentin and N-cadherin and promoted levels of E-cadherin, whereas β-catenin produced the opposite effects to PFD. In both tissues and cells, Wnt/GSK-3β/β-catenin and TGF-β1/Smad2/3 signaling pathways were activated, which could be suppressed by PFD.ConclusionsPFD alleviated pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3β/β-catenin and TGF-β1/Smad2/3 signaling pathways, which might further improve the action mechanism of anti-fibrosis effect of PFD.
Highlights
Pirfenidone (PFD) is effective for pulmonary fibrosis (PF), but its action mechanism has not been fully explained
In the early stage of research, PFD was used in the treatment of hermansky-pudlak syndrome (HPS)associated pulmonary fibrosis, which initially showed that the drug may delay the decline of forced vital capacity (FVC) (Gahl et al 2002)
PFD intervention reduced the level of TNFα, and IL-6 in lung tissues, inhibited the epithelialmesenchymal transition and pulmonary fibrosis in rat silicosis model, which effects may be related to the TGFβ1/smad pathway (Guo et al 2019)
Summary
Pirfenidone (PFD) is effective for pulmonary fibrosis (PF), but its action mechanism has not been fully explained. This study explored the signaling pathways involved in anti-fibrosis role of PFD, laying a foundation for clinical application. PFD intervention reduced the level of TNFα, and IL-6 in lung tissues, inhibited the epithelialmesenchymal transition and pulmonary fibrosis in rat silicosis model, which effects may be related to the TGFβ1/smad pathway (Guo et al 2019). The therapeutic role of PFD in fibrosis-related diseases has been recognized, its mechanism of action in vivo and in vitro is still not fully understood. Exploration of the action mechanism and latent signaling pathways of PFD in PF, especially TGF-β, TNF-α and IL-6, contributes to better understanding on the role of drugs, laying a foundation for clinical application
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