Figure 1.

Proposed mechanisms of action for pirfenidone. Pirfenidone’s most recognized mechanism of action is the reduction of transforming growth factor (TGF)-β1, which leads to a subsequent reduction in TGF-β1-mediated fibroblast proliferation, myofibroblast differentiation, TGFβR1 signaling/SMAD3 phosphorylation, and extracellular matrix production. Pirfenidone has also been proposed to (1) reduce platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) thereby decreasing PDGF/FGF signaling; (2) inhibit redox reactions to relieve oxidative stress from hydroxyl radicals and mitochondrial dysfunction; (3) reduce expression of cytokines tumor necrosis factor alpha (TNF-α), interleukin-6, interleukin-8 (IL-8), interleukin 10 (IL-10), interleukin 12 subunit p40 (IL12p40), interferon gamma (IFN-γ), and monocyte chemoattractant protein-1 (MCP1); and (4) modulate the cellular immune system by reducing macrophage cytokine secretion, reducing dendritic cell mediated T cell activation, and inhibiting Th1/Th2 polarization. ⁴⁸