Targeting Inflammatory and Oxidative Pathways in Idiopathic Pulmonary Fibrosis: Synergistic Effects of Quercetin and Pirfenidone in Modulating Nrf2/PPAR-γ and TLR-4/NF-κB Pathways.

Pulmonary fibrosis (PF) is a progressive condition characterized by inflammation and excessive fibrous tissue formation. Pirfenidone, an FDA-approved drug, slows PF progression through reducing TGF-β production and antioxidant effects. Quercetin (Quer) has emerged as a promising candidate for PF management, exhibiting anti-inflammatory and antioxidant effects and inhibiting collagen synthesis in various tissues. Our study was designed to explore the therapeutic potential of combining Pirf and Quer in mitigating bleomycin-induced lung fibrosis in vivo. Using a bleomycin (BLM)-induced lung fibrosis model, the study evaluated the anti-fibrotic effects of Pirf and Quer, both individually and together. Oxidative stress biomarkers (MDA, SOD, GSH-Px), inflammatory cytokines (TNF-α, IL-1β), and gene expression of NF-κB, PPAR-γ, PI3K, TLR-4, and MAPK were measured to assess the cellular response. BLM exposure markedly upregulated inflammatory markers and oxidative stress, with reducing antioxidant defense mechanisms. Treatment with Pirf moderately decreased these fibrotic changes. Quer, known for its potent antioxidant properties, exhibited a stronger reduction in these parameters. BLM treatment increased the expression of NF-κB, PI3K, TLR-4, and MAPK while Pirf and Quer were shown to reduce them significantly. However, PPAR-γ mRNA levels were reduced by BLM treatment and increased by both Pirf and Quer. Notably, the concomitant administration of Pirf and Quer always provided an augmented effect. The combined administration of Pirf and Quer significantly alleviated BLM-induced lung fibrosis more effectively than either drug alone, suggesting that this combination therapy could enhance anti-fibrotic treatments and should be further investigated in clinical settings.