Repurposing of Pirfenidone (Anti-Pulmonary Fibrosis Drug) for Treatment of Rheumatoid Arthritis

Abstract

Clinical studies have shown that pirfenidone (PFD) effectively relieves joint pain in rheumatoid arthritis (RA) patients. However, the detailed mechanisms underlying the anti-RA effects of PFD have not been investigated. This study was undertaken to investigate the repurposing of PFD for the treatment of RA, and explore its anti-rheumatic mechanisms. A collagen-induced arthritis (CIA) rat model was used to observe joint pathological changes following PFD treatment. Based on bioinformatics to predict the mechanism of PFD anti-RA, using EA. hy926 and TNF-α-induced MH7A cells to establish in vitro model to explore its biological mechanism from the perspectives of synovial inflammation and angiogenesis. PFD significantly relieved pathological changes, including joint swelling, synovial hyperplasia, inflammatory cell infiltration and joint destruction. PFD was also associated with reduced expression of MMP-3 and VEGF in articular chondrocytes and synovial cells of CIA rats (p < 0.05). Using bioinformatic methods, we predicted that PFD inhibits cell inflammation and migration by interfering with the JAK2/STAT3 and Akt pathways. These results were verified using in vitro models. In particular, PFD effectively reduced the expression of pro-inflammatory, chondrogenic, and angiogenic cytokines, such as IL-1β, IL-6, IL-8, MMP-1/3/2/9 and VEGF (p < 0.05), in TNF-α-induced MH7A cells. In addition, PFD significantly reduced the production of MMP-2/9 and VEGF in EA. hy926 cells, thereby weakening migration and inhibiting angiogenesis (p < 0.05). These findings suggest that PFD may alleviate the pathological process in CIA rats, by inhibiting inflammation and angiogenesis through multiple pathways, and serve as a potential therapeutic drug for RA.

RA Fibroblast-Like Synoviocytes Derived Extracellular Vesicles Promote Angiogenesis by miRNA-1972 Targeting p53/mTOR Signaling in Vascular Endotheliocyte

“…Thus, it is a potential target by blocking angiogenesis in the treatment of RA ( 8 ). Indeed, vascular targeted candidates have been developed in pre-clinic study ( 9 ). However, the current candidate development cannot meet the urgent demand of RA patients.…”

“…Interestingly, pirfenidone (PFD), a vascular targeted candidate, has been verified to suppress endothelial cells (ECs) migration and angiogenesis ( 8 ). Moreover, PFD can mitigate the pathological changes of CIA rats, and may serve as a potential drug for the treatment of RA ( 9 ).…”

Highlights of Strategies Targeting Fibroblasts for Novel Therapies for Rheumatoid Arthritis

“…In Simian Vacuolating Virus 40 large T antigen transformed human synovial fibroblast cell line, MH7A cells, pirfenidone significantly reduced TNF-induced production of inflammatory cytokines, VEGF, and MMPs. Moreover, pirfenidone significantly inhibited VEGF by vascular endothelial cell line, EA.hy926 cells ( 118 ). Further studies are required to delineate whether these effects of pirfenidone fibroblast selective.…”

“…Pirfenidone can also suppress TGF-β induced collagen type I production and inhibit myofibroblasts activity to reduce extracellular matrix deposition ( 117 ). In a rat CIA model, pirfenidone was shown to ameliorate arthritis and reduction of MMP3 and vascular endothelial growth factor (VEGF) expression in the joint ( 118 ). In Simian Vacuolating Virus 40 large T antigen transformed human synovial fibroblast cell line, MH7A cells, pirfenidone significantly reduced TNF-induced production of inflammatory cytokines, VEGF, and MMPs.…”

Layered Double Hydroxides-Loaded Sorafenib Inhibit Hepatic Stellate Cells Proliferation and Activation In Vitro and Reduce Fibrosis In Vivo

“…However, herbal medicines such as curcumin ( Hanafy, 2021 ) and silybin ( Ou et al, 2018 ) are insoluble in water, resulting in low bioavailability in the body. Other drugs, such as pirfenidone ( Gan et al, 2021 ), have toxic side effects that limit their effectiveness in the treatment of liver fibrosis. With the development of nano drug delivery system, more and more nano carriers have been designed to deliver drugs, which increases the high efficiency of drug targeting and greatly reduces the adverse reactions of drugs ( Panyam and Labhasetwar, 2003 ; Hanafy et al, 2019 ; Hanafy et al, 2020 ).…”