Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy

Abstract

BackgroundPirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy.MethodsTransforming growth factor-β (TGF-β)-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice.ResultsWe found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-β. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD.ConclusionsThese results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.

Pirfenidone in the kaleidoscope: reflecting mechanisms through different angles

“…The present study validates prior impressions that pirfenidone has pleiotropic actions on both the immune system and ECM (table 1) [16][17][18]. The study also reports, for the first time, that pirfenidone may influence metabolism of hyaluronan, a major component of the ECM that regulates tissue injury and repair [19].…”

“…In vivo (BLM model) KURITA [17] Restoration of insufficient mitophagy/enhancement of PARK2 expression In vitro (fibroblasts) DIDIASOVA [18] Inhibition of GLI transcription factors In vitro (fibroblasts) TGF: transforming growth factor; FGF: fibroblast growth factor; IL: interleukin; BLM: bleomycin; CEMIP: cell migration-inducing and hyaluronan-binding protein; GLI: glioma-associated oncogene homologue.…”

PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis

“…Although PRKN-mediated direct regulation of inflammation cannot be completely excluded, we speculate that SASP attributed to accelerated cellular senescence is responsible for the inflammatory phenotype in CS-exposed prkn KO mice PRKN overexpression was sufficient for inducing mitophagy and inhibiting cellular senescence in response to CSE exposure ( Figure 5), indicating that PRKN induction is a potentially promising geroprotective modality of treatment for COPD with reduced PRKN and accelerated cellular senescence. We have recently reported that anti-fibrotic PFD is a candidate agent for inducing PRKN expression [23]. Although a significant increase in PRKN expression levels was detected at 10 μg/ml PDF in HBEC, which is comparable to the levels of maximum plasma concentration of PFD in a clinical setting, 5-fold higher concentration (50 μg/ml) was needed to demonstrate sufficient mitophagy with an anti-senescence property ( Figures S6 and 7).…”

“…We have recently reported that pirfenidone (PFD), an antifibrotic modality of treatment for idiopathic pulmonary fibrosis, induces autophagy/mitophagy through the enhancement of PRKN expression in lung fibroblasts (LF) [23]. Hence, the role of PFD-mediated autophagy/mitophagy in the regulation of CSE-induced cellular senescence was examined in HBEC.…”

lncRNA PFAL promotes lung fibrosis through CTGF by competitively binding miR‐18a

“…It is generally recognized that alveolar epithelial cell injury and inflammation lead to aberrant proliferation of fibroblasts, resulting in an exaggerated deposition of extracellular matrix (ECM) in the lung parenchyma and eventually leading to lung function damage (2). However, the molecular mechanism underlying IPF is not fully understood, and there is still lack of effective treatment for IPF aside from lung transplantation, even though a number of studies have reported the anti-fibrotic effects of nintedanib and pirfenidone on lung fibrosis (3)(4)(5). Therefore, it is of great value to reveal the pathogenesis of IPF and to explore more effective therapeutic strategies and drugs for the treatment of IPF.…”