Pirfenidone Attenuates the IL-1β–Induced Hyaluronic Acid Increase in Orbital Fibroblasts From Patients With Thyroid-Associated Ophthalmopathy

Chung, Seung Ah; Jeon, Bo Kyung; Choi, Youn Hee; Back, Keum Ok; Lee, Jong Bok; Kook, Koung Hoon

doi:10.1167/iovs.13-13759

Cited by 17 publications

(13 citation statements)

References 34 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanism of insulin action to increase Has2 expression appears to be mediated through multiple pathways, including both AKT and MAPK kinase. Other studies have shown that the direct activation of MAP kinase can regulate Has2 gene expression 46 ; however, our findings suggest that p-Akt may also be important.…”

Section: Discussioncontrasting

confidence: 68%

Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes

Xia

et al. 2019

Nat Commun

View full text Add to dashboard Cite

Insulin and IGF-1 actions in vascular smooth muscle cells (VSMC) are associated with accelerated arterial intima hyperplasia and restenosis after angioplasty, especially in diabetes. To distinguish their relative roles, we delete insulin receptor (SMIRKO) or IGF-1 receptor (SMIGF1RKO) in VSMC and in mice. Here we report that intima hyperplasia is attenuated in SMIRKO mice, but not in SMIGF1RKO mice. In VSMC, deleting IGF1R increases homodimers of IR, enhances insulin binding, stimulates p-Akt and proliferation, but deleting IR decreases responses to insulin and IGF-1. Studies using chimeras of IR(extracellular domain)/IGF1R(intracellular-domain) or IGF1R(extracellular domain)/IR(intracellular-domain) demonstrate homodimer IRα enhances insulin binding and signaling which is inhibited by IGF1Rα. RNA-seq identifies hyaluronan synthase2 as a target of homo-IR, with its expression increases by IR activation in SMIGF1RKO mice and decreases in SMIRKO mice. Enhanced intima hyperplasia in diabetes is mainly due to insulin signaling via homo-IR, associated with increased Has2 expression.

show abstract

Section: Discussioncontrasting

confidence: 68%

Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes

Xia

et al. 2019

Nat Commun

View full text Add to dashboard Cite

show abstract

“…PFD is known to exert both anti-inflammatory and anti-fibrotic properties via suppressing inflammatory and pro-fibrotic cytokine expression during bleomycin-induced lung fibrosis development [7]. PFD regulates inflammatory cytokine expression through modulating cell signaling, including nuclear factor kappa B(NF-kB) and P38 mitogen-activated protein kinase (MAPK) pathways [8, 9]. Anti-fibrotic mechanisms for PFD have been postulated to be mainly attributed to attenuating protein levels and signaling pathways of pro-fibrotic growth factors, including transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), and basic-fibroblast growth factor (bFGF) [7, 10, 11].…”

Section: Introductionmentioning

confidence: 99%

Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

“…For example, PFD inhibits the non-canonical hedgehog (Hh) pathway by shortening the half-life of endogenous full-length glioma-associated oncogene homolog 2 (GLI2), a transcription factor, by more than 3-fold, and thereby reduces Hh/TGF-β signaling and expression of collagen type I 32 . PFD has also been shown to reduce IL-1β-induced hyaluronan production in orbital fibroblasts 33 . PFD has shown pain relief in RA 34 and may also be able to block nitric oxide release in articular chondrocytes 35 , but PFD has not yet been tested in vivo against post-traumatic OA.…”

Section: Introductionmentioning

confidence: 99%

“…32 PFD has also been shown to reduce IL-1b-induced hyaluronan production in orbital fibroblasts. 33 PFD has shown pain relief in RA 34 and may also be able to block nitric oxide release in articular chondrocytes, 35 but PFD has not yet been tested in vivo against posttraumatic OA.…”

mentioning

confidence: 99%

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury

Chan

Luo

et al. 2017

Journal Orthopaedic Research

View full text Add to dashboard Cite

Pirfenidone is an anti-inflammatory and anti-fibrotic drug that has shown efficacy in lung and kidney fibrosis. Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint-wide fibrosis in mice that lack hyaluronan synthase 1 (Has1 ) in comparison to wild-type. Femoral cartilage was surgically injured in wild-type and Has1 mice, and Pirfenidone was administered in food starting after 3 days. At 4 weeks, Pirfenidone reduced the appearance, on micro-computed tomography, of pitting in subchondral bone at, and cortical bone surrounding, the site of cartilage injury. This corresponded with a reduction in fibrotic tissue deposits as observed with gross joint surface photography. Pirfenidone resulted in significant recovery of trabecular bone parameters affected by joint injury in Has1 mice, although the effect in wild-type was less pronounced. Pirfenidone also increased Safranin-O staining of growth plate cartilage after cartilage injury and sham operation in both genotypes. Taken together with the expression of selected extracellular matrix, inflammation, and fibrosis genes, these results indicate that Pirfenidone may confer chondrogenic and bone-protective effects, although the well-known anti-fibrotic effects of Pirfenidone may occur earlier in the wound-healing response than the time point examined in this study. Further investigations to identify the specific cell populations in the joint and signaling pathways that are responsive to Pirfenidone are warranted, as Pirfenidone and other anti-fibrotic drugs may encourage tissue repair and prevent progression of post-traumatic osteoarthritis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:365-376, 2018.

show abstract

Pirfenidone Attenuates the IL-1β–Induced Hyaluronic Acid Increase in Orbital Fibroblasts From Patients With Thyroid-Associated Ophthalmopathy

Abstract: Pirfenidone attenuates the IL-1β-induced HA production in orbital fibroblasts from patients with TAO, at least in part, through suppression of the MAPK-mediated HAS expression. These results support the potential use of pirfenidone for treatment of patients with TAO.

Cited by 17 publications

References 34 publications

Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes

Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes

Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury

Contact Info

Product

Resources

About