Fenofibrate inhibits TGF‐β‐induced myofibroblast differentiation and activation in human lung fibroblasts <i>in vitro</i>

Kikuchi, Ryota; Maeda, Yoshinobu; Tsuji, Takao; Yamaguchi, Kazuhiro; Abe, Shinji; Nakamura, Hiroyuki; Aoshiba, Kazutetsu

doi:10.1002/2211-5463.13247

Cited by 5 publications

(4 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our focus on the effect of anti-hyperlipidemic drugs in the context of asthma progression was the result of several reports indicating that asthma progression with enhanced remodeling of the airways is associated with metabolic dysfunctions, such as obesity or hyperlipidemia, and dysregulation of the function of PPARs [18,49]. Fenofibrate is known as an agonist of PPARα, and its inhibitory effect on bronchial [23], lung [24,50], subretinal [51], and liver [52] fibrosis has been observed. However, little is known about the involvement of another type of peroxisome proliferator-activated receptor, PPARδ, in fibrosis-related processes, especially in asthma subepithelial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…For this reason, the effects of clinically used anti-hyperlipidemic drugs on asthma progression are intensively studied [21][22][23]. Fenofibrate, known as a lipid-lowering agent and a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, decreases experimental pulmonary fibrosis (PF) and subepithelial fibrosis in asthma [23,24]. PPARs are part of the hormone receptor superfamily, including PPARα, PPARδ (also called β), and PPARγ, activated by subtype-specific or pan-PPAR agonist ligands that promote their nuclear translocation and regulation of gene transcription by binding to their peroxisome proliferator response elements (PPREs) [25].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PPARδ Agonist GW501516 Suppresses the TGF-β-Induced Profibrotic Response of Human Bronchial Fibroblasts from Asthmatic Patients

Paw

Wnuk

Madeja

et al. 2023

IJMS

View full text Add to dashboard Cite

The airway wall remodeling observed in asthma is associated with subepithelial fibrosis and enhanced activation of human bronchial fibroblasts (HBFs) in the fibroblast to myofibroblast transition (FMT), induced mainly by transforming growth factor-β (TGF-β). The relationships between asthma severity, obesity, and hyperlipidemia suggest the involvement of peroxisome proliferator-activated receptors (PPARs) in the remodeling of asthmatic bronchi. In this study, we investigated the effect of PPARδ ligands (GW501516 as an agonist, and GSK0660 as an antagonist) on the FMT potential of HBFs derived from asthmatic patients cultured in vitro. This report shows, for the first time, the inhibitory effect of a PPARδ agonist on the number of myofibroblasts and the expression of myofibroblast-related markers—α-smooth muscle actin, collagen 1, tenascin C, and connexin 43—in asthma-related TGF-β-treated HBF populations. We suggest that actin cytoskeleton reorganization and Smad2 transcriptional activity altered by GW501516 lead to the attenuation of the FMT in HBF populations derived from asthmatics. In conclusion, our data demonstrate that a PPARδ agonist stimulates antifibrotic effects in an in vitro model of bronchial subepithelial fibrosis. This suggests its potential role in the development of a possible novel therapeutic approach for the treatment of subepithelial fibrosis during asthma.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PPARδ Agonist GW501516 Suppresses the TGF-β-Induced Profibrotic Response of Human Bronchial Fibroblasts from Asthmatic Patients

Paw

Wnuk

Madeja

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…7A-C). Accumulating evidence indicated that PPAR-α-independent mechanisms are involved in the pleiotropic effects of FF on various pathophysiological processes (36,37). However, the knockdown of the PPARA gene with siRNA transfection reduced the stimulatory effect of FF on AhR gene transcription, although the AhR gene inhibition by the PPARA siRNA transfection was not statistically significant (P= 0.08) (Fig.…”

Section: Ff Treatment Enhanced Nrf2 Expression By Stimulating Ahr Exp...mentioning

confidence: 93%

Fenofibrate attenuates the cytotoxic effect of cisplatin on lung cancer cells by enhancing the antioxidant defense system in vitro

et al. 2023

Self Cite

View full text Add to dashboard Cite

Fenofibrate (FF) is a peroxisome proliferatoractivated receptor (PPAR)-α agonist that is widely used for the treatment of hyperlipidemia. It has been shown to have pleiotropic actions beyond its hypolipidemic effect. FF has been shown to exert a cytotoxic effect on some cancer cells when used at higher than clinically relevant concentrations; on the other hand, its cytoprotective effect on normal cells has also been reported. The present study assessed the effect of FF on cisplatin (CDDP) cytotoxicity to lung cancer cells in vitro. The results demonstrated that the effect of FF on lung cancer cells depends on its concentration. FF at ≤50 µM, which is a clinically achievable blood concentration, attenuated CDDP cytotoxicity to lung cancer cells, whereas FF at ≥100 µM, albeit clinically unachievable, had an anticancer effect. The mechanism of FF attenuation of CDDP cytotoxicity involved PPAR-α-dependent aryl hydrocarbon receptor (AhR) expression, which in turn stimulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and antioxidant production, resulting in lung cancer cell protection from CDDP-evoked oxidative damage. In conclusion, the present study revealed that FF, at clinically relevant concentrations, attenuated CDDP cytotoxicity to lung cancer cells by enhancing the antioxidant defense system through activation of a pathway that involves the PPAR-α-PPAR response element-AhR xenobiotic response element-Nrf2-antioxidant response element. These findings suggested that concomitant use of FF with CDDP may compromise the efficacy of chemotherapy. Although the anticancer property of FF has recently attracted much attention, concentrations that exceed clinically relevant concentrations are required.

show abstract

“…Treatment with ciprofibrate or pemafibrate promotes peroxisome proliferation and downregulates myofibroblast differentiation of fibroblasts ( 138 , 142 ). Additionally, fenofibrate suppresses TGF-β-induced myofibroblast differentiation independent of PPARα activation by downregulating mitochondrial respiration ( 140 ). Fibrates suppress neutrophil infiltration, increase vascular permeability, and promote inflammatory cytokine production in bleomycin-induced or LPS-induced lung injury models and reduce lung compliance ( 162 – 164 ).…”

Section: Aging-related Respiratory Diseases and Cellular Senescencementioning

confidence: 99%

Drugs against metabolic diseases as potential senotherapeutics for aging-related respiratory diseases

et al. 2023

View full text Add to dashboard Cite

Recent advances in aging research have provided novel insights for the development of senotherapy, which utilizes cellular senescence as a therapeutic target. Cellular senescence is involved in the pathogenesis of various chronic diseases, including metabolic and respiratory diseases. Senotherapy is a potential therapeutic strategy for aging-related pathologies. Senotherapy can be classified into senolytics (induce cell death in senescent cells) and senomorphics (ameliorate the adverse effects of senescent cells represented by the senescence-associated secretory phenotype). Although the precise mechanism has not been elucidated, various drugs against metabolic diseases may function as senotherapeutics, which has piqued the interest of the scientific community. Cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are aging-related respiratory diseases. Large-scale observational studies have reported that several drugs, such as metformin and statins, may ameliorate the progression of COPD and IPF. Recent studies have reported that drugs against metabolic diseases may exert a pharmacological effect on aging-related respiratory diseases that can be different from their original effect on metabolic diseases. However, high non-physiological concentrations are needed to determine the efficacy of these drugs under experimental conditions. Inhalation therapy may increase the local concentration of drugs in the lungs without exerting systemic adverse effects. Thus, the clinical application of drugs against metabolic diseases, especially through an inhalation treatment modality, can be a novel therapeutic approach for aging-related respiratory diseases. This review summarizes and discusses accumulating evidence on the mechanisms of aging, as well as on cellular senescence and senotherapeutics, including drugs against metabolic diseases. We propose a developmental strategy for a senotherapeutic approach for aging-related respiratory diseases with a special focus on COPD and IPF.

show abstract

Fenofibrate inhibits TGF‐β‐induced myofibroblast differentiation and activation in human lung fibroblasts in vitro

Cited by 5 publications

References 43 publications

PPARδ Agonist GW501516 Suppresses the TGF-β-Induced Profibrotic Response of Human Bronchial Fibroblasts from Asthmatic Patients

PPARδ Agonist GW501516 Suppresses the TGF-β-Induced Profibrotic Response of Human Bronchial Fibroblasts from Asthmatic Patients

Fenofibrate attenuates the cytotoxic effect of cisplatin on lung cancer cells by enhancing the antioxidant defense system in vitro

Drugs against metabolic diseases as potential senotherapeutics for aging-related respiratory diseases

Contact Info

Product

Resources

About