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

Abstract

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.

Five Novel Polymorphs of Cardarine/GW501516 and Their Characterization by X-ray Diffraction, Computational Methods, Thermal Analysis and a Pharmaceutical Perspective

“…PPAR-δ receptor activation plays a role in metabolism and promotes the burning of fatty acids via the mechanism of up-regulation of fatty acid uptake and oxidation [4,5]. The studies carried out indicate that GW501516 is a compound that shows potential for improvement in the treatment of several conditions such as preventing fatty-acid-induced insulin resistance [6] and treatment of subepithelial fibrosis during asthma [7]. Being a compound that increases the body's ability to metabolize fats, thus increasing the overall cardiovascular output, it has become popular as a performance-enhancement drug [8,9].…”

Bronchial Asthma, Airway Remodeling and Lung Fibrosis as Successive Steps of One Process

“…Excessive proliferation of smooth muscle cells producing a wide range of pro-inflammatory and pro-fibrotic mediators may lead to amplified airflow obstruction and extracellular matrix (ECM) deposition, ultimately resulting in fibrosis in individuals affected by asthma [6,7]. Subepithelial fibrosis observed in asthma is associated with enhanced differentiation of bronchial fibroblasts into myofibroblasts-fibroblast-to-myofibroblast transition (FMT)-induced mainly by transforming growth factor-β (TGF-β) [8].…”

“…In asthma treatment, drugs targeting chronic inflammation and bronchodilators control asthma but have a negligible effect on the structural changes in the bronchi. Recent studies indicate that inflammation and remodeling of asthmatic bronchi can be driven independently [8,12]. Therefore, lung fibrosis can be considered a long-term and eventually irreversible consequence of asthma-induced airway inflammation and remodeling.…”