Rosiglitazone Treatment Prevents Postoperative Fibrosis in a Rabbit Model of Glaucoma Filtration Surgery

Abstract

PURPOSE. To evaluate the potential antifibrotic effect of rosiglitazone (RSG), a peroxisome proliferator-activated receptor c (PPARc)-selective agonist, on subconjunctival fibrosis in a rabbit model of glaucoma filtration surgery (GFS) in vivo, and to investigate the underlying mechanisms in human Tenon's fibroblasts (HTFs) in vitro. METHODS. GFS were performed on adult male New Zealand white rabbits with chronic ocular hypertension previously established by injections of 2% methylcellulose into the anterior chamber. Rabbits were treated by RSG, mitomycin C (MMC) or 5-fluorouracil (5-FU) intraoperatively. The morphology of filtering blebs was evaluated by Indiana Bleb Appearance Grading Scale (IBAGS) scoring. Expression of profibrotic genes was determined by quantitative PCR, immunoblot, and/or histochemical analysis. In vitro studies were performed in a transforming growth factor (TGF)-b1-based cell model of fibrosis. Autophagy was evaluated by the formation of autophagosomes and autolysosomes using fluorescent and transmission electron microscopy and by expression of key mediators in the autophagic pathway. RESULTS. RSG treatment ameliorated a rebound intraocular pressure (IOP) elevation, prolonged the survival of filtering blebs, and attenuated subconjunctival fibrosis in rabbits following trabeculectomy. Pretreatment of HTFs with RSG inhibited TGF-b1-induced expression of profibrotic genes encoding specificity protein 1, connective tissue growth factor, and a smooth muscle actin. RSG augmented TGF-b1-induced autophagy in HTFs via a beclin1/VPS34-dependent mechanism. Augmentation of autophagy is associated with inhibition of TGF-b1-induced profibrotic gene expression by RSG. CONCLUSIONS. RSG treatment prevents subconjunctival fibrosis after GFS by inhibition of profibrotic gene expression through a mechanism involved in promoting autophagy in local fibroblasts. RSG represents a novel antifibrotic drug with the potential to improve the success rate of GFS.

Rosiglitasone and ROCK Inhibitors Modulate Fibrogenetic Changes in TGF-β2 Treated Human Conjunctival Fibroblasts (HconF) in Different Manners

“…Based upon the fact that PPAR-γ belongs to the nuclear hormone receptor superfamily of ligand-activated transcription factors, and has been found to regulate fibrosis in multiple organs [ 62 , 63 ], a previous study revealed that Rosi, a synthetic PPAR-γ agonist, could moderately antagonize TGF-β-induced fibrosis by blocking the TGF-β/Smad pathway in vitro [ 61 ]. In fact, Luo et al demonstrated that Rosi can exert the anti-fibrotic activity of human tenon fibroblasts, thus suggesting that Rosi might be useful for modulating the scar formation that is frequently observed post-surgery [ 26 , 64 ]. Zhang et al recently investigated the effects and toxicities of a poly (3-hydroxybutyric acid-co-3-hydroxyvaleric acid) (PHBV)-loading Rosi membrane toward scar formation after glaucoma filtration surgery (GFS) in a rabbit model and found following results: (1) the concentration of Rosi does not affect the morphology of the RSG/PHBV membrane, and (2) the RSG/PHBV membrane effectively and safely prevents the formation of fibrosis after GFS in a rabbit model.…”

The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders

“…Let-7a miRNA expression has been found decreased in mouse models of liver fibrosis and in the liver and blood samples from liver fibrosis patients. Let-7a suppresses the activation of HSCs and its overexpression induces apoptosis of these cells, by interfering with the TGF-β/SMAD signaling pathway (Zhang et al, 2019). Thus, the administration of miRNAs may represent an interesting therapeutic opportunity to combat liver fibrosis.…”

“…It has been shown that RSG treatment prevents subconjunctival fibrosis after GFS through the inhibition of profibrotic gene expression by a mechanism that promotes autophagy in local fibroblasts. Thus, the use of RSG may represent a novel antifibrotic approach with the potential to improve the success rate of GFS (Zhang et al, 2019) (Figure 8).…”

Combination of Peroxisome Proliferator-Activated Receptor (PPAR) Alpha and Gamma Agonists Prevents Corneal Inflammation and Neovascularization in a Rat Alkali Burn Model

“…TGF-β is also an important profibrotic element, especially in fibrosis [ 34 , 35 ]. Rosglitazone, which is a PPARγ agonist, suppresses TGF-β1 expression and prevents conjunctival fibrosis after glaucoma filtration surgery [ 36 ]. In our current study, PPARγ treatment suppressed fibrotic changes in the corneal stroma, which may be induced by anti-TGF-β effects of PPARγ.…”