A PPAR-Gamma Agonist Rosiglitazone Suppresses Fibrotic Response in Human Pterygium Fibroblasts by Modulating the p38 MAPK Pathway

作者：Nuwormegbe, Selikem Abla; Sohn, Joon Hyung; Kim, Sun Woong^*

来源：Investigative Ophthalmology & Visual Science, 2017, 58(12): 5217-5226.

DOI：10.1167/iovs.17-22203

• pterygium
• cornea
• fibrosis
• PPAR-gamma
• rosiglitazone

PURPOSE. Fibroblast activation may play an important role in pterygium progression. Synthetic peroxisome proliferator-activated receptor gamma (PPAR-gamma) ligands have been shown to be effective antifibrotic agents against transforming growth factor 31 (TGF-beta 1) induced fibrosis in several tissues. We aimed to investigate the antifibrotic effects of the PPAR-gamma ligand rosiglitazone in pterygium fibroblasts and the underlying mechanisms.
MEMODS. Profibrotic activation was induced by TGF-beta 1 in primary cultured human pterygium fibroblasts and the effect of rosiglitazone treatment on c-smooth muscle actin (alpha-SMA), and extra cellular matrix proteins synthesis was detected by western blotting, real-time PCR, immunostaining, and flow cytometry. Pharmaceutical inhibition of PPAR-gamma receptor was used to determine the dependency or otherwise of rosiglitazone's action on PPAR-gamma signaling. Major signaling pathways downstream of TGF-beta 1 were investigated by western blotting to assess their possible association with rosiglitazone's effect. Cell viability and apoptosis were investigated to assess drug-induced cytotoxicity, and the effect of rosiglitazone treatment on cell migration was further determined.
RESULTS. alpha-SMA and fibronectin synthesis induced by TGF-beta 1 were suppressed by rosiglitazone treatment in a dose-dependent manner. Rosiglitazone also inhibited intrinsic TGF-beta 1 expression. Smad2/3, ERK1/2, and P38 pathways were activated in response to TGF-beta 1. Rosiglitazone suppressed TGF-beta 1-induced P38 MAPK activation, while ERK1/2 and Smad2/3 signaling remained unaffected. The observed antifibrotic effect of rosiglitazone was not affected by the PPAR-gamma antagonist GW9662, indicating it is not PPAR-gamma dependent. Rosiglitazone also inhibited the proliferation and migration of pterygium fibroblasts.
CONCLUSIONS. Rosiglitazone suppresses TGF-beta 1-induced myofibroblast activation and extra cellular matrix synthesis in pterygium fibroblasts at least partly through the modulation of the p38 MAPK pathway.

• 出版日期2017-10