title: Rosiglitazone inhibits TGF-β 1 induced activation of human Tenon fibroblasts via p38 signal pathway.
abstract: OBJECTIVE
  Transdifferentiation of human Tenon fibroblasts to myofibroblasts and subsequent deposition of extracellular matrix is a key step in the scarring after glaucoma filtration surgery. The p38 signaling pathway plays an important role in cell proliferation and differentiation, and its upstream regulators and downstream molecules are widely distributed in the eye. We aimed to investigate the role of p38 in the activation of Tenon fibroblasts and that of the anti-fibrotic mechanism of rosiglitazone in the modulation of the p38 signaling pathway.
  
  
  METHODS
  Cultured Tenon fibroblasts were stimulated with transforming growth factor (TGF)-β1. Activation of p38 was examined by western blot analysis. Rosiglitazone and blocking of the p38 signaling pathway by SB203580 were used to antagonize stimulation by TGF-β1. Fibroblast motility was examined by wound closure assay; alpha-smooth muscle actin, connective tissue growth factor, and collagen type I were determined by qPCR and western blot. Expression and localization of alpha-smooth muscle actin were determined by immunofluorescence staining.
  
  
  RESULTS
  Phosphorylated p38 was upregulated in fibroblasts stimulated with TGF-β1, and this effect was substantially inhibited by rosiglitazone. Proliferation and migration of fibroblasts were suppressed by rosiglitazone and SB203580. Expression of alpha-smooth muscle actin, connective tissue growth factor, and collagen type I were decreased at the mRNA and protein levels by rosiglitazone and SB203580. However, the inhibitory effect of SB203580 on transcription and protein expression was weaker than that of rosiglitazone. Similar phenomena were found on immunofluorescence microscopy of alpha-smooth muscle actin.
  
  
  CONCLUSIONS
  The p38 signaling pathway mediates the TGF-β1-induced transdifferentiation of human Tenon fibroblasts to myofibroblasts. Rosiglitazone can exert anti-fibrotic activity by interfering with the TGF-β/p38 signaling pathway and might be useful for modulating scar formation after glaucoma filtration surgery.
authors.affiliation: Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Yong-Heng
authors.initials: YH
authors.lastname: Luo
authors.affiliation: Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Ping-Bo
authors.initials: PB
authors.lastname: Ouyang
authors.affiliation: Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Guo
authors.affiliation: Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Xuan-Chu
authors.initials: XC
authors.lastname: Duan
mesh_terms: D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D000077154:Rosiglitazone; D058475:Tenon Capsule / Q000166:cytology / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007093:Imidazoles; D011725:Pyridines; C508960:TGFB1 protein, human; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D000077154:Rosiglitazone; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580