title: Inhibitory effects of PPARγ ligands on TGF-β1-induced corneal myofibroblast transformation.
abstract: Corneal scarring, whether caused by trauma, laser refractive surgery, or infection, remains a significant problem for humans. Certain ligands for peroxisome proliferator-activated receptor gamma (PPARγ) have shown promise as antiscarring agents in a variety of body tissues. In the cornea, their relative effectiveness and mechanisms of action are still poorly understood. Here, we contrasted the antifibrotic effects of three different PPARγ ligands (15-deoxy-Δ12,14-prostaglandin J2, troglitazone, and rosiglitazone) in cat corneal fibroblasts. Western blot analyses revealed that all three compounds reduced transforming growth factor (TGF)-β1-driven myofibroblast differentiation and up-regulation of α-smooth muscle actin, type I collagen, and fibronectin expression. Because these effects were independent of PPARγ, we ascertained whether they occurred by altering phosphorylation of Smads 2/3, p38 mitogen-activated protein kinase, stress-activated protein kinase, protein kinase B, extracellular signal-regulated kinase, and/or myosin light chain 2. Only p38 mitogen-activated protein kinase phosphorylation was significantly inhibited by all three PPARγ ligands. Finally, we tested the antifibrotic potential of troglitazone in a cat model of photorefractive keratectomy-induced corneal injury. Topical application of troglitazone significantly reduced α-smooth muscle actin expression and haze in the stromal ablation zone. Thus, the PPARγ ligands tested here showed great promise as antifibrotics, both in vitro and in vivo. Our results also provided new evidence for the signaling pathways that may underlie these antifibrotic actions in corneal fibroblasts.
authors.affiliation: Flaum Eye Institute, University of Rochester, Rochester, New York.
authors.forename: Kye-Im
authors.initials: KI
authors.lastname: Jeon
authors.affiliation: Department of Medicine, University of Rochester, Rochester, New York.
authors.forename: Ajit
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, New York.
authors.forename: Collynn F
authors.initials: CF
authors.lastname: Woeller
authors.affiliation: Flaum Eye Institute, University of Rochester, Rochester, New York; Department of Medicine, University of Rochester, Rochester, New York; Department of Environmental Medicine, University of Rochester, Rochester, New York.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.affiliation: Department of Medicine, University of Rochester, Rochester, New York; Department of Environmental Medicine, University of Rochester, Rochester, New York.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.affiliation: Flaum Eye Institute, University of Rochester, Rochester, New York; Center for Visual Science, University of Rochester, Rochester, New York.
authors.forename: Holly B
authors.initials: HB
authors.lastname: Hindman
authors.affiliation: Flaum Eye Institute, University of Rochester, Rochester, New York; Center for Visual Science, University of Rochester, Rochester, New York. Electronic address: huxlin@cvs.rochester.edu.
authors.forename: Krystel R
authors.initials: KR
authors.lastname: Huxlin
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002415:Cats; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D024042:Collagen Type I / Q000378:metabolism; D003315:Cornea / Q000473:pathology*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D008024:Ligands; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D000077288:Troglitazone; D014945:Wound Healing / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000199:Actins; D002839:Chromans; D024042:Collagen Type I; D005353:Fibronectins; D008024:Ligands; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D000077154:Rosiglitazone; C037112:9-deoxy-delta-9-prostaglandin D2; D048051:p38 Mitogen-Activated Protein Kinases; D000077288:Troglitazone; D015230:Prostaglandin D2