Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells

Lab Invest. 2005 Jul;85(7):838-50. doi: 10.1038/labinvest.3700294.


Proliferative vitreoretinopathy (PVR) is one of the major causes of the failure of retinal detachment surgery. Its pathogenesis includes a fibrotic reaction by the retinal pigment epithelium and other retina-derived non-neural cells, leading to fixation of the detached retina. We examined the role of p38 mitogen-activated protein kinase (MAPK) in transforming growth factor (TGF)-beta2-dependent enhancement of the fibrogenic reaction in a human retinal pigment epithelial cell line, ARPE-19, and also evaluated the therapeutic efficacy of inhibiting p38MAPK by adenoviral gene transfer of dominant-negative (DN) p38MAPK in a mouse model of PVR. Exogenous TGF-beta2 activates p38MAPK in ARPE-19 cells. It also suppresses cell proliferation, but this was unaffected by addition of the p38MAPK inhibitor, SB202190. SB202190 interfered with TGF-beta2-dependent cell migration and production of collagen type I and fibronectin, but had no effect on basal levels of these activities. While SB202190 did not affect phosphorylation of the C-terminus of Smads2/3, it did suppress the transcriptional activity of Smads3/4 as indicated by a reporter gene, CAGA12-Luc. Gene transfer of DN-p38MAPK attenuated the post-retinal detachment fibrotic reaction of the retinal pigment epithelium in vivo in mice, supporting its effectiveness in preventing/treating PVR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Collagen Type I / metabolism
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Fibronectins / metabolism
  • Fibrosis / genetics
  • Fibrosis / pathology
  • Fibrosis / prevention & control*
  • Genetic Therapy
  • Humans
  • Imidazoles / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pigment Epithelium of Eye / drug effects*
  • Pigment Epithelium of Eye / enzymology
  • Pigment Epithelium of Eye / pathology
  • Pyridines / pharmacology*
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta2
  • Vitreoretinopathy, Proliferative / genetics
  • Vitreoretinopathy, Proliferative / pathology
  • Vitreoretinopathy, Proliferative / therapy
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / genetics


  • Collagen Type I
  • Enzyme Inhibitors
  • Fibronectins
  • Imidazoles
  • Pyridines
  • TGFB2 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta2
  • p38 Mitogen-Activated Protein Kinases
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole