1. ¹Department of Ophthalmology, Wakayama Medical University, Kimiidera, Wakayama, Japan
2. ²Department of Anatomy, Graduate School of Medicine, Osaka City University, Asahimachi, Abeno, Osaka, Japan
3. ³Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Science, Kumamoto, Japan
4. ⁴Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
5. ⁵Department of Pathology, Wakayama Medical University, Kimiidera, Wakayama, Japan

Correspondence: Dr S Saika, MD, PhD, Department of Ophthalmology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan. E-mail: shizuya@wakayama-med.ac.jp

^*Current address: Department of Microbiology/Research Institute of Life Science, Gyeongsang National University, Jinju 660-701, Korea.

Received 28 February 2005; Revised 11 April 2005; Published online 16 May 2005.

Abstract

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)-2-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-2 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-2-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.